antimony-sodium-gluconate and Leishmaniasis--Visceral

Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal complication of visceral leishmaniasis (VL). To provide a basis for early and correct diagnosis and to improve prognosis in the future, we describe a case series of VL-associated HLH in adults in our center in the past decade after review of all reported cases of adult VL-associated HLH in English through May 2022. In our case series, a total of 111 patients were diagnosed with VL. Among these patients, only six cases were diagnosed with VL-associated HLH. All patients tested positive for serology. Leishmania was detected for the first time by bone marrow aspiration (BMA) in three of the six patients and in the other three patients after three or four BMAs. It took more than 1 month from onset to diagnosis of VL for all the six cases, and the longest time was 6 months. Five of the six patients recovered after receiving sodium stibogluconate. VL-associated HLH is rare but potentially life-threatening in adults and predisposes to early delays in diagnosis. However, diagnostic techniques are not complicated or difficult, so it is more important to consider that it is not recognized by physicians. Although guidelines recommend liposomal amphotericin B as the most effective therapy, our experience suggests that sodium stibogluconate can be an alternative option when liposomal amphotericin B is unavailable or unaffordable.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Leishmaniasis, Visceral; Lymphohistiocytosis, Hemophagocytic

Leishmaniasis remains a public health concern around the world that primarily affects poor folks of the developing world spanning across 98 countries with mortality of 0.2 million to 0.4 million annually. Post kala-azar dermal leishmaniasis (PKDL) is the late skin manifestation of visceral leishmaniasis (VL). It has been reported that about 2.5% to 20% of patients recovered from VL develop PKDL having stilted macular or nodular lesions with parasites. In the Indian subcontinent (ISC), it manifests a few months after recovery from VL, though in Africa it can occur simultaneously with VL or a little later. New cases of PKDL are also observed without prior VL in the ISC. These individuals with PKDL represent an important but largely neglected reservoir of infection that perpetuates anthroponotic Leishmania donovani transmission in the ISC and can jeopardize the VL elimination program as these cases can infect the sand flies and spread the endemic. Therefore, it becomes imperative to eradicate PKDL as a part of the VL elimination program. With the limited treatment options besides little knowledge on PKDL, this review stands out in focusing on different aspects that should be dealt for sustained VL elimination.

Topics: Antimony Sodium Gluconate; Biomarkers; Genetic Predisposition to Disease; Humans; Immunologic Memory; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

The kingdom of Saudi Arabia (KSA) has succeeded in bringing the reported numbers of Visceral leishmaniasis (VL) cases from hundreds during the 1980s and 1990s to zero case in 2019. The endemicity of VL has been confined mainly to the Southwest regions, namely Jazan and Aseer regions. Leishmania donovani species have been identified as the causative species of VL, while L. infantum have been isolated only from dogs in the endemic areas. Many species of sand flies were caught in Southwest, but P. orientalis is the probable transmitter of the disease. The black rat (Rattus ratus) was found to be contributing to maintenance of the parasite life cycle. VL is primarily a disease of children, and 80% of cases were Saudi's, while cases from Yeminis nationality represent the majority of non- Saudi patients. The common clinical presentation consist of chronic fever, abdominal distention, weight loss, anemia and hepatosplenomegaly. Laboratory findings include: anemia, leukopenia, thrombocytopenia, hypoalbuminemia, hyperproteinaemia and hypergammaglobulinemia, low serum iron, and abnormal liver enzymes. Occurrence of jaundice has been identified as a bad prognostic sign. Diagnosis relying on direct smears from bone marrow aspirates was the commonest tool used, and also is advocated by the National Leishmaniasis Control Program (NLCP). Sodium stibogluconate (SSG) is the main drug used to treat VL cases, while Ambisome is preserved for complicated cases. Chemical control of sand flies using indoor residual spraying (IRS) with synthetic pyrethroids has been the most effective measure applied to prevent vector-human contact and disease transmission. The geographical overlap of VL and Malaria has facilitated the adoption and implementation of integrated vector control strategies. After reaching a zero case in 2019, the Ministry of Health (MoH) has a new commitment and facing a great challenge which are maintenance of current situation and elimination of VL. Through the support of stakeholders, encouragement of community participation, preparedness and readiness of leishmaniasis personnel, the new mission of the NLCP now is elimination of the scourge of VL from the country.

Topics: Animals; Antimony Sodium Gluconate; Humans; Insect Vectors; Leishmania donovani; Leishmaniasis, Visceral; Psychodidae; Saudi Arabia

Ethiopia has the highest number of visceral leishmaniasis (VL) cases after Sudan in Sub-Saharan Africa. However, there was lack of comprehensive data on VL treatment outcome despite the huge burden of the diseases in the country. Hence, we aimed to perform a systematic review and meta-analysis on this topic to obtain stronger evidence on treatment outcomes of VL from the existing literature in Ethiopia.. The Cochrane guidelines to conduct meta-analysis following the Preferred Reporting Items for Systematic review and Meta-Analysis statement was used to conduct a computerized systematic search of the PubMed, Google Scholar, and ScienceDirect databases. Random effects model was used to combine studies showing heterogeneity of Cochrane Q P < 0.10 and I. Fifteen studies were included in the final analyses. At end of treatment, an overall treatment success rate of 82.6% was noticed. At 6 months follow-up, the overall treatment success rate was 72.2%. For patients treated with sodium stibogluconate (SSG), the treatment success rates at the end of treatment and at six-month follow-up were 81.5% and 80.7%, respectively. Multiple doses of liposomal-amphotericin B (L-AMB) had treatment success rates of 96.7 and 71-100% at the end of treatment and at 6 months follow-up, respectively. The combination of SSG with paromomycin (PM) gave treatment success rates of up to 90.1% at the end of treatment. HIV-infected individuals were found to have a higher mortality (odds ratio = 4.77, 95% CI: 1.30-17.43, P = 0.009) rate at 6 months follow-up.. SSG alone has shown lower treatment efficacy in the management of VL when compared to combination of SSG with PM and multiple doses of L-AMB. The combination of SSG with PM gave good treatment success rates with shorter duration of treatment. Hence, the combination of SSG with PM should be used preferentially over SSG monotherapy. Multiple doses of L-AMB showed great efficacy especially among patients with complications, severe disease, HIV co-infection, and intolerance to the adverse effects of antimonials. HIV-infected individuals had a worse prognosis than their HIV-negative counterparts.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Coinfection; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Odds Ratio; Treatment Outcome

Leishmaniasis is a parasitic infection endemic to more than 90 countries worldwide. As travel to endemic areas increases, dermatologists need to keep this entity in the differential for any chronic skin lesion in persons who may have had a possible exposure for any duration. It can be difficult to diagnose because manifestations are varied and sometimes subclinical. This article discusses the current state of epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment options. A special focus is placed on cutaneous manifestations and their treatment.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; Incidence; Leishmania braziliensis; Leishmania donovani; Leishmania mexicana; Leishmania tropica; Leishmaniasis, Diffuse Cutaneous; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral; Phosphorylcholine; Polymerase Chain Reaction; Travel

Leishmaniasis broadly manifests as visceral leishmaniasis (VL), cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The treatment of VL is challenging. The duration of treatment is long, and drugs are toxic thereby needing monitoring and hospitalization.. Novel therapies such as single dose of liposomal amphotericin B (L-AmB) and multidrug therapy are important breakthrough for VL in the Indian subcontinent and have been recommended as the treatment of choice in this region. African Leishmania donovani is less susceptible to L-AmB, miltefosine and paromomycin as compared to the Indian strains, and the treatment of choice remains a 17-day combination therapy of pentavalent antimonials (SB(v)) and paromomycin. L-AmB at a total dose of 18 - 21 mg/kg is the recommended regimen in the Mediterranean region and South America. It is also the treatment of choice for HIV-VL coinfection. Treatment of CL should be decided by the clinical lesions, etiological species and its potential to develop into mucosal leishmaniasis. A literature search on treatment of leishmaniasis was done on PubMed and through Google.. There is an urgent need for exploratory studies with short course, highly efficient regimens such as single dose L-AmB or combination therapy for all the endemic regions of VL. Shorter and more acceptable regimens are needed for the treatment of post-kala-azar dermal leishmaniasis. Treatment of CL remains one of the neglected areas of leishmaniasis as data are scarce and drawn from uncontrolled studies.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Therapy, Combination; Humans; Leishmania donovani; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Parasitic Sensitivity Tests; Paromomycin; Phosphorylcholine; Practice Guidelines as Topic; Species Specificity; Treatment Outcome

Several attempts have been made to combine drugs for treating visceral leishmaniasis, but only recently have effective drugs become available and combinations been tested systematically.. Sequential treatments with liposomal amphotericin B followed by miltefosine or paromomycin (as short as 7 days), as well as the concomitant administration of miltefosine and paromomycin (for 10 days) are very effective in India (>95%). Sodium stibogluconate plus paromomycin for 17 days is more than 90% effective in East Africa. The shortened combination regimens are cost-effective in India. No combination has been tested so far in Brazil, Nepal and Bangladesh, although studies may be expected in the near future. No cost-effectiveness analysis has been done as yet outside India.. There is evidence of high efficacy and benefits with sequential and co-administration treatments in India. More studies are needed in other endemic areas. Introducing combinations and scaling up their use will be challenging. Experience acquired with malaria may be useful. Proper monitoring of use and effects (efficacy and safety) will be required. Currently there are no options for fixed-dose combination treatments for leishmaniasis.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Cost-Benefit Analysis; Drug Resistance; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Leishmaniasis, Visceral; Paromomycin; Phosphorylcholine

Topics: Adult; AIDS-Related Opportunistic Infections; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Therapy, Combination; HIV Seropositivity; Humans; Leishmaniasis, Visceral; Male; Phosphorylcholine; Treatment Outcome

Visceral Leishmania infantum leishmaniasis is endemic in the south of France. For many years the mainstay for treatment of infected children was pentavalent antimony: meglumine antimoniate (Glucantime) or sodium stibogluconate (Pentostam). However these drugs are poorly tolerated and resistance similar to that observed in the treatment of Indian visceral Leishmania donovani leishmaniasis has been reported. Currently liposomal amphotericin B is being used instead of antimony for treatment of visceral leishmaniasis in children in France. In addition to being well tolerated, liposomal amphotericin B is almost 100% effective. It can be administered in six intravenous injections of 3-4 mg/kg each (days 1 to 5 then day 10). A two-day protocol (10 mg/kg/d) that would reduce overall cost by shortening the duration of hospitalization is now being studied. Another oral drug, i.e., miltefosine, has been successfully used for treatment of visceral leishmaniasis in India. However it has not been evaluated for treatment of Mediterranean visceral leishmaniasis.

Topics: Amphotericin B; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Humans; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Phosphorylcholine

Major therapeutic obstacles in the treatment of visceral leishmaniasis (VL) include the alarming increase in antimonial unresponsiveness especially in Bihar, India and relapses in HIV-Leishmania co-infected patients. The therapeutic armamentarium for VL is currently plagued with several limitations as the available drugs are toxic, majority are effective only parenterally and need to be administered for extended periods. The first orally effective drug, miltefosine has been approved for treating VL. In antimony refractory zones, pentavalent antimony has been largely replaced by amphotericin B deoxycholate, but prolonged hospitalization, toxic effects, and requirement for monitoring greatly hamper its widespread application in endemic regions. Lipid formulations of amphotericin B, a remarkable advance in amphotericin B therapy, have greatly reduced toxicity enabling large doses to be delivered over a short period. Even a single dose treatment with liposomal amphotericin B cures > 90 per cent patients; however, the stumbling block is its prohibitive cost that precludes its widespread accessibility in endemic countries. Studies using paromomycin in VL are encouraging, and judging by the preliminary results of a recently concluded phase III trial, it could be an extremely useful and affordable antileishmanial drug. Other orally effective drugs include the azoles and allopurinol but these have met with limited success owing to either poor efficacy or unacceptable toxicity. Sitamaquine has undergone limited evaluation, and the data suggest effective antileishmanial activity; its role has to be delineated for which additional developmental studies are proposed. This review highlights the progress made in the treatment of VL, including the multiple mechanisms of action of antileishmanial drugs with a view to enable the researcher to undertake the challenge of providing affordable and effective chemotherapy.

Topics: Administration, Oral; Amphotericin B; Animals; Antimony Sodium Gluconate; Antineoplastic Agents; Antiprotozoal Agents; Humans; Immunologic Factors; Leishmania; Leishmaniasis, Visceral; Pentamidine

Visceral leishmaniasis (VL) is caused by the protozoan parasite Leishmania donovani and transmitted by the bite of infected sandfly Phlebotomus argentipes. Nearly half of the VL cases occur in children (childhood or paediatric VL). The clinical manifestations of childhood VL are more or less same as in the adults. Prolonged fever with anorexia and loss of appetite are the major presenting features. Marked enlargement of the spleen and liver (spleen larger than liver) with moderate to severe anaemia and changes in hair take place. Bacterial infection is a common coinfection and intestinal parasitic infestations are very common in children with VL. Liver function tests, blood, urine and stool may show abnormalities. Confirmation of diagnosis is made by demonstration of parasite by microscopic examination and culture of materials obtained by bone marrow aspiration or splenic puncture. Sodium antimony gluconate (stibogluconate) has been the drug of choice for over past 50 yr. Pentamidine isothionate, though effective is relatively toxic. Amphotericin B is the most effective drug for the treatment of VL. Miltefosine is the first-ever oral drug, is highly effective. Post kala-azar dermal leishmaniasis (PKDL) in children poses a therapeutic challenge. In the absence of an ideal vaccine for VL, control measures would essentially include prevention of transmission through vector control and community awareness.

Topics: Administration, Oral; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Leishmania donovani; Leishmaniasis, Visceral; Phosphorylcholine; Psychodidae

The leishmaniases are protozoan diseases caused by Leishmania parasites. The first-line treatment of its visceral forms is pentavalent antimony (meglumine antimoniate or sodium stibogluconate), but toxicity is frequent with this drug. Moreover antimony unresponsiveness is increasing in Leishmania infantum and L. donovani foci, both in immunocompetent and in immunosuppressed patients. Amphotericin B is a polyene macrolide antibiotic that binds to sterols in cell membranes. It is the most active antileishmanial agent in use. Its infusion-related and renal toxicity may be reduced by lipid-based delivery. Liposomal amphotericin B (AmBisome); Gilead Science, Paris, France) seems to be less toxic than other amphotericin B lipid formulations (Amphocil); Liposome Technology Inc., Menlo Park, CA, USA, Amphotec); Ben Venue Laboratories Inc., Bedford, OH, USA). Optimal drug regimens of AmBisome) vary from one geographical area to another. In the Mediterranean Basin, a total dose of 18 mg/kg (3 mg/kg on days 1-5 and 3 mg/kg on day 10) could be used as first-line treatment of visceral leishmaniasis in immunocompetent patients. In immunocompromised patients, especially those co-infected with HIV, relapses are frequent with AmBisome), as with other drugs.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Humans; Immunocompromised Host; Leishmania; Leishmaniasis, Visceral; Liposomes; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Phosphatidylcholines; Phosphatidylglycerols; Treatment Failure

The standard treatment of visceral leishmaniasis is pentavalent antimony (meglumine antimoniate or sodium stibogluconate), but toxicity is frequent with this drug. Moreover, antimony unresponsiveness is increasing, both in immunocompetent and in immunosuppressed patients. Amphotericin B is a polyene macrolide antibiotic that binds to sterols in cell membranes. It is the most active antileishmanial agent in use. Its infusion-related and renal toxicity may be reduced by lipid-based delivery. Liposomal amphotericin B (Ambisome) seems to be less toxic than other amphotericin B lipid formulations (Amphocil, Amphotec). Optimal drug regimens of Ambisome vary from one geographical area to another. In the Mediterranean Basin, a total dose of 18 to 24 mg/kg is safe and effective. Shortening the duration of treatment without decreasing the total dose (i.e., 10 mg/kg/day for 2 days) seems promising to reduce the global cost of the therapy.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Humans; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Phosphorylcholine

Visceral leishmaniasis is a vector-borne systemic infection, which affects half a million people each year in many areas of the world. Typical disease manifests with fever, hepatosplenomegaly, pancytopenia, and progressive deterioration of the host. Although molecular methods appear promising as a non-invasive diagnostic tool, definite diagnosis still relies on the demonstration of the parasite in tissue. Pentavalent antimonial compounds remain the mainstay of treatment worldwide, except in India. During the past decade, short courses of lipid formulations of amphotericin B were assessed and proved effective; however, their cost precludes their wide use in developing countries. Miltefosine, an oral active agent, was recently identified, and might fulfil our expectations for an effective, safe, easily administered and affordable antileishmanial treatment.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Child; Disease Vectors; Humans; Leishmania donovani; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Prevalence

Visceral leishmaniasis is an endemic disease in the Mediterranean Basin. Children are one of the targets of the infection. Treatment usually requires parenteral injections of pentavalent antimony (Glucantime or Pentostam), but the high frequency of adverse events and the occurrence of primary or secondary resistance cases limit the use of these medications. Diamidines (Pentacarinat) or amphotericin B derivatives are alternatives to antimony. Unfortunately, pharmacokinetics and optimal dosage of diamidines are not well-known, and numerous adverse events are described. Liposomal preparations of amphotericin B enhance its efficiency and tolerance, and the duration of treatment may be reduced to 5 days. Moreover, primary resistance to amphotericin B is not described in immunocompetent children. Allopurinol associated with antimony seems no more efficient than antimony alone. Aminosidine is not evaluated.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Drug Resistance; Drug Therapy, Combination; Humans; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Time Factors; Treatment Outcome

Topics: AIDS-Related Opportunistic Infections; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Female; Humans; Immunocompromised Host; Leishmania; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds

A 25-year-old woman of Yugoslavian origin came to Germany two years before and did not leave Germany since this time. She developed a phlebothrombosis during pregnancy which was treated surgically and with subsequent heparinisation. The pregnancy had to be terminated by section because of abnormal liver functions and increased blood pressure. These values returned to normal within two months. Further tests again showed raised liver function tests (GOT 57 U/l, GPT 71 U/l) and antibodies against smooth muscle and actin. Autoimmune hepatitis was diagnosed and prednisolone given (100 mg daily). In the subsequent 4 months the patient progressively lost more weight and a pancytopenia developed. Suspected of having a systemic haematological syndrome she was admitted to hospital.. Physical examination was unremarkable except for hepato- and splenomegaly (spleen 15.6 cm in diameter by sonography). Laboratory tests showed hypergammaglobulinaemia (50 g/l, 53%), increased WBC count, as well as decreased haemoglobin concentration and platelet count (900 WBC/microliter, Hb 10.9 g/l, 146,000 platelets/microliter). Bone marrow puncture unexpectedly revealed a large number of Leishmania donovani.. Five-valent antimony was administered (sodium stibogluconate 20 mg/kg daily intravenously as bolus for 14 days). She has been free of symptoms since then (follow-up period of one year).. Visceral leishmaniasis is a rare disease in Europe. Incubation periods of several years have been reported and the infection can be easily mistaken for other chronic liver disease, in this case for an autoimmune hepatitis. Leishmaniasis should be included in the differential diagnosis of unclear liver disease if there is a suggestive history (country of origin or journey into an endemic area).

Topics: Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Chronic Disease; Diagnosis, Differential; Female; Germany; Hepatitis, Viral, Human; Humans; Leishmania donovani; Leishmaniasis, Visceral; Pregnancy; Time Factors; Yugoslavia

Topics: Allopurinol; Amphotericin B; Antimony Sodium Gluconate; Humans; Incidence; Ketoconazole; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

Topics: Allopurinol; Amphotericin B; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Pentamidine

Topics: Allopurinol; Amphotericin B; Antimony Sodium Gluconate; Child; Combined Modality Therapy; Humans; Ketoconazole; Leishmaniasis, Visceral; Pentamidine; Predictive Value of Tests; Reproducibility of Results; Sensitivity and Specificity; Splenectomy

Pentavalent antimonial compounds have been the mainstay of the treatment of visceral, cutaneous, and mucosal leishmaniasis for approximately half a century. Pentostam (sodium stibogluconate) is the pentavalent antimonial compound available in the United States (through the Centers for Disease Control). As dosage regimens for treating leishmaniasis have evolved, the daily dose of antimony and the duration of therapy have been progressively increased to combat unresponsiveness to therapy. In the 1980s, the use of 20 mg/kg/day (instead of 10 mg/kg/day) of antimony was recommended, but only to a maximum daily dose of 850 mg. The authors have concluded on the basis of recent efficacy and toxicity data that this 850-mg restriction should be removed; the evidence to date, which is summarized here, suggests that a regimen of 20 mg/kg/day of pentavalent antimony, without an upper limit on the daily dose, is more efficacious and is not substantially more toxic than regimens with lower daily doses. We recommend treating all forms of leishmaniasis with a full 20 mg/kg/day of pentavalent antimony. We treat cutaneous leishmaniasis for 20 days and visceral and mucosal leishmaniasis for 28 days. Our judgment of cure is based on clinical criteria.

Topics: Antimony Sodium Gluconate; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral

A brief review of the spread of visceral leishmaniasis in Bulgaria and data about the disease are presented. A case of probably nonautochtonous form of visceral leishmaniasis is described. The clinical evolution of the disease is followed up and the large number of examinations which were carried out for the etiological diagnosis are presented. The diagnosis is based on the characteristic clinical symptoms, epidemiological history, positive serologic tests but with a negative myelogram. The diagnosis was proved ex juvantibus by the antimony treatment and the full recovery of the patient. This is the first case of visceral leishmaniasis in the 40 year history of the hospital.

Topics: Adult; Antimony; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Male

Topics: Allopurinol; Amidines; Animals; Antimony Sodium Gluconate; Gluconates; Glycolysis; Leishmania; Leishmaniasis, Visceral; Lipid Metabolism; Pentamidine

Topics: Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Models, Animal; Glycolipids; Humans; Leishmaniasis; Leishmaniasis, Visceral; Liposomes; Lysosomes; Malaria; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Primaquine; Protozoan Infections; Trypanosomiasis

This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.. An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.. Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults.. PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.. NCT03129646.

Topics: Adult; Africa, Eastern; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Drug Therapy, Combination; Humans; Leishmaniasis, Visceral; Paromomycin; Phosphorylcholine; Treatment Outcome

In Ethiopia, visceral leishmaniasis (VL) is a growing public health threat. Among the key challenges in VL control in Ethiopia is lack of an effective test of cure. The recommended test of cure is parasite detection. As sterile cure is not expected with the current widely used drugs, the value of parasite detection as test of cure is questionable. Moreover, the sampling is invasive, requires a well-equipped facility and highly skilled personnel, which are all hardly found in endemic set-ups.. Our aim was to assess the value of sCD40L, MMP9 and IL-10 serum levels as signature biomarkers of clinical cure in VL cases from Ethiopia.. A total of 45 VL cases before and after treatment and 30 endemic healthy controls were included in the study. Sandwich ELISA was used to measure serum levels of sCD40L, MMP9 and IL-10.. The mean sCD40L, MMP9 and IL-10 serum levels changed significantly at clinical cure. At individual case level sCD40L and MMP9 showed an increasing trend. Yet, the degree of increase in serum level of MMP9 seems to be affected by nutritional status of the individual VL case. The mean IL-10 serum level was significantly reduced at clinical cure. As seen on case by case basis, all demonstrated a declining trend except that two VL cases had a high IL10 level at clinical cure.. Our result is suggestive of the possibility of developing a signature biomarker to monitor VL treatment in Ethiopia using one or a combination of parameters.

Topics: Adult; Antimony Sodium Gluconate; CD40 Ligand; Ethiopia; Female; Humans; Interleukin-10; Leishmaniasis, Visceral; Male; Matrix Metalloproteinase 9

SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa.. A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments.. In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults.. No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated.. The study was registered with ClinicalTrials.gov, number NCT01067443.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Drug Therapy, Combination; Female; Humans; Kenya; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged; Parasite Load; Phosphorylcholine; Sudan; Treatment Outcome; Young Adult

Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.. A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.. The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.. The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.. www.clinicaltrials.govNCT00255567.

Topics: Adolescent; Adult; Africa, Eastern; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Paromomycin; Treatment Outcome; Young Adult

Treatment options for visceral leishmaniasis (VL) in East Africa are far from satisfactory due to cost, toxicity, prolonged treatment duration or emergence of parasite resistance. Hence there is a need to explore alternative treatment protocols such as miltefosine alone or in combinations including miltefosine, sodium stibogluconate (SSG) or liposomal amphotericin B. The aim of this trial is to identify regimen(s) which are sufficiently promising for future trials in East Africa.. A phase II randomized, parallel arm, open-labelled trial is being conducted to assess the efficacy of each of the three regimens: liposomal amphotericin B with SSG, Liposomal amphotericin B with miltefosine and miltefosine alone. The primary endpoint is cure at day 28 with secondary endpoint at day 210 (6 months). Initial cure is a single composite measure based on parasitologic evaluation (bone marrow, spleen or lymph node aspirate) and clinical assessment. Repeated interim analyses have been planned after recruitment of 15 patients in each arm with a maximum sample size of 63 for each. These will follow group-sequential methods (the triangular test) to identify when a regimen is inadequate (<75% efficacy) or adequate (>90% efficacy). We describe a method to ensure consistency of the sequential analysis of day 28 cure with the non-sequential analysis of day 210 cure.. A regimen with adequate efficacy would be a candidate for treatment of VL with reasonable costs. The design allows repeated testing throughout the trial recruitment period while maintaining good statistical properties (Type I & II error rates) and reducing the expected sample sizes.. ClinicalTrials.gov: NCT01067443.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Child; Drug Therapy, Combination; Humans; Kenya; Leishmaniasis, Visceral; Middle Aged; Phosphorylcholine; Research Design; Sudan; Time Factors; Treatment Outcome; Trypanocidal Agents; Young Adult

To investigate maternal and perinatal outcomes when pregnant women with visceral leishmaniasis (VL, also known as kala-azar) are treated with the antimonial sodium stibogluconate.. Forty-two pregnant women with VL were treated with sodium stibogluconate at Gadarif Hospital, Gadarif, Sudan, and mother and child were followed up for 1 year.. The treatment began at a mean+/-SD of 24.4+/-9.2 weeks of pregnancy. None of the patients had malaria or HIV. Two (4.7%) who received the treatment in the first trimester had miscarriages; 4 (4.9%) died from hepatic encephalopathy during the second week of treatment; and 2 (4.7%) had preterm deliveries. One of the newborns had a myelomeningocele and died at 2 hours, and the other died from VL at 2 months.. Preventive measures against VL should be employed in the region, and more research on VL and its treatment during pregnancy is needed.

Topics: Abortion, Spontaneous; Adolescent; Adult; Antimony Sodium Gluconate; Antiparasitic Agents; Female; Humans; Infant, Newborn; Injections, Intramuscular; Leishmaniasis, Visceral; Pregnancy; Pregnancy Complications, Parasitic; Sudan; Young Adult

Present treatment strategies for kala-azar (visceral leishmaniasis, VL) include use of first line drug sodium antimony gluconate (SAG) to all patients but a large number of patients do not get relief with this drug. If a patient does not respond to a full course of SAG, a second or third line drug is given. We undertook this study to test whether an improved outcome can be achieved by employing a strategy of treatment based on culture and sensitivity of amastigotes to SAG compared with conventional empirical treatment.. In a double-blind, randomized, controlled trial done in Balaji Utthan Sansthan, Patna, of the 181 patients screened,140 were finally randomly allocated to two groups A and B; group A patients were treated with SAG if their amastigotes were sensitive to SAG, and all patients in group B were treated with SAG to start with. Primary outcome measured was as no relapse within 6 months of follow up after cure and other outcomes measured were period of stay of patients in hospital, expenditure involved in the treatment, and infectivity periods of two groups, two-third of treatment period and whole of untreated period were taken as infectivity period. SAG was used at a dosage of 20 mg/kg given deep intramuscular injections in buttock for 28 days, amphotericin B (AMB) given at a dose of 1 mg/kg body wt daily for 20 days as a slow intravenous infusion in 5 per cent dextrose.. Of the 70 patients in group A, 29 patients whose amastigotes were sensitive to SAG were treated with SAG, 2 patients were withdrawn due to drug toxicity; and 2 relapsed within 6 months of follow up and ultimate cure occurred in 25 (86.2%) patients only. Of the 70 patients in group B treated with SAG, 5 (7.1%) patients withdrew due to drug toxicity, 35 patients (50%) did not respond to treatment, 5 (7.1%) relapsed during 6 months of follow up and thus only 25 patients (35.7%) were ultimately cured. The difference between the two groups was significant (P<0.001). No patient died during treatment due to any toxicity because of early withdrawal of patients from treatment apprehending toxicity. Patients whose amastigotes were resistant to SAG, withdrawn from the study due to SAG toxicity, relapsed after cure with SAG, and who did not respond to SAG in both the groups were treated with AMB and all were cured. Groups B and A patients spent 3065 and 2340 days respectively in hospital, group B 1.3 times more than group A. The likely period of spread of parasites in society was 1965 days in group B and 1644 days in group A, group B 1.4 times more than group A. The total expenditure on treatment in groups B and A was dollars 65,575 and dollars 50,590 respectively; group B patient had to spend 1.3 times more than group A.. A new strategy for treatment of kala-azar based on culture and sensitivity of amastigotes improved the cure rate, saved expenditure on the patient's treatment, patients had to stay for shorter periods in hospital and reduced the chance of spread of SAG resistant disease in society. Till the government opts for better drugs, the treatment based on culture and sensitivity of the parasites to SAG may be a better method.

Topics: Adolescent; Adult; Aged; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Double-Blind Method; Drug Resistance; Female; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Middle Aged

Post-kala-azar dermal leishmaniasis (PKDL) is a recognized dermatosis that follows successful treatment of visceral leishmaniasis in the Sudan. This randomized and double-blind study aimed to assess safety, immunogenicity and curative potentials of a novel immunochemotherapy regimen in patients with persistent PKDL. Following informed consent, 30 patients were randomized to receive alum-precipitated autoclaved Leishmania major (Alum/ALM) vaccine+Bacille Calmette-Guérin (BCG) and sodium stibogluconate (SSG) or vaccine diluent and SSG. The SSG+Alum/ALM+BCG proved safe with minimal local adverse events. In the SSG+vaccine group, 87% of the patients were cured by day 60 compared with 53% in the SSG alone group (SSG+vaccine efficacy=71%, 95% CI for risk ratio 0.7-1.16). On day 90 of follow-up there were two relapses in the SSG alone arm and none in the SSG+vaccine arm. Pre-treatment cytokines showed high IFN-gamma or high IFN-gamma/IL-10 levels and leishmanin skin test (LST) non-reactivity, while healing/clinical improvement were associated with LST reactivity and low IFN-gamma levels in both study groups (P=0.004). In conclusion, SSG+Alum/ALM+BCG is safe and immunogenic with significant healing potentials in persistent PKDL lesions. Immunochemotherapy probably augmented IFN-gamma production, which induced healing. Leishmanin skin reactivity is a good surrogate marker of cure in persistent PKDL lesions.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; BCG Vaccine; Child; Double-Blind Method; Female; Humans; Interferon-gamma; Interleukin-10; Leishmaniasis Vaccines; Leishmaniasis, Visceral; Male; Middle Aged; Statistics as Topic; Sudan; Treatment Outcome; Vaccines, Combined

We evaluated lymph node aspiration (LNA) as a simple diagnostic procedure for visceral leishmaniasis (VL). Lymph node aspiration was compared with the direct agglutination test (DAT) using a diagnostic titer > or = 1:6,400 in 7,880 suspected VL patients in eastern Sudan. Compared with DAT, LNA had a sensitivity of 65.1% (95% confidence interval = 63.5-66.6%). Parasite density in LNA correlated strongly with DAT titers (P < 0.0001), and low parasite density accounted for 78.1% of positive LNA results with DAT titers < 1:6,400 (n = 782). Risk factors predictive of a positive LNA result were an age of 1-29 years, male sex, a hemoglobin level < 10.0 g/dL, a DAT titer > or = 1:800, and a location with a higher prevalence of VL. Lymph node and splenic aspirations were similarly accurate as tests of cure after treatment of 50 VL patients in southern Sudan. Pre-treatment LNA results were negative in 20 cases of severe post kala-azar dermal leishmaniasis.

Topics: Adolescent; Adult; Agglutination Tests; Antimony Sodium Gluconate; Antiprotozoal Agents; Biopsy, Needle; Child; Child, Preschool; Female; Humans; Infant; Leishmaniasis, Visceral; Lymph Nodes; Male; Seasons; Sensitivity and Specificity; Sudan

Visceral leishmaniasis (VL) or kala-azar is known to be associated with a mixed Th1-Th2 response, and effective host defense requires the induction of IFN-gamma and IL-12. We address the role of the differential decline of IL-10 and TGF-beta in response to sodium antimony gluconate (SAG) and amphotericin B (AmB), the therapeutic success of SAG and AmB in Indian VL, and the significance of IL-10 and TGF-beta in the development and progression of post-kazla-azar dermal leishmaniasis (PKDL). In the active disease, PBMC from VL patients showed suppressed Ag-specific lymphoproliferation, IFN-gamma and IL-12 production, and elevation of IL-10 and TGF-beta. Cure corresponded with an elevation in IFN-gamma and IL-12 production and down-regulation of IL-10 and TGF-beta. Both CD4(+) and CD8(+) T cells were involved in IFN-gamma and IL-10 production. Interestingly, the retention and maintenance of residual IL-10 and TGF-beta in some SAG-treated individuals and the elevation of IL-10 and TGF-beta in PKDL, a sequel to kala-azar, probably reflects the role of these cytokines in reactivation of the disease in the form of PKDL. Contrastingly, AmB treatment of VL resulted in negligible TGF-beta levels and absolute elimination of IL-10, reflecting the better therapeutic activity of AmB and its probable role in the recent decline in PKDL occurrences in India. Moreover, elucidation of immune responses in Indian PKDL patients revealed a spectral pattern of disease progression where disease severity could be correlated inversely with lymphoproliferation and directly with TGF-beta, IL-10, and Ab production. In addition, the enhancement of CD4(+)CD25(+) T cells in active VL, their decline at cure, and reactivation in PKDL suggest their probable immunosuppressive role in these disease forms.

Topics: Adolescent; Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Cells, Cultured; Coculture Techniques; Disease Susceptibility; Female; Humans; India; Interleukin-10; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Recurrence; Transforming Growth Factor beta

We have evaluated levels of 6 cytokines in sera of 35 patients of kala azar (KA), 29 post kala azar dermal leishmaniasis (PKDL), and 18 healthy controls using cytometric bead array technology. Results indicated significantly high levels of interferon gamma (IFN-gamma), interleukin (IL)-10, and IL-6 during active KA, while tumor necrosis factor alpha (TNF-alpha), IL-2, and IL-4 were minimal. Serum level of cytokines in PKDL was comparable to the controls while TNF-alpha was significantly elevated compared to KA or control. At post-treatment stage, KA patients showed a significant decrement in the levels of IFN-gamma, IL-10, and IL-6; however, IL-6 remained significantly elevated above control levels. Further, comparison of cytokine levels in children and adults revealed elevated level of IL-10 in pediatric cases. SAG unresponsive cases showed significantly elevated levels of IFN-gamma in comparison with the responsive cases. The results depict that type1 response is not depressed during active KA and suggest the possibility that unresponsiveness to type1 stimuli may prevail.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Cytokines; Female; Humans; India; Leishmaniasis, Visceral; Male; Middle Aged; Th1 Cells; Th2 Cells

Antimonials are the mainstay of visceral leishmaniasis (VL) treatment in Africa. The increasing incidence of human immunodeficiency virus (HIV) coinfection requires alternative safe and effective drug regimens. Oral miltefosine has been proven to be safe and effective in the treatment of Indian VL but has not been studied in Africa or in persons with HIV and VL coinfection.. We compared the efficacy of miltefosine and sodium stibogluconate (SSG) in the treatment of VL in persons in Ethiopia. A total of 580 men with parasitologically and/or serologically confirmed VL were randomized to receive either oral miltefosine (100 mg per day for 28 days) or intramuscular SSG (20 mg/kg per day for 30 days).. The initial cure rate was 88% in both treatment groups. Mortality during treatment was 2% in the miltefosine group, compared with 10% in the SSG group. Initial treatment failure was 8% in the miltefosine group, compared with 1% in the SSG group. Among the 375 patients (65%) who agreed to HIV testing, HIV seroprevalence was 29%. Among patients not infected with HIV, initial cure, mortality, and initial treatment failure rates were not significantly different (94% vs. 95%, 1% vs. 3%, and 5% vs. 1% for the miltefosine and SSG groups, respectively). Initial treatment failure with miltefosine occurred in 18% of HIV-coinfected patients, compared with treatment failure in 5% of non-HIV-infected patients. At 6 months after treatment, 174 (60%) of the 290 miltefosine recipients and 189 (65%) of the 290 SSG recipients experienced cure; 30 (10%) of 290 in the miltefosine group and 7 (2%) of 290 in the SSG group experienced relapse, and the mortality rate was 6% in the miltefosine group, compared with 12% in the SSG group. HIV-infected patients had higher rates of relapse (16 [25%] of 63 patients), compared with non-HIV-infected patients (5 [5%] of 131).. Treatment with miltefosine is equally effective as standard SSG treatment in non-HIV-infected men with VL. Among HIV-coinfected patients, miltefosine is safer but less effective than SSG.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Comorbidity; Ethiopia; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Phosphorylcholine; Prevalence; Treatment Outcome

Miltefosine, an alkyl phospholipid has been found effective against visceral leishmaniasis (VL) in adults in various studies. The authors safety, tolerance and efficacy of Miltefosine and compared with available gold standard anti-Ieishmanial drug, Amphotericin B, a parenteral formulation in children with VL.. All consecutive children aged 1 yr to 14 yr, presented with fever, splenomegaly and positive LD body in splenic smear examination, admitted in pediatric ward of Nalanda Medical college and Child care center between 1st July 03 to 30th June 05 were taken for study. Patients were randomized into four groups. Group-l and 2 patients were given Miltefosine in dose of 2.5 mg/Kg day o.d. or b.i.d. per orally to a maxiIpum of 100 mg and group 3 and 4 Amphotericin B at a dose of 1 mg/Kg/day (total: 15 mg/Kg). All patients were followed at completion of therapy, 3 months and 6 months for clinical response, splenic size and parasitologically.. Out of 125 children, 44 were in group-I, 20 in group-2, 38 in group-3 and 23 in group- 4, 124 patients had parasitological cure with relapse in one patient of group 1 during follow up. One patient in-group II had no response with first course but became parasitologically negative with 2nd course of Miltefosine. In-group I, one patient had persistent splenomegaly and found to have associated portal hypertension. Final cure rate with Miltefosine and Amphotericin B was 93.2%, 95%, 92.1% and 91.3% in-group 1, 2, 3 and 4 respectively, which are statistically insignificant. Majority of patients had pancytopenia. Eievated". AL T (>3 times of normal) were seen in 28, 11, 19 and 13 patients of group 1, 2, 3 and group 4 respectively which returned to normal in subsequent follow up. Raised BUN was observed more in patients who got Amphotericin B i.e. 65.42% and 73.91 % in-group 3 and 4 respectively. GI side effects i.e. diarrhea and vomiting were observed in 26 and 23 patients in-group 1 and 2 respectively.. Miltefosine is safe, well tolerable, and highly effective and has same efficacy as Amphotericin B in newly diagnosed and SAG resistant children with visceral leishmaniasis.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Cross-Sectional Studies; Drug Resistance; Humans; Leishmaniasis, Visceral; Phosphorylcholine; Prospective Studies; Treatment Outcome

In a study to evaluate the relative efficacies of sodium antimony gluconate (SAG) and amphotericin B (AMB), each drug was used to treat 60 Indian cases of visceral leishmaniasis (VL). At the time of treatment, each case had recently been parasitologically confirmed. The patients received either 20 mg SAG/kg daily, by intramuscular injection, for 4 weeks, or 1 mg AMB/kg daily, infused slowly over 2 h, with no incremental dosage, for 20 days. The response of the patients was followed clinically and by the microscopical examination of bone-marrow aspirates (BMA). The infected macrophages in subsamples of the BMA collected pre-treatment were cultured so that the drug sensitivities of the parasites, to 20 microg SAG or 1 microg AMB/ml medium, could be determined in vitro. Other subsamples of the BMA were used to set up promastigote cultures that were then used to infect BALB/c mice. The responses of the mice to 5 days of treatment with SAG or AMB (at the same daily dosages as used in the clinical trials) were subsequently explored. SAG only cured 46.6% of the patients given the drug, only cleared amastigotes from 38.3% of the macrophage cultures, and only cured 53.3% of the infected mice. The corresponding values for AMB - 100%, 100% and 100% - were markedly higher (P <0.001 for each comparison). Although nine patients had to be withdrawn from the SAG group (all because of cardiac toxicity), all of the patients given AMB completed their treatment without any serious adverse effects (P <0.01). Two of the patients withdrawn from the SAG arm died shortly after their withdrawal; earlier withdrawal may have saved them. At least in the setting of the present study, AMB appears far superior to SAG as a first-line drug against VL and should replace it.

Topics: Adolescent; Adult; Aged; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow; Cells, Cultured; Child; Female; Humans; India; Infusions, Parenteral; Injections, Intramuscular; Leishmaniasis, Visceral; Macrophages; Male; Mice; Mice, Inbred BALB C; Middle Aged; Treatment Outcome

To compare the use of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis (kala-azar).. A total of 102 patients with confirmed kala-azar were treated in a mission hospital in West Pokot region, Kenya, with sodium stibogluconate (20 mg/kg/day for 30 days)--either as Pentostam (PSM) or generic sodium stibogluconate (SSG); 51 patients were allocated alternately to each treatment group.. There were no significant differences in baseline demographic characteristics or disease severity, or in events during treatment. There were 3 deaths in the PSM group and 1 in the SSG group; 2 patients defaulted in each group. Only 1 out of 80 test-of-cure splenic aspirates was positive for Leishmania spp.; this patient was in the SSG group. Follow-up after > or = 6 months showed that 6 out of 58 patients had relapsed, 5 in the SSG group and 1 in the PSM group. No outcome variable was significantly different between the two groups.. The availability of cheaper generic sodium stibogluconate, subject to rigid quality controls, now makes it possible for the health authorities in kala-azar endemic areas to provide treatment to many more patients in Africa.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Evaluation; Drugs, Generic; Female; Humans; Kenya; Leishmaniasis, Visceral; Male; Treatment Outcome

The clinical presentation and duration of therapy for visceral leishmaniasis varies in different countries. The sodium stibogluconate is costly, and a trial of short course therapy has not yet been studied in Hajjah governorate. The aim of this study was to evaluate the efficacy of a 20 days regimen of sodium stibogluconate and to ascertain the epidemiological, clinical and laboratory features of visceral leishmaniasis in children.. This was a prospective hospital-based study in Hajjah Governorate, Republic of Yemen. Children of 12 years of age or less with a confirmed diagnosis were included. Sodium stibogluconate was given in a dose of 15mg/kg/dose daily for 20 days, then the patients were re-evaluated and the data required for achieving the other objective was collected.. Thirty-two patients fulfilled the inclusion criteria. The age ranged from 12 months to 144 months (67.7 +/- 35). Females formed 53% of this criteria. The duration of symptoms ranged from 2 weeks to 116 weeks. Fever, fatigability and abdominal distension were the most common symptoms. The hematological findings showed anemia in all patients, leukopenia in 81% and thrombocytopenia in 56%. Formol gel test was negative in 20 patients (63%). Malaria smear was positive in 11 patients (34%). Splenic aspiration was carried out in 25 patients (78%) and bone marrow aspiration in 7 patients (22%). Blood transfusion were required for 24 patients (73%). After 20 days treatment with pentostam, 20 patients (63%) came for follow-up and re-tested for parasitological cure. Half of those were still positive for leishmania donovan bodies. The mortality rate was 5%.. The clinical features were of the Mediterranean type. Twenty days treatment with sodium stibogluconate was not adequate.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Cohort Studies; Drug Administration Schedule; Female; Humans; Infant; Leishmaniasis, Visceral; Male; Treatment Outcome; Yemen

To compare the outcome of treatment of Sudanese kala-azar patients treated under field conditions with either branded sodium stibogluconate (SSG) (Pentostam GlaxoWellcome) or generic SSG (Albert David Ltd, Calcutta, supplied by International Dispensary Association, Amsterdam).. Randomised comparison. 271 patients were treated with Pentostam and 245 with generic SSG.. No statistically significant differences in cure rate or mortality were detected between Pentostam and generic SSG. No differences in side-effects between the two drugs were noted. The initial cure rate at the time of discharge was 93.7 and 97.6%, respectively; the death rate during treatment 5.9 and 2.4%. Six months follow up was achieved in 88.5% of the discharged patients. Two patients had died in the Pentostam group and two had died in the generic SSG group, giving a final death rate of 7.5 and 3.7%. The number of relapses in the Pentostam and generic SSG groups were 3 and 1, respectively. The final cure rates, calculated at 6 months after discharge, were 91.3% and 95.9%.. No difference was observed in the performance of generic SSG compared to Pentostam for the treatment of visceral leishmaniasis in Sudan. Generic SSG can be routinely and safely used for the treatment of kala-azar. Generic SSG costs only 1/14 of the price of Pentostam. The use of generic SSG may make treatment of kala-azar affordable for national governments in Africa.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Follow-Up Studies; Humans; Leishmaniasis, Visceral; Male

In India, 320 patients with visceral leishmaniasis (209 in the state of Bihar and 11 in the neighboring state of Uttar Pradesh) received identical pentavalent antimony (Sb) treatment. Sb induced long-term cure in 35% (95% confidence interval [CI], 28%-42%) of those in Bihar versus 86% (95% CI, 79%-93%) of those in Uttar Pradesh. In Bihar, the center of the Indian epidemic, traditional Sb treatment should be abandoned.

Topics: Adolescent; Adult; Aged; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Disease Outbreaks; Female; Humans; India; Infant; Leishmaniasis, Visceral; Male; Middle Aged; Treatment Failure

The currently recommended protocol for treatment of kala-azar (KA) necessitates repeated bone marrow/splenic aspiration to monitor the response and duration of therapy as well as to detect resistance and change to alternative drugs. These procedures being invasive, there is a pressing need for less invasive diagnostic tools for this purpose. We have evaluated the role of C-reactive protein (CRP) in 201 children with visceral leishmaniasis at different stages of the disease to work out the relationship, if any, between CRP levels and disease activity, including response to therapy. The subjects belonged to the 2-12 year age group in whom CRP estimation was done on admission, every 5th day during treatment, and repeated on follow-up at 2 and 6 months. The levels were compared with those of 50 randomly chosen age-matched healthy children who served as controls. The mean serum CRP value in the study group before the commencement of treatment was 62.96 +/- 1.03 mg/l, which was significantly higher (p < 0.001) in comparison to the control group. Commencement of treatment resulted in a simultaneous decline in serum CRP. Parasitic clearance from the spleen was faster in patients with an initial low serum CRP level (< 60 mg/l) in comparison to patients with high levels (> 60 mg/l). During treatment, mean serum CRP levels were significantly higher in late responders than in early responders (p < 0.001). Correlation of CRP levels to indicate the presence or absence of parasites suggested a cut-off level of 12 mg/l by day 10, with a sensitivity of 82.5 per cent, specificity of 78.5 per cent, positive predictive value of 92 per cent, and negative predictive value of 60.2 per cent. Our observations suggest a promising role for CRP estimation every 5-10 days during therapy in visceral leishmaniasis for monitoring the response to therapy and to detect possible resistance.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Drug Monitoring; Female; Humans; Leishmaniasis, Visceral; Male; Prognosis

To assess the efficacy and tolerability of aminosidine compared with sodium stibogluconate for treating visceral leishmaniasis.. Randomised, unblinded, controlled trial with 180 day follow up.. Kala-Azar Research Centre, Brahmpura, Muzaffarpur, Bihar, India.. People of either sex aged 6-50 years with symptoms and signs suggestive of visceral leishmaniasis (fever, loss of appetite, enlarged spleen) with leishmania amastigotes detected in Giemsa stained aspirates of spleen or bone marrow.. Aminosidine at three daily doses (12, 16, and 20 mg/kg) for 21 days and sodium stibogluconate 20 mg/kg/day for 30 days.. Laboratory measures of efficacy: parasite count, haemoglobin concentration, white cell count, platelet count, serum albumin concentration. Clinical measures of efficacy: spleen size, fever, body weight, and liver size. Measures of safety: liver and renal function tests, reports of adverse events.. Of the 120 patients enrolled (30 per treatment arm), 119 completed treatment and follow up. Cure at end of follow up was achieved in 23 (77%), 28 (93%), and 29 (97%) patients treated with 12, 16, and 20 mg aminosidine/kg/day respectively, and in 19 (63%) patients given sodium stibogluconate. At 16 and 20 mg/kg/day, aminosidine was significantly more active than sodium stibogluconate in both clinical and laboratory measures of efficacy. No significant clinical or laboratory toxicity occurred in any treatment group.. A 21 day course of aminosidine 16 or 20 mg/kg/day should be considered as first line treatment for visceral leishmaniasis in Bihar.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antimony Sodium Gluconate; Child; Dose-Response Relationship, Drug; Humans; Injections, Intramuscular; Leishmaniasis, Visceral; Middle Aged; Paromomycin; Risk Assessment; Schistosomicides; Treatment Outcome

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Humans; Leishmaniasis, Visceral; Male

Twenty-seven cases of Kala-azar were treated with sodium stibogluconate at a dose of 20 mg/kg/day for 20 days (group A) and an equal number of cases were treated with the same dose but for a longer duration of 30 days (group B). Clinical and laboratory evaluation of these cases were carried out before and after therapy, during a follow up of cases every month, upto 6 months. Renal and liver function tests and electrocardiography were carried out of monitor any toxic effect of the drug during therapy. The cure rates of patients were 77.78% and 92.59% in group A and B cases respectively. Six and two patients in group A and B respectively were unresponsive to the treatment and showed relapse. Results of the study show that treatment of cases of Kala-azar with sodium stibogluconate in a dosage of 20 mg/kg/day for a longer period of 30 days is effective with a higher cure rate and minimum side effects, for treatment of cases of Kala-azar in this eastern part of Nepal, endemic for the disease.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Nepal

Twelve dogs naturally infected with Leishmania infantum were treated subcutaneously with aminosidine at a dose of 10 mg kg-1 per day for four weeks. Antimonial compounds were used as reference drugs in twelve Leishmania-infected dogs. Eleven of the twelve dogs submitted to aminosidine therapy responded within 30 days. The treatment with the aminoglycoside antibiotic presented a marked decrease of anti-Leishmania antibody titres than the controls. Aminosidine also reduced urinary protein, serum IgG, and circulating immune complex concentrations. Side effects were observed only in a dog with pre-existent renal lesions. This study proved that aminosidine is an effective, tolerable and safe drug for the treatment of canine leishmaniasis and that it could be used as a suitable substitute for antimonial therapy.

Topics: Amebicides; Animals; Antibodies, Protozoan; Antigen-Antibody Complex; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Dog Diseases; Dogs; Female; Immunoglobulin G; Leishmania infantum; Leishmaniasis, Visceral; Male; Paromomycin; Proteinuria; Time Factors

Parasitologically confirmed cases of post-kala-azar dermal leishmaniasis (PKDL) were treated by infusion with amphotericin B deoxycholate (ABD; 1 mg/kg.day on days 1-20, 21-40 and 61-80) or by intramuscular injection with sodium antimony gluconate (SAG; 20-day courses at 20 mg/kg day, with 20-day, drug-free intervals). Of the 11 patients given ABD, all were cured with the three courses, none relapsed in 12 months of follow-up, all developed mild adverse effects (shivering and fever) because of the infusion, five lost their appetites, and three showed increases in their serum creatinine concentrations (although none exceeded 'normal' limits). In contrast, only seven (63%) of the 11 patients given SAG were considered treatment successes (improvement in lesions by the end of the third course) and these took six courses (two cases), nine courses (four cases) or 10 courses (one case) to cure completely. Two of the patients given SAG developed arthralgia and two others developed non-specific ST changes in their electrocardiograms (ECG), although their ECG were normal between courses. The better cure rate with ABD was not statistically significant, probably because of the small sample size. However, ABD appears to be a superior to SAG in terms of the speed of response and cure, although it is more expensive and has some nephrotoxicity. As the effectiveness of SAG against PKDL is apparently declining over time and the cost of ABD is prohibitive in poor countries such as India, a safe, cheap and more effective drug for the treatment of PKDL is needed.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Female; Follow-Up Studies; Humans; India; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Treatment Outcome

Twenty-one Indian patients with visceral leishmaniasis who did not respond to or relapsed after 28-60 days of pentavalent antimony therapy were treated with amphotericin B lipid complex (ABLC). Five infusions (3 mg/kg each) given every second day over 9 days (total dose, 15 mg/kg) resulted in a 100% apparent cure response. In 4 other patients who had not responded to antimony, apparent cure was also induced by ABLC given 3 mg/kg a day 5 consecutive days (total dose, 15 mg/kg). Fever and chills developed routinely during the initial 2-h infusions; these reactions were tolerated and diminished with successive infusions. Six months after treatment, all 25 patients were healthy, had parasite-free bone marrow aspirates, and were considered cured. ABLC is effective short-course therapy for kala-azar patients who do not respond to conventional antimony treatment.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Resistance; Female; Fever; Humans; India; Leishmaniasis, Visceral; Lipids; Liposomes; Male

To assess the effectiveness of two regimens with allopurinol or pentavalent antimony as secondary prophylaxis for visceral leishmaniasis (VL) in human immunodeficiency virus (HIV)-infected patients.. Retrospective, nonrandomized, open trial.. A 1,000-bed academic tertiary institutional hospital in Barcelona.. Forty-six individuals over 14 years old with HIV infection, who recovered from an episode of VL between January 1988 and February 1995.. Twenty patients did not receive any prophylaxis, nine received 300 mg/8 h of allopurinol, and 17 received 850 mg once-a-month of pentavalent antimony. Patients were followed-up every 3 months, and the endpoint of study was relapse of VL.. Twenty-one patients had recurrent VL: 13 of 20 in the control group (65%), 5 of 9 in the allopurinol group (56%), and 3 of 17 in the antimonial group (18%). Kaplan-Meier estimates of the probability of remaining relapse-free at 12 months were 9% without prophylaxis (95% CI, 0-22%), 21% with allopurinol (95% CI, 0-51%), and 93% with antimonials (95% CI, 82-100%) (P < 0.001). Multivariate analysis showed that the only significant variables related to relapsing course of VL were assignment to the antimonial group, and the fact that the patient had experienced a previous episode of VL.. Pentavalent antimony given once a month is effective in the prevention of VL relapses in HIV-infected individuals. It is a low-cost treatment that proved to be well tolerated. Therefore, pentavalent antimony should be considered a suitable agent for secondary prophylaxis against VL.

Topics: Adult; Aged; Allopurinol; Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Data Interpretation, Statistical; Female; Follow-Up Studies; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Middle Aged; Multivariate Analysis; Organometallic Compounds; Recurrence; Retrospective Studies; Time Factors

One hundred cases of Indian Kala-azar unresponsive to sodium stibogluconate (SSG) were treated with amphotericin B. The drug was given in the dose schedule of 0.75 mg/kg body weight on alternate days intravenously dissolved in 5 percent dextrose solution. After 15 infusions given over a period of 30 days, all cases became clinically and parasitologically cured. Mild adverse reactions were noted during therapy. No relapse was observed at follow up after 12 months.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Drug Resistance; Female; Humans; India; Leishmaniasis, Visceral; Male; Middle Aged

Patients do not always respond to treatment of visceral leishmaniasis with pentavalent antimony, and the drug has toxic effects. Amphotericin B might be useful as an alternative first-line treatment for the disease. We compared the efficacy of amphotericin and sodium stibogluconate in a prospective randomised trial in 80 uncomplicated and parasitologically confirmed cases of Indian kala-azar. None of the patients had received an antileishmanial agent before. Sodium stibogluconate was given at 20 mg/kg in two divided doses daily for 40 days, and amphotericin in fourteen doses of 0.5 mg/kg infused in 5% dextrose on alternate days. All 40 patients randomised to amphotericin were cured; of the 40 patients assigned to sodium stibogluconate, 28 (70%) showed initial cure and 25 (62.5%) showed definitive cure (p < 0.001). With amphotericin, there was quicker abatement of fever and more complete spleen regression with no serious adverse effects. Amphotericin is effective in the first-line treatment of Indian kala-azar and superior to antimony therapy.

Topics: Adult; Amphotericin B; Antimony Sodium Gluconate; Drug Administration Schedule; Female; Humans; India; Leishmaniasis, Visceral; Male; Treatment Outcome

Twenty-four Kenyan patients with visceral leishmaniasis were treated for 30 days with either conventional therapy (daily pentavalent antimony, n = 14) or experimental immunochemotherapy (daily antimony plus interferon-gamma [IFN-gamma] every other day, n = 10). All 24 patients responded clinically to treatment, and microscopic splenic aspirate scores rapidly decreased in both groups. As judged by splenic aspirate culture results, IFN-gamma-treated patients responded more quickly (50% versus 22% culture-negative after one week and 75% versus 58% culture-negative after two weeks). While not statistically significant, these differences raise the possibility that combination therapy using IFN-gamma, which was safe and well-tolerated, may accelerate the early parasitologic response in patients with visceral leishmaniasis.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Child; Child, Preschool; Drug Therapy, Combination; Drug Tolerance; Female; Follow-Up Studies; Humans; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Male; Pilot Projects; Prospective Studies; Recombinant Proteins; Spleen

In a comparative trial of treatment in southern Sudan, visceral leishmaniasis was diagnosed by the following symptoms: fever for > 1 month, splenomegaly, and antileishmanial direct agglutination test (DAT) titer of > or = 1:25,600. Patients (200) were randomized to receive sodium stibogluconate (Sbv) at 20 mg/kg/day for 30 days (groups S, n = 99) or Sbv at 20 mg/kg/day plus aminosidine at 15 mg/kg/day for 17 days (group AS, n = 101). Of 192 patients who had spleens or lymph nodes aspirated at entry, 134 (70%) were positive for parasites. During treatment, 7% in group S and 4% in group AS died. All 184 patients who completed treatment were clinically cured. At days 15-17, microscopy of aspirates showed that 57 (95%) of 60 in group AS were negative for parasites compared with 47 (81%) of 58 in group S (P = .018). At day 30, 57 (93.4%) of 61 group S aspirates were negative.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Disease Outbreaks; Drug Therapy, Combination; Female; Giardiasis; Humans; Infant; Leishmaniasis, Visceral; Malaria; Male; Middle Aged; Nutrition Disorders; Paromomycin; Pregnancy; Sudan; Weight Loss

A total of 150 patients of kala-azar matched for age and sex and parasitologically proved were randomly allocated to two equal treatment groups. Patients in one group received amphotericin B(AMB) in a dose of 1 mg/kg body weight (BW) on alternate days starting with 0.05 mg/kg/bw on first day with daily increments, till a total dose of 20 mg/kg/bw was given; the patients in the second group received sodium stibogluconate (SAG) in the dose of 20 mg/kg/bw, im daily for 30 days. The efficacy, safety and cost-effectiveness of the two drugs were compared. Apparent cure (afebrile at the end of therapy) in 75 (100%) and 69 (92%) patients and ultimate cure (no relapse in six months of follow up) in 75 (100%) and 60 (80%) patients occurred in the AMB and SAG groups respectively. The difference between the ultimate cure in the two groups was significant (P < 0.001). Six (8%) and 9(12%) patients of SAG group showed primary (with no response to SAG during treatment) and secondary unresponsiveness (with no response to SAG after relapse) respectively and they were cured with amphotericin B.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Female; Humans; India; Leishmaniasis, Visceral; Male

40 parasitologically confirmed cases of kala azar, were randomly allocated into four treatment groups to assess the effect of verapamil on fresh and antimony resistant cases of kala azar. Untreated patients received sodium stibogluconate only or in combination with oral verapamil. Antimony-resistant patients were treated with sodium stibogluconate combined with oral verapamil or pentamidine. The patients were followed up for six months. Verapamil neither shortened the duration of treatment nor increased parasitological cure rate nor improved the ultimate cure. In antimony unresponsive patients it did not reverse unresponsiveness.

Topics: Administration, Oral; Adult; Antimony Sodium Gluconate; Drug Resistance; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Injections, Intramuscular; Leishmaniasis, Visceral; Male; Pentamidine; Splenomegaly; Verapamil

We compared the efficacy of amphotericin B and pentamidine isethionate in a prospective randomised trial in 120 uncomplicated and parasitologically confirmed cases of antimony-unresponsive kala-azar. Doses were twenty intramuscular injections of pentamidine 4 mg/kg on alternate days or fourteen definitive doses of amphotericin 0.5 mg/kg infused in 5% dextrose on alternate days. 48 (80%) patients given pentamidine showed initial cure and 46 (77%) showed definitive cure compared with 60 (100%) and 59 (98%) cases, respectively, on amphotericin (p < 0.001). Amphotericin also brought about quicker abatement of fever and more complete spleen regression.

Topics: Adult; Amphotericin B; Antimony Sodium Gluconate; Female; Humans; Leishmaniasis, Visceral; Male; Pentamidine; Prospective Studies

The efficacy and safety of three regimens of treatment for kala-azar (visceral leishmaniasis) with sodium stibogluconate were evaluated in a randomised clinical trial to ascertain the optimal duration of treatment for Indian patients. The study included a total of 312 (226 male, 86 female) patients with fresh kala-azar, confirmed by demonstration of parasites in aspirates from bone marrow or spleen, who were randomly allocated into three treatment groups of 104 patients in each to receive sodium stibogluconate intramuscularly. The dose of the drug was 20 mg/kg/body weight/daily with a maximum of 8.5 ml for 20, 30 and 40 days (groups A, B, C respectively). The response of treatment was assessed under blind conditions and patients were followed up each month for a period of six months. The number of patients who were apparently cured (i.e., those whose temperature had returned to normal at the end of their respective regimen and aspirates were free of parasites) was 91 (87%) in group A, 98 (94%) in group B, and 102 (98%) in group C. The difference between groups A and C was significant (P less than 0.01). The number of patients who were ultimately cured at six months was 74 (71%) in group A, 86 (83%) in group B and 98 (94%) in group C. These patients had not relapsed and were cured as confirmed by a bone marrow aspirate which was free of parasites. The difference between groups A and C (P less than 0.001) and groups B and C (P less than 0.05) were significant. However, the difference between groups A and B was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antimony Sodium Gluconate; Child; Female; Follow-Up Studies; Humans; Leishmaniasis, Visceral; Male; Pentamidine; Recurrence

Three hundred twelve patients with antimony-resistant kala-azar were randomized into three groups. The first group (A) received pentamidine isethionate intravenously three times each week until parasitological cure was achieved. Group B received pentamidine concomitantly with a 20-day regimen of sodium stibogluconate. Group C received pentamidine injections that were followed by 20 days of sodium stibogluconate therapy. All patients became afebrile after 10 injections of pentamidine. Parasitologic cure was achieved in approximately 98% of the patients who had 33 or more injections of this drug. The addition of the antimony compound did not appear to enhance the rate of parasitologic cure. Three patients continued to have parasites after 40 injections of pentamidine. After six months, the rate of parasitologic cure was significantly higher in Group C (pentamidine followed by sodium stibogluconate) than in either Group A or B. Forty patients relapsed after apparent parasitologic cure and were successfully treated with five additional injections of pentamidine, followed by a course of antimony therapy. Minor side effects with pentamidine included an uneasy feeling during intravenous injection (12%), intestinal disturbances (6%), cellulitis (5%), abscess formation (1%), and allergic manifestations (2%). Major reactions to this drug included hyperglycemia (10%; reversible in 6% and irreversible in 4%), and delayed hypoglycemia (8%). Four deaths were associated with the administration of this compound. It is concluded that pentamidine is an effective but toxic drug for the treatment of antimony-resistant kala-azar.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Leishmaniasis, Visceral; Male; Middle Aged; Pentamidine; Recurrence; Retrospective Studies; Spleen

The efficacy and safety of six regimens of treatment for kala-azar (visceral leishmaniasis) with sodium stibogluconate were evaluated in a prospective randomised study to ascertain the optimal treatment for Indian patients. Altogether 371 patients with kala-azar were randomised to receive sodium stibogluconate intramuscularly at a dose of 10 mg/kg body weight/day for 20 or 40 days (groups A and A1, respectively), 15 mg/kg body weight/day for 20 or 40 days (groups B and B1, respectively), or 20 mg/kg body weight/day for 20 or 40 days (groups C and C1, respectively). Patients were examined blind before and at the end of treatment and every month for six months. The number of patients who were apparently cured--that is, those whose temperature had returned to normal at the end of their regimen of treatment--was 45 (78%) in group A, 53 (87%) in group A1, 50 (81%) in group B, 60 (95%) in group B1, 58 (92%) in group C, and 62 (97%) in group C1. At six months 62 patients (97%) in group C1, 51 (81%) in group C, 54 (86%) in group B1, 42 (68%) in group B, 45 (74%) in group A1, and 33 (57%) in group A had not relapsed and were cured as confirmed by a bone marrow aspirate free of parasites. The differences between groups C1 and C, B1 and B, and A1 and A were significant. Logistic regression of the proportion cured with the dose and length of treatment showed that both factors were significant in improving the rate of cure; the highest dose for the longer time (group C1) had the best rate of cure. One patient in group C1, 12 in group C, nine in group B1, 18 in group B, 15 in group A1, and 23 in group A were cured with extended courses of 20 mg sodium stibogluconate. One patient in each of groups C1, B, A1, and A became unresponsive to antimony and were cured with pentamidine. One patient in each of groups C1, B, and A became unresponsive to both antimony and pentamidine. The patients tolerated the longer duration of treatment safely, and side effects were minor. Sodium stibogluconate should be given intramuscularly in the dosage of 20 mg/kg for at least 40 days, when patients should be assessed for further treatment if necessary. Such a regimen should achieve the highest rate of cure with low toxicity and low rates of relapse and unresponsiveness.

Topics: Antimony Sodium Gluconate; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gluconates; Humans; India; Injections, Intramuscular; Leishmaniasis, Visceral; Male; Prospective Studies; Random Allocation; Time Factors

Topics: Adolescent; Adult; Aged; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Gluconates; Humans; Leishmaniasis; Leishmaniasis, Visceral; Male; Middle Aged

Topics: Allopurinol; Antimony Sodium Gluconate; Clinical Trials as Topic; Gluconates; Humans; Leishmaniasis, Visceral; Time Factors

Topics: Amidines; Antimony Sodium Gluconate; Clinical Trials as Topic; Gluconates; Humans; India; Leishmaniasis, Visceral; Pentamidine; Random Allocation

One hundred and twenty six patients with kala-azar (visceral leishmaniasis) were allocated at random to one of two groups for treatment with sodium stibogluconate. One group was treated for 20 days; in the other group the patients were assessed after 20 days' treatment and treatment was continued if necessary. Both groups were followed up for six months. There was no significant difference in symptomatic outcome between the two groups at 20 days. At six months eight of the patients in the group treated for 20 days had relapsed and 54 were cured. Of the group given more than 20 days' treatment if necessary, 62 were cured and none had relapsed (12 required more than 20 days' treatment). This difference between the two groups was significant. One patient in each group did not respond to sodium stibogluconate, but both were were cured with pentamidine. Altogether 104 patients were cured after 20 days' treatment; 20, including the eight who relapsed, were cured after more than 20 days' treatment. There was no significant difference between the two groups in the side effects of the drug, which were minor. The longer courses of treatment (50 days in one patient) were well tolerated. It is suggested that the traditional six day course of treatment with sodium stibogluconate for kala-azar is grossly inadequate and that a longer course is required to prevent relapse.

Topics: Adolescent; Antimony Sodium Gluconate; Bone Marrow; Child; Drug Administration Schedule; Female; Gluconates; Humans; Leishmania; Leishmaniasis, Visceral; Male; Recurrence; Time Factors

The efficacy and safety of a single daily dose of sodium stibogluconate, 20 mg/kg body weight, given by deep intramuscular injection was compared with the conventional dose of 10 mg Sb/kg body weight in a randomised trial in Kenyan children and adults with visceral leishmaniasis. Splenic aspiration proved a safe and simple method for assessing parasitological response to treatment. In children the higher dose was associated with a faster clinical and parasitological response, and 100% were cured within 4 weeks, compared with 60% receiving the lower dosage. This difference is statistically significant by life-table analysis (x2 = 4.41, p less than 0.05). The superiority of the higher dose was not, however, seen in adults. In both children and adults the higher dose given daily for 2--4 weeks and in one patient for up to 7 weeks was found to be safe and well tolerated. It is likely, but not proven, that the use of sodium stibogluconate in a dose of 20 mg/kg bw daily for 4 weeks will reduce the relapse-rate in Kenyan children with visceral leishmaniasis.

Topics: Adult; Antimony Sodium Gluconate; Child; Clinical Trials as Topic; Disease Outbreaks; Female; Gluconates; Humans; Injections, Intramuscular; Kenya; Leishmania; Leishmaniasis, Visceral; Male; Random Allocation; Spleen

A prospective randomized trial of three dosage regimens of sodium stibogluconate (Pentostam; Wellcome Foundation, London) to treat visceral leishmaniasis was conducted. Previously untreated patients were randomized to receive 31 doses of sodium stibogluconate (10 mg Sb/kg of body weight per dose) administered once daily for 31 days (group A), every 12 hr for 15 days (group B), or every 8 hr for 10 days (group C). Of the 29 patients who completed treatment, seven of 10 in group B and all of the patients in groups A and C responded to treatment and remained well for one year. One patient in group B failed to respond to treatment, and two others in group B initially responded to treatment but relapsed six weeks after discharge. None of the treatment regimens was toxic. Parasites disappeared from splenic aspirates most quickly and hemoglobin levels rose most rapidly in patients receiving sodium stibogluconate every 8 hr. Treatment of visceral leishmaniasis in Kenya with sodium stibogluconate at a dose of 10 mg Sb/kg every 8 hr for 10 days appears to be a safe alternative to conventional treatment. Its efficacy should be confirmed in a larger number of patients.

Topics: Adolescent; Adult; Alanine Transaminase; Antimony Sodium Gluconate; Aspartate Aminotransferases; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Gluconates; Hemoglobins; Humans; Kenya; Leishmaniasis, Visceral; Male; Splenomegaly

Leishmaniasis, an infectious disease, manifests itself mostly in two forms, cutaneous leishmaniasis (CL) and, a more severe and potentially deadly form, visceral leishmaniasis (VL). The current control strategy for leishmaniasis relies on chemotherapy drugs such as sodium antimony gluconate (SAG) and meglumine antimoniate (MA). However, all these chemotherapy compounds have poor efficacy, and they are associated with toxicity and other adverse effects, as well as drug resistance. While research in vaccine development for leishmaniasis is continuously progressing, no vaccine is currently available. However, some experimental vaccines such as LEISH-F1+MPL-SE (

Topics: Antimony Sodium Gluconate; Humans; Leishmaniasis; Leishmaniasis, Visceral; Meglumine Antimoniate; Models, Biological; Vaccines

Visceral leishmaniasis (VL) is one of the most neglected tropical infectious diseases. It is fatal if left untreated. The objective of this study was to assess the efficacy and safety of 17-day injections of combined regimen of sodium stibogluconate and paromomycin (SSG/PM) in HIV-negative VL patients.. A retrospective analysis of medical records of VL patients treated in the University of Gondar Hospital during period 2012-2019 was carried out.. A total of 2836 patients were treated for VL from 2012 to 2019. Of these 1233 were treated with SSG-PM, and 1000 of them were included in the study. Initial cure was achieved in 922 (92.2%) patients. The frequency of treatment failure, treatment interruptions, default and deaths respectively were 30 (3%), 20 (2%), 13 (1.3%) and 15 (1.5%). Among 280 patients who completed 6-month follow up, the final cure was 93.9% (263/280), 4 (1.4%) relapsed and 13 (4.6%) developed post-kala-azar dermal leishmaniasis (PKDL). The most common adverse events (AEs) were raised liver transaminases (35.1%; 351 patients), injection site pain (29.1%, 291 patients) and raised serum alpha-amylase (29.1%, 291 patients). Factors associated with poor treatment outcomes were sepsis, pneumonia, and adverse events.. A combination of SSG at 20mg/kg with upper daily maximum dose of 850mg and PM was effective for achieving initial cure at end of treatment and safe for treatment of HIV negative VL patients in northwestern Ethiopia. Our data are consistent with previous reports and confirms effectiveness of SSG/PM treatment regimen in the Eastern African countries. Efficacy at 6-months (93.9%) was estimated on data derived from patients who completed follow up and needs to be interrogated by future studies.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Dosage Calculations; Drug Therapy, Combination; Ethiopia; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Paromomycin; Retrospective Studies; Treatment Outcome; Young Adult

Visceral leishmaniasis (VL) is a life-threatening parasitic disease next to malaria, which is responsible for the death of 50,000 patients annually. It has three major clinical stages, including visceral, cutaneous, and mucocutaneous leishmaniasis. Ethiopia is one of the east African countries commonly affected with leishmanisis disease. There are many drugs for leishmaniasis, including sodium stibogluconate and paromomycin combined therapy. However, the adverse effect of those combined drugs is not well-defined. Therefore, the purpose of this study was to assess serum amylase, lipase, and associated factors among patients with VL treatment with those combined drugs.. Hospital-based cross-sectional study was conducted at the University of Gondar Comprehensive Specialized Hospital Leishmaniasis Research and Treatment Center from February to September 2020 G.C. Simple random sampling technique was utilized to select study participants. The study participants who fulfill the inclusion criteria were included in the study with written informed consent. 5 ml of blood was withdrawn by an experienced health professional to analyze serum amylase and lipase level. Descriptive data was presented by tables, charts and graphs. Data was cleared, entered by Epi-data version 3.1 then transfer to STATA 14.1 SE version and for analysis paired t-test was used, for factors correlation and regression was used. Those factor variable who have p-value <0.25 was filtered and goes to multivariate regression and p-value <0.05 was considered as significant variables.. The result of this study showed that there was a significant mean difference between serum pancreatic amylase and lipase before and after treatment. The mean ± SD level of serum amylase after treatment showed a statistically significant elevation (P<0.001) as compared to its level before treatment. Similarly, the mean ± SD level of serum lipase after treatment showed a statistically significant elevation (P<0.001) as compared to its level before treatment. There was also significant association between age and baseline serum amylase as compared to serum amylase after treatment. Similarly, there was also significant relation of age and serum lipase with serum lipase after treatment.. In this study, the level of serum amylase and lipase at treatment of cure was higher and there was an increase in mean serum amylase and lipase after a patient taking sodium stibogluconate and paromomycin combined drugs. Consequently, the elevated result of these biochemical profiles mainly associated with drug induced adverse effect and associated risk factors in VL patients.

Topics: Adolescent; Adult; Amylases; Antimony Sodium Gluconate; Antiprotozoal Agents; Cross-Sectional Studies; Ethiopia; Female; Hospitals, Special; Humans; Leishmaniasis, Visceral; Lipase; Male; Paromomycin; Treatment Outcome; Young Adult

Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics.. Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients.. The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Kenya; Leishmaniasis, Visceral; Paromomycin

Visceral leishmaniasis (VL) or Kala-azar, primarily caused by Leishmania donovani, is a major health concern in many countries including India. Growing unresponsiveness among the parasites toward the available drugs is alarming, and so, it is necessary to decipher the underlying mechanism of such development for designing new therapeutics. Moreover, even after successful treatment, some VL patients develop apparently harmless skin lesions known as post-kala-azar dermal leishmaniasis (PKDL) which may serve as a reservoir of the parasite in the transmission cycle. Furthermore, recent reports of para-kala-azar dermal leishmaniasis (para-KDL) cases having PKDL manifestation with concomitant VL, emphasize the necessity of more attention to address complex nature of the parasite for eradicating the disease effectively. In the present study, whole genome sequencing is performed with sodium stibogluconate (SSG) sensitive and resistant L. donovani strains along with SSG sensitive para-KDL strains, derived from the clinical isolates of Indian patients to identify the genomic variations among them. Notably, the analyses of chromosome somy values and genome wide mutation profile in the coding regions reveal distinct clustering of the para-KDL strains with 24 genes being mutated uniquely in this group. Such distinguishing genomic changes among the para-KDL strains could be significant for the parasites to become dermatotropic. Overall, the study reveals a possible correlation of the development of SSG resistance and the transition towards the manifestation of PKDL with chromosome aneuploidy and non-synonymous genetic variations in the coding sequences of the L. donovani strains from Indian patients.

Topics: Antimony Sodium Gluconate; Genome, Protozoan; Humans; India; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

54 cases of drug resistant kala-azar patients, some cases were resistant to sodium stibogluconate, some to even single dose of ambisome and some to miltefosine came to us for treatment. All necessary investigations were done and splenic aspirations were positive for LD bodies. All these patients were treated with Fungizone at a dose of 1mg/kg body wt diluted with 5% glucose and given slowly in 4 hours. On the day 21st splenic aspiration was done and other necessary investigations were repeated. LD body was not found in any splenic aspirate except one case with HIV. Initially all the patients were divided into two groups, one group was fed adequate milk during their course of treatment and other group adequate amount of fish in their diet. The patients in both the groups were compared in the end. There was no difference between two groups regarding parasitological clearance. All the patients had parasitological cure except one patient with HIV. The weight of the patients improved in both groups. The patient with HIV needed 3 courses of anti kala-azar drug to become negative for parasites of kala-azar i.e LD body. That cases was given treatment for HIV also. The moment he became negative of kala-azar, he fled away.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Male; Spleen

Immunomodulation is an emerging concept to combat infection in recent years. Immunomodulators like arabinosylated-lipoarabinomannan (Ara-LAM) and glycyrrhizic-acid (GA) possess anti-leishmanial property, whereas sodium-antimony-gluconate (SAG) is still considered as the first choice for chemotherapy against leishmaniasis. During infection, invasion of Leishmania donovani needs the potential requirement of Ca

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Calcium; Calcium-Transporting ATPases; Cell Line; Cell Membrane; Ceramides; Culture Media, Serum-Free; Densitometry; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glycyrrhizic Acid; Imipramine; Immunoblotting; Immunologic Factors; Leishmania donovani; Leishmaniasis, Visceral; Lipopolysaccharides; Macrophages; Mice; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; RNA, Protozoan; RNA, Small Interfering; Transfection

Human visceral leishmaniasis (HVL) is a parasitic disease infecting children in the Mediterranean region. Here, we portray a case of a 2-year-old child with an epidemiological description of the situation surrounding the case. The patient was suffering from recurrent fever, weakness, and abdominal discomfort associated with loss of appetite. Routine blood investigations showed pancytopenia, whereas examination revealed hepatomegaly. A diagnosis of HVL was made by demonstrating amastigotes in a Giemsa-stained smear from a bone marrow aspirate followed by genotyping by PCR and sequencing. In conclusion, early detection of VL infection followed by appropriate treatment protocols is essential to saving the patient.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow; Child, Preschool; Disease Reservoirs; Dogs; Early Diagnosis; Female; Humans; Insect Vectors; Leishmania infantum; Leishmaniasis, Visceral; Middle East; Phlebotomus

In Algeria, the treatment of visceral and cutaneous leishmanioses (VL and CL) has been and continues to be based on antimony-containing drugs. It is suspected that high drug selective pressure might favor the emergence of chemoresistant parasites. Although treatment failure is frequently reported during antimonial therapy of both CL and VL, antimonial resistance has never been thoroughly investigated in Algeria. Determining the level of antimonial susceptibility, amongst Leishmania transmitted in Algeria, is of great importance for the development of public health policies.. Within the framework of the knowledge about the epidemiology of VL and CL amassed during the last 30 years, we sampled Leishmania isolates to determine their susceptibility to antimony. We analyzed a total of 106 isolates including 88 isolates collected between 1976 and 2013 in Algeria from humans, dogs, rodents, and phlebotomines and 18 collected from dogs in France. All the Algerian isolates were collected in 14 localities where leishmaniasis is endemic. The 50% inhibitory concentrations (IC50) of potassium antimony tartrate (the trivalent form of antimony, Sb(III)) and sodium stibogluconate (the pentavalent form of antimony, Sb(V)) were determined in promastigotes and intramacrophage amastigotes, respectively. The epidemiological cutoff (ECOFF) that allowed us to differentiate between Leishmania species causing cutaneous or visceral leishmaniases that were susceptible (S+) or insusceptible (S-) to the trivalent form of antimony was determined. The computed IC50 cutoff values were 23.83 μg/mL and 15.91 μg/mL for VL and CL, respectively. We report a trend of increasing antimony susceptibility in VL isolates during the 30-year period. In contrast, an increase in the frequency of S- phenotypes in isolates causing CL was observed during the same period. In our study, the emergence of S- phenotypes correlates with the inclusion of L. killicki (syn: L. tropica) isolates that cause cutaneous leishmaniasis and that have emerged in Algeria during the last decade.. Our results provide insight into the spatiotemporal dynamics of Leishmania antimony susceptibility in Algeria. We highlight the need for the future implementation of an effective methodology to determine the antimony susceptibility status of Leishmania isolates to detect the emergence of and prevent the dissemination of drug-resistant strains.

Topics: Algeria; Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Dogs; Drug Resistance; Humans; Inhibitory Concentration 50; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Psychodidae; Rodentia

Leishmaniasis is a neglected tropical disease with diverse clinical phenotypes, determined by parasite, host and vector interactions. Despite the advances in molecular biology and the availability of more Leishmania genome references in recent years, the association between parasite species and distinct clinical phenotypes remains poorly understood. We present a genomic comparison of an atypical variant of Leishmania donovani from a South Asian focus, where it mostly causes cutaneous form of leishmaniasis.. Clinical isolates from six cutaneous leishmaniasis patients (CL-SL); 2 of whom were poor responders to antimony (CL-PR), and two visceral leishmaniasis patients (VL-SL) were sequenced on an Illumina MiSeq platform. Chromosome aneuploidy was observed in both groups but was more frequent in CL-SL. 248 genes differed by 2 fold or more in copy number among the two groups. Genes involved in amino acid use (LdBPK_271940) and energy metabolism (LdBPK_271950), predominated the VL-SL group with the same distribution pattern reflected in gene tandem arrays. Genes encoding amastins were present in higher copy numbers in VL-SL and CL-PR as well as being among predicted pseudogenes in CL-SL. Both chromosome and SNP profiles showed CL-SL and VL-SL to form two distinct groups. While expected heterozygosity was much higher in VL-SL, SNP allele frequency patterns did not suggest potential recent recombination breakpoints. The SNP/indel profile obtained using the more recently generated PacBio sequence did not vary markedly from that based on the standard LdBPK282A1 reference. Several genes previously associated with resistance to antimonials were observed in higher copy numbers in the analysis of CL-PR. H-locus amplification was seen in one cutaneous isolate which however did not belong to the CL-PR group.. The data presented suggests that intra species variations at chromosome and gene level are more likely to influence differences in tropism as well as response to treatment, and contributes to greater understanding of parasite molecular mechanisms underpinning these differences. These findings should be substantiated with a larger sample number and expression/functional studies.

Topics: Aneuploidy; Antimony Sodium Gluconate; Antiprotozoal Agents; Base Sequence; Chromosomes; Gene Dosage; Gene Ontology; Genome; Heterozygote; Homozygote; Humans; INDEL Mutation; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Open Reading Frames; Phylogeny; Polymorphism, Single Nucleotide; Virulence

To assess the rate of default from treatment in the visceral leishmaniasis (VL) elimination programme and to identify risk factors and its underlying causes.. Case-control study conducted between December 2009 and June 2012 in three primary health centres (PHCs) of Muzaffarpur district, India. Patients who defaulted from treatment from the PHCs were considered as 'cases' and those who completed their treatment as 'controls'. Two controls were included in the study for each case. Respondents' opinion and satisfaction with the services provided at the PHCs were also elicited. Logistic regression was performed to assess the contribution of sociodemographic variables on patient status, and a discriminant analysis was used (after decomposing the original data) to identify factors that can predict the patient status as defaulter or not, based on factor scores of the components as predictor variables.. During the study period, 16.3% (89/544) of patients defaulted; 87 cases and 188 controls were interviewed through a semistructured questionnaire. Women tended to be more at risk for default (OR, 1.6, 95% CI (0.9 -2.9). Treatment received was miltefosine in 55.6% and sodium stibogluconate (SSG) in 44.4%. Most (86%) defaulters completed their treatment at other healthcare facilities; 70% of them preferred non-governmental institutions. Most cited reasons for default were seeking a second opinion for VL treatment and preferring to be treated in specialised VL centres. Discriminant analysis showed only one significant predictor: dissatisfaction with the medical care received in PHCs.. Efforts are needed to enhance the quality of VL care at PHC level, which will be beneficial in increasing treatment completion rates.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Health Facilities; Humans; India; Leishmaniasis, Visceral; Male; National Health Programs; Patient Satisfaction; Phosphorylcholine; Primary Health Care; Private Sector; Public Sector; Specialization; Young Adult

Sri Lanka is a new focus of human cutaneous leishmaniasis caused by a genetic variant of usually visceralizing parasite Leishmania donovani. Over 3000 cases have been reported to our institution alone, during the past two decades. Recent emergence of visceral leishmaniasis is of concern.. Patients suspected of having visceral leishmaniasis (n = 120) fulfilling at least two of six criteria (fever > 2 weeks, weight loss, tiredness affecting daily functions, splenomegaly, hepatomegaly and anemia) were studied using clinic-epidemiological, immunological and haematological parameters. Seven cases (four progressive, treated (group A) and 3 non- progressive, potentially asymptomatic and observed (group B) were identified. Clinical cases were treated with systemic sodium stibogluconate or amphotericin B and all were followed up at the leishmaniasis clinic of University of Colombo for 3 years with one case followed up for 9 years.. All treated cases responded well to anti leishmanial treatment. Relapses were not noticed. Clinical features subsided in all non-progressive cases and did not develop suggestive clinical features or change of laboratory parameters. Visceral leishmaniasis cases have been originated from different districts within the country. Majority had a travel history to identified local foci of cutaneous leishmaniasis.. Visceral leishmaniasis is recognized as an emerging health threat in Sri Lanka. At least a proportion of locally identified strains of L. donovani possess the ability to visceralize. Apparent anti leishmanial sensitivity is encouraging. Timely efforts in disease containment will be important in which accurate understanding of transmission characteristics, increased professional and community awareness, improved diagnostics and availability of appropriate treatment regimens.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Communicable Diseases, Emerging; Female; Humans; Infant; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged; Sri Lanka; Young Adult

Topics: Age Distribution; Ambulatory Care Facilities; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Incidence; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Sex Distribution; Somalia

Adult cases of visceral leishmaniasis (VL), predominantly males, have been reported in the past decade from natives of high altitude areas of North Indian state of Uttarakhand. We report 14 pediatric cases of VL, who were diagnosed and treated successfully over the past 7 years. All these children were born and brought up in this area and had never visited any of the endemic areas. High prevalence of pallor, splenohepatomegaly, thrombocytopenia and poor association with HIV are cardinal features of VL in this region. Although newer drugs have become available, the protozoan continues to be sensitive to sodium stibogluconate. We conclude that the transmission cycle of VL has been established in this region and VL should be considered in the differential diagnosis of any child presenting with fever and hepatosplenomegaly. However, molecular and epidemiological studies are needed to identify the ancestry, vector and animal reservoir if any in this region.

Topics: Altitude; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Female; Hepatomegaly; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Lymphadenopathy; Male; Pallor; Splenomegaly

In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of intravenous (IV) or intramuscular (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clinical practice a pharmacovigilance (PV) programme was developed.. A prospective PV cohort was developed. Regulatory approval was obtained in Sudan, Kenya, Uganda and Ethiopia. Twelve sentinel sites sponsored by the Ministries of Health, Médecins Sans Frontières (MSF) and Drugs for Neglected Diseases initiative (DNDi) participated. VL patients treated using the new treatment were consented and included in a common registry that collected demographics, baseline clinical characteristics, adverse events, serious adverse events and treatment outcomes. Six-monthly periodic safety update reports (PSUR) were prepared and reviewed by a PV steering committee.. Overall 3126 patients were enrolled: 1962 (62.7%) from Sudan, 652 (20.9%) from Kenya, 322 (10.3%) from Ethiopia and 190 (6.1%) from Uganda. Patients were mostly male children (68.1%, median age 11 years) with primary VL (97.8%). SSG-PM initial cure rate was 95.1%; no geographical differences were noted. HIV/VL co-infected patients and patients older than 50 years had initial cure rates of 56 and 81.4%, respectively, while 1063 (34%) patients had at least one adverse event (AE) during treatment and 1.92% (n = 60) had a serious adverse event (SAE) with a mortality of 1.0% (n = 32). There were no serious unexpected adverse drug reactions.. This first regional PV programme in VL supports SSG-PM combination as first-line treatment for primary VL in Eastern Africa. SSG-PM was effective and safe except in HIV/VL co-infected or older patients. Active PV surveillance of targeted safety, effectiveness and key VL outcomes such us VL relapse, PKDL and HIV/VL co-infection should continue and PV data integrated to national and WHO PV databases.

Topics: Administration, Intravenous; Adolescent; Adult; Africa, Eastern; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Coinfection; Drug Therapy, Combination; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Paromomycin; Pharmacovigilance; Prospective Studies; Recurrence; Treatment Outcome; Young Adult

Asymptomatic leishmaniasis may drive the epidemic and an important challenge to reach the goal of joint Visceral Leishmaniasis (VL) elimination initiative taken by three Asian countries. The role of these asymptomatic carriers in disease transmission, prognosis at individual level and rate of transformation to symptomatic VL/Post Kala-azar Dermal Leishmaniasis (PKDL) needs to be evaluated. Asymptomatic cases were diagnosed by active mass survey in eight tribal villages by detecting antileishmanial antibody using rK39 based rapid diagnostic kits and followed up for three years to observe the pattern of sero-conversion and disease transformation. Out of 2890 total population, 2603 were screened. Antileishmanial antibody was detected in 185 individuals of them 96 had a history of VL/PKDL and 89 without such history. Seventy nine such individuals were classified as asymptomatic leishmaniasis and ten as active VL with a ratio of 7.9:1. Out of 79 asymptomatic cases 2 were lost to follow up as they moved to other places. Amongst asymptomatically infected persons, disease transformation in 8/77 (10.39%) and sero-conversion in 62/77 (80.52%) cases were noted. Seven (9.09%) remained sero-positive even after three years. Progression to clinical disease among asymptomatic individuals was taking place at any time up to three years after the baseline survey. If there are no VL /PKDL cases for two or more years, it does not mean that the area is free from leishmaniasis as symptomatic VL or PKDL may appear even after three years, if there are such asymptomatic cases. So, asymptomatic infected individuals need much attention for VL elimination programme that has been initiated by three adjoining endemic countries.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Asymptomatic Diseases; Child; Child, Preschool; Female; Follow-Up Studies; Humans; India; Infant; Leishmaniasis, Visceral; Male; Young Adult

Topics: Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Blotting, Western; Drug Resistance; Electrophoresis, Gel, Two-Dimensional; Genomics; Humans; Immune Sera; Immunodominant Epitopes; Immunoglobulin G; India; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mass Spectrometry; Microscopy, Fluorescence; Proteomics; Protozoan Proteins

Post kala-azar dermal leishmaniasis (PKDL) is a neglected parasitic disease that occurs after apparent cure from visceral leishmaniasis (VL) and poses a challenge for elimination of VL, being its proposed reservoir. Several epidemiological studies have proposed that sex hormones may account for the increased susceptibility of males towards infectious diseases, including leishmaniasis; however, the role of testosterone and sex bias, if any, in PKDL has not been evaluated.. The study population included 87 patients with PKDL and 39 with VL; levels of testosterone were measured by competitive enzyme-linked immunosorbent assay along with their levels of antileishmanial immunoglobulin and IgG. The association of testosterone, if any, was then correlated with age, gender, humoral response, lesional profile, disease duration, and lag period.. A male predominance was evident in PKDL, not in VL; importantly, this male bias was predominant postpubertal, strongly indicative of an association between sex hormone and disease progression. Male patients with PKDL had significantly higher levels of testosterone, which regressed significantly with miltefosine, not with sodium antimony gluconate. Additionally, a significant correlation was found between plasma testosterone and antileishmanial IgG.. Taken together, our study has established a male dominance in PKDL, which showed a strong association with testosterone. This information should be taken into consideration for disease monitoring and control.

Topics: Adolescent; Adult; Amphotericin B; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Progression; Female; Humans; Immunoglobulin G; India; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Neglected Diseases; Phosphorylcholine; Sex Factors; Testosterone; Young Adult

To determine the clinical and biochemical characteristics of Yemeni adults and children with visceral leishmaniasis (VL) and the differences between them.. A prospective cross-sectional study on patients with bone marrow aspirate confirmed VL evaluated at Al-Jomhori Teaching Hospital in Sana'a, Yemen.. Twenty-eight (59.6%) patients were adults with a mean age (± SD) of 24.3 years ± 9.2 and 19 (40.4%) patients were children with a mean age (± SD) of 7.1 years ± 4.7. Fever, pallor, splenomegaly and hepatomegaly were the most common clinical findings. Hypoalbuminaemia, hyperglobulinaemia, elevated LDH, hypocalcaemia and elevated CRP were common biochemical abnormalities. There was no significant difference in splenomegaly size or biochemical parameters with regard to grade of parasitic load. Both children and adults showed similar significant improvement after treatment.. Biochemical abnormalities were not related to degree of parasitic load and there were no clinical, biochemical or treatment differences between adults and children.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Cross-Sectional Studies; Female; Fever; Hepatomegaly; Hospitals, Teaching; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged; Prospective Studies; Splenomegaly; Treatment Outcome; Yemen; Young Adult

Visceral leishmaniasis (VL) is a ftial and growing public health problem in Ethiopia. VL is recently reported outside the major endemic foci, the lowlands in the northwest and the Omo and Abaroba-plain, Segen and Woito valleys in the southwest. Here, we report a visceral leishmaniasis case from Benishangul-Gumuz Regional state near the Guba area. The patient had no history of travel to known VL endemic areas. The patient is a temporary farm laborer from West Go'jam Zone, Wanbermna District in Amhara Regional State. While in Benishangul-Gumuz, the patient was diagnosed with prolonged and intermittentfever, epistaxis, splenomegaly, skin pallor, diarrhea, cough and oedema. Laboratory diagnosis results showed that he had marked leucopenia, thrombocytopenia and anemia. The patient was suspected of having VL and checked with rK39 immunochromnatography and direct agglutination tests which were positive for anti leishmanial antibodies. After getting full dose of sodium stibogluconate as per the national visceral leishmaniasis treatment guideline, was clinically cured. As the area in Benshangul-Gumuz where this patient contracted visceral leishmaniasis is under social and ecological transformation with large scale projects attracting huge influx of temporary laborers and settlers, due attention is needed with respect to introduction or emergence of VL transmission.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Ethiopia; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Serologic Tests; Treatment Outcome; Young Adult

Visceral leishmaniasis is a neglected tropical disease endemic in East Africa where improved patient-adapted treatments are needed. The Leishmaniasis East Africa Platform (LEAP) was created in 2003 to strengthen clinical research capacity, serve as a base for training, and evaluate and facilitate implementation of new treatments. Major infrastructure upgrades and personnel training have been carried out. A short course of Sodium Stibogluconate and Paramomycin (SSG&PM) was evaluated and is now first-line treatment in the region; alternative treatments have also been assessed. LEAP can serve as a successful model of collaboration between different partners and countries when conducting clinical research in endemic countries to international standards.

Topics: Africa, Eastern; Antimony Sodium Gluconate; Antiprotozoal Agents; Biomedical Research; Capacity Building; Cooperative Behavior; Endemic Diseases; Humans; Leishmaniasis, Visceral; Neglected Diseases; Paromomycin

Visceral leishmaniasis (VL), with the squeal of Post-kala-azar dermal leishmaniasis (PKDL), is a global threat for health. Studies have shown sodium stibogluconate (SSG) resistance in VL patients with chronic arsenic exposure. Here, we assessed the association between arsenic exposure and risk of developing PKDL in treated VL patients.. In this retrospective study, PKDL patients (n = 139), earlier treated with SSG or any other drug during VL, were selected from the study cohort. Trained physicians, unaware of arsenic exposure, interviewed them and collected relevant data in a questionnaire format. All probable water sources were identified around the patient's house and water was collected for evaluation of arsenic concentration. A GIS-based village-level digital database of PKDL cases and arsenic concentration in groundwater was developed and individual point location of PKDL cases were overlaid on an integrated GIS map. We used multivariate logistic regression analysis to assess odds ratios (ORs) for association between arsenic exposure and PKDL development.. Out of the 429 water samples tested, 403 had arsenic content of over 10 μg/L, with highest level of 432 μg/L among the seven study villages. Multivariate adjusted ORs for risk of PKDL development in comparison of arsenic concentrations of 10.1-200 μg/L and 200.1-432.0 μg/L were 1.85 (1.13-3.03) and 2.31 (1.39-3.8) respectively. Interestingly, similar results were found for daily dose of arsenic and total arsenic concentration in urine sample of the individual. The multivariate-adjusted OR for comparison of high baseline arsenic exposure to low baseline arsenic exposure of the individuals in the study cohort was 1.66 (95% CI 1.02-2.7; p = 0.04).. Our findings indicate the need to consider environmental factors, like long time arsenic exposure, as an additional influence on treated VL patients towards risk of PKDL development in Bihar.

Topics: Adolescent; Adult; Aged; Antimony Sodium Gluconate; Antiprotozoal Agents; Arsenic; Child; Child, Preschool; Cohort Studies; Drinking Water; Environmental Exposure; Environmental Pollutants; Female; Humans; India; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Logistic Models; Male; Middle Aged; Odds Ratio; Retrospective Studies; Time Factors; Young Adult

Visceral leishmaniasis (VL) in north-west Ethiopia is causing an overwhelming case load among adult migrant workers that masked the disease burden in children. This study describes the clinical profile and explores comorbidities in paediatric VL patients.. A prospective study at two hospitals in this region (Gondar and Humera) was conducted in a year period, 2011-2012. The clinical manifestations and comorbidities such as malnutrition, intestinal parasitosis and vitamin D deficiency and HIV infection were assessed, and treatment outcomes noted.. A total of 122 children with VL were detected during the study period with median age of 8.5 years (IQR 5-12 years); 23% were under 5 years. Eighty-five (69.7%) cases were male. The clinical manifestations were similar to the adult patients. High rates of malnutrition, intestinal parasitosis (47.5%) and hypovitaminosis D (56.4%) were detected. The proportion of stunting and wasting was 63% and 22.2% in children aged under five years, and 50.5% and 75.9% in 5-year and older children, respectively, using WHO standard growth curves. Only one child had HIV infection. In 95% of the cases, sodium stibogluconate (20 mg/kg/day for 30 days) was used for treatment. The treatment success rate at end of therapy was 98.3%, but the definitive outcome at 6 months could not be determined because of a high loss to follow-up (80.2%).. While HIV co-infection was rare, malnutrition, intestinal parasitosis and vitamin D deficiency were frequent indicating the need for further research on their role in the pathophysiology. Meanwhile, systematic assessment and management of malnutrition and intestinal parasitosis in VL programmes is recommended.

Topics: Amebicides; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Comorbidity; Cross-Sectional Studies; Ethiopia; Female; HIV Infections; Humans; Intestinal Diseases, Parasitic; Leishmaniasis, Visceral; Male; Malnutrition; Paromomycin; Prospective Studies; Treatment Outcome; Vitamin D Deficiency

Pentavalent antimonials have been the first-line treatment for leishmaniasis for decades. However, the development of resistance to sodium stibogluconate (SSG) has limited its use, especially for treating visceral leishmaniasis (VL). The present work aims to optimize a cationic liposomal formulation of SSG for the treatment of both SSG-sensitive (AG83) and SSG-resistant (GE1F8R and CK1R) Leishmania donovani infections. Parasite killing was determined by the 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) assay and microscopic counting of Giemsa-stained macrophages. Macrophage uptake studies were carried out by confocal microscopic imaging. Parasite-liposome interactions were visualized through transmission electron microscopy. Toxicity tests were performed using assay kits. Organ parasite burdens were determined by microscopic counting and limiting dilution assays. Cytokines were measured by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry. Although all cationic liposomes studied demonstrated leishmanicidal activity, phosphatidylcholine (PC)-dimethyldioctadecylammonium bromide (DDAB) vesicles were most effective, followed by PC-stearylamine (SA) liposomes. Since entrapment of SSG in PC-DDAB liposomes demonstrated enhanced ultrastructural alterations in promastigotes, PC-DDAB-SSG vesicles were further investigated in vitro and in vivo. PC-DDAB-SSG could effectively alleviate SSG-sensitive and SSG-resistant L. donovani infections in the liver, spleen, and bone marrow of BALB/c mice at a dose of SSG (3 mg/kg body weight) not reported previously. The parasiticidal activity of these vesicles was attributed to better interactions with the parasite membranes, resulting in direct killing, and generation of a strong host-protective environment, necessitating a very low dose of SSG for effective cures.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow; Cricetinae; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Liver; Macrophages; Mice; Mice, Inbred BALB C; Parasitic Sensitivity Tests; Spleen

Since there are very few affordable antileishmanial drugs available, antimonial resistance has crippled antileishmanial therapy, thereby emphasising the need for development of novel therapeutic strategies. This study aimed to evaluate the antileishmanial role of combined therapy with sodium antimony gluconate (SAG) and the triterpenoid glycyrrhizic acid (GA) against infection with SAG-resistant Leishmania (GE1F8R). Combination therapy with GA and SAG successfully limited infection with SAG-resistant Leishmania in a synergistic manner (fractional inhibitory concentration index <1.0). At the same time, mice infected with SAG-resistant Leishmania and co-treated with GA and SAG exhibited a significant reduction in hepatic and splenic parasite burden. In probing the mechanism, it was observed that GA treatment suppressed the expression and efflux activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), two host ABC transporters responsible for antimony efflux from host cells infected with SAG-resistant parasites. This suppression correlated with greater intracellular antimony retention during SAG therapy both in vitro and in vivo, which was reflected in the reduced parasite load. Furthermore, co-administration of GA and SAG induced a shift in the cytokine balance towards a Th1 phenotype by augmenting pro-inflammatory cytokines (such as IL-12, IFNγ and TNFα) and inducing nitric oxide generation in GE1F8R-infected macrophages as well as GE1F8R-infected mice. This study aims to provide an affordable leishmanicidal alternative to expensive antileishmanial drugs such as miltefosine and amphotericin B. Furthermore, this report explores the role of GA as a resistance modulator in MRP1- and P-gp-overexpressing conditions.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Biological Transport, Active; Disease Models, Animal; Drug Resistance; Drug Therapy, Combination; Enzyme Inhibitors; Glycyrrhizic Acid; Leishmania; Leishmaniasis, Visceral; Liver; Mice, Inbred BALB C; Parasite Load; Spleen; Treatment Outcome

Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.

Topics: 3' Untranslated Regions; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Aquaglyceroporins; Aquaporin 1; Cell Movement; Drug Resistance; Gene Expression Regulation; Humans; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; RNA, Messenger; RNA, Protozoan

In the late twentieth century, emergence of high rates of treatment failure with antimonial compounds (SSG) for visceral leishmaniasis (VL) caused a public health crisis in Bihar, India. We hypothesize that exposure to arsenic through drinking contaminated groundwater may be associated with SSG treatment failure due to the development of antimony-resistant parasites.. A retrospective cohort design was employed, as antimony treatment is no longer in routine use. The study was performed on patients treated with SSG between 2006 and 2010. Outcomes of treatment were assessed through a field questionnaire and treatment failure used as a proxy for parasite resistance. Arsenic exposure was quantified through analysis of 5 water samples from within and surrounding the patient's home. A logistic regression model was used to evaluate the association between arsenic exposure and treatment failure. In a secondary analysis survival curves and Cox regression models were applied to assess the risk of mortality in VL patients exposed to arsenic.. One hundred and ten VL patients treated with SSG were analysed. The failure rate with SSG was 59%. Patients with high mean local arsenic level had a non-statistically significant higher risk of treatment failure (OR = 1.78, 95% CI: 0.7-4.6, p = 0.23) than patients using wells with arsenic concentration <10 μg/L. Twenty one patients died in our cohort, 16 directly as a result of VL. Arsenic levels ≥ 10 μg/L increased the risk of all-cause (HR 3.27; 95% CI: 1.4-8.1) and VL related (HR 2.65; 95% CI: 0.96-7.65) deaths. This was time dependent: 3 months post VL symptom development, elevated risks of all-cause mortality (HR 8.56; 95% CI: 2.5-29.1) and of VL related mortality (HR 9.27; 95% CI: 1.8-49.0) were detected.. This study indicates a trend towards increased treatment failure in arsenic exposed patients. The limitations of the retrospective study design may have masked a strong association between arsenic exposure and selection for antimonial resistance in the field. The unanticipated strong correlation between arsenic exposure and VL mortality warrants further investigation.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Arsenic; Child; Child, Preschool; Cohort Studies; Drug Resistance; Female; Humans; India; Leishmaniasis, Visceral; Logistic Models; Male; Middle Aged; Retrospective Studies; Treatment Failure

In C57BL/6 mice, Leishmania donovani infection in the liver provoked IFN-γ-induced expression of the immunity-related GTPases (IRG), Irgm1 and Irgm3. To gauge the antileishmanial effects of these macrophage factors in the liver, intracellular infection was analyzed in IRG-deficient mice. In early- (but not late-) stage infection, Irgm3(-/-) mice failed to properly control parasite replication, generated little tissue inflammation and were hyporesponsive to pentavalent antimony (Sb) chemotherapy. Observations limited to early-stage infection in Irgm1(-/-) mice demonstrated increased susceptibility and virtually no inflammatory cell recruitment to heavily-parasitized parenchymal foci but an intact response to chemotherapy. In L. donovani infection in the liver, the absence of either Irgm1 or Irgm3 impairs early inflammation and initial resistance; the absence of Irgm3, but not Irgm1, also appears to impair the intracellular efficacy of Sb chemotherapy.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Gene Expression Regulation; GTP Phosphohydrolases; GTP-Binding Proteins; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Liver Diseases, Parasitic; Macrophages; Mice; Microarray Analysis

Visceral form of leishmaniasis (also known as Kala-azar) is a fatal neglected tropical disease affecting 95 countries worldwide. Recently, substantial proportion of resistance related treatment failure cases have been reported against its first line drug, sodium-antimony gluconate (SAG). We report an easy, fast, sensitive and cheap visual diagnosis and SAG susceptibility profiling for this disease based on recently recognized genetic biomarker and gold nanoparticle based plasmonic detection phenomenon. This is a non-gel, non-culture based detection technique, which can be used as simultaneous high throughput detection and SAG-susceptibility profiling in Leishmania endemic resource stringent countries.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Susceptibility; Drug Resistance; Female; Genetic Markers; Humans; Leishmania donovani; Leishmaniasis, Visceral; Polymerase Chain Reaction

Among patients with primary and relapse visceral leishmaniasis (VL) in eastern Sudan, we determined the proportion eligible for treatment with sodium stibogluconate and paromomycin (SSG/PM) and, of these, their demographic and clinical characteristics; initial treatment outcomes including adverse side effects requiring treatment discontinuation; treatment outcomes by 6 months; and risk factors associated with initial (slow responders) and late treatment failure (relapses and post-kala-azar dermal leishmaniasis, PKDL).. A retrospective cohort study in Tabarak Allah Hospital, Gedaref Province, eastern Sudan, from July 2011 to January 2014.. Of 1252 individuals diagnosed with VL (1151 primary and 101 relapses), 65% were eligible for SSG/PM including 83% children, almost half of them malnourished and anaemic. About 4% of individuals discontinued treatment due to side effects; 0.7% died during treatment. Initial cure was achieved in 93% of 774 primary cases and 77% of 35 relapse cases (P < 0.001). Among the 809 patients eligible for SSG/PM, 218 (27%) were lost to follow-up. Outcomes by six months among the 591 patients with available follow-up data were: definitive cure (n = 506; 86%), relapse (n = 38; 6%), treatment discontinuation (n = 33; 6%), PKDL (n = 7; 1%) and death (n = 7; 1%). Among those completing a full course of SSG/PM, relapses and under-fives were at significantly higher risk of early and late treatment failure, respectively.. Whether SSG/PM as a first-line regimen is an undeniable progress compared to SSG monotherapy, it excluded a considerable proportion of VL patients due to drug safety concerns. We call for accelerated development of new drugs and treatment regimens to improve VL treatment in Sudan.

Topics: Adolescent; Adult; Anemia; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Leishmaniasis, Visceral; Lost to Follow-Up; Male; Malnutrition; Paromomycin; Patient Selection; Prevalence; Recurrence; Retrospective Studies; Sudan; Treatment Failure

Post Kala-azar Dermal Leishmaniasis (PKDL) is a chronic but not life-threatening disease; patients generally do not demand treatment, deserve much more attention because PKDL is highly relevant in the context of Visceral Leishmaniasis (VL) elimination. There is no standard guideline for diagnosis and treatment for PKDL. A species-specific PCR on slit skin smear demonstrated a sensitivity of 93.8%, but it has not been applied for routine diagnostic purpose. The study was conducted to determine the actual disease burden in an endemic area of Malda district, West Bengal, comparison of the three diagnostic tools for PKDL case detection and pattern of lesion regression after treatment. The prevalence of PKDL was determined by active surveillance and confirmed by PCR based diagnosis. Patients were treated with either sodium stibogluconate (SSG) or oral miltefosine and followed up for two years to observe lesion regression period. Twenty six PKDL cases were detected with a prevalence rate of 27.5% among the antileishmanial antibody positive cases. Among three diagnostic methods used, PCR is highly sensitive (88.46%) for case confirmation. In majority of the cases skin lesions persisted after treatment completion which gradually disappeared during 6-12 months post treatment period. Reappearance of lesions noted in two cases after 1.5 years of miltefosine treatment. A significant number of PKDL patients would remain undiagnosed without active mass surveys. Such surveys are required in other endemic areas to attain the ultimate goal of eliminating Kala-azar. PCR-based method is helpful in confirming diagnosis of PKDL, referral laboratory at district or state level can achieve it. So a well-designed study with higher number of samples is essential to establish when/whether PKDL patients are free from parasite after treatment and to determine which PKDL patients need treatment for longer period.

Topics: Administration, Oral; Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Disease Transmission, Infectious; Epidemiological Monitoring; Female; Humans; India; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Phosphorylcholine; Polymerase Chain Reaction; Prevalence; Recurrence; Rural Population; Young Adult

Between 2000 and 2010, Médecins Sans Frontières diagnosed and treated 4,831 patients with visceral leishmaniasis (VL) in the Pokot region straddling the border between Uganda and Kenya. A retrospective analysis of routinely collected clinical data showed no marked seasonal or annual fluctuations. Males between 5 and 14 years of age were the most affected group. Marked splenomegaly and anemia were striking features. An rK39 antigen-based rapid diagnostic test was evaluated and found sufficiently accurate to replace the direct agglutination test and spleen aspiration as the first-line diagnostic procedure. The case-fatality rate with sodium stibogluconate as first-line treatment was low. The VL relapses were rare and often diagnosed more than 6 months post-treatment. Post-kala-azar dermal leishmaniasis was rare but likely to be underdiagnosed. The epidemiological and clinical features of VL in the Pokot area differed markedly from VL in Sudan, the main endemic focus in Africa.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Endemic Diseases; Female; Humans; Kenya; Leishmaniasis, Visceral; Male; Middle Aged; Retrospective Studies; Sudan; Uganda; Young Adult

Previously, through a proteomic analysis, proliferating cell nuclear antigen (PCNA) was found to be overexpressed in the sodium antimony gluconate (SAG)-resistant clinical isolate compared to that in the SAG-sensitive clinical isolate of Leishmania donovani. The present study was designed to explore the potential role of the PCNA protein in SAG resistance in L. donovani. For this purpose, the protein was cloned, overexpressed, purified, and modeled. Western blot (WB) and real-time PCR (RT-PCR) analyses confirmed that PCNA was overexpressed by ≥ 3-fold in the log phase, stationary phase, and peanut agglutinin isolated procyclic and metacyclic stages of the promastigote form and by ~5-fold in the amastigote form of the SAG-resistant isolate compared to that in the SAG-sensitive isolate. L. donovani PCNA (LdPCNA) was overexpressed as a green fluorescent protein (GFP) fusion protein in a SAG-sensitive clinical isolate of L. donovani, and modulation of the sensitivities of the transfectants to pentavalent antimonial (Sb(V)) and trivalent antimonial (Sb(III)) drugs was assessed in vitro against promastigotes and intracellular (J774A.1 cell line) amastigotes, respectively. Overexpression of LdPCNA in the SAG-sensitive isolate resulted in an increase in the 50% inhibitory concentrations (IC50) of Sb(V) (from 41.2 ± 0.6 μg/ml to 66.5 ± 3.9 μg/ml) and Sb(III) (from 24.0 ± 0.3 μg/ml to 43.4 ± 1.8 μg/ml). Moreover, PCNA-overexpressing promastigote transfectants exhibited less DNA fragmentation compared to that of wild-type SAG-sensitive parasites upon Sb(III) treatment. In addition, SAG-induced nitric oxide (NO) production was found to be significantly inhibited in the macrophages infected with the transfectants compared with that in wild-type SAG-sensitive parasites. Consequently, we infer that LdPCNA has a significant role in SAG resistance in L. donovani clinical isolates, which warrants detailed investigations regarding its mechanism.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Base Sequence; Cell Line; Cricetinae; Drug Resistance; Gene Expression; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Models, Molecular; Molecular Sequence Data; Nitric Oxide; Proliferating Cell Nuclear Antigen; Proteomics; Sequence Analysis, DNA

It is well established that visceral leishmaniasis (VL; also known as Kala azar) causes immunosuppression, and a successful drug treatment is associated with the development of cell-mediated immunity. Therefore combining a drug with an immune enhancer can provide a better approach for the treatment of the disease. Keeping this in mind, the in vivo antileishmanial efficacy of immunochemotherapy was evaluated with the use of a 78 kDa antigen with or without monophosphoryl lipid A (MPL-A) along with a traditional drug sodium stibogluconate (SSG) in Leishmania donovani infected BALB/c mice. Mice were infected intracardially with promastigotes of L. donovani, and 30 days after infection, these animals were given specific immunotherapy (78 kDa/78 kDa+MPL-A) or chemotherapy (SSG) or immunochemotherapy (SSG+78 kDa/SSG+78 kDa+MPL-A). Animals were euthanased on 1, 15 and 30 post-treatment days. The antileishmanial potential of the immunochemotherapy was revealed by significant reduction in the parasite burden (P<0·001). These animals were also found to exhibit increased delayed type hypersensitivity (DTH) responses, higher IgG2a levels, lower IgG1 levels and greater cytokine (IFN-γ and IL-2) concentrations compared with chemotherapy or immunotherapy alone, pointing towards the generation of a strong protective (Th1) type of immune response. Immunochemotherapy with SSG+78 kDa+MPL-A was found to be most effective in protecting mice against VL and therefore can be an alternative option for treatment of VL.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Cytokines; Drug Therapy, Combination; Female; Immunity, Cellular; Leishmania donovani; Leishmaniasis Vaccines; Leishmaniasis, Visceral; Lipid A; Male; Mice; Mice, Inbred BALB C; Parasite Load

Antimonials are still being used for visceral leishmaniasis (VL) treatment among HIV co-infected patients in East-Africa due to the shortage of alternative safer drugs like liposomal amphotericin B. Besides tolerability, emergence of resistance to antimonials is a major concern.. This study was aimed at assessing the clinical outcome of VL-HIV co-infected patients when treated with sodium stibogluconate (SSG).. Retrospective patient record analysis of VL-HIV co-infected patients treated at a clinical trial site in north-west Ethiopia was done. Patients with parasitologically confirmed VL and HIV co-infection treated with SSG were included. The dose of SSG used was 20 mg Sb5 (pentavalent antimony)/kg and maximum of 850 mg Sb5 for 30 days. The clinical outcomes were defined based on the tissue aspiration results as cure or failure, and additionally the safety and mortality rates were computed.. The study included 57 patients treated with SSG and by the end of treatment only 43.9% of patients were cured. The parasitological treatment failure and the case fatality rate were 31.6% and 14.0% respectively. SSG was discontinued temporarily or permanently for 12 (21.1%) cases due to safety issues. High baseline parasite load (graded more than 4+) was significantly associated with treatment failure (odds ratio = 8.9, 95% confidence interval = .5-51.7).. SSG is not only unsafe, but also has low effectiveness for VL-HIV patients. Safe and effective alternative medications are very urgently needed. Drug sensitivity surveillance should be introduced in the region.

Topics: Adult; Anti-Retroviral Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Coinfection; Ethiopia; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Male; Parasite Load; Retrospective Studies; Treatment Outcome

Visceral leishmaniasis is protozoonosis that occurs worldwide and still requires effective therapies with less toxicity. In this study, we examined the antileishmanial effect of nerve growth factor (NGF) using a murine infection model. NGF blocked the infection of macrophages by Leishmania donovani, which was completely cancelled by a hydrogen peroxide inhibitor. In vivo, not only did NGF show antileishmanial effects, but combination therapy of NGF and sodium stibogluconate synergistically exhibited the activity more potently than each monotherapy. These results indicate that NGF exerts antileishmanial effect by stimulating hydrogen peroxide production in macrophages and can be a novel therapy for leishmaniasis.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Models, Animal; Drug Synergism; Female; Hydrogen Peroxide; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mice, Inbred BALB C; Nerve Growth Factor; Treatment Outcome

The efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kala-azar patients infected with antimony-resistant Leishmania donovani (Sb(R)LD). Previously we showed that MDR-1 upregulation in Sb(R)LD infection is IL-10-dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children, inhibits IL-10 production from Sb(R)LD-infected macrophages (Sb(R)LD-Mϕs) and favors accumulation of surrogates of antimonials. It inhibits IL-10-driven nuclear translocation of c-Fos/c-Jun, critical for enhanced MDR-1 expression. The drug upregulates histone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from Sb(R)LD-Mϕs. It abrogates Sb(R)LD-mediated p50/c-Rel binding to IL-10 promoter and preferentially recruits p65/RelB to IL-12 p35 and p40 promoters, causing a decrease in IL-10 and overproduction of IL-12 in Sb(R)LD-Mϕs. Histone deacetylase 11 per se does not influence IL-12 promoter activity. Instead, a imipramine-mediated decreased IL-10 level allows optimal IL-12 production in Sb(R)LD-Mϕs. Furthermore, exogenous rIL-12 inhibits intracellular Sb(R)LD replication, which can be mimicked by the presence of Ab to IL-10. This observation indicated that reciprocity exists between IL-10 and IL-12 and that imipramine tips the balance toward an increased IL-12/IL-10 ratio in Sb(R)LD-Mϕs. Oral treatment of infected BALB/c mice with imipramine in combination with sodium stibogluconate cleared organ Sb(R)LD parasites and caused an expansion of the antileishmanial T cell repertoire where sodium stibogluconate alone had no effect. Our study deciphers a detailed molecular mechanism of imipramine-mediated regulation of IL-10/IL-12 reciprocity and its impact on Sb(R)LD clearance from infected hosts.

Topics: Acetylation; Animals; Antibodies; Antimony; Antimony Sodium Gluconate; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cells, Cultured; Cricetinae; Drug Resistance; Histone Deacetylase 6; Histone Deacetylases; Imipramine; Interleukin-10; Interleukin-12; Interleukin-12 Subunit p35; Interleukin-12 Subunit p40; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B p50 Subunit; Promoter Regions, Genetic; Signal Transduction; T-Lymphocytes; Transcription Factor RelA; Trypanocidal Agents

Leishmaniasis threatens more than 350 million people worldwide specially in tropical and subtropical region. Antileishmanial drugs that are currently available have various limitations. The search of new drugs from natural products (plants, animals) possessing antileishmanial activity is ventured throughout the world. The present study deals with the antileishmanial activity of Bungarus caeruleus snake venom (BCV) on in vitro promastigotes and amastigotes of Leishmania donovani parasite and leishmania infected BALB/c mice. The effect of BCV on peritoneal macrophage, release of cytokines from the activated macrophages, production of nitric oxide, reactive oxygen species and cytokines were studied in vivo and in vitro. IC50 value of BCV on L. donovani promastigote was 14.5 μg/ml and intracellular amastigote was 11.2 μg/ml. It activated peritoneal macrophages, significantly increased cytokines and interleukin production. BCV (20 μg/kg and 40 μg/kg body weight of mice) decreased parasite count by 54.9% and 74.2% in spleen and 41.4% and 60.4% in liver of infected BALB/c mice. BCV treatment significantly increased production of TNF-α, IFN-γ, ROS, NO in infected mice. Histological studies showed decreased granuloma formation in treated liver as compared with control. Liver and spleen structure was partially restored due to BCV treatment in infected mice. The present study revealed that BCV possessed antileishmanial activity against L. donovani parasite in vivo and in vitro and this activity was partly mediated through immunomodulatory activity involving macrophages.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bungarotoxins; Bungarus; Cricetinae; Dose-Response Relationship, Drug; Female; Inhibitory Concentration 50; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages, Peritoneal; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Nitric Oxide; Phagocytosis; Reactive Oxygen Species; Spleen; Tumor Necrosis Factor-alpha

Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L. donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb(III) drug pressure.

Topics: Adaptation, Physiological; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Differentiation; Cell Membrane; Chromatography, Liquid; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Mass Spectrometry; Membrane Fluidity; Metabolomics; Oxidative Stress; Phenotype; Signal Transduction

Resistance to sodium antimony gluconate (SAG) is a major cause of therapeutic failure in a large proportion of visceral leishmaniasis (VL) cases. Determinants of SAG resistance have been widely studied; however, the mechanism operating in clinical isolates is poorly understood. In the present study, expression of parasite surface antigen-2 (PSA-2) gene was studied in clinical isolates of Leishmania donovani comprising of antimony resistant (n=10) and sensitive (n=4) parasites. The expression of PSA-2 gene was found to be consistently high in SAG resistant clinical isolates (≥1.5-fold) at both transcript and protein level. Further, over-expression of PSA-2 in L. donovani isolates (LdPSA-2(++)) resulted in conversion of SAG sensitive phenotype to resistant. The LdPSA-2(++) parasites showed significantly decreased susceptibility towards SAG (>12-fold), amphotericin B (>4-fold) and miltefosine (>2.5-fold). Marked decrease in antimony accumulation and enhanced tolerance towards complement mediated lysis was evident in LdPSA-2(++) parasites. The study established the role of PSA-2 gene in SAG resistance and its potential as a biomarker to distinguish resistant and sensitive clinical isolates of L. donovani.

Topics: Amphotericin B; Antigens, Protozoan; Antigens, Surface; Antimony Sodium Gluconate; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Protozoan Proteins; Trypanocidal Agents

The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg · mL(-1) Pentostam compared with the control passage group (38.5 μg · mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Arsenic; Cell Line; Drinking Water; Drug Resistance; Environmental Exposure; India; Leishmania; Leishmaniasis, Visceral; Macrophages; Mass Screening; Mass Spectrometry; Mice; Mice, Inbred BALB C; Water Pollutants, Chemical

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

Topics: Administration, Oral; Aminoquinolines; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Apoptosis; DNA Fragmentation; Drug Resistance; Glutathione; Inhibitory Concentration 50; Injections, Intraperitoneal; Leishmania donovani; Leishmaniasis, Visceral; Lipid Peroxidation; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Protozoan Proteins; Quinaldines; Reactive Oxygen Species; Tetrahydrofolate Dehydrogenase

We have evaluated the effect of combining CD2 with conventional antimonial (sb) therapy in protection in BALB/c mice infected with either drug sensitive or resistant strain of Leishmania donovani with 3×10(7) parasites via-intra-cardiac route. Mice were treated with anti CD2 adjunct SAG sub-cutaneously twice a week for 4 weeks. Assessment for measurement of weight, spleen size, anti-Leishmania antibody titer, T cell and anti-leishmanial macrophage function was carried out day 0, 10, 22 and 34 post treatments. The combination therapy was shown boosting significant proportion of T cells to express CD25 compared to SAG monotherapy. Although, the level of IFN-γ was not statistically different between combination vs monotherapy (p=0.298) but CD2 treatment even alone significantly influenced IFN-γ production than either SAG treatment (p=0.045) or with CD2 adjunct SAG treatment (p=0.005) in Ld-S strain as well as in Ld-R strain. The influence of CD2 adjunct treatment was also documented in anti-leishmanial functions in macrophages. As shown, the super-oxide generation began enhancing very early on day 10 after SAG treatment with CD2 during which SAG action was at minimum. Interestingly, the super-oxide generation ability remained intact in macrophage after treatment with immuno-chemotherapy even in mice infected with Leishmania resistant strain. Unlike SAG treatment, treatment of SAG with CD2 also led to production of nitric oxide and TNF-α, resulting in resulting in most effective clearance of L. donovani from infected macrophages. Our results indicate that CD2, which can boost up a protective Th1 response, might also be beneficial to enable SAG to induce Macrophages to produce Leishmanicidal molecules and hence control the infection in clinical situation like Kala-azar. Drug resistance is the major impedance for disease control but the encouraging results obtained after infecting mice with resistant strain of the parasite strongly imply that this drug can be effective even in treating resistant cases of Kala-azar.

Topics: Animals; Antibodies, Monoclonal; Antimony Sodium Gluconate; Antiprotozoal Agents; CD2 Antigens; Drug Resistance; Drug Therapy, Combination; Humans; Immunologic Factors; Interferon-alpha; Leishmania donovani; Leishmaniasis, Visceral; Leukocytes, Mononuclear; Macrophages; Mice; Mice, Inbred BALB C; Nitric Oxide; Prospective Studies; Respiratory Burst; Spleen; Superoxides; Th1 Cells; Tumor Necrosis Factor-alpha

A 43-year-old HIV-positive Ethiopian immigrant presented with persistent diarrhoea, hepatosplenomegaly and pancytopaenia. Visceral leishmaniasis was diagnosed by multiple gastrointestinal tract biopsies. Blood polymerase chain reaction (PCR) was positive for Leishmania donovani. Despite highly active antiretroviral therapy (HAART) and multiple courses of antileishmanial treatments, including liposomal amphotericin and sodium stibogluconate, the patient had multiple relapses. CD4 counts remained at 40-60 cells/µL although viral loads were undetectable. Splenectomy resulted in resolution of the patient's pancytopaenia and in rising CD4 levels, which enabled a long-lasting remission.

Topics: Adult; Amphotericin B; Anti-HIV Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Blood; CD4 Lymphocyte Count; DNA, Protozoan; Emigrants and Immigrants; HIV; HIV Infections; Humans; Israel; Leishmania donovani; Leishmaniasis, Visceral; Male; Polymerase Chain Reaction; Recurrence; Splenectomy; Treatment Outcome; Viral Load

The current standard to assess pentavalent antimonial (SSG) susceptibility of Leishmania is a laborious in vitro assay of which the result has little clinical value because SSG-resistant parasites are also found in SSG-cured patients. Candidate genetic markers for clinically relevant SSG-resistant parasites identified by full genome sequencing were here validated on a larger set of clinical strains. We show that 3 genomic locations suffice to specifically detect the SSG-resistant parasites found only in patients experiencing SSG treatment failure. This finding allows the development of rapid assays to monitor the emergence and spread of clinically relevant SSG-resistant Leishmania parasites.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; DNA, Protozoan; Drug Resistance; Genetic Markers; Genome, Protozoan; Haplotypes; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Mice; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Predictive Value of Tests; Sensitivity and Specificity

The development of new therapeutic leads against leishmaniasis relies primarily on screening of a large number of compounds on multiplication of clinically irrelevant transgenic promastigotes. The advent of the successful in vitro culture of axenic amastigotes allows the development of transgenic axenic amastigotes as a primary screen which can test compounds in a high throughput mode like promastigotes, still representative of the clinically relevant mammalian amastigotes stage. The present study reports the development of luciferase-tagged axenic amastigotes of Leishmania donovani, the causative agent of Indian Kala-azar, for in vitro drug screening. Luciferase expressing promastigotes were transformed to axenic amastigotes at a low pH and high temperature without the loss of luciferase expression. As compared to transgenic promastigotes, the luciferase expressing axenic amastigotes exhibited more sensitivity to antileishmanial drugs, particularly to pentavalent antimony (~2.8-fold) and also to the test compounds. Hence, the developed luciferase expressing axenic amastigotes make an ideal choice for high throughput drug screening for antileishmanial compounds.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Culture Media; Drug Evaluation, Preclinical; Humans; Leishmania donovani; Leishmaniasis, Visceral; Luciferases; Parasitic Sensitivity Tests

In India, the eastern state of Bihar is particularly badly affected by visceral leishmaniasis (VL). It was in Bihar in the 1980s that the first clear signs of resistance to pentavalent antimonials, which had then been the standard antileishmanial treatment for several decades, were observed. New drugs and new formulations of old drugs have since been developed for the treatment of VL. However, despite some initial signs of benefit after each major revision in the method of treatment of VL in India, the VL-related case fatality rates recorded in India since the 1970s show no clear evidence of long-term success. In fact, the most recent data indicate that such rates have stabilised or even increased, probably because of the continued usage of sodium stibogluconate in northern Bihar.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Humans; India; Leishmaniasis, Visceral; Mortality; Treatment Failure

Kala-azar or visceral leishmaniasis is a disseminated protozoal infection caused by parasites of the genus Leishmania (Leishmania donovani in India). Conventional therapy for visceral leishmaniasis continues to be pentavalent antimony (sodium antimony gluconate [SAG]). Amphotericin B is widely used for SAG-unresponsive cases and sometimes even as a first-line drug, especially in endemic areas. With the conventional regimen of SAG, cardiac toxicity has been reported in 8% to 17% of cases with 5% to 7% of them having fatal toxicity. Cardiac toxicity is uncommon with amphotericin B with only few isolated reports. We report some patients with kala-azar in whom coadministration of SAG and amphotericin B led to arrhythmia and sudden death.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Arrhythmias, Cardiac; Child; Child, Preschool; Drug Therapy, Combination; Fatal Outcome; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male

One obstacle faced in the effective control of visceral leishmaniasis (VL) is the limited number of available treatment options. Furthermore, control efforts have been hindered further by the emergence of Leishmania resistance to many of the available drugs. In this study, we investigated the anti-leishmanial properties of 30 medicinally important plants from the VL endemic area of Bihar, India and compared them to two available anti-leishmanial drugs (sodium antimony gluconate and amphotericin B) and two plant lectins (phytohemagglutinin and concanavalin A) on Leishmania donovani promastigotes in vitro at 24 and 48 h after initiation of culture. We identified eight plant extracts in addition to phytohemagglutinin and amphotericin B that significantly inhibited the growth of promastigotes (p < 0.03). We further studied the minimum effective concentrations as well as the effect on axenic amastigotes viability and the cell cytotoxicity on human peripheral blood of four (Agave americana, Azadirachta indica, Eclipta alba and Piper longum) of the eight plant extracts that induced significant promastigotes killing (p = 0.00098). Effect-based dose finding analysis revealed that the threshold concentration of A. americana required to eliminate L. donovani after 24h was 0.05 mg/ml. A. indica and P. longum plant extracts eliminated L. donovani promastigotes after 48 h at concentrations of 0.1 and 0.5mg/ml, respectively. E. alba eliminated the promastigotes at a concentration of 0.5mg/ml within 24h. The axenic amastigote killing response was 1.90-, 2.52- and 1.3-fold higher than the promastigote killing response with A. indica, A. americana and E. alba plant extracts, respectively. A. americana and A. indica, respectively, led to approximate 2.5- and 1.3-fold declines in mitochondrial dehydrogenase activity compared with control. E. alba stimulation resulted in an up-regulation of dehydrogenase activity (p = 0.00329). The CSA from P. longum was found to be least cytotoxic; the observed difference in mitochondrial activity was insignificant (p = 0.16314). Further studies may reveal the pharmacological significance of many of the plants with anti-leishmanial properties identified in the present study.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Concanavalin A; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Leukocytes, Mononuclear; Phytohemagglutinins; Plant Extracts

The oleanane triterpene saponin PX-6518, with known potent in vitro and in vivo activity against Leishmania donovani, was investigated for its spectrum against the cutaneous species Leishmania mexicana, Leishmania panamensis and Leishmania major.. In vitro activity was based on the reduction of amastigotes in primary peritoneal mouse macrophages. BALB/c mice were injected with 2 × 10(6) amastigotes in the base of the tail (L. panamensis and L. major) or the foot (L. mexicana) and subcutaneously treated with PX-6518 [1-10 mg/kg body weight (BW)] or Pentostam(®) (250 mg/kg BW Sb(V) eq). Evolution of skin lesions was monitored in a prophylactic dose-finding study, and early curative [6 weeks post-infection (pi)] and late curative (>8-10 weeks pi) studies.. While moderate susceptibility to PX-6518 was obtained in vitro (IC(50): 1-4 µg/mL), excellent in vivo activity was demonstrated. In the prophylactic study (six administrations on alternate days, starting at 1 day pi), PX-6518 was 100% effective at 1 mg/kg BW against L. mexicana and L. panamensis, whereas L. major lesions could be prevented at 2 mg/kg BW. In the early curative (1 mg/kg BW once a week for 4 weeks) and late curative (1 mg/kg BW twice a week for 4 weeks) studies, PX-6518 completely healed L. mexicana and L. panamensis lesions, whereas L. major lesions were reduced by ∼ 50%.. This study demonstrates that PX-6518 possesses potent and broad-spectrum prophylactic and curative efficacy against cutaneous leishmaniasis in the BALB/c mouse model. L. major was the least susceptible species tested and parasitological cure could not be obtained.

Topics: Animals; Antibiotic Prophylaxis; Antimony Sodium Gluconate; Leishmania donovani; Leishmania major; Leishmania mexicana; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred BALB C; Saponins; Triterpenes

This prospective study evaluated the usefulness of the kala-azar latex agglutination test (KAtex) for the diagnosis and laboratory assessment of initial cure of visceral leishmaniasis (VL) (or kala-azar) patients following 30 days of sodium antimony gluconate treatment at Rajshahi Medical College Hospital (Bangladesh). KAtex detects a low molecular weight, heat-stable, carbohydrate antigen in the urine of VL patients. KAtex was performed using freshly voided urine samples obtained from 36 parasitologically confirmed cases of VL before and after treatment as well as from 40 healthy controls (20 each from kala-azar-endemic and non-endemic zones). KAtex was found to be positive in 27 (75%) of the 36 patients at diagnosis and was negative in all the controls. The diagnostic sensitivity and specificity of KAtex were 75% (95% CI 57-87%) and 100% (95% CI 89-100%), respectively. Following treatment, all 36 VL cases were negative for Leishman-Donovan bodies by splenic smear microscopy and 34 (94.4%) were negative by KAtex. This limited study suggests that KAtex is a satisfactorily sensitive, highly specific, rapid and completely non-invasive urine-based antigen detection test for the diagnosis of VL. Currently, this is the only non-invasive laboratory tool useful for the assessment of initial cure in VL patients.

Topics: Adolescent; Adult; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Bangladesh; Case-Control Studies; Female; Humans; Latex Fixation Tests; Leishmania; Leishmaniasis, Visceral; Male; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Young Adult

Resistance of Leishmania donovani to pentavalent antimonials, the first-line treatment of visceral leishmaniasis (VL), has become a critical issue worldwide. Second-line and new drugs are also not devoid of limitations. Suitable drug-delivery systems can improve the mode of administration and action of the existing antimonials, thus increasing their clinical life.. We investigated the efficacy of sodium stibogluconate (SSG) in phosphatidylcholine (PC)-stearylamine-bearing liposomes (PC-SA-SSG), PC-cholesterol liposomes (PC-Chol-SSG) and free amphotericin B (AmB) against SSG-resistant L. donovani strains in 8-wk infected BALB/c mice. Animals were sacrificed and parasites in liver, spleen and bone marrow were estimated 4-wk post-treatment by microscopic examination of stamp smears and limiting dilution assay. A set of PC-SA-SSG and AmB treated mice were further studied for protection against reinfection. Serum antibodies and cytokine profiles of ex-vivo cultured splenocytes were determined by ELISA. Uptake of free and liposomal SSG in intracellular amastigotes was determined by atomic absorption spectroscopy. Rhodamine 123 and 5-carboxyfluorescein, known substrates of Pgp and MRP transporter proteins, respectively, were used in free and liposomal forms for efflux studies to estimate intracellular drug retention. Unlike free and PC-Chol-SSG, PC-SA-SSG was effective in curing mice infected with two differentially originated SSG-unresponsive parasite strains at significantly higher levels than AmB. Successful therapy correlated with complete suppression of disease-promoting IL-10 and TGF-β, upregulation of Th1 cytokines and expression of macrophage microbicidal NO. Cure due to elevated accumulation of SSG in intracellular parasites, irrespective of SSG-resistance, occurs as a result of increased drug retention and improved therapy when administered as PC-SA-SSG versus free SSG.. The design of this single-dose combination therapy with PC-SA-SSG for VL, having reduced toxicity and long-term efficacy, irrespective of SSG-sensitivity may prove promising, not only to overcome SSG-resistance in Leishmania, but also for drugs with similar resistance-related problems in other diseases.

Topics: Amines; Animals; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Proliferation; Cytokines; Drug Resistance; Fluoresceins; Immunity, Humoral; Immunomodulation; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Mice; Mice, Inbred BALB C; Nitric Oxide; Phosphatidylcholines; Rhodamine 123; Spleen

Visceral leishmaniasis (VL) is an important cause of morbidity and mortality that affects multiple organs. Post-kala-azar ocular involvement is a serious complication that can manifest as blepharo-conjuctivitis or pan-uveitis. Failure of prompt diagnosis and treatment can result in blindness. We report five cases with pan-uveitis that followed the successful treatment of VL and consequent post-kala-azar dermal leishmaniasis were presented. Two patients lost their sight permanently but the rest were successfully treated. A high index of suspicion and prompt treatment are of paramount importance in order to avoid blindness following post-kala-azar ocular uveitis.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Blindness; Child; Eye Infections, Parasitic; Female; Humans; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Panuveitis

Mathematical models predict that the future of epidemics of drug-resistant pathogens depends in part on the competitive fitness of drug-resistant strains. Considering metacyclogenesis (differentiation process essential for infectivity) as a major contributor to the fitness of Leishmania donovani, we tested its relationship with pentavalent antimony (SbV) resistance in clinical lines. Different methods for the assessment of metacyclogenesis were cross-validated: gene expression profiling (META1 and SHERP), morphometry (microscopy and FACS), in vitro infectivity to macrophages and resistance to complement lysis. This was done on a model constituted by 2 pairs of reference strains cloned from a SbV-resistant and -sensitive isolate. We selected the most adequate parameter and extended the analysis of metacyclogenesis diversity to a sample of 20 clinical lines with different in vitro susceptibility to the drug. The capacity of metacyclogenesis, as measured by the complement lysis test, was shown to be significantly higher in SbV-resistant clinical lines of L. donovani than in SbV-sensitive lines. Together with other lines of evidence, it is concluded that L. donovani constitutes a unique example and model of drug-resistant pathogens with traits of increased fitness. These findings raise a fundamental question about the potential risks of selecting more virulent pathogens through massive chemotherapeutic interventions.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Flow Cytometry; Gene Expression Profiling; Humans; Leishmania donovani; Leishmaniasis, Visceral; Life Cycle Stages; Macrophages; Molecular Typing; Protozoan Proteins; Real-Time Polymerase Chain Reaction

Recent clinical isolates of Leishmania donovani from the hyperendemic zone of Bihar were characterised in vitro in terms of their sensitivity towards sodium stibogluconate in a macrophage culture system. The resulting half maximal effective concentration (EC(50)) values were compared with those of known sensitive isolates. Fifteen of the isolates showed decreased sensitivity towards SSG with an average EC(50) of 25.7 ± 4.5 μg/ml pentavalent antimony (defined as antimony resistant), whereas nine showed considerable sensitivity with an average EC(50) of 4.6 ± 1.7 μg/ml (defined as antimony sensitive). Out of those nine, seven were recent clinical isolates and the remaining two were known sensitive isolates. Compared with the antimony sensitive, resistant isolates showed enhanced expression of thiol metabolising enzymes in varying degrees coupled with increased intracellular non-protein thiol content, decreased fluorescence anisotropy (inversely proportional with membrane fluidity) and over-expression of the terminal glycoconjugates (N-acetyl-d-galactosaminyl residue). Macrophages infected with resistant but not with sensitive showed up-regulation of the ATP Binding Cassette transporter multidrug resistance protein 1 and permeability glycoprotein, while the supernatant contained abundant IL-10. The above results reinforce the notion that antimony resistant parasites have undergone a number of biochemical and biophysical changes as part of their adaptation to ensure their survival in the host.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Cricetinae; Drug Resistance; Female; Gene Expression Regulation; Host-Parasite Interactions; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Middle Aged; Protozoan Proteins; Young Adult

Leishmaniasis is an uncommon infectious disease in the UK with a variety of clinical presentations. Physicians should remember to consider this diagnosis in patients with an appropriate travel history (including the Mediterranean basin) and seek help with diagnostics from a specialised parasitology laboratory. Treatment regimens may be unfamiliar to the general physician, and thus should also be discussed with an expert.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Immunocompromised Host; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged

We report an unusual case of visceral leishmaniasis occurring in a patient from Sichuan China. The patient presented with a remitting fever, anemia, and pancytopenia. The case was confirmed as visceral leishmaniasis by microscopical detection of the Leishmania species amastigote in bone marrow aspirate. The patient was treated with 10 mg/kg/day of sodium stibogluconate for 5 days, with no therapeutic response. As a result, the patient was treated with liposomal amphotericin B (LAB) at 10 mg/day as an initial dosage. After treatment with an increasing drug dosage for 7 days, acute renal injury was evident as indicated by increased serum creatinine and urea nitrogen. LAB administration was discontinued until serum creatinine and serum urea nitrogen regressed on Day 15. Two maintenance treatments of 100 mg/day LAB were given on Days 19 and 26 (total 870 mg, 14.5 mg/kg). Bone marrow aspirate and clinical examination suggested total remission.

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male

Post-kala-azar dermal leishmaniasis (PKDL) is a cutaneous complication appearing after treatment of visceral leishmaniasis, and PKDL patients are considered infectious to sand flies and may therefore play a role in the transmission of VL. We estimated the risk and risk factors of PKDL in patients with past VL treatment in south-eastern Nepal.. Between February and May 2010 we traced all patients who had received VL treatment during 2000-2009 in five high-endemic districts and screened them for PKDL-like skin lesions. Suspected cases were referred to a tertiary care hospital for confirmation by parasitology (slit skin smear (SSS)) and/or histopathology. We calculated the risk of PKDL using Kaplan-Meier survival curves and exact logistic regression for risk factors.. Out of 680 past-treated VL patients, 37(5.4%) presented active skin lesions suspect of PKDL during the survey. Thirty-three of them underwent dermatological assessment, and 16 (2.4%) were ascertained as probable (2) or confirmed (14) PKDL. Survival analysis showed a 1.4% risk of PKDL within 2 years of VL treatment. All 16 had been previously treated with sodium stibogluconate (SSG) for their VL. In 5, treatment had not been completed (≤ 21 injections). Skin lesions developed after a median time interval of 23 months [interquartile range (IQR) 16-40]. We found a higher PKDL rate (29.4%) in those inadequately treated compared to those who received a full SSG course (2.0%). In the logistic regression model, unsupervised treatment [odds ratio (OR) = 8.58, 95% CI 1.21-374.77], and inadequate SSG treatment for VL in the past (OR = 11.68, 95% CI 2.71-45.47) were significantly associated with PKDL.. The occurrence of PKDL after VL treatment in Nepal is low compared to neighboring countries. Supervised and adequate treatment of VL seems essential to reduce the risk of PKDL development and active surveillance for PKDL is needed.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cohort Studies; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Nepal; Prevalence; Psychodidae; Retrospective Studies; Risk Factors; Time Factors; Young Adult

Drug-related factors and parasite resistance have been implicated in the failure of pentavalent antimonials (Sb(v)) in the Indian subcontinent; however, little information is available on host-related factors. Parasitologically confirmed kala-azar patients, treatment naïve to Sb(v), were prospectively recruited at a referral hospital in Nepal and were treated under supervision with 30 doses of quality-assured sodium stibogluconate (SSG) 20mg/kg/day and followed for 12 months to assess cure. Analysis of risk factors for treatment failure was assessed in those receiving >or=25 doses and completing 12 months of follow-up. One hundred and ninety-eight cases were treated with SSG and the overall cure rate was 77.3% (153/198). Of the 181 cases who received >or=25 doses, 12-month follow-up data were obtained in 169, comprising 153 patients (90.5%) with definite cure and 16 (9.5%) treatment failures. In the final logistic regression model, increased failure to SSG was significantly associated with fever for >or=12 weeks [odds ratio (OR)=7.4], living in districts bordering the high SSG resistance zone in Bihar (OR=6.1), interruption of treatment (OR=4.3) and ambulatory treatment (OR=10.2). Early diagnosis and supervised treatment is of paramount importance to prevent treatment failures within the control programme.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Epidemiologic Methods; Female; Humans; Leishmaniasis, Visceral; Male; Nepal; Treatment Failure; Young Adult

The study evaluated the usefulness of Leishmania-nested polymerase chain reaction (Ln-PCR) for diagnosis of kala-azar and assessed its role as a test of cure among kala-azar patients in Bangladesh. Peripheral blood buffy coat Ln-PCR was done in ninety-seven (97) clinically suspected patients of kala-azar, in forty (40) healthy controls from both endemic and non-endemic areas, and in forty-six (46) patients after completion of treatment with sodium stibogluconate (SSG). The Ln-PCR results were compared with Leishmania donovani parasite load graded by 1+ to 6+ in all smear-positive L. donovani cases. Out of 97 clinically suspected kala-azar patients, 94 were parasitologically confirmed. Ln-PCR was found positive in 91 of 94 parasitologically positive patients of kala-azar at diagnosis, indicating its diagnostic sensitivity as 97%. None of the controls was found positive for Ln-PCR, indicating its diagnostic specificity to be 100%. About 9% of kala-azar patients having been graded 1+ parasitic load had negative Ln-PCR results. After completion of treatment, Ln-PCR was positive in 4 patients (8.4%) out of 46 cases, indicating its role in demonstrating the absence of parasites 30 days after completion of treatment in 91.6% of the treated patients. This limited study suggests that Ln-PCR is a highly sensitive and specific test for the diagnosis of visceral leishmaniasis and can be used as a test of cure. Thus, efforts should be made to establish this useful method at least in the tertiary care hospitals and, if possible, at the district-level hospitals, especially in the endemic areas of Bangladesh.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Bangladesh; Female; Humans; Leishmania; Leishmaniasis, Visceral; Leukocytes; Male; Polymerase Chain Reaction; Sensitivity and Specificity

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Infant; Leishmaniasis, Visceral; Liver Failure, Acute

Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4(+) T cells, TNF, and IFN-gamma, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4(+) T cell expansion without modulating Treg cell function or protecting conventional CD4(+) T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4(+) T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.

Topics: Animals; Antibodies, Monoclonal; Antimony Sodium Gluconate; Antiprotozoal Agents; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Synergism; Female; Glucocorticoid-Induced TNFR-Related Protein; Immunity, Cellular; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Liver Diseases, Parasitic; Male; Mice; Mice, Inbred C57BL; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the factors associated with acute kidney injury (AKI) in patients with visceral leishmaniasis (VL). The study patients had a diagnosis of VL and were admitted to a tertiary hospital. A multivariate analysis was performed to analyze the risk factors for AKI. A total of 224 patients were included. The mean age was 36 +/- 15 years. AKI was observed in 33.9% of cases. Risk factors associated with AKI were male gender (odds ratio [OR] = 2.2; P = 0.03), advanced age (OR = 1.05; P < 0.001), and jaundice (OR = 2.9; P = 0.002). There was an association between amphotericin B use and AKI (OR = 18.4; P < 0.0001), whereas glucantime use was associated with lower incidence of AKI compared with amphotericin B use (OR = 0.05; P < 0.0001). Mortality was 13.3%, and it was higher in AKI patients (30.2%). Therefore, factors associated with AKI were male gender, advanced age, and jaundice. Amphotericin B was an important cause of AKI in VL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Kidney Diseases; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Middle Aged; Organometallic Compounds; Risk Factors; Young Adult

Drug unresponsiveness in patients with visceral leishmaniasis (VL) is a problem in many endemic areas. This study aimed to determine genetic diversity of Leishmania donovani isolates from a VL endemic area in Sudan as a possible explanation for drug unresponsiveness in some patients. Thirty clinically stibogluconate (SSG)-sensitive isolates were made SSG-unresponsive in vitro by gradually increasing SSG concentrations. The sensitive isolates and their SSG-unresponsive counterparts were typed using mini-circle kDNA and categorized using PCR-RAPD. All the isolates were typed as L. donovani, the resulting PCR-RAPD characterization of the SSG-sensitive isolates gave three distinct primary genotypes while, the SSG-unresponsive isolates showed only a single band. L. donovani isolates from eastern Sudan are diverse; this probably resulted from emergence of new L. donovani strains during epidemics due to the pressure of widespread use of antimonials. In this communication the possible role of isolates diversity in antimonial unresponsiveness and the in vitro changing PCR-RAPD band pattern in SSG-unresponsive strains were discussed.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; DNA, Kinetoplast; Genetic Variation; Genotype; Humans; Leishmania donovani; Leishmaniasis, Visceral; Polymerase Chain Reaction; Random Amplified Polymorphic DNA Technique; Sudan

The inability of sodium antimony gluconate (SAG)-unresponsive kala-azar patients to clear Leishmania donovani (LD) infection despite SAG therapy is partly due to an ill-defined immune-dysfunction. Since dendritic cells (DCs) typically initiate anti-leishmanial immunity, a role for DCs in aberrant LD clearance was investigated. Accordingly, regulation of SAG-induced activation of murine DCs following infection with LD isolates exhibiting two distinct phenotypes such as antimony-resistant (Sb(R)LD) and antimony-sensitive (Sb(S)LD) was compared in vitro. Unlike Sb(S)LD, infection of DCs with Sb(R)LD induced more IL-10 production and inhibited SAG-induced secretion of proinflammatory cytokines, up-regulation of co-stimulatory molecules and leishmanicidal effects. Sb(R)LD inhibited these effects of SAG by blocking activation of PI3K/AKT and NF-kappaB pathways. In contrast, Sb(S)LD failed to block activation of SAG (20 microg/ml)-induced PI3K/AKT pathway; which continued to stimulate NF-kappaB signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs with Sb(S)LD also inhibited SAG (20 microg/ml)-induced activation of PI3K/AKT and NF-kappaB pathways and leishmanicidal effects, which was restored by increasing the dose of SAG to 40 microg/ml. In contrast, Sb(R)LD inhibited these SAG-induced events regardless of duration of DC exposure to Sb(R)LD or dose of SAG. Interestingly, the inhibitory effects of isogenic Sb(S)LD expressing ATP-binding cassette (ABC) transporter MRPA on SAG-induced leishmanicidal effects mimicked that of Sb(R)LD to some extent, although antimony resistance in clinical LD isolates is known to be multifactorial. Furthermore, NF-kappaB was found to transcriptionally regulate expression of murine gammaglutamylcysteine synthetase heavy-chain (mgammaGCS(hc)) gene, presumably an important regulator of antimony resistance. Importantly, Sb(R)LD but not Sb(S)LD blocked SAG-induced mgammaGCS expression in DCs by preventing NF-kappaB binding to the mgammaGCS(hc) promoter. Our findings demonstrate that Sb(R)LD but not Sb(S)LD prevents SAG-induced DC activation by suppressing a PI3K-dependent NF-kappaB pathway and provide the evidence for differential host-pathogen interaction mediated by Sb(R)LD and Sb(S)LD.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Dendritic Cells; Drug Resistance; Female; Gene Expression; Glutamate-Cysteine Ligase; Host-Parasite Interactions; Interleukin-10; Leishmania donovani; Leishmaniasis, Visceral; Male; Mesocricetus; Mice; Mice, Inbred BALB C; NF-kappa B; Phenotype; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Nitric oxide (NO) plays a vital role in maintaining the survivability of circulating erythrocytes. Here we have investigated whether NO depletion associated with visceral leishmaniasis (VL) is responsible for the reduced survival of erythrocytes observed during the disease.. Infected hamsters were treated with standard anti-leishmanial sodium stibogluconate (SAG) and NO donor isosorbide dinitrate (ISD). Erythrophagocytosis by macrophages was determined by labelling the cells with FITC followed by flow cytometry. Aggregation of band3 was estimated from band3 associated EMA fluorescence. Caspase 3 activity was measured using immunosorbent assay kit. Phosphatidylserine (PS) externalization and cell shrinkage were determined using annexin V. Aminophspholipid translocase and scramblase activities were measured following NBD-PS and NBD-PC internalization, respectively.. Impairment of both synthesis and uptake of NO resulted in decreased bioavailability of this signaling molecule in erythrocytes in VL. NO level was replenished after simultaneous treatment with ISD and SAG. Combination treatment decreased red cell apoptosis in infected animals by deactivating caspase 3 through s-nitrosylation. Drug treatment prevented infection-mediated ATP depletion and altered calcium homeostasis in erythrocytes. Improved metabolic environment effectively amended dysregulation of aminophospholipid translocase and scramblase, which in turn reduced cell shrinkage, and exposure of phosphatidylserine on the cell surface under the diseased condition.. In this study, we have identified NO depletion to be an important factor in promoting premature hemolysis with the progress of leishmanial infection. The study implicates NO to be a possible target for future drug development towards the promotion of erythrocyte survival in VL.

Topics: Adenosine Triphosphate; Animals; Anion Exchange Protein 1, Erythrocyte; Antimony Sodium Gluconate; Antiprotozoal Agents; Calcium; Caspase 3; Cell Survival; Cricetinae; Erythrocytes; Hemolysis; Humans; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Mesocricetus; Nitric Oxide; Phagocytosis; Signal Transduction

Topics: Amphotericin B; Antimony Sodium Gluconate; Drug Resistance; Female; Humans; Leishmaniasis, Visceral; Middle Aged

Leishmania donovani is an intracellular protozoan parasite that causes a lethal systemic disease, visceral leishmaniasis (VL), and is transmitted between mammalian hosts by phlebotomine sandflies. Leishmania expertly survives in these 'hostile' environments with a unique redox system protecting against oxidative damage, and host manipulation skills suppressing oxidative outbursts of the mammalian host. Treating patients imposes an additional stress on the parasite and sodium stibogluconate (SSG) was used for over 70 years in the Indian subcontinent.. We evaluated whether the survival capacity of clinical L. donovani isolates varies significantly at different stages of their life cycle by comparing proliferation, oxidative stress tolerance and infection capacity of 3 Nepalese L. donovani strains in several in vitro and in vivo models. In general, the two strains that were resistant to SSG, a stress encountered in patients, attained stationary phase at a higher parasite density, contained a higher amount of metacyclic parasites and had a greater capacity to cause in vivo infection in mice compared to the SSG-sensitive strain.. The 2 SSG-resistant strains had superior survival skills as promastigotes and as amastigotes compared to the SSG-sensitive strain. These results could indicate that Leishmania parasites adapting successfully to antimonial drug pressure acquire an overall increased fitness, which stands in contrast to what is found for other organisms, where drug resistance is usually linked to a fitness cost. Further validation experiments are under way to verify this hypothesis.

Topics: Animals; Antimony Sodium Gluconate; Drug Resistance; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Metals; Mice; Nitroso Compounds; Oxidative Stress; Stress, Physiological; Temperature

Topics: Antimony Sodium Gluconate; Bhutan; Humans; Leishmaniasis, Visceral; Prevalence; Treatment Outcome

Post kala-azar dermal leishmaniasis (PKDL) is a rare disease. This is a solitary case report from Orissa, India. We describe a case of PKDL in a 55-year-old male who presented with multiple nodular lesions over face, trunk, and extremities. The patient had been to an endemic area of kala-azar and had a previous history of leishmaniasis. Fine needle aspiration cytology samples from skin nodules revealed Leishmania amastigotes.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; India; Leishmania; Leishmaniasis, Visceral; Male; Middle Aged; Skin

Kala azar (KA) is one of the most important tropical diseases. More so is the issue of KA in pregnancy. In this retrospective study we tried to find out the out come of pregnant patient treated with Sodium Antimony Gluconate (SAG) for KA in one of the most endemic area of Bangladesh, Fulbaria. SAG is the available and registered drug for treatment of KA patient with pregnancy in Bangladesh. A total of 16 pregnant women presented with KA during the study period of 2005 to 2009. Out of the 16 patients 11 had abortion and they were all with in the 16 to 22nd week of pregnancy. The abortion took place mostly on the 22nd to 24th day of treatment when the patient had become afebrile. Rest of the 5 patients was in their 30 to 34th week of pregnancy and had good obstetric outcome. All the 16 patients were clinically cured at the end of treatment. No follow up records were available and there was no data regarding the 5 children. It is of our opinion that the abortions were induced by SAG and therefore we recommend that SAG should not be used in early or mid pregnancy for treating KA.

Topics: Antimony Sodium Gluconate; Female; Humans; Leishmaniasis, Visceral; Pregnancy; Pregnancy Complications, Parasitic

Antimony resistance is frequently encountered during treatment of visceral leishmaniasis (VL) and the differences are well characterized by inadequate IFN-gamma dominant type-1 protection mechanisms. The part played by Leishmania parasites derived from antimony treated patients in the outcome of an immune response largely remains to be investigated. In the present study we observed that macrophages of BALB/c mice infected with antimony non-responder (SAG-NR) isolates had a greater amastigote burden than antimony responder (SAG-R) isolates. Later it was observed that antigen from SAG-NR and R L. donovani isolates elicit different cytokine responses in peritoneal blood mononuclear cells (PBMCs) from patients with VL. The production of IFN-gamma by T-cells in VL patients increased in response to Leishmania derived from responder patients but this response within same T-cells was lower when sensitized from Leishmania from a non-responder VL patient. On the other hand, IL-4 and IL-10 expression was increased when primed with parasites from non-responder VL source. Such a differential pattern of cytokine expression by the same T-cell population produced to Leishmania from different donors, needs further exploration.

Topics: Animals; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Cytokines; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Leishmania donovani; Leishmaniasis, Visceral; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; T-Lymphocytes

Indian Leishmania donovani isolates (n = 19) from regional zones representing various levels of antimony resistance displayed significantly (P < 0.01) correlated results with respect to in vitro susceptibility to the antileishmanial drugs sodium antimony gluconate, amphotericin B, and Miltefosine, raising the possibility of cross-resistance mechanisms operating in the field isolates. The results of gene expression analysis of LdMT and LdRos3 were suggestive of alternate mechanisms of Miltefosine susceptibility in the isolates.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; DNA Primers; Drug Resistance; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Phosphorylcholine; Reverse Transcriptase Polymerase Chain Reaction

Sodium Antimony Gluconate (SAG) is currently used worldwide as the first-line drugs for the treatment of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) since 1940s. Unfortunately, the resistance of Leishmania parasite to this drug is increasing in several parts of the world. The mechanism of drug resistance in clinical isolates is still not very clear. Earlier, we have established a differentiation between six clinical isolates as sensitive and resistant on the basis of their sensitivity to SAG in vitro and in vivo as well as expression of proteophosphoglycan contents. In this preliminary study, we have further analyzed these isolates on the basis of their genetic diversity, molecular variance and phylogenetic structure using for the first time, a fingerprinting approach--amplified fragment length polymorphism (AFLP). Altogether 2338 informative AFLP bands were generated using 10 selective primer combinations. Percentage of polymorphism was 55.35%. A number of unique AFLP markers (217) were also identified in these strains. It was deduced that a higher rate of variations occurred among Leishmania clinical isolates which indicate the shifting of drug sensitive nature of parasite towards resistant condition.

Topics: Amplified Fragment Length Polymorphism Analysis; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cluster Analysis; DNA Fingerprinting; DNA, Protozoan; Drug Resistance; Genetic Markers; Genetic Variation; Genotype; India; Leishmania donovani; Leishmaniasis, Visceral

We demonstrate that the combination of sub-optimal doses of Sodium Antimony Gluconate (SAG) and the diperoxovanadate compound K[VO(O2)2(H2O)], also designated as PV6, is highly effective in combating experimental infection of BALB/c mice with antimony resistant (Sb(R)) Leishmania donovani (LD) as evident from the significant reduction in organ parasite burden where SAG is essentially ineffective. Interestingly, such treatment also allowed clonal expansion of antileishmanial T-cells coupled with robust surge of IFN-c and concomitant decrease in IL-10 production. The splenocytes from the treated animals generated significantly higher amounts of IFN-c inducible parasiticidal effector molecules like superoxide and nitric oxide as compared to the infected group. Our study indicates that the combination of sub-optimal doses of SAG and PV6 may be beneficial for the treatment of SAG resistant visceral leishmaniasis patients.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Ascitic Fluid; Cell Survival; Cricetinae; Drug Combinations; Drug Resistance; Interferon-gamma; Interleukin-10; Leishmania donovani; Leishmaniasis, Visceral; Liver; Mesocricetus; Mice; Mice, Inbred BALB C; Nitric Oxide; Peroxides; Spleen; Superoxides; T-Lymphocytes; Vanadates

Reason for post-kala-azar dermal leishmaniasis (PKDL) is yet to be established. Earlier it was observed that morphology and biochemical properties of host peroxisomes were impaired during Leishmania infection. As peroxisome is known to be involved in various metabolic pathways to monitor normal function of the host cells, it is essential that Leishmania-induced dysfunction of this organelle should totally be repaired during treatment of visceral leishmaniasis (VL). In this paper it has been shown that resumption of normal peroxisomal function could not be attained when one of the existing drugs sodium antimony gluconate (SAG) was used for chemotherapy against VL. Although Leishmania parasite was found to be completely eliminated from host liver and spleen after SAG treatment, normal activities of peroxisomal catalase and superoxide dismutase could not be restored. Also unusual peptides were found to be present due to abnormal proteolytic cleavage of proteins. It is proposed that peroxisomal disorder which exists even after successful chemotherapy of VL may be figured out as one of the possible reasons to develop PKDL. It may also be pointed out that continued effect of peroxisomal disorder even after complete treatment of this parasitic disease may also lead to genetic disorders not yet been explored in post-kala-azar patients.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Catalase; Cricetinae; Electrophoresis, Polyacrylamide Gel; Humans; Leishmaniasis, Visceral; Mesocricetus; Peroxisomes; Proteins; Superoxide Dismutase

With expanding travel activities, visceral leishmaniasis increasingly occurs in non-endemic areas and affects immunocompetent individuals with no other risk factor than holidays at the Mediterranean coast. We report 3 instructive Swiss cases of visceral leishmaniasis presenting with fever of unknown origin and pancytopenia and review current diagnostic and therapeutic concepts.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Diagnosis, Differential; Female; Fever; HIV Infections; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Mediterranean Region; Travel

25 years old HIV-positive farmer on Anti-retroviral therapy from North Ethiopia with PKDL occurring as IRIS is reported. He developed popular and nodular lesions on the face, chest and arms (Grade II severe PKDL) one month after anti-retroviral therapy initiation, who had history of therapy for visceral leishmaniasis (VL) one year back. PKDL manifesting as IRIS after ART initiation in previously treated case for VL was among the few reported case in the world. The case is presented and discussed with the few available review literatures.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antimony Sodium Gluconate; HIV Seropositivity; Humans; Immune Reconstitution Inflammatory Syndrome; Leishmaniasis; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male

The lymphocytic phenotypes involved in the pathogenesis of visceral leishmaniasis (VL) in Iraqi children have recently been investigated, in a study based on cluster-of-differentiation (CD) markers. Each case of VL investigated was confirmed parasitologically by the observation of amastigotes in a bone-marrow smear. Compared with the values for the healthy children used as controls, a lymphocyte from an untreated VL case was significantly less likely to be CD3+ or CD4+, significantly more likely to be CD8+, and more (but not significantly more) likely to be CD22+. The untreated cases also had significantly lower CD4+/CD8+ ratios than the controls. Among the untreated cases, gender and age had no apparent effect on any of these variables. After 28 days of treatment with sodium stibogluconate, there was a trend towards normalization in the lymphocytic phenotypes of the VL cases, with significant increases in the CD4+/CD8+ ratios and the percentages of lymphocytes that were CD3+ or CD4+, and a significant decrease in the percentages of lymphocytes that were CD22+.

Topics: Antigens, Differentiation; Antimony Sodium Gluconate; Antiprotozoal Agents; B-Lymphocytes; Child, Preschool; Female; Humans; Immunophenotyping; Iraq; Leishmaniasis, Visceral; Lymphocyte Subsets; Male; Sex Factors; T-Lymphocytes

Topics: Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Biopsy; Female; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Phosphorylcholine; Pregnancy; Treatment Outcome

Until the early 1990s, pentavalent antimony was the only documented first-line drug employed for the treatment of zoonotic visceral leishmaniasis (VL) in the Mediterranean, with reported cure rates exceeding 95% in immunocompetent patients. The emergence of antimony resistance in other endemic settings and the increase in drug options have stimulated re-evaluation of the current therapeutic approaches and outcomes in Mediterranean countries. A scientific consortium ('LeishMed' network) collected updated information from collaborating clinical health centres of 11 endemic countries of Southern Europe, Northern Africa and the Middle East. In contrast with the previous situation, VL is now treated differently in the region, basically through three approaches: (1) In Northern Africa and in part of the Middle East, pentavalent antimony is still the mainstay for therapy, with no alternative drug options for treating relapses; (2) In some European countries and Israel, both pentavalent antimony and lipid-associated amphotericin B (AmB) formulations are used as first-line drugs, although in different patients' categories; (3) In other countries of Europe, mainly liposomal AmB is employed. Importantly, cure rates exhibited by different drugs, including antimonials in areas where they are still in routine use, are similarly high (>/=95%) in immunocompetent patients. Our findings show that antimony resistance is not an emerging problem in the Mediterranean. A country's wealth affects the treatment choice, which represents a balance between drug efficacy, toxicity and cost, and costs associated with patient's care.

Topics: Adolescent; Adult; Africa, Northern; Aged; Aged, 80 and over; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Clinical Protocols; Europe; Female; Humans; Immunocompromised Host; Israel; Leishmaniasis, Visceral; Male; Meglumine; Middle Aged; Middle East

The emergence of antimony (Sb) resistance has jeopardized the treatment of visceral leishmaniasis in various countries. Previous studies have considered the part played by leishmanial parasites in antimony resistance, but the involvement of host factors in the clinical scenario remained to be investigated. Here we show that unlike infection with Sb-sensitive (Sbs) Leishmania donovani, infection with Sb-resistant (Sb r) L. donovani induces the upregulation of multidrug resistance-associated protein 1 (MRP1) and permeability glycoprotein (P-gp) in host cells, resulting in a nonaccumulation of intracellular Sb following treatment with sodium antimony gluconate (SAG) favoring parasite replication. The inhibition of MRP1 and P-gp with resistance-modifying agents such as lovastatin allows Sb accumulation and parasite killing within macrophages and offers protection in an animal model in which infection with Sb r L. donovani is otherwise lethal. The occurrence of a similar scenario in clinical cases is supported by the findings that unlike monocytes from SAG-sensitive kala-azar (KA) patients, monocytes from SAG-unresponsive KA patients overexpress P-gp and MRP1 and fail to accumulate Sb following in vitro SAG treatment unless pretreated with inhibitors of ABC transporters. Thus, the expression status of MRP1 and P-gp in blood monocytes may be used as a diagnostic marker for Sb resistance and the treatment strategy can be designed accordingly. Our results also indicate that lovastatin, which can inhibit both P-gp and MRP1, might be beneficial for reverting Sb resistance in leishmaniasis as well as drug resistance in other clinical situations, including cancer.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cricetinae; Drug Resistance; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Macrophages, Peritoneal; Mesocricetus; Mice; Mice, Inbred BALB C; Multidrug Resistance-Associated Proteins

Because of the large number of cases of visceral leishmaniasis (VL) recorded in Brazil over the last few years, this disease has been showing characteristics different from previously known ones. We report cases of pregnant women treated for VL, describing their course and outcome and the chemotherapeutic medication used according to the clinical signs and symptoms of each patient.. We report five cases of pregnant women treated for VL in a central-western region of Brazil.. No case of vertical transmission was observed, even in patients who were treated after delivery. One of the patients with a late diagnosis made after the onset of symptoms died. Thus, the treatment of VL during pregnancy reduces maternal mortality and the rate of vertical transmission of the disease, being safe and effective as long as the disease is diagnosed early.. At present, amphotericin B and its derivatives appear to be the best therapeutic option for the mother-child binomial.

Topics: Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Brazil; Deoxycholic Acid; Drug Combinations; Female; Fever; Hepatomegaly; Humans; Leishmaniasis, Visceral; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Splenomegaly

Visceral leishmaniasis (VL) is endemic in many countries worldwide, including India. Globally, sodium stibogluconate (Sb) remains the cornerstone of therapy, except in some parts of India owing to increasing drug resistance. Although electrocardiographic changes associated with Sb therapy have been described, global cardiac function using tools such as colour Doppler echocardiography is less well studied. We evaluated the cardiac function of 14 newly diagnosed VL patients using two-dimensional M-mode and Doppler echocardiography. The evaluations were performed before, during and at the end of Sb therapy. Left ventricular function and dimensions remained within normal limits in all patients. Pericardial effusion was noted in four patients with heavy parasitaemia. Effusions were small, haemodynamically insignificant and resolved spontaneously. We conclude that pericardial effusion may occur in VL patients with heavy parasitaemia.

Topics: Adolescent; Adult; Aged; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Echocardiography, Doppler, Color; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Parasitemia; Pericardial Effusion; Ventricular Function, Left

The resistance of clinical isolates of Leishmania donovani to sodium antimony gluconate (SAG), the mainstay of treatment in Indian visceral leishmaniasis, has become a critical issue in India. The present work investigates the mechanism of resistance to SAG in parasites isolated from patients who are unresponsive to SAG.. Susceptibility to SAG as determined in vitro with intracellular amastigotes correlated well with the clinical response. The ABC transporter gene MRPA was amplified in resistant field isolates as part of an extrachromosomal circle. Co-amplification of the pterin reductase gene (PTR1) and MRPA suggests amplification of the H locus in SAG-resistant isolates. Amplification of MRPA was correlated to increased RNA as determined by real-time PCR. MRPA is an ABC-thiol transporter, and cysteine and glutathione were increased in the resistant isolates. Ornithine decarboxylase (a rate limiting enzyme in polyamine biosynthesis), and gamma-glutamylcysteine synthetase (a rate limiting enzyme in glutathione biosynthesis), the two building blocks of the main cellular thiol trypanothione, were overexpressed in some of the resistant isolates.. A variety of resistance mechanisms to SAG, most of them consistent with a model based on the study of resistance in vitro, were present in clinical isolates from the same geographical region.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; ATP-Binding Cassette Transporters; Blotting, Western; Drug Resistance; Glutamate-Cysteine Ligase; Humans; Leishmania donovani; Leishmaniasis, Visceral; Membrane Glycoproteins; Ornithine Decarboxylase; Protozoan Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sulfhydryl Compounds

In this study, cDNA microarray analysis of a closely related species, Leishmania major, was used as a screening tool to compare antimonial-resistant and susceptible clinical isolates of Leishmania donovani in order to to identify candidate genes on the basis of antimony resistance. Clinically confirmed resistant isolate 39 and sensitive isolate 2001 were used in this study. Many differentially regulated genes were identified whose expression levels differ in sodium antimony gluconate (SAG)-treated patients. Interestingly, genes on the array, showing changes in expression of over 2-fold revealed the identity of ABC transporters, which are known determinants of drug resistance in laboratory mutants. The functionality of the transporters was validated by flow cytometry which, being biologically informative, provides direct clues to gene function. The results suggest that isolate 39 could have developed resistance by an increased multidrug resistance protein (MRP)-like pump. This study provides preliminary clues to the role of a thiol-dependent efflux system in antimonial resistant clinical isolates of Leishmania donovani.

Topics: Animals; Antimony Sodium Gluconate; ATP-Binding Cassette Transporters; Blotting, Northern; Computational Biology; Drug Resistance; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Genes, Protozoan; Humans; Leishmania donovani; Leishmania major; Leishmaniasis, Visceral; Oligonucleotide Array Sequence Analysis; Sulfhydryl Compounds

We conducted an analytic case-control study in Kala-azar patients during Sodium Antimony Gluconate (SAG) therapy to assess the changes in serum copper. A total of 89 subjects were included in the study. Diagnosed patients of Kala-azar with parasitological evidence of Leishmania Donovani (LD) bodies in bone marrow, were selected as cases (n=54). They were selected from Medicine and Paediatric wards of Mymensingh Medical College Hospital, Mymensingh and nearby Fulbaria upazila of Mymensingh district. Physically healthy volunteers of similar age, sex and body mass index (BMI) as cases, were included in control group (n=35). The study period was from July 2003 to June 2004. SAG was given intramuscularly (20 mg/kg/day) to Kala-azar patients for 30 days. Blood samples were collected from controls, Kala-azar cases before therapy and same cases during 15-20 days of SAG therapy. Serum copper was higher in cases before therapy than those of controls (p<0.001). However, serum copper reduced significantly (p<0.001) during SAG therapy. So biochemical monitoring may be considered in the management of the disease.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Bangladesh; Case-Control Studies; Child; Child, Preschool; Copper; Drug Monitoring; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged

In most of the Indian subcontinent, the first line treatment for visceral leishmaniasis (VL) is sodium stibogluconate (SSG), an antimonial drug, but the efficacy of the drug varies according to region. We aimed to characterize the in vitro antimony susceptibility of clinical isolates of Nepalese VL patients, and to correlate this in vitro parasite phenotype to clinical therapy outcome. Thirty-three clinical isolates of L. donovani were taken from patients with known disease history. These isolates were typed and the susceptibility of intracellular amastigotes to pentavalent (SbV) and trivalent (SbIII) antimonials was determined. We observed (i) 22 SbV-resistant isolates out of 33 tested and (ii) 3 SbIII-resistant isolates out of 12 tested. Amongst the latter, there were three combinations of in vitro phenotypes: (i) parasites sensitive (n=4) or (ii) resistant to both drugs (n=3) and (iii) resistant to SbV only (n=5). There was no geographical clustering in terms of in vitro susceptibility. The relation between the in vitro susceptibility to antimonials and the corresponding in vivo treatment outcome was ambiguous. Our results highlight the need to adjust the currently used Leishmania drug susceptibility assays if they are to be used for prognosis of in vivo SSG treatment outcome.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance, Microbial; Humans; Leishmania donovani; Leishmaniasis, Visceral; Prognosis; Treatment Outcome

Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) some of which are secreted while others are found on the surface of promastigotes and amastigotes. These proteins are thought to be important in the transmission, invasion and subsequent intracellular survival of parasites. The structure and function of PPGs are species and stage-specific in the case of L. major and L. mexicana, but no such information has hitherto been available for L. donovani. This study presents, for the first time, an initial characterization (localization) of PPG in sodium stibogluconate (SSG)-resistant and sensitive clinical isolates of L. donovani from Bihar (India) by confocal microscopy, flow cytometry and Western blotting using antibodies to L. major PPG. Confocal microscopy analysis revealed that both promastigotes and amastigotes possess PPG on their cell membrane and flagellar pocket membrane but its expression was variable in different isolates. The quantitative analysis by FACS and Western blotting showed that the expression and intensity of PPG bands was higher in SSG-resistant isolates. This study suggests the possibilities of involvement of PPG in drug-resistant mechanisms and of using PPG abundance as a marker for identifying drug-resistant clinical isolates in Indian kala azar.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Line; Cricetinae; Drug Resistance; India; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Membrane Proteins; Mesocricetus; Mice; Proteoglycans; Protozoan Proteins; Spleen

Although visceral leishmaniasis (VL) is endemic in various parts of India, mainly Bihar, West Bengal and Orissa, and neighbouring countries such as Nepal and Bangladesh, it is rarely reported from the hilly areas of India. We report on nine male VL cases from the non-endemic Garhwal region of Uttarakhand who were treated successfully with sodium stibogluconate. We conclude that sodium stibogluconate-sensitive VL is emerging in this region and that urgent and effective vector control measures may be warranted to prevent the disease from becoming a major health problem and to ensure that resistance to sodium stibogluconate does not emerge.

Topics: Adult; Aged; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Outbreaks; Drug Resistance; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged

Infection with Leishmania donovani is associated with IL-10 as well as with GM-CSF. Immune complexes (IC) exert important functions by stimulation of monocytes/macrophage-mediated production of pro- and anti-inflammatory cytokines in rheumatic diseases. In this investigation, we have explored IC-induced cytokine production during Leishmania infection. Sera from 43 patients with visceral leishmaniasis (VL), 17 patients with post-kala-azar dermal leishmaniasis, and 20 healthy Sudanese controls were precipitated with polyethylene glycol (PEG). The PEG precipitates were added to serum-free PBMC for 20 h,whereupon supernatant levels of IL-1beta, IL-6, IL-10, IL-1 receptor antagonist protein, TNF-alpha, TNF receptor p75, and GM-CSF were investigated using ELISA. Circulating levels of C1q-binding IC were also measured in the serum samples. PEG precipitates from Leishmania-infected patients induced significantly higher levels of GM-CSF (p = 0.0037) and IL-10 (p < 0.0001), as well as of IL-6 (p < 0.0001) and IL-1 receptor antagonist (p = 0.0238) as compared with PEG precipitates from controls. Patients with acute VL as well as VL patients receiving sodium stibogluconate treatment displayed significantly increased levels of PEG precipitate-induced GM-CSF. The induction of GM-CSF by circulating IC was especially prominent in acute VL patients receiving sodium stibogluconate treatment; ANOVA revealed significant interaction between disease activity and treatment for PEG precipitate-induced levels of GM-CSF (disease activity, p = 0.0006; treatment, p = 0.0005; interaction, p = 0.0046). Parallel associations were determined for C1q-binding immune complexes, but not for any cytokine other than GM-CSF. The importance of IC-induced GM-CSF in leishmaniasis warrants further study.

Topics: Animals; Antigen-Antibody Complex; Antimony Sodium Gluconate; Antiprotozoal Agents; Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leishmania donovani; Leishmaniasis, Visceral; Polyethylene Glycols; Receptors, IgG

Topics: Adolescent; Agglutination Tests; Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Female; Humans; Injections, Intramuscular; Isoptera; Leishmania donovani; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Reagent Kits, Diagnostic; Risk Factors; Seroepidemiologic Studies; Travel; Uganda

In this study we sought to determine if there is alteration in nitric oxide (NO) production and adenosine deaminase (ADA) activity among patients with visceral leishmaniasis (VL) and the effect of four weeks of chemotherapy on these levels. Fifty-three VL patients diagnosed clinically and by direct demonstration of the LD bodies in the bone marrow smear were studied. They were treated with Sodium Stibogluconate and sampled at the baseline and four weeks. Forty-three healthy individuals coming from the same endemic area were taken as control. Total nitrite (NO2- and NO3-) as an index of NO production and ADA activity was measured spectrophotometrically. Serum nitrite level decreased significantly in patients as compared to the healthy individuals but significantly increased following 4 weeks of chemotherapy. Conversely, Increased ADA activity was observed in the beginning of treatment and decreased significantly with successive 4 weeks of chemotherapy. It seems a negative correlation between NO level and ADA activity. This result indicates parasite induced evasion of NO and activation of T lymphocytes during immunopathogenesis of VL. Therefore, assessment of NO metabolites may be useful marker in the evaluation of the effector mechanism of macrophages and clinical manifestation of patients.

Topics: Adenosine Deaminase; Adult; Analysis of Variance; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Leishmaniasis, Visceral; Male; Nitric Oxide; Nitrites

Médecins sans Frontières-Holland has treated > 67,000 patients with kala-azar (KA) in southern Sudan since 1989. In 2002, we replaced the standard regimen of 30 days of daily sodium stibogluconate (SSG) with a 17-day regimen of daily SSG combined with paromomycin (PM). We analyzed data for 4,263 primary KA patients treated between 2002 and 2005 in southern Sudan to determine the relative efficacy of the combination therapy regimen (PM/SSG). The initial cure rate among patients treated with PM/SSG was 97.0% compared with 92.4% among patients treated with SSG monotherapy. Relative efficacy of PM/SSG compared with SSG increased over the study period: odds of death in the PM/SSG group were 44% lower (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.37-0.84) in 2002, 78% lower (OR = 0.22, 95% CI = 0.10-0.50) in 2003, and 86% lower (OR = 0.14, 95% CI = 0.07-0.27) in 2004-2005. In remote field settings, 17 days of SSG combined with PM gives better survival and initial cure rates than 30 days of SSG monotherapy.

Topics: Adolescent; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Leishmaniasis, Visceral; Male; Medical Records; Paromomycin; Retrospective Studies; Sudan; Treatment Outcome

Sodium antimony gluconate (SAG) and miltefosine used in the treatment of kala-azar are known to cause several side effects but severe thrombocytopenia has not been reported. Four cases of severe thrombocytopenia, two caused by SAG and two by miltefosine were promptly detected and treated by immediate withdrawal of the offending drugs, platelet and blood transfusions and dexamethasone. After improvement Leishman-Donovan (LD) bodies were demonstrated in splenic aspirates of both patients of SAG group and one of miltefosine and they were treated with 1 mg/kg body wt of amphotericin B for 20 days and cured. One patient of miltefosine group treated outside only on the basis of rK-39 positivity did not show LD bodies in splenic aspirates and improved without any antikala- azar drug. None of the patients relapsed within 6 months of follow up. Prompt detection of side effects under the concept of pharmacovigilance can save life of such patients.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Leishmaniasis, Visceral; Male; Phosphorylcholine; Thrombocytopenia

Topics: Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Treatment Outcome

The control of canine leishmaniasis largely depends on the success of treatment. Drugs currently available to treat this disease are toxic and partially effective. The curative effect of marbofloxacin, a third-generation fluoroquinolone developed for veterinarian individual treatment, was evaluated in vitro in the presence of Leishmania infantum promastigotes and dog-monocyte-derived macrophages; meglumine antimoniate and sodium stibogluconate were used as comparative treatments. We observed that the killing of Leishmania promastigotes and intracellular amastigotes by marbofloxacin was dose-dependent. We demonstrated that successful treatment of canine infected macrophages for 48 h was possible with 500 microg/ml of marbofloxacin. Leishmanicidal activity acted through a TNF-alpha and nitric oxide pathway and correlated with the generation of nitric oxide (NO(2)) production by monocytes derived macrophages from infected (23+/-5 microM) or healthy (21+/-6 microM) dogs, in comparison with NO(2) concentration in infected/non-treated macrophages (< 3 microM, P<0.01). This significant induced parasiticidal effect correlated with extensive elimination of amastigotes by macrophages derived from infected (11+/-5) and healthy dogs (6+/-2), when compared to infected/non-treated macrophages (530+/-105 and 472+/-86 amastigotes, respectively, P< 0.01). Marbofloxacin was shown to be non-toxic at 500 microg/ml in vitro and no cell apoptosis was observed. The molecule was able to induce a parasitic process after significant elimination of amastigotes in leishmania-infected dog macrophages. We propose that marbofloxacin, compared to standard chemotherapeutic agents (meglumine antimoniate and sodium stibogluconate), could be an effective and pragmatic oral route alternative to treat canine leishmaniasis.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibroblasts; Fluoroquinolones; Interleukin-6; Leishmania infantum; Leishmaniasis, Visceral; Macrophages; Meglumine; Meglumine Antimoniate; Mice; Nitric Oxide; Organometallic Compounds; Parasitic Sensitivity Tests; Quinolones; Tumor Necrosis Factor-alpha

We present a 42-year-old man who was admitted with worsening of his general condition and facial skin lesions. He had previously been diagnosed with HIV infection and visceral leishmaniasis (VL). Diagnostic work-up revealed a new relapse of VL paralleled by the diagnosis of post-kala-azar dermal leishmaniasis (PKDL). The patient was treated with IV liposomal amphotericin B as well as sodium stibogluconate followed by oral hexadecylphosphocholine (miltefosine) over a period of 9 months. PKDL lesions began to disappear after 8 months of treatment. In addition, severe and relapsing VL so far remains in remission. This case demonstrates successful treatment of PKDL and relapsing VL in a Western European patient with HIV infection.

Topics: Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Europe; Germany; HIV Infections; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Liposomes; Male; Phosphorylcholine; Recurrence; Treatment Outcome

We report the case of a patient with Indian post-kala-azar dermal leishmaniasis (PKDL) who failed to show any response to 2 months' treatment with sodium stibogluconate. Six months later he was treated with oral miltefosine on a compassionate basis as an off-label indication. Miltefosine was given 100mg daily in divided doses for an initial 8 weeks. Due to insufficient response, the treatment was extended up to a total of 12 weeks. The patient showed an excellent response to treatment, and after 12 months of follow-up there was complete healing of all cutaneous lesions. Oral miltefosine appears to be an important alternative for the treatment of PKDL in India and confirmatory studies in controlled clinical trials are needed.

Topics: Administration, Oral; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Injections, Intravenous; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Phosphorylcholine; Treatment Outcome

Sequencing studies showed that the gamma-glutamylcysteine synthetase (gamma-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were identical, indicating that SSG resistance was related to quantitative differences in gamma-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host gamma-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of gamma-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection against oxidative stress and facilitating SSG efflux. However a similar differential effect on host and parasite gamma-GCS expression was not obtained when using tissues from infected mice. In this case gamma-GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on gamma-GCS expression. Consistent with the proposed mechanism from in vitro studies, increasing tissue GSH levels in the presence of SSG by cotreatment of L. donovani-infected mice with SSG solution and GSH incorporated into nonionic surfactant vesicles was more effective in reducing liver, spleen, and bone marrow parasite burdens than monotherapy with SSG. Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels by L. donovani.

Topics: Animals; Antimony Sodium Gluconate; Drug Resistance; Glutamate-Cysteine Ligase; Leishmania donovani; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C

Visceral leishmaniasis VL, caused by Leishmania donovani is endemic over several parts of Sudan. The disease is fatal if not treated. Although sodium stibogluconate Pentostam, a pentavalent antimonial is not free from toxicity, it has been in use for treatment of VL for the last 50 years. Like other infectious diseases, neurological manifestations of VL and sodium stibogluconate have been documented. In this report, we present 2 cases of cerebellar ataxia most likely induced by Pentostam, and explain the probable cause.

Topics: Adult; Amphotericin B; Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Cerebellar Ataxia; Electroencephalography; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Sudan

Drug sensitivity of clinically antimony-unresponsive Leishmania donovani isolates from Eastern Sudan was evaluated in an in vitro culture system against sodium stibogluconate (Pentostam) and Amphotericin B. Eight isolates, six from antimony-resistant and two from clinically responsive patients were included in the study. Parasites were tested as promastigotes and four of them were selected to be tested as amastigotes using a murine macrophage-like cell line. The results indicated that the conventional promastigotes and amastigotes-screening assays did not correlate with the clinical picture of patients. In vivo unresponsiveness does not necessarily mean primary parasite resistance. Amphotericin B could be a suitable second line drug in patients unresponsive to pentostam and without concomitant diseases, if close hospital monitoring is available. Promastigotes sensitivity testing concentrations are virtually incomparable with the in vivo clinically curable doses and the amastigotes/macrophage test concentrations.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow; Cell Line; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Lymph Nodes; Macrophages; Mice; Parasitic Sensitivity Tests; Sudan

Mice deficient in phagocyte oxidase (phox) and inducible nitric oxide synthase (iNOS), which are primary macrophage killing mechanisms, generated tissue granulomas but showed unrestrained Leishmania donovani visceral replication and suboptimal initial responsiveness to antimony treatment. Nevertheless, visceral infection was controlled post-treatment and did not recur. A phox/iNOS-independent macrophage mechanism, which was not triggered by L. donovani, emerges after chemotherapy.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Gene Expression Profiling; Granuloma, Foreign-Body; GTP Phosphohydrolases; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Oxidoreductases; Phagocytes; Spleen

Individuals with visceral leishmaniasis, or kala azar (KA) and individuals with post-KA dermal leishmaniasis (PKDL) are considered to be reservoirs of transmission of Leishmania donovani in India. When intracellular amastigotes were used to assess the natural susceptibility that PKDL isolates and KA isolates have to sodium antimony gluconate (SAG), the mean ED(50) was found to be 12.0+/-2.49 and 11.0+/-1.38 microg/mL, respectively; and there was a significant correlation with the clinical response (r rank=0.99). All KA isolates, as well as a significant proportion (55%) of PKDL isolates from high-endemicity zones, were resistant to SAG. The median ED(50) for SAG-resistant PKDL isolates (20.0 microg/mL) was significantly higher (P<.05) than that for SAG-resistant KA isolates (15.7 microg/mL). SAG-resistant PKDL isolates may contribute to KA's increased refractoriness to SAG, via anthroponotic transmission of SAG-resistant strains.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Disease Reservoirs; Disease Transmission, Infectious; Drug Resistance; Endemic Diseases; Female; Humans; India; Insect Vectors; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Mice; Middle Aged; Rhodamine 123

Immunity to Leishmania donovani is associated with an interleukin (IL)-12 driven T helper 1 (Th1) response. In addition, the ability to respond to chemotherapy with sodium stibogluconate (SSG) requires a fully competent immune response and both Th1 and Th2 responses have been shown to positively influence the outcome of drug treatment. In the present study, the influence of IL-18, which can modulate both interferon (IFN)-gamma and IL-4 production, on the outcome of primary L. donovani infection and SSG therapy following infection was assessed using BALB/c IL-18-deficient and wild type mice. IL-18 deficiency was associated with an increased susceptibility to L. donovani infection, evident by day 40 post infection, resulting in higher parasite burdens in the spleen, liver, and bone marrow compared with wild type control animals. Infected IL-18-deficient mice had significantly lower splenocyte concanavalin A (ConA) induced IFN-gamma production as well as lower serum IL-12 and IFN-gamma levels, indicating a reduced Th1 response. However, drug treatment was equally effective in both mouse strains and restored serum IL-12 and IFN-gamma levels, and IFN-gamma production by ConA stimulated splenocytes of IL-18-deficient mice, to levels equivalent to similarly treated wild type mice.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Cells, Cultured; Disease Susceptibility; Immunoglobulin G; Interferon-gamma; Interleukin-12; Interleukin-18; Leishmania donovani; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Spleen; Th1 Cells; Treatment Outcome

Little is known about the treatment of visceral leishmaniasis (VL) in pregnancy, especially in resource-poor settings. We present a series of pregnant women with VL treated with either sodium stibogluconate or liposomal amphotericin B (AmBisome), or both, in eastern Sudan over 16 months.. We did a retrospective analysis of all pregnant VL patients treated in the Médecins sans Frontières (MSF) Um el Kher centre between January 2004 and April 2005. We diagnosed VL with laboratory confirmation of clinical suspects, and recorded the outcomes of treatment for pregnant women and their foetuses. We carried out a manual search of relevant publications and a systematic search of the literature in the MEDLINE database.. We treated 23 women with sodium stibogluconate, 4 with AmBisome and sodium stibogluconate and 12 with AmBisome alone. There were 13 (57%) spontaneous abortions in the sodium stibogluconate monotherapy group, and none in either of the other two groups. All spontaneous abortions occurred in the first two trimesters. All patients, except one in the sodium stibogluconate group who defaulted, were discharged as cured in good clinical condition.. AmBisome treatment for VL appears to be safe and effective for pregnant women and their foetuses. We recommend the use of AmBisome as first-line treatment for these patients.

Topics: Abortion, Spontaneous; Adolescent; Adult; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Leishmaniasis, Visceral; Middle Aged; Pregnancy; Pregnancy Complications, Parasitic; Sudan; Treatment Outcome

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Drug-Related Side Effects and Adverse Reactions; Heart; Humans; Leishmaniasis, Visceral

Fifty (50) cases of Leishmaniasis were included in a prospective study after making the diagnosis based on the demonstration of L D Bodies on bone marrow aspirate. Hemoglobin (Hb) and total leucocyte count (TLC) were less than 10 gm/dl and 4000 per/ml respectively in 22 out of 50 cases. Among 50 cases, 30 showed macrocytic red cell and hypersegmented neutrophils on peripheral blood smear as features of megaloblastic anemia. Out of 30 cases of leishmaniasis with megaloblastic anemia, 10 cases showed decreased reticulocyte count. Bone marrow aspiration cytology showed megaloblastic maturation in erythroid series and giant metamyelocytes in myeloid series in all 30 cases of leishmaniasis with megaloblastic changes. Bone marrow iron was also increased in these cases. However megakaryocyte was normal in all. Among 30 cases of leishmaniasis with megaloblastic changes, 15 cases were treated with sodium antimony gluconate (SAG) only and other 15 with SAG, folic acid and Vit. B12. Rest 20 cases of leishmaniasis without megaloblastic changes were also treated with SAG only. After treatment with SAG alone as well as with SAG, folic acid and vit. B12, hemoglobin and TLC improved in all 50 cases. Of 15 cases of leishmaniasis with megaloblastic changes, who were treated with SAG, folic acid and vit. B12, the reticulocyte count reached at peak on the 7th day and normalized at the end of 4th week. Red blood cells (RBC) also became normocytic normochromic and neutrophils became normal on peripheral blood smear. But no change was observed in reticulocyte count, RBC and white blood cell (WBC) morphology on peripheral blood smear in cases of leishmaniasis without megaloblastic changes and other 15 cases of leishmaniasis with megaloblastic changes, who received SAG only.

Topics: Anemia, Megaloblastic; Antimony Sodium Gluconate; Drug Therapy, Combination; Female; Folic Acid; Hospitals; Humans; Incidence; Leishmaniasis, Visceral; Male; Nepal; Prospective Studies; Reticulocyte Count; Treatment Outcome; Vitamin B 12

Seven dogs with parasitologically proven clinical visceral leishmaniosis (Leishmania infantum infection) were treated with a combination of allopurinol and sodium stibogluconate. The dogs received first orally 15 mg/kg of allopurinol every 12 h until the clinical signs improved, in the following 1 month period allopurinol at same dose and subcutaneously 30 mg/kg of sodium stibogluconate combination were given daily and at the end of the combined treatment, allopurinol was continued alone at the same dose till the end of 8 months. During the treatment period, dogs were supported by additional proteins, vitamins, and minerals. A long acting insecticide (collar or drop) was also used in order to prevent further parasite transmission. Follow-up was maintained by clinical, clinicopathological evaluation, and parasitological examination of lymph node, serology using the indirect immunofluorescent antibody test (IFAT). Before treatment commenced, the most important clinical signs were exfoliative dermatitis, ulcerations, peripheral lymhadenopathy, pale mucous membranes, weight loss, and ocular lesions. Clinicopathological findings included commonly anaemia, hyperproteinaemia, hyperglobulinaemia and hypoalbuminaemia. Before the treatment, amastigotes were seen in six of the seven dogs by examination of lymph node aspiration, and IFAT-titers were positive in all dogs. At the end of 8 months treatment, remission of clinical signs, restoration to normal of clinicopathological abnormalities were noticed. Lymph node aspiration was performed on three out of the seven dogs at the end of the treatment because of the very small sizes of the lymph nodes, and no amastigotes were observed. Although the mean IFAT-titer of the dogs were significantly (P < 0.001) lower compared with pretreatment, IFAT-titers of dogs were still positive. No relapses occurred during treatment period and a 6-24-month duration after the end of therapy. Based on the above results, long-term use of allopurinol combined with sodium stibogluconate together with support treatment concluded to have enough therapeutic efficacies in the treatment of dogs with visceral leishmaniosis. Observations of the cases for possible relapses were still going on and insecticide application was carefully carrying on in order preventing a possible re-infection.

Topics: Allopurinol; Animals; Antibodies, Protozoan; Antimetabolites; Antimony Sodium Gluconate; Antiprotozoal Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Fluorescent Antibody Technique, Indirect; Leishmania infantum; Leishmaniasis, Visceral; Lymph Nodes; Male

Numerous antimicrobials including pentavalent antimonials are implicated in causing prolong QT-interval and ventricular tachycardia. Torsades de pointes is rarely documented with use of sodium stibogluconate. Here is described a 12-yr-old girl with visceral leishmaniasis, who developed syncopal attacks, prolong QT-interval, polymorphic ventricular tachycardia and torsades de pointes after completing a course of Stibogluconate (20 mg/kg/day for 30 days). Prolong lidocaine infusion and cardioversion were life saving.

Topics: Anti-Arrhythmia Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Electric Countershock; Female; Humans; Leishmaniasis, Visceral; Lidocaine; Tachycardia, Ventricular

The semi-automated MTT colorimetric assay has previously been applied on Leishmania promastigotes based on the ability of viable parasites to reduce the tetrazolium salt to an insoluble formazan product. As promastigotes are non-adherent, application of the MTT assay in its original form has a major drawback of a high and variable background absorbance due to incomplete removal of phenol red, a component of most media. We have accordingly optimised a modified MTT assay wherein the absorbance linearity was maintained for cells ranging from 1x10(4) to 1x10(7) being 0.04+/-0.003-2.38+/-0.04. In contrast, the original MTT assay had a narrower linearity range of 1x10(6)-1x10(7) cells, absorbances being 0.05+/-0.005-1.54+/-0.005. The modified MTT assay was effectively applied to study growth kinetics and identification of antimonial resistant field isolates. Considering the growing problem of antimonial unresponsiveness in the Indian subcontinent, this modified MTT assay is a useful tool for Leishmania research.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Parasitic Sensitivity Tests; Phosphorylcholine; Tetrazolium Salts; Thiazoles

Ever since their discovery about 60 years ago as therapeutic agent for visceral leishmaniasis (VL) or kala-azar, pentavalent antimonials (Sb(v)) have remained the first line treatment of choice all over the world including India. But recently, the number of kala-azar patients unresponsive to sodium stibogluconate (SSG) therapy, is steadily increasing in India. In this study, three clinical isolates, of which two were from SSG unresponsive and one from SSG responsive patients were evaluated for their infectivity and for their chemotherapeutic responses in vitro (macrophage-amastigote system) and in vivo (in hamsters). Persistence of SSG resistance was also checked by repeated passages in vitro as well as in vivo. The drug resistant strains (2039 and 2041) did not respond to SSG therapy both in vitro as well as in vivo but strains 2001 and Dd8 showed full sensitivity to SSG treatment. All the four strains responded well to amphotericin B and miltefosine treatment both in macrophages and in hamsters. The specific chemotherapeutic responses of all the strains to SSG were consistently persistent after repeated passages in cultures and in vivo, which indicates that these isolates are truly refractory to SSG treatment in field conditions. Two isolates were also transfected with green fluorescent protein (GFP) for the development of in vitro assay for studying antileishmanial activities of new and reference drugs in macrophages by flow cytometry.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Line; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Mesocricetus; Mice; Parasitic Diseases, Animal; Phosphorylcholine

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Injections, Intramuscular; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged

Topics: Amebicides; Amphotericin B; Antimony Sodium Gluconate; Antiparasitic Agents; Antiprotozoal Agents; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immunoglobulin G; Leishmaniasis, Visceral; Paromomycin; Pentamidine; Phosphorylcholine

Visceral leishmaniasis (VL) commonly known as Kala-azar in India is one of the several clinically important infections, where Th1 sub-population of CD4+ T-cells, despite a pre-requisite, fails to express macrophage migration inhibition factor (MIF) and interferon-gamma which both activate the macrophage and coordinate the immune response to intra-cellular Leishmania sp. Expression of CD2 receptors before and after antileishmanial therapy on CD4+ T-cells of VL patients and their corresponding effect on MIF were examined. Before treatment the number of T-cells expressing CD2 was low which incorporated insignificant MIF response. The immunological reconstitution was, however, observed after treatment as manifested through upregulation of CD2+ T-cells with pronounced MIF generation response. The study, therefore, identifies a possible role of CD2 antigen in immunity to VL.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Case-Control Studies; CD2 Antigens; Cells, Cultured; Female; Humans; Immunity, Cellular; Leishmania donovani; Leishmaniasis, Visceral; Macrophage Migration-Inhibitory Factors; Male; T-Lymphocytes

Currently available primary screens for the selection of candidate antileishmanial compounds are not ideal. These techniques are time-consuming, laborious, and difficult to scale and require macrophages, which limit their use for high-throughput screening. We have developed Leishmania donovani field isolates that constitutively express the firefly luciferase reporter gene (luc) as a part of an episomal vector. An excellent correlation between parasite number and luciferase activity was observed. luc expression was stable, even in the absence of drug selection, for 4 weeks. The transfectants were infective to macrophages, and intracellular amastigotes exhibited luciferase activity. The suitability of these recombinant field isolates for in vitro screening of antileishmanial drugs was established. The luciferase-expressing sodium stibogluconate-resistant cell lines offer a model for the screening of compounds for resistance. The system is in routine use at the Central Drug Research Institute, Lucknow, India, for high-throughput screening of newly synthesized compounds.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cells, Cultured; DNA, Protozoan; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance; Genes, Reporter; Humans; Leishmania donovani; Leishmaniasis, Visceral; Luciferases; Macrophages; Organisms, Genetically Modified; Reproducibility of Results; Transfection

Recurrent cytomegalovirus (CMV) disease is a frequent complication of liver transplantation. Visceral leishmaniosis in a transplant recipient is, on the other hand, extremely rare and only two cases of kala-azar have been described after liver transplantation. Immunosuppressed patients are known to be at risk of Legionella infection and the relationship between infection with this organism and hospital water supplies has been well described. These three diseases carry a high mortality rate. Our report examines the potential relationship between these complications.. We describe the case of a liver transplant recipient who presented the three complications successively and survived. After reviewing the literature, we explore hypotheses linking these infections and discuss treatment strategies.. In the patient described, infection with leishmania probably occurred months prior to the clinical presentation, a delay that matches the incubation period of kala-azar. The simultaneous onset of leishmaniosis and of a high CMV viremia may have been a coincidence. However, CMV infection has been shown to be an independent predictor of invasive fungal infection in liver transplant recipients. CMV does indeed have a suppressive effect on the humoral and cellular immune response in vitro as well as in vivo. The clinical manifestations of leishmaniosis may, therefore, have been precipitated in this patient by the additive immunosuppressive effect of antirejection drugs and CMV.

Topics: Anti-Bacterial Agents; Antimony Sodium Gluconate; Antiviral Agents; Bone and Bones; Clarithromycin; Cross Infection; Cytomegalovirus Infections; Foscarnet; Ganciclovir; Humans; Legionnaires' Disease; Leishmaniasis, Visceral; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Schistosomicides; Viral Load

We analyzed data obtained from 3365 patients with kala-azar (KA) or post-KA dermal leishmaniasis (PKDL) treated by Medecins Sans Frontieres-Holland in south Sudan from October 1998-May 2002. Patients were malnourished (median body mass index [BMI], 15.5; median weight for height [WFH], 75.5%) and anemic (median hemoglobin (Hb) level, 8.5 g/dL). The proportion of patients with primary KA who were children <5 years old increased from 2.5%, in 1998, to 19.8%, in 2002 (P<.0001). Therapy with sodium stibogluconate cured 91.9% of patients with primary KA, and dosages of >850 mg per day did not decrease the chances of survival. Risk factors for death among adults were age > or =45 years (odds ratio [OR], 4.6), malnutrition (BMI, <13; OR, 11.0), anemia (Hb level, <8 g/dL; OR, 4.0), and duration of illness (duration, > or =5 months; OR, 2.3). Risk factors for death among children and adolescents were age <2 years (OR, 5.4,), malnutrition (WFH, <60%; OR, 5.0), anemia (Hb level, <6 g/dL; OR, 3.7), and splenomegaly (OR, 2.9). A higher risk of death was associated with episodes of diarrhea (OR, 1.4), vomiting (OR, 2.7), and bleeding (OR, 2.9). Relapse and PKDL occurred in 3.9% and 10.0% of cases, respectively.

Topics: Adolescent; Age Factors; Animals; Antimony Sodium Gluconate; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Leishmaniasis, Visceral; Male; Recurrence; Risk Factors; Sudan; Treatment Outcome; Warfare

In this work we report the activity seen with combination therapy using sodium antimony gluconate in liposomes composed of egg phosphatidyl choline and stearylamine for elimination of Leishmania donovani parasites from the liver and spleen of BALB/c mice with established and chronic infections.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Chronic Disease; Drug Carriers; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred BALB C; Phosphatidylcholines; Spleen

Sodium antimony gluconate (SAG) is reported to be losing its efficacy in Bihar as a first line drug for treatment of visceral leishmaniasis (VL). Concerned with the increasing incidence of antimony-resistant VL patients in Bihar, we undertook an epidemiological, clinical and pharmacological study to formulate a scientific basis for choosing a suitable first line drug for VL.. Consecutive, fresh and parasitologically confirmed patients of VL from different geographical areas of Bihar were considered for inclusion in the study. Parasites isolated from patients were tested in vitro to assess their response to sodium antimony gluconate (SAG) to 20 microg/ml, response to 20 mg/kg of SAG for 5 days in experimentally induced VL in BALB/c mice from those isolates, and response to SAG in patients treated with SAG for 28 days. Similarly response in culture (1 microg/ml) to amphotericin B (AMB) of all 282 isolates, (1 mg/kg body wt for 20 days) in patients and infected BALB/c mice (1 mg/kg body wt for 5 days) was determined. Antimony levels of plasma were determined at 2, 8 and 24 h after intramuscular injection of SAG. Patients unwilling for SAG treatment or relapsed after SAG treatment and withdrawn from SAG group because of toxicity were treated with AMB. Plasma antimony levels were estimated by atomic absorption spectrometer.. Though antimony sensitive and resistant patient were distributed in all 14 districts of Bihar studied, there was a significant variation from district to district. Of the 123 patients included in the SAG treatment group, 19 were withdrawn due to development of toxicity and 2 died; 178 patients were treated with AMB. No patient in AMB group developed any toxicity or died. Only 47 (46%) of 102 patients, 106 (37.6%) of 282 infected macrophages, 90 (52.9%) of 170 experimental infections were cured with SAG. Mc Nemar's test on paired comparisons showed statistical significance difference (P<0.01) between infected macrophage and experimental infection. AMB cured all patients, infected mice and cleared parasites from all isolates.. Antimony resistant strains of L. donovani were wide spread over different geographical areas in Bihar. SAG cured lesser percentage of VL cases clinically compared to AMB and should be replaced by AMB as a first line drug.

Topics: Adult; Amphotericin B; Analysis of Variance; Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Drug Resistance; Humans; India; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Spectrophotometry, Atomic

The characteristic feature of visceral leishmaniasis (VL) is the profound impairment of immune system of the infected host, which contributes significantly to the partial success of antileishmanial chemotherapy. Since in VL, cure is the combinatorial effect of drug and immune status of the host, the rationale approach towards antileishmanial chemotherapy would be to potentiate the immune functioning of the host to extract desired results. Towards this direction several rationally designed analogues of human beta-casein fragment (54-59) were evaluated for their ability to stimulate the non-specific resistance in hamsters against Leishmania donovani infection. By virtue of being derived from the food protein casein derivatives may be devoid of unwanted side effects associated with the substances of microbial origin, e.g. muramyl dipeptide (MDP). Out of this one peptide Val-Glu-Gly-Ile-Pro-Tyr (compound 89/215) had been reported to have such activity. In this communication, the prophylactic and therapeutic efficacy of the peptide along with its natural sequence has been evaluated in detail against experimental VL in hamsters. Their use as an adjunct to chemotherapy was also explored. Human beta-casein fragment, compound 89/215 and MDP were tested in vivo at various dose levels wherein compound 89/215 showed superiority over MDP at 3 mg/kg x 2 given intraperitoneally (i.p.). Compound 89/215 sensitized peritoneal macrophages acquired considerable resistance and only 24% of the cells were found infected in comparison to control peritoneal macrophages where 76.4% of the cells were found infected. Similarly, the efficacy of sodium antimony gluconate (SAG) in hamsters pretreated with compound 89/215 enhanced significantly (P < 0.001). This peptide also exhibited considerably good therapeutic efficacy when evaluated either alone or in combination with SAG in established infection of L. donovani.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Amino Acid Sequence; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Caseins; Cells, Cultured; Cricetinae; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Host-Parasite Interactions; Humans; Injections, Intraperitoneal; Leishmania donovani; Leishmaniasis, Visceral; Macrophages, Peritoneal; Male; Mesocricetus; Peptide Fragments; Time Factors

Visceral leishmaniasis (VL) is a major public health problem in many tropical countries of the world. The available chemotherapeutics require parenteral administration and have other limitations like cost, toxicity, variable efficacy or restricted supplies. There is no effective treatment for immunosuppressed patients with leishmaniasis- HIV co-infection. Hence, new therapies, that are effective when treatment with the currently available drugs fails, must be developed. One of the major strategies for effective and safe treatment of leishmaniasis and other infectious diseases, in the last decade, involves the use of immunomodulators as adjunct to chemotherapy. In this context, we studied the immunomodulatory activity of a hexapeptide Val-Glu-Pro-Ile-Gly-Tyr (CDRI compound 89-215) corresponding to (54-59) fragment of human beta-casein in mice and its efficacy in adjunct chemotherapy with SSG using L. donovani/hamster model. The hexapeptide was found to enhance both humoral and CMI responses. In animal model the hexapeptide per se showed no antileishmanial activity. However, when given alongwith suiboptimal dose of SSG, it enhanced the efficacy of SSG from 24% to 80%. The activity was very close to the efficacy (85%) recorded for curative dose of SSG. Adjunct chemotherapy with immunomodulator in visceral leishmaniasis appears to be a fruitful preposition.

Topics: Adjuvants, Immunologic; Animals; Antimony Sodium Gluconate; Caseins; Cell Migration Inhibition; Cell Proliferation; Cricetinae; Disease Models, Animal; Drug Therapy, Combination; Glucosamine; Hemagglutination Tests; Humans; Leishmania donovani; Leishmaniasis, Visceral; Lymphocytes; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Thymus Gland

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Commerce; Developing Countries; Drug Costs; Humans; Kenya; Leishmaniasis, Visceral; Poverty; Research

The role of the essential nutrients, vitamins A, B (complex), C and E and iron, as prophylactic as well as supportive therapy in experimental visceral leishmaniasis (VL), was studied in hamsters. Prophylactic administration of vitamin C (50, 100 and 250 mg/kg) from day 15 to day 0 (15 doses) significantly reduced the intake of Leishmania donovani in hamsters but had no therapeutic effect. In contrast, vitamins A, B complex and E and iron, whether used prophylactically or therapeutically, promoted parasite multiplication. The efficacy of sodium stibogluconate, a reference antileishmanial drug, was appreciably improved in animals administered prophylactically with vitamin C. However, supplementation of vitamin C during established infections resulted in reduced drug action. The results show that the prophylactic use of vitamin C may prevent the onset of leishmania infection and cautions against the indiscriminate use of nutrient supplements such as vitamin A, B complex, and E and iron in VL endemic areas.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Ascorbic Acid; Cricetinae; Dietary Supplements; Dose-Response Relationship, Drug; Drug Therapy, Combination; Iron; Leishmania donovani; Leishmaniasis, Visceral; Nutritional Physiological Phenomena; Vitamin A; Vitamin B Complex; Vitamin E; Vitamins

Resistance to pentavalent antimonial (Sb(v)) agents such as sodium stibogluconate (SSG) is creating a major problem in the treatment of visceral leishmaniasis. In the present study the in vivo susceptibilities of Leishmania donovani strains, typed as SSG resistant (strain 200011) or SSG sensitive (strain 200016) on the basis of their responses to a single SSG dose of 300 mg of Sb(v)/kg of body weight, to other antileishmanial drugs were determined. In addition, the role of glutathione in SSG resistance was investigated by determining the influence on SSG treatment of concomitant treatment with a nonionic surfactant vesicle formulation of buthionine sulfoximine (BSO), a specific inhibitor of the enzyme gamma-glutamylcysteine synthetase which is involved in glutathione biosynthesis, and SSG, on the efficacy of SSG treatment. L. donovani strains that were SSG resistant (strain 200011) and SSG sensitive (strain 200016) were equally susceptible to in vivo treatment with miltefosine, paromomycin and amphotericin B (Fungizone and AmBisome) formulations. Combined treatment with SSG and vesicular BSO significantly increased the in vivo efficacy of SSG against both the 200011 and the 200016 L. donovani strains. However, joint treatment that included high SSG doses was unexpectedly associated with toxicity. Measurement of glutathione levels in the spleens and livers of treated mice showed that the ability of the combined therapy to inhibit glutathione levels was also dependent on the SSG dose used and that the combined treatment exhibited organ-dependent effects. The SSG resistance exhibited by the L. donovani strains was not associated with cross-resistance to other classes of compounds and could be reversed by treatment with an inhibitor of glutathione biosynthesis, indicating that clinical resistance to antimonial drugs should not affect the antileishmanial efficacies of alternative drugs. In addition, it should be possible to identify a treatment regimen that could reverse antimony resistance.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Buthionine Sulfoximine; Drug Resistance; Female; Glutathione; Leishmania donovani; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Paromomycin; Phosphorylcholine

Apparently for the first time, the peripheral blood monocytes of individuals with active visceral leishmaniasis (VL) have been found to show reduced expression of interferon gamma receptor-1 (IFNGR1). Since interferon gamma is the main cytokine responsible for defence against leishmanial parasites, it was thought possible that effective antileishmanial drugs may up-regulate IFNGR1. Confocal microscopy confirmed that monocytes from VL patients who had been treated, with sodium antimony gluconate (SAG), did display IFNGR1 up-regulation. To see if this effect could be mimicked in vitro, IFNGR1 expression was investigated using a human macrophage cell line (THP1), northern blotting and confocal microscopy. When the THP1 cells were treated with SAG or pentamidine, their expression of the receptor was increased. This drug-induced up-regulation was more intense if the macrophages were infected with Leishmania donovani than if they were left uninfected. The possibility that at least some antileishmanial drugs act by up-regulating IFNGR1 expression needs to be explored further. A good model for investigating the mechanisms of action of antileishmanial drugs might be based on the THP1 cell line.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Blotting, Northern; Cell Line; Child; Female; Humans; Interferon gamma Receptor; Leishmania donovani; Leishmaniasis, Visceral; Male; Microscopy, Confocal; Middle Aged; Monocytes; Pentamidine; Receptors, Interferon; Up-Regulation

The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (V(SS)) was also increased (V(SS) for SSG, 0.21 liters/kg; V(SS) for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Aspartate Aminotransferases; Chemistry, Pharmaceutical; Dextrans; Dogs; Excipients; Female; Injections, Intravenous; Iron; Leishmania infantum; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Surface-Active Agents; Suspensions

Post-kala-azar dermal leishmaniasis (PKDL) is condition characterized by non-ulcerative lesions of the skin caused by Leishmania donovani that is usually seen after the completion of treatment of kala-azar (visceral leishmaniasis). We document the first case report of PKDL in Nepal.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Nepal

A longitudinal study was done in a leishmaniasis -endemic region in eastern Sudan during the period November 2001-February 2003 to determine the incidence of failure of sodium stibogluconate treatment. We studied 820 confirmed visceral leishmaniasis patients. All were treated with sodium stibogluconate, 20 mg/kg body weight for at least 28 days. Parasites were isolated from lymph node aspirates from 22 participants identified as relapsed patients. All isolates were typed as Leishmania donovanibased on polymerase chain reaction (PCR) amplification of parasite kDNA. Six parasites showed in vitro resistance to sodium stibogluconate using murine J774 macrophage amastigote testing method. The resistant isolates showed different restriction profiles when the amplified kDNA PCR products were digested with ALU1 restriction enzyme, indicating that resistance was mediated by different parasite clones.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; DNA, Kinetoplast; DNA, Protozoan; Drug Administration Schedule; Drug Resistance; Endemic Diseases; Female; Humans; Incidence; Leishmania donovani; Leishmaniasis, Visceral; Longitudinal Studies; Lymph Nodes; Male; Middle Aged; Parasitic Sensitivity Tests; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Sudan; Time Factors; Treatment Failure

Despite the endemic distribution of visceral leishmaniasis in certain parts of our country, there are only a few reports of this infection in renal transplant recipients. We report one renal transplant recipient from non-endemic area with visceral leishmaniasis and graft dysfunction that responded to treatment with stibogluconate. The infection should be considered in the differential diagnosis of a febrile transplant recipient with pancytopenia and allograft dysfunction.

Topics: Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Kidney Transplantation; Leishmania donovani; Leishmaniasis, Visceral; Male; Pancytopenia

The United Nations Mission to Eritrea and Ethiopia deployed to monitor a cease-fire in a mutually agreed upon Temporary Security Zone. Support for the United Nations (UN) troops included a Field Dressing Station supplied by the Dutch Navy, augmented by Canadian personnel. As with most missions of this type, the health of the deployed Canadian and Dutch soldiers is such that there is time to provide some medical support to local civilian institutions. This article describes this interaction in Eritrea through the illustration of the diagnosis and management of a specific illness through the cooperative use of high-technology laboratory equipment coupled with what we believe to be common sense. Although there was no specific United Nations Mission to Eritrea and Ethiopia humanitarian medical assistance mandate, the expanded use of CIMIC# projects was employed to allow this activity. The guiding principle of sustainability once UN facilities leave is also illustrated in the approach taken to provide this assistance.

Topics: Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Diagnosis, Differential; Eritrea; Female; Humans; International Cooperation; Leishmania donovani; Leishmaniasis, Visceral; Maintenance; Male; Middle Aged; Military Medicine; Ovarian Neoplasms; Ultrasonography; United Nations

Sera from Indian patients with parasitologically confirmed visceral leishmaniasis were studied by immunoblot analysis in order to identify a specific pattern for Leishmania infection. A soluble extract of Leishmania donovani was used as antigen. At diagnosis the sera from patients with visceral leishmaniasis specifically recognized fractions represented by bands of 201 kDa (50% of serum samples), 193 kDa (60%), 147 kDa (50%), 120 kDa (60%), 100 kDa (50%), 80 kDa (80%), 70 kDa (70%), 65 kDa (100%), 50 kDa (50%), 36 kDa (50%), 20 kDa (70%), and 18 kDa (50%). The 65-kDa band, common to all patients infected with Leishmania parasites, was found at the time of diagnosis. However, the immunoblot pattern changed after patients were treated and cured with sodium antimony gluconate (SAG; n =10) or miltefosine (n =10), as was evident from blots of sera obtained pretreatment and at 1, 3, and 6 months posttreatment. At 6 months posttreatment, immunoblots of sera from patients on the SAG regimen showed the disappearance of all bands except the 70-kDa band. Similarly, sera from those on the miltefosine regimen showed the disappearance of all bands except the 65- and 70-kDa bands. This study shows that Western blot analysis is a sensitive test for detection of anti-Leishmania antibodies. Moreover, the persistence of reactivity with the 65- and 70-kDa bands in the sera of all groups shows its promise as a diagnostic and prognostic tool.

Topics: Adult; Animals; Antibodies, Protozoan; Antibody Formation; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Immunoblotting; Leishmania donovani; Leishmaniasis, Visceral; Peptides; Phosphorylcholine; Predictive Value of Tests; Prognosis

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Child, Preschool; Electrocardiography; Humans; Leishmaniasis, Visceral; Male; Ventricular Fibrillation

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Genes, Protozoan; Humans; Leishmania donovani; Leishmaniasis, Visceral; Molecular Sequence Data; Mutation; Transfection

Sixty-six laboratory confirmed cases of Kala-azar from Uttar Pradesh attending various hospitals of Delhi over a period of 10 years (1989-1999) have been analysed. The geographical distribution showed that the disease involved widespread areas varying from a height of 10,000 ft. extending up-to the plains. Male, female ratio was 2:1 and maximum patients were in the age group of 5-15 years. L.D. bodies could be demonstrated in 59 patients in bone marrow aspirate smears while in 7 in splenic aspirate smears. One patient was co-infected with HIV. Indirect immuno fluorescent test was positive in 65 patients in titres ranging from 1:100 to 1:25,600 except in one HIV co-infected patient where no antibodies could be detected. Sixty-two (93.9%) patients responded completely to sodium stibogluoconate.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Female; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged

2-(2"-Dichloroacetamidobenzyl)-3-(3'-indolylquinoline), designated indolylquinoline derivative A, reduced the splenic and the liver parasite burdens by >93.0% in Leishmania donovani-infected hamsters, whereas sodium antimony gluconate (SAG) reduced the burdens approximately 80.0%. Complete clearance of parasitemia from the livers and spleens was noticed when infected animals received indolylquinoline derivative A plus SAG, suggesting that indolylquinoline derivative A has potential as a new agent for sole or conjunctive therapy for leishmaniasis.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Disease Models, Animal; Drug Therapy, Combination; Indoles; Leishmaniasis, Visceral; Quinolines; Treatment Outcome

Topics: Adult; Animals; Antimalarials; Antimony Sodium Gluconate; Antiprotozoal Agents; Biopsy, Needle; Drug Therapy, Combination; Humans; Leishmania donovani; Leishmaniasis, Visceral; Lymph Nodes; Malaria, Falciparum; Male; Plasmodium falciparum; Quinine; Treatment Outcome

The old short course regimens of pentavalent antimonial (sb(v)) therapy of visceral leishmaniasis (VL) have largely been abandoned worldwide as they are associated with increasing problems of relapse and unresponsiveness. In Ethiopia, some hospitals still use the old interrupted and short course regimen partly because of fear of drug toxicity.. To evaluate the safety of the WHO recommended uninterrupted therapy at a dose of 20 mg sb(v)/kg for up to thirty days.. A prospective study.. Patients were recruited from Addis Ababa hospitals and from Konso VL endemic area in southern Ethiopia.. Forty nine patients who included, ten HIV-positive and 39 HIV-negative, were enrolled for the study.. Twenty three HIV-negative patients got treatment for 20 days and the rest, 16 HIV-negative and 10 HIV-positive, were treated for 28 to 30 days. Among HIV-seronegatives, the mean QT interval corrected for heart rate (QTc) at the end of therapy in patients treated for 20 days and 28-30 days was comparable (0.419 +/- 0.031 seconds versus 0.424 +/- 0.027 seconds, respectively). Among patients treated for 28-30 days, the mean QTc in HIV co-infected patients was comparable to that of HIV-negatives (0.416 +/- 0.018 seconds versus 0.424 +/- 0.027). Comparable rates of new ECG changes involving the T waves were observed in two HIV-positive (20%) and two HIV-negative (12.5%) patients treated for 28-30 days, and in seven (30.4%) HIV-negative patients treated for 20 days. Overall, only two (4.1%) patients (all HIV-negative males) had QTc interval > or = 0.50 seconds at the end of therapy. In one patient, the prolonged QTc was noted on the twentieth day with bradycardia of 44/minute.. In Ethiopian VL patients with normal renal function, sb(v) therapy at a daily dose of 20 mg/kg for up to 30 days is safe and only rarely associated with clinically significant bradycardia which resolves after temporary cessation of therapy. Furthermore, in areas with limited facilities, monitoring the pulse rate during antimonial therapy may help detect impending cardiotoxicity.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Bradycardia; Child; Electrocardiography; Ethiopia; Female; Humans; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Treatment Outcome

This paper describes a new latex agglutination test ('KATEX') for the detection of leishmanial antigen in the urine of patients with visceral leishmaniasis. In preliminary laboratory trials, using urine collected from well-defined cases and controls from Brazil, Yemen and Nepal, the test had 100% specificity and a sensitivity between 68 and 100%. When used in a time-course experiment in cotton rats infected with Leishmania donovani, the test became positive 1 week after inoculation and antigen levels in urine declined rapidly after chemotherapy (the test was negative before the end of the course of treatment). Finally, in an integrated study performed in Sudan, KATEX was compared to microscopy and four different serological tests in a group of 73 patients having presented with clinical manifestations suggestive of visceral leishmaniasis. Compared to microscopy, KATEX performed better than any single serological test in predicting positivity and a particularly good result was obtained by combining KATEX and the direct agglutination test (DAT).

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Latex Fixation Tests; Leishmania donovani; Leishmaniasis, Visceral; Protozoan Proteins; Rabbits; Sensitivity and Specificity; Sigmodontinae; Sudan

In both scid and BALB/c mouse-Leishmania donovani models, hexadecyphosphocholine (miltefosine) and AmBisome had similar levels of activity. In contrast, sodium stibogluconate (Pentostam) was significantly less active against L. donovani in scid mice than in BALB/c mice. The in vitro anti-leishmanial activity of miltefosine was similar in peritoneal macrophages derived from both scid and BALB/c mice, whereas Pentostam and AmBisome were significantly more active in the latter.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mice, SCID; Phosphorylcholine; Species Specificity

Significant levels of IgG3 and IgG4 and high levels of IgG1 leishmania-specific antibody differentiated the immune states in 10 patients with visceral leishmaniasis from those of virtually all 20 drug-cured and 18 subclinically infected subjects, whereas the level of IgG2 antibody was nondiscriminating. The most extreme "subclinically infected" outlier subsequently developed disease. Overall, the immune states in subclinically infected and drug-cured persons were mutually indistinguishable but were readily distinguished from those of patients. These findings may have implications for the immunologic mechanism underlying drug cure in visceral leishmaniasis.

Topics: Adolescent; Adult; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Ethiopia; Female; Humans; Immunoglobulin G; Leishmaniasis, Visceral; Male; Middle Aged; Skin Tests

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male

A retrospective study was undertaken of 33 children with visceral leishmaniasis admitted to Sultan Qaboos University Hospital (SQUH), Oman between 1993 and 1999. The aim was to study the epidemiological and clinical characteristics of visceral leishmaniasis in children in Oman. All presented with fever, anaemia and splenomegaly. Hepatomegaly and lymphadenopathy were present in 88% and 39% of children, respectively. All had iron deficiency anaemia. Hypertriglyceridaemia is a new observation. Diagnosis in all cases was confirmed by histological demonstration of Leishmania amastigotes in bone marrrow (32 subjects) or splenic aspirate (one subject). All children were treated with sodium stibogluconate, 14 needed blood transfusion or blood products and all but two responded well. There were two deaths from associated complications (6% mortality).

Topics: Age Distribution; Antimony Sodium Gluconate; Antiprotozoal Agents; Blood Transfusion; Child; Child, Preschool; Female; Humans; Infant; Leishmaniasis, Visceral; Male; Oman; Prognosis; Retrospective Studies; Sex Distribution; Treatment Outcome

Studies with 26 clones of L. donovani promastigotes derived from three different Indian isolates indicated that wild type parasites are mixture of stibanate sensitive and resistant cells. Both forms of the parasite were resistant to the drug. Infection with resistant parasites appears to be the primary reason of high rate of pentavalent antimony unresponsiveness among Indian kala-azar patients. It was observed that the resistant parasites originated as a result of irregular and often incomplete treatment of kala-azar patients with pentavalent antimonials.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Humans; India; Leishmania donovani; Leishmaniasis, Visceral

Kala-azar in India is becoming increasingly difficult to treat, which may be due to the presence of species other than Leishmania donovani; Leishmania tropica was reported to cause the same clinical syndrome in the area. Over the past 3 years, we have collected samples from 241 patients with visceral leishmaniasis from across the region. Of the 189 isolates that grew on diphasic medium, 159 were successfully transferred to liquid medium for typing. Clinically, 80% of these were resistant to antimony. Lipophosphoglycan-specific monoclonal antibodies were used to distinguish the 2 species by agglutination of promastigotes; all 159 were shown to be L. donovani. Eighty-three isolates were confirmed to be L. donovani by isoenzyme analysis, by amplification of kinetoplast DNA, or both, in comparison with multiple reference strains; none were L. tropica. Thus, the rising incidence of clinical resistance to treatment is unlikely to be due to a different species causing kala-azar in north Bihar.

Topics: Adolescent; Adult; Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; DNA, Kinetoplast; DNA, Protozoan; Drug Resistance; Electrophoresis, Cellulose Acetate; Female; Humans; India; Leishmania donovani; Leishmania tropica; Leishmaniasis, Visceral; Male; Middle Aged; Parasitemia

In this study, the in vitro and in vivo efficacies of free sodium stibogluconate (SSG) and a nonionic surfactant vesicular formulation of SSG (SSG-NIV) against a laboratory strain of Leishmania donovani (MHOM/ET/67:LV82) and different clinical isolates of L. donovani were determined. Treatment with SSG-NIV was more effective against intramacrophage amastigotes than treatment with SSG. In vivo murine studies showed that there was interstrain variability in the infectivity of the different L. donovani strains, with two of the strains (20001 and 20003) giving low parasite burdens. In addition, interstrain variability in the antileishmanial efficacy of SSG in a single dose containing 300 mg of Sb(V)/kg of body weight was observed. This dose of free drug either caused a >97% reduction in liver parasite burdens or had no significant effect on parasite burdens compared with the result with the respective control. In some instances, treatment with this free SSG dose also caused a significant reduction in spleen (strain 20006) or bone marrow (strains 20001 and 20009) parasite burdens. Treatment with SSG-NIV was more effective than that with SSG against all of the strains tested. In SSG-responsive strains, the reduction in liver parasite burdens by SSG-NIV treatment was similar to that caused by free SSG. In SSG-nonresponsive strains, SSG-NIV treatment caused at least a 95% reduction in liver parasite burdens. Overall, these results indicate that the use of a vesicular formulation of SSG is likely to increase its clinical efficacy against visceral leishmaniasis.

Topics: Animals; Antimony Sodium Gluconate; Cricetinae; Drug Carriers; Female; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Parasite Egg Count; Schistosomicides; Surface-Active Agents

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow Cells; Erythroid Precursor Cells; Humans; Leishmaniasis, Visceral; Male

Neopterin, a product of gamma-interferon-activated macrophages, was measured in sera from 28 patients (12 patients with cutaneous leishmaniasis and 16 patients with visceral leishmaniasis) to determine the utility as a marker of disease activity and therapeutic efficacy. Patients originated from Kenya (n=5) and from the Academic Medical Center, Amsterdam, The Netherlands (n=23). In seven patients follow-up sera after treatment were available. Two patients at the time of diagnosis of visceral leishmaniasis were co-infected with HIV. The 12 patients with cutaneous leishmaniasis had serum neopterin levels below the upper limit of the normal range. All 16 patients with visceral leishmaniasis had elevated levels of serum neopterin before treatment. In six out of seven patients with visceral leishmaniasis followed during treatment neopterin levels decreased to values below the upper limit of the normal range (10 nmol l(-1)). Sequential measurements of serum neopterin levels may be useful for monitoring therapeutic efficacy in patients with visceral leishmaniasis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Female; HIV Infections; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Neopterin; Pentamidine; Treatment Outcome

Post-kala-azar dermal leishmaniasis (PKDL) is a common complication following kala-azar (visceral leishmaniasis). In a prospective study in a village in the endemic area for kala-azar in the Sudan, 105 of 183 (57%) kala-azar patients developed PKDL. There was a significantly higher PKDL rate (69%) in those who received inadequate and irregular treatment of kala-azar than in those who were treated with stibogluconate 20 mg kg-1 daily for 15 days (35%). The group of patients who developed PKDL did not differ from those who did not develop PKDL with regard to age and sex distribution, reduction in spleen size, and conversion in the leishmanin skin test (LST). In a clinical study, 416 PKDL patients were analysed and divided according to grade of severity. Severe PKDL was more frequent in younger age groups (P < 0.001); there was an inverse correlation between grade and conversion in the LST (P < 0.01). In 16% of patients tested, parasites were demonstrated in inguinal lymph node or bone marrow aspirates, indicating still visceral disease (para-kala-azar dermal leishmaniasis); there was no correlation between the presence of parasites and grade of severity. Conversion rates in the LST were lower than in those who did not have demonstrable parasites (11% and 37%, respectively; P < 0.01). In the absence of reliable and practical diagnostic tests, PKDL may be diagnosed on clinical grounds and differentiated from other conditions, of which miliaria rubra was the most common. Differentiation from leprosy was most difficult.

Topics: Adolescent; Adult; Age Factors; Aged; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Diagnosis, Differential; Endemic Diseases; Female; Humans; Infant; Infant, Newborn; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Sudan

Sodium stibogluconate (Sbb), a leishmanicidal drug, was studied for its in vivo effect on the formation of reactive oxygen species (ROS), assessed by chemiluminescence (CL) in the whole blood of mice infected with Leishmania infantum. Stimulation of ROS formation induced ex vivo by zymosan particles or the protein kinase C activator phorbol myristate acetate (PMA) was reduced by approximately 25% (P < 0.05) after infection of mice. Treatment of infected mice with Sbb (50 to 400 mg/kg of body weight) enhanced the blood CL induced by zymosan and PMA (47 to 96%, P < 0.01). The drug potentiation effect also occurred in uninfected mice. In vitro treatment of normal human blood with Sbb (1, 10, or 100 microg/ml) for 1 h primed the CL response to PMA (29 to 54%). The priming effect of Sbb was also observed on the production of superoxide by isolated polymorphonuclear leukocytes stimulated either by PMA and zymosan or by the chemoattractants N-formyl-Met-Leu-Phe and platelet-activating factor. These data provide the first evidence of priming of the phagocyte respiratory burst by Sbb. This novel property of Sbb may contribute to the drug's leishmanicidal effect.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Models, Animal; Humans; Leishmaniasis, Visceral; Leukocytes, Mononuclear; Mice; Mice, Inbred BALB C; Oxidants; Phagocytes; Reactive Oxygen Species; Respiratory Burst

It is well established that a fully competent immune response is required for the successful drug treatment of visceral leishmaniasis. However, recent studies have cast some doubt as to which elements of the immune response synergize with chemotherapeutic treatment. The role of the Th2 response and IL-4 in particular during visceral leishmaniasis awaits clarification. We, therefore, examined the effectiveness of sodium stibogluconate treatment on Leishmania donovani infection in BALB/c wild-type and IL-4-/- mice. Parasite burdens in L. donovani-infected IL-4+/- and IL-4-/-, as we have previously shown for B6/129 mice, were similar, despite an apparent type 1 antibody response in infected IL-4-/- mice, demonstrated by increased levels of parasite-specific IgG2a and decreased IgG1. Unexpectedly IL-4-/- mice responded poorly to sodium stibogluconate treatment with increased parasite burdens in all tissues examined. Furthermore, drug therapy of IL-4-/- but not IL-4+/+ mice resulted in significant reductions in splenocyte IFN-gamma mRNA transcripts and in serum IFN-gamma levels. These results demonstrate that IL-4 has an important role in effective anti-leishmanial chemotherapy which seems to be related to modulation of IFN-gamma production.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Immunoglobulin G; Interferon-gamma; Interleukin-10; Interleukin-4; Leishmania donovani; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; RNA, Messenger; Spleen; Th1 Cells; Th2 Cells

Visceral leishmaniasis is a zoonotic disease that can be transmitted from dogs to humans by a sand-fly vector. Endemic cases of visceral leishmaniasis among dogs in Oklahoma, Texas, and Ohio have been reported. Recent reports of visceral leishmaniasis in Foxhounds in the eastern coastal states has raised new concerns about the importance of this disease in the United States.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Blood Chemical Analysis; Centers for Disease Control and Prevention, U.S.; Depression; Dog Diseases; Dogs; Erythrocyte Count; Fatal Outcome; Female; Hematocrit; Humans; Leishmania donovani; Leishmaniasis, Visceral; Leukocyte Count; Male; Maryland; Paraproteinemias; Platelet Count; Proteins; United States; Weight Loss; Zoonoses

Human immunodeficiency virus (HIV) and hepatitis B and hepatitis C viruses have emerged as major blood-borne infections. Several cases of infections through the use of unsterile injection needles also are on record. Kala-azar, or visceral leishmaniasis, is a hemoparasitic disease caused by Leishmania donovani. All the anti-kala-azar medications require multiple intramuscular injections of the anti-leishmanial drugs. To find whether these patients were at higher risk of contracting blood-borne infection, than those who were not on medication, a community-based study was conducted in the kala-azar-endemic state of Bihar, India.. Five villages (4050 families) of three highly endemic districts of Bihar were included in this study. The sociodemographic data of the affected families and their annual income were determined as per Government of India guidelines. The diagnosis of kala-azar and its sequelae, post-kala-azar dermal leishmaniasis (PKDL), was made, and their therapeutic details were noted. All the leishmania-infected patients, their spouses, family members, and villagemates were tested for hepatitis B surface antigen, hepatitis C virus antibodies, and anti-HIV (1 + 2) antibodies, using commercially available kits.. Of the 4050 families, 61 (1.5%) were found affected with kala-azar or PKDL. These 61 families had 77 cases of leishmaniasis, of which 64 (83%) had kala-azar and 13 (17%) PKDL. The most affected (4.5%) age group was 11 to 40 years. Of the 61 families, 57 (93.4%) families belonged to so-called untouchable castes, and 9 of them could not afford to have any anti-kala-azar treatment. Only 64 patients received treatment in the form of injectables. The number of injections received by these patients ranged from 3 to 120. Hepatitis B and C viral infections were found to be significantly more prevalent in those who received multiple injections. Compared to their male counterparts infected with L. donovani, females who received injectable medicines were at higher risk of contracting hepatitis B infections (20% vs. 11.3%) and hepatitis C virus infection (26.7% vs. 18.9%). Overall, hepatitis C virus infections were more common (20.6%) than hepatitis B virus infection (13.2%) in this group of patients. Villagemates with a history of injections for other ailments also were found to have a high rate of infection with hepatitis viruses. One patient with kala-azar was found to be co-infected with HIV, although probably not related to injections.. The treatment of Indian kala-azar and post-kala-azar dermal leishmaniasis consists of multiple intramuscular injections of sodium stibogluconate, pentamidine, or amphotericin B. Though the original disease gets cured, all these therapeutic regimens were found to carry a significantly high risk of transmitting yet more dangerous blood-borne infections, such as HIV and hepatitis B and C viruses, through the shared use of unsterile injection needles. All needles should be appropriately sterilized, if they are to be re-used.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Equipment Contamination; Female; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis C; Hepatitis C Antibodies; HIV Antibodies; HIV Infections; Humans; India; Injections, Intramuscular; Leishmaniasis, Visceral; Male; Needles; Pentamidine; Prevalence; Social Class

Topics: Antimony Sodium Gluconate; HIV Infections; Humans; Leishmaniasis, Visceral; Pancreatitis; Schistosomicides

Single-dose treatment with sodium stibogluconate solution (SSG) and treatment with a nonionic surfactant vesicular formulation of sodium stibogluconate (SSG-NIV) were compared for the ability to protect BALB/c mice against infection with Leishmania donovani. Prophylactic treatment with SSG-NIV protected against infection, although its effects were time and organ dependent; protection was not obtained with SSG. Protection against reinfection with L. donovani was observed only in mice cured by treatment with SSG-NIV. However, this protective effect was probably due to the presence of residual drug rather than an immune effect, since prophylactic SSG-NIV treatment gave similar results. Transfer of enriched spleen T-cell populations from L. donovani-infected mice or from infected SSG-NIV-treated mice gave no protection against L. donovani infection in the recipients. T cells from infected mice, but not from infected SSG-NIV-treated mice, were infectious to recipients. SSG-NIV treatment was equally effective against visceral leishmaniasis in immunocompetent and SCID mice, whereas SSG treatment was less effective in the latter. The results of this study suggest that the high antileishmanial activity of SSG-NIV is due to favorable modification of SSG delivery and does not require a fully functional immune response. Cure of visceral leishmaniasis by SSG-NIV treatment in the BALB/c mouse did not protect against reinfection.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Drug Carriers; Female; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Mesocricetus; Mice; Mice, Inbred BALB C; Mice, SCID; Phenotype; Recurrence; Surface-Active Agents

The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of Leishmania donovani to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37 degrees C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant L. donovani mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in Leishmania tarentolae. These data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Arsenites; Drug Resistance, Multiple; Humans; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Meglumine; Meglumine Antimoniate; Organometallic Compounds

The role of the immunomodulator Protein A (PA) (from Staphylococcus aureus, Cowan I strain) in the control of leishmanial infection was studied in experimental animals. Treatment of Leishmania donovani infected hamsters with PA led to a moderate level of reduction of parasite load in their spleen (68%) and liver (46%). However, combination therapy of PA with the antileishmanial drug stibanate induced a more marked reduction of the spleen (88%) and liver (85%) parasitemia compared to that induced by PA or drug treatment alone. Similar results were also obtained with L. donovani infected BALB/c mice as the combination therapy of PA and stibanate led to a significant reduction (84%) of liver parasite load in comparison to that induced by PA (38%) or drug (61%) treatment alone. Apart from its therapeutic use, PA could also be used as a prophylactic agent in the control of leishmanial infection. Thus, treatment of hamsters with PA before leishmanial challenge significantly reduced their organ parasite load (by 59-78%) compared to that observed in infected controls without prior PA treatment. The antileishmanial effect of PA was likely to be mediated through the activation of macrophages leading to an enhancement of their phagocytic as well as leishmaniacidal activities. Subsequent studies demonstrated that PA treatment led to an increased production of nitric oxide by macrophages which could primarily be responsible for their enhanced parasite killing ability.

Topics: Adjuvants, Immunologic; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cells, Cultured; Cricetinae; Drug Therapy, Combination; Female; Leishmania donovani; Leishmaniasis, Visceral; Macrophage Activation; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Staphylococcal Protein A

Reports are scanty regarding kala-azar in children in Nepal. In this communication we document 20 children diagnosed to have kala-azar who were admitted and treated at B. P. Koirala Institute of Health Sciences, Dharan, Nepal. The children were between 2 and 14 years old. The duration of illness varied between 12 days and 24 months with a majority (65 per cent) of children being ill for less than 6 months. Hepatomegaly and splenomegaly were seen in 95 and 90 per cent of cases respectively. Splenomegaly was not found in two (10 per cent) children. Anaemia, leucopenia, and thrombocytopenia were seen in 95, 60, and 75 per cent of children respectively. Amastigotes of Leishmania donovani (LD bodies) were demonstrated in Giemsa-stained smears of bone marrow aspirates in 16 (80 per cent) children. All the children responded to treatment with sodium stibogluconate. No mortality was observed. This study emphasizes the importance of kala-azar in children in endemic areas of eastern Nepal.

Topics: Adolescent; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Female; Humans; Leishmaniasis, Visceral; Male; Nepal; Splenomegaly

A Leishmania donovani species-specific monoclonal antibody (monoclonal antibody D2) was evaluated for its diagnostic and prognostic potential by a competitive enzyme-linked immunosorbent assay (C-ELISA) in sera from Indian patients with visceral leishmaniasis (VL) and seven patients with post-kala-azar dermal leishmaniasis (PKDL). These results were compared with those obtained by microscopy with Giemsa-stained tissue smears and a direct enzyme-linked immunosorbent assay (direct ELISA) with crude parasite antigen. Of 121 patients with clinically diagnosed VL examined, 103 (85.1%) were positive and 11 (9.1%) were negative by all three methods. An additional 7 (5.8%) who were negative by microscopy were positive by both C-ELISA and direct ELISA. Seven PKDL patients were also examined and were found to be positive by all three methods. Analysis of the chemotherapeutic response to sodium antimony gluconate of these 110 serologically positive VL patients showed that 57 (51.8%) were drug responsive and 53 (48.2%) were drug resistant. The C-ELISA with sera from 20 longitudinally monitored VL patients before and after chemotherapy showed a significant decrease in percent inhibition of monoclonal antibody D2 in drug-responsive patients. However, in drug-unresponsive patients, the percent inhibition of D2 was unchanged or was slightly increased. Our results therefore indicate (i) the applicability of L. donovani species-specific monoclonal antibody D2 for sensitive and specific serodiagnosis by C-ELISA, (ii) that the C-ELISA is more sensitive than microscopy, especially for early diagnosis, (iii) that L. donovani is still the main causative agent of VL, irrespective of the chemotherapeutic response, and (iv) that the C-ELISA can be used to evaluate the success of drug treatment.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Humans; India; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Leprosy; Malaria; Prognosis; Tuberculosis

The possibility that the high frequency of treatment failures in Indian kala-azar might be due to infection with antimony-resistant strains of Leishmania donovani has not been experimentally addressed. L. donovani isolates were obtained from splenic aspiration smears of 24 patients in Bihar, India, who either did not respond (15) or did respond (9) to 1 or more full courses of treatment with sodium antimony gluconate (SAG). A strong correlation (P<.001) between clinical response and SAG sensitivity in vitro was observed only when strains were assayed as intracellular amastigotes: responsive isolates ED50=2.4+/-2.6, ED90=6.4+/-7.8 microgram SAG/mL; unresponsive isolates ED50=7.4+/-3.7 microgram SAG/mL, ED90=29.1+/-11.1 SAG/mL. No correlation with clinical response was found by use of extracellular promastigotes (ED50=48+/-22 vs. 52+/-29 microgram/mL). The emergence of antimony-resistant L. donovani strains appears to be a cause of treatment failures in India.

Topics: Adolescent; Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Drug Resistance; Female; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged; Spleen; Treatment Failure

Topics: Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Counterimmunoelectrophoresis; Diagnosis, Differential; Hemagglutination Tests; Humans; Hypersensitivity, Delayed; Leishmania donovani; Leishmaniasis, Visceral; Leprosy; Male; Skin

We demonstrate that golden hamsters infected with Leishmania donovani amastigotes develop the capacity to eliminate intracellular pathogens on treatment with low-dose standard antileishmanial sodium stibogluconate (Stibanate) in combination with polyinosinic-polycytidilic acid stabilized with polylysine and carboxymethycellulose (poly ICLC), a potent inducer of interferon (IFN) and immune enhancer, plus L-arginine. Data suggest that low doses of both Stibanate and poly ICLC plus L-arginine provide marginal inhibition against L. donovani infection in golden hamsters. When given in combination, however, a significant inhibition was achieved without toxicity, as all the animals survived up to 45 or 60 days. These results suggest that combination therapy using Stibanate and poly ICLC plus L-arginine may be very effective in reducing the dose of Stibanate and, hence, its dose-dependent toxicity in clinical situations.

Topics: Animals; Antimony Sodium Gluconate; Carboxymethylcellulose Sodium; Combined Modality Therapy; Cricetinae; Dose-Response Relationship, Drug; Immunotherapy; Interferon Inducers; Leishmania donovani; Leishmaniasis, Visceral; Male; Mesocricetus; Poly I-C; Polylysine

Pathogenesis in kala-azar is associated with depressed cellular immunity and significant elevation of antileishmanial antibodies. Since these antibodies are present even after cure, analysis of the parasite-specific isotypes and immunoglobulin G (IgG) subclasses in kala-azar patients may shed new light on the immune responses during progression and resolution of infection. Using leishmanial membrane antigenic extracts, we investigated the relative levels of specific IgG, IgM, IgA, IgE, and IgG subclasses in Indian kala-azar patient sera during disease, drug resistance, and cure. Acute-phase sera showed strong stimulation of IgG, followed by IgE and IgM and lastly by IgA antibodies. IgG subclass analysis revealed expression of all of the subclasses, with a predominance of IgG1 during disease. Following sodium stibogluconate (SAG) resistance, the levels of IgG, IgM, IgE, and IgG4 remained constant, while there was a decrease in the titers of IgG2 and IgG3. In contrast, a significant (2.2-fold) increase in IgG1 was observed in these individuals. Cure, in both SAG-responsive and unresponsive patients, correlated with a decline in the levels of IgG, IgM, IgE, and all of the IgG subclasses. The stimulation of IgG1 and the persistence, most importantly, of IgE and IgG4 following drug resistance, along with a decline in IgE, IgG4, and IgG1 with cure, demonstrate the potential of these isotypes as possible markers for monitoring effective treatment in kala-azar.

Topics: Adolescent; Adult; Aged; Amphotericin B; Animals; Antibodies, Protozoan; Antibody Specificity; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Resistance; Female; Humans; Immunoblotting; Immunoglobulin Isotypes; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; HIV Infections; Humans; Leishmaniasis, Visceral

Topics: Anorexia; Antimony Sodium Gluconate; Antiprotozoal Agents; Biopsy, Needle; Child; Diagnosis, Differential; Diagnostic Errors; Female; Fever; Humans; Leishmaniasis, Visceral; Lymphadenitis; Nepal; Weight Loss

Cytokine mRNA levels were measured in serial splenic aspirates from 27 patients with visceral leishmaniasis during monotherapy with interferon-gamma (IFN-gamma; n = 9), sodium antimony gluconate (SAG; n = 8), or amphotericin B lipid complex (ABLC; n = 10). At baseline, mRNA for IFN-gamma was detected in 18 (86%) of 21 patients, and mRNA for interleukin (IL)-10 and IL-4 was detected in 21 (100%) and 10 (48%) of 21 patients, respectively. With IFN-gamma treatment alone, levels of IFN-gamma mRNA decreased by day 10 and then returned to baseline levels; IL-10 mRNA levels were high throughout treatment. In the SAG and ABLC groups, levels of IFN-gamma and IL-10 mRNA decreased significantly. Polarized Th2 cell type responses do not appear to develop in Indian kala-azar; instead, there is an initial mixed Th1-Th2 cell picture. With successful treatment and resolution of infection, both components of the immune response appear to involute.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Cytokines; Drug Combinations; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Leishmaniasis, Visceral; Phosphatidylcholines; Phosphatidylglycerols; Spleen

Serum erythropoietin (Epo) concentrations and variables of red cell and iron status were studied in 27 Sudanese patients who were treated with sodium stibogluconate for visceral leishmaniasis (kala-azar). Blood haemoglobin increased from 6.4 (+/- 1.7 SD) to 9.5 (+/- 1.4) g/dl during treatment. Serum ferritin decreased concomitantly. Serum iron levels were unchanged whereas the total iron binding capacity increased slightly. The pre-treatment serum Epo concentration in relation to the blood haemoglobin concentration was not as high as expected from the one in primary haematological diseases, indicating that there is a relative lack of Epo in anaemic kala-azar patients. Serum Epo further decreased during stibogluconate therapy. The normal dependence of the serum Epo level on the blood haemoglobin concentration was lost during mid-term antimonial treatment, but it recovered thereafter. Cell culture studies with the human hepatoma cells HepG2 showed that stibogluconate (> or = 30 microg/ml) inhibited Epo gene expression. Thus, effective treatment of kala-azar with stibogluconate results in improvement of anaemia, although the drug itself may impair Epo production.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Erythropoietin; Female; Hemoglobins; Humans; Leishmaniasis, Visceral; Male

Only a few cases of Post-kala-azar dermal leishmaniasis have been reported in Japan, especially recently. We describe a case of a 32-year-old woman who developed rose-colored nodules on her forearms two years after Kala-azar. A skin biopsy specimen from a nodule revealed not only granulomatous changes but also many amastigotes of Leishmania donovani in macrophages. Rose-colored nodules were also distributed on her face and neck. Treatment with antimony compound was very effective.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Biopsy, Needle; Disease-Free Survival; Face; Female; Humans; Japan; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

Almost all (98%) of 1593 visceral leishmaniasis (VL) patients treated with sodium stibogluconate (Pentostam; Wellcome) in Sudan between 1989 and 1995 and follow-up responded well to treatment. However, the other 33 patients, all of whom were seronegative for HIV, showed partial or no response. The two main causes of unresponsiveness were primary drug resistance (39.3%) and low drug dosages given at peripheral dispensaries (30.3%). All of those who had been sub-optimal doses were cured when adequate doses of the drug were given. A third cause was concurrent disease, particularly pulmonary tuberculosis (18%). With treatment of the concurrent disease, patients responded well to Pentostam. Eight patients who failed to respond to repeated courses of Pentostam did not benefit from pentamidine or sterol inhibitors. Three of these patients responded to liposomal amphotericin B, two responded to splenectomy in association with Pentostam therapy, and three died. Pentostam, given in adequate doses, still appears to be the drug of choice for the treatment of VL in the Sudan Liposomal amphotericin B is a suitable second-line drug.

Topics: Adolescent; Adult; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Leishmaniasis, Visceral; Male; Splenectomy; Sudan; Tuberculosis, Pulmonary

In India, sodium antimony gluconate is the drug of choice for kala-azar. Due to increasing unresponsiveness to this drug in the current epidemic that began in the early 1970s, daily doses of 20 mg/kg/day for 30 days or more is recommended as opposed to the 10 mg/kg/day dose for 6-10 days used in the past. Of the 130-150 patients treated annually at our center with locally made sodium antimony gluconate, serious cardiotoxicity has occurred in less than 10%. During April 1995 at the University Hospital in Varanasi, we encountered life-threatening cardiotoxicity after 3-28 days of therapy in each of the eight patients being treated with a new lot of this drug made by a different manufacturer. Of the eight patients, six each developed congestive heart failure and/or prolongation of the corrected QT interval (QTc), and three died as a direct consequence of drug-induced toxicities. In three instances, the life-threatening complications occurred with a cumulative dose of less than 300 mg/kg. In patients with prolonged QTc, ventricular premature beats and ventricular tachycardia were recorded; in one patient, the ventricular tachycardia progressed to torsade de pointes, culminating in ventricular fibrillation and death. Since switching to different lots of this drug, we have not seen further clustering of dangerous cardiotoxicity. The antimony content of the implicated drug was comparable with that in lots from other manufacturers that did not show overt toxicity, but the osmolarity was approximately 300 mOsm/L higher. The simple technique of measuring of osmolarity may help identify inappropriately manufactured drug.

Topics: Adult; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Electrocardiography; Fatal Outcome; Female; Heart; Heart Diseases; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Osmolar Concentration

In this study, treatment efficacies of a nonionic surfactant vesicle formulation of sodium stibogluconate (SSG-NIV) and of several formulations of amphotericin B were compared in a murine model of visceral leishmaniasis. Treatment with multiple doses of AmBisome, Abelcet, and Amphocil (total dose, 12.5 mg of amphotericin B/kg of body weight) resulted in a significant suppression of parasite burdens in liver (P < 0.0005) and spleen (P < 0.0005) compared with those of controls, with Abelcet having the lowest activity. Only AmBisome and Amphocil gave significant suppression of parasites in bone marrow (compared to control values, P < 0.005). In the acute-infection model, single-dose treatments of SSG-NIV (296 mg of SbV/kg), SSG solution (296 mg of SbV/kg), or AmBisome (8 mg of amphotericin B/kg) were equally effective against liver parasites (compared to control values, P < 0.0005). SSG-NIV and AmBisome treatment also significantly suppressed parasites in bone marrow and spleen (P < 0.005), with SSG-NIV treatment being more suppressive (>98% suppression in all three sites). Free-SSG treatment failed to suppress spleen or bone marrow parasites. Infection status influenced treatment outcome. In the chronic-infection model, the AmBisome single-dose treatment was less effective in all three infection sites and the SSG-NIV single-dose treatment was less effective in the spleen. The results of this study suggest that the antileishmanial efficacy of SSG-NIV compares favorably with those of the novel amphotericin B formulations.

Topics: Acute Disease; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Chronic Disease; Female; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Surface-Active Agents

Post-kala-azar dermal leishmaniasis can present as hypopigmented macules, erythematous to skin-coloured papules, nodules and photosensitive butterfly erythema on the face. We present a patient with disseminated annular lesions of post-kala-azar dermal leishamaniasis. The patient was treated with daily intravenous injections of sodium antimony gluconate for 120 days at a dose of 20 mg/kg body weight with complete clearance of lesions.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Skin

Eighty parasitologically confirmed cases of visceral leishmaniasis (kala-azar) in Bihar, India, were treated daily with 20 mg sodium stibogluconate/kg for 30 days, to assess the current efficacy and toxicity of this 30-day regimen. Clinical and parasitological cure was obtained in 48 (60%) of the patients. However, 26 (33%) patients did not respond to the first course of treatment (primary unresponsiveness), two relapsed after initial clinical and parasitological cure, and two were withdrawn from the study (one on day 6 of treatment because of cardiotoxicity in the form of supraventricular tachycardia and the other on day 24 because of severe loss of appetite). All 30 patients who were not entirely cured with sodium stibogluconate were successfully treated with amphotericin B. Electrocardiographic changes occurred in many of the patients as the result of treatment with sodium stibogluconate. Diminution in the height of the T wave was seen in 32 (40%), inversion of the T wave (Minnesota code 5-1, 5-2) in seven (9%), elevation of the ST segment (Minnesota code 4-1) in three (4%), prolonged QT interval (compared with baseline findings) in six (8%), and diminution in the height of the P, R and T waves in two (3%). Cardiac arrhythmia occurred in five patients (6%), supraventricular arrhythmia (coarse atrial fibrillation) occurred in one patient and ventricular tachycardia, ventricular fibrillation, torsade de pointes and multifocal ventricular ectopics occurred in the four patients (5%) who died of cardiotoxicity. Minor side-effects, such as pain at the site of injection (two cases), mild diminution in appetite (12 cases), metallic taste in mouth (six cases), and joint pain (two cases), were also observed. It was concluded that the efficacy of sodium stibogluconate in the study area has declined over the years and that its toxicity has increased. A more efficacious, safer and cheaper, alternative drug is required as the first line of treatment of kala-azar.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Arrhythmias, Cardiac; Child; Drug Resistance; Electrocardiography; Female; Heart Arrest; Humans; India; Leishmaniasis, Visceral; Male; Middle Aged; Treatment Outcome

The prevalent drugs for treatment of kala azar viz. sodium stibogluconate (SSG) and pentamidine cause severe toxic side effects and acute immunosuppression in the treated individuals. Picroliv, a standardized mixture of iridoid glycosides, prepared from the alcoholic extract of the root and rhizome of Picrorhiza kurroa has shown strong hepatoprotective activity against several models of hepatotoxicity. Therefore, the present study was undertaken with an objective to study the effects of Picroliv (12.5 mg/kg x 7 days oral) alone and in combination with SSG on parasitemia, lipid peroxidation and hepatic marker enzymes of golden hamsters during Leishmania donovani infection. The results indicated a marked hepatoprotective effect of Picroliv in terms of biochemical markers, and a significant antileishmanial activity implying that it can be utilized as an adjunct to chemotherapy or in combination therapy of kala azar along with sodium stibogluconate, thus enhancing the efficacy of antileishmanials.

Topics: Administration, Oral; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Bilirubin; Cinnamates; Cricetinae; Drug Therapy, Combination; Glucose-6-Phosphatase; Glutamate Synthase; Glycosides; Leishmania donovani; Leishmaniasis, Visceral; Lipid Peroxidation; Liver; Mesocricetus; Plant Extracts; Succinate Dehydrogenase; Vanillic Acid

A 32-year-old man with acquired immunodeficiency syndrome (AIDS) admitted to the hospital for treatment of visceral leishmaniasis was inadvertently given 10 times the prescribed first dose of sodium stibogluconate ([Sb] 6.5 g instead of 0.65 g). He experienced no immediate major toxicity during the first 48 hours, but a significant rise of pancreatic enzyme activities was observed (amylase at 10 times the upper limit of normal, lipase at 50 times the upper limit of normal) without clinical signs or indications on computed tomography (CT) of pancreatitis. The third day after the overdose, he developed appendicitis, which appeared coincidental; he recovered uneventfully from surgery. Most of the overdose of Sb was eliminated within the first few hours. Pharmacokinetics remained linear; the rapid, long elimination half-lives (2.7 hours and 54 hours, respectively) were similar to those in previously published results. The administration of a chelating agent, dimercaptosuccinic acid (DMSA), 72 hours after the Sb overdose did not modify the pharmacokinetics of the medication.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amylases; Antimony Sodium Gluconate; Antiprotozoal Agents; Half-Life; Humans; Leishmaniasis, Visceral; Lipase; Male; Medication Errors; Succimer; Time Factors; Tomography Scanners, X-Ray Computed

South Sudan has five million inhabitants and has been fighting a war of independence with North Sudan since 1959. The hostilities have totally disrupted society and the country is the most inaccessible of Africa. International non-government organizations co-operate in relief activities in the 'Operation Life Line'. Semi-nomadic pastoral tribes populate South Sudan. Doctors Without Borders assisted in fighting a major epidemic of kala azar in the late eighties which cost some 200,000 lives; the organization still provides medical aid in the country.. South Sudan has 5 million inhabitants and has been fighting a war of independence with North Sudan since 1959. The hostilities have totally disrupted the society and its government. In this region, international nongovernmental organizations (NGOs) are cooperating in relief activities in Operation Life Line, providing assistance to semi-nomadic pastoral tribes such as the Nuers and the Dinkas. The NGO Doctors Without Borders assisted in fighting a major epidemic of kala azar in the late 1980s; it cost some 200,000 lives, half of the Nuers' total population. The report of these doctors flying to different spots in the South of the country recounted how medical consultations were carried out under trees where possible. Kala azar was treated with ampules of Pentostam, and brucellosis patients were picked from the waiting group. Tuberculosis, whose indications are heavy coughing and expectoration, was also rampant. The abscess of a woman caused by a human bite was treated under local anesthesia with ketamine. The team had examined 70 patients by midday. In Duar, a site where Doctors Without Borders has treated 20,000 kala azar patients, basic health care and vaccinations were performed. In a marshy region, the Dinkas allow their livestock to graze, and there is a small but acceptable clinic in this location to which 3 patients with cerebral malaria were admitted by noon. There were also many TB patients. The doctors prescribed routine medications before conducting further examinations.

Topics: Adolescent; Adult; Aged; Antimony Sodium Gluconate; Child; Child, Preschool; Disease Outbreaks; Female; Humans; Leishmaniasis, Visceral; Male; Medical Missions; Medically Underserved Area; Middle Aged; Relief Work; Sudan; Volunteers

Topics: Animals; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Blotting, Western; Child; Glucocorticoids; Humans; Leishmania infantum; Leishmaniasis, Visceral; Male; Prednisone

Topics: Administration, Inhalation; Amebicides; Antimony Sodium Gluconate; Antiprotozoal Agents; Diabetes Mellitus, Type 1; Humans; Insulin; Leishmaniasis, Visceral; Paromomycin

Topics: Adams-Stokes Syndrome; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Electrocardiography; Female; Humans; Leishmaniasis, Visceral

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Dermatomyositis; Fever; Humans; Leishmaniasis, Visceral; Male; Pain

Levels of circulating antigen in a group of cotton rats infected with Leishmania donovani were followed over a 28-week period, using a modified, polyethylene-glycol (PEG) ELISA. Circulating antigen could be detected from 1 week post-infection and gradually increased over time. In infected cotton rats treated with a curative dose of Pentostam at 12 weeks post-infection, antigen levels peaked and then declined. Antigen was still detected in some of the treated animals at 28 weeks post-infection. The antibodies used in the PEG-ELISA were also used in a capture ELISA to detect parasite antigens in urine. Urine samples which were positive by capture ELISA were also analysed by western blotting, in an attempt to identify the parasite antigens present. Three components, of 45, 47 and 58 kDa, were detected.

Topics: Animals; Antibodies, Protozoan; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Immunoglobulin G; Immunoglobulin M; Leishmania donovani; Leishmaniasis, Visceral; Longitudinal Studies; Rats; Sigmodontinae; Time Factors

During L. donovani infection in golden hamsters, tremendous hepatic damage was observed as apparent from increased activities of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, succinate dehydrogenase, glucose-6-phosphatase and acid ribonuclease. The levels of cytochrome P-450 and related monooxygenases, viz. aniline hydroxylase and aminopyrine-N-demethylase registered significant decrease in infected animals. Sodium stibogluconate, a standard antileishmanial drug, though caused the removal of parasites from infected tissues, but did not help in the recovery of deranged hepatic markers. The results explain the higher mortality of stibanate treated infected animals as compared to untreated animals infected with L. donovani.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Leishmania donovani; Leishmaniasis, Visceral; Liver; Male; Mesocricetus; Mixed Function Oxygenases

The anti-parasitic efficacy of free and a non-ionic surfactant vesicular (NIV) sodium stibogluconate (SSG) formulation of the drug, and their effect on the immune responses of Leishmania donovani infected BALB/c mice, was compared. The SSG NIV formulation maintained a significant suppression of splenic, hepatic and bone marrow parasite burdens (P < 0.005) compared to control values throughout the study. Infected controls and drug treated animals had high levels of L. donovani specific antibodies by day 14 of the study and the titre of these antibodies increased throughout the study for infected controls and free SSG treated animals. Initially SSG NIV treated animals had significantly higher specific IgG2a levels (P < 0.01, day 16) compared with infected controls and free SSG treated mice, but by day 31 the levels of this isotype and other antibodies (IgG1, IgG3 and IgM) were significantly lower (P < 0.05) than values for the other two groups. There was no difference in the proliferative responses of spleen cells taken from infected controls and drug treated animals to both specific and non-specific stimulation at day 16 of the study. On day 31, only spleen cells taken from infected mice given SSG NIV displayed a significant proliferative response to parasite antigen preparations and Concanavalin A stimulation (P < 0.01). No IL4 was detected in supernatants from in vitro spleen cells cultures. Significant levels of IFN-gamma was induced by stimulation of cells from vesicular drug treated animals with a frozen parasite preparation compared with medium controls (P < 0.05) on day 49 but not day 16. Similar stimulation did not induce IFN gamma production in spleen cells from infected controls or free drug treated animals. Only SSG NIV treated animals gave a significant positive DTH response to an L. donovani parasite preparation (P < 0.05) given on day 31. The results of this study indicate that there was a formulation dependent qualitative difference in the post-treatment immune responses of L. donovani infected animals, with SSG NIV animals displaying immune responses expected for a cured phenotype.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Chemistry, Pharmaceutical; Drug Carriers; Female; Interferon-gamma; Interleukin-4; Leishmania donovani; Leishmaniasis, Visceral; Liver; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Organ Size; Spleen; Surface-Active Agents

1) To determine the proportions of patients with visceral leishmaniasis who had various treatment outcomes when cared for under wartime conditions and with limited resources and 2) to identify patient characteristics associated with the outcomes.. Cohort study.. Médecins sans Frontières-Holland's treatment center in Duar, Western Upper Nile Province, an area in southern Sudan that has been severely affected by Sudan's civil war and a massive epidemic of visceral leishmaniasis.. 3076 consecutive patients who had visceral leishmaniasis, were admitted to the treatment center the first year the center was operational (August 1990 to July 1991), and were treated with the pentavalent antimonial compound sodium stibogluconate.. Patient characteristics on admission and four mutually exclusive treatment outcomes (default during first admission, death during first admission, discharge and readmission for retreatment [relapse], and discharge and no readmission for retreatment [successful treatment]).. The patients had a median age of 15 years and were notably anemic (median hemoglobin level, 77g/L) and malnourished (median body mass index of adults [> or = 18 years of age], 15.2 kg/m2); most (91.0%) had been sick less than 5 months. Although patients could not be monitored after treatment to document cure, most (2562 [83.3%]) were successfully treated; 336 (10.9%) died during their first admission, and 79 are known to have relapsed (3.0% of those discharged alive [that is, those whose final treatment outcome was successful treatment or relapse]). In univariable analysis, young and older age (<5 or > or = 45 years of age), long duration of illness (> or = 5 months), markedly low hemoglobin level or body mass index, large spleen, high parasite density, and vomiting at least once during the treatment course were associated with death. In multiple logistic regression analysis of data for a subgroup of 1207 adults (those who did not default or relapse and for whom data were recorded on age, sex, duration of illness, hemoglobin level, body mass index, and spleen size), the approximate risk ratios for death were 2.2 (95% Cl, 1.4 to 3.6) for those with a long duration of illness, 3.6 (Cl, 2.1 to 5.9) for those 45 years of age or older, 4.6 (Cl, 2.2 to 9.4) for those with a hemoglobin level less than 60 g/L, and 12.2 (Cl, 3.2 to 47.2) for those with a body mass index less than 12.2 kg/m2. CONCLUSION; Despite the severe debility of the patients and the exceptionally difficult circumstances under which they were treated, most fared remarkably well.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Cohort Studies; Disease Outbreaks; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Prognosis; Risk Factors; Statistics as Topic; Sudan; Treatment Outcome; Warfare

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Leishmaniasis, Visceral; Pancreatitis

Visceral leishmaniasis is infrequently reported in renal transplant recipients. A 40-year-old renal transplant recipient developed hepatosplenomegaly and pyrexia of unknown origin 5 months after transplantation. Visceral leishmaniasis was confirmed on bone marrow examination. The usual dose of antiparasitic therapy with stibogluconate sodium failed to eradicate Leishmania donovani. High-dose conventional therapy with stibogluconate sodium for an extended period of time was successful in the treatment of a relapse of leishmaniasis.

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Humans; Kidney Transplantation; Leishmaniasis, Visceral

Control of infections by the obligate intramacrophage protozoan parasite Leishmania donovani is traditionally done with pentavalent antimonial drugs. It was of interest to determine if immunotherapy with IL-2-stimulated splenocytes would enhance drug action in an in vitro model system. It is confirmed that nontoxic doses of Pentostam decrease infection in a dose-dependent manner in vitro in terms of both the number of amastigotes/100 macrophages and the % of infected macrophages; the curative effect was most apparent when the drug was used on the 7th day of the infection, when the parasite was in its proliferative phase. It is also confirmed that recombinant IL-2-stimulated splenocytes induced infected macrophages to reduce significantly their parasite burden, especially when the infection was treated in the nonproliferative phase of the parasite, also in a dose-dependent manner. Leishmanicidal action in the infected macrophages was induced by cytokine(s) released from the lymphokine-stimulated cells. Immunotherapy in the nonproliferative phase, combined with drug treatment in the proliferative phase, reduced the infection to levels significantly below those produced by either treatment alone. Immunotherapy with IL-2-stimulated splenocytes in combination with Pentostam is, therefore, an excellent candidate treatment for the effective reduction of experimental infections by L. donovani.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Combined Modality Therapy; Cricetinae; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Female; Immunotherapy; In Vitro Techniques; Interleukin-2; Leishmania donovani; Leishmaniasis, Visceral; Mesocricetus; Mice; Mice, Inbred C57BL; Spleen; Time Factors

Pentavalent antimony-mannan (Sb[V]-mannan) was 10-fold more potent than sodium stibogluconate in a murine model of visceral leishmaniasis. Liver antimony concentrations were six-fold higher after Sb[V]-mannan therapy compared with a dose of sodium stibogluconate that was equipotent in reducing liver parasite burdens. Murine toxicity of Sb[V]-mannan was variable, with a 50% lethal dose (LD50) for one preparation that was well above the concentration that killed 90% of the parasites, and for another preparation was only modestly higher than the concentration that killed 90% of the parasites.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Disease Models, Animal; Drug Carriers; Injections, Intraperitoneal; Leishmania donovani; Leishmaniasis, Visceral; Liver; Mannans; Mice; Mice, Inbred BALB C

Topics: Amphotericin B; Anti-Bacterial Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance, Microbial; Humans; Leishmaniasis, Visceral; Pentamidine

Twenty-seven out of five hundred and fifty three patients hospitalized for visceral leishmaniasis (Kala-azar) died during treatment with sodium antimony gluconate. Data from these patients were evaluated to find out the cause of death. Eight patients had associated diseases such as pulmonary tuberculosis (3), severe malnutrition (1), acute gastroenteritis (1), spleenic infarction (1), acute renal failure (1) and atrial septal defect (1) which could be attributed to death. Twelve patients developed spontaneous haemorrhages from nose, gums and gastrointestinal tract and died, despite of adequate supportive measures. Seven other patients who were improving slowly with antimony therapy died unexpectedly. Though, cause of death could be explained in some patients with associated disease conditions, it could not be explained in others as significant clinical manifestations, haematological, biochemical and electrocardiographic alterations were not evident prior to death. Our impression is that mortality in Kala-azar patients during standard antimonial therapy is more related to the drug rather than the disease process.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Bangladesh; Female; Humans; Leishmaniasis, Visceral; Male; Middle Aged

Frequent relapses after treatment for visceral leishmaniasis and apparent parasitological cure is not commonly reported. Seven year old boy who relapsed four times with clinical and parasitological evidence of the disease at each two months follow-up period is presented. He had Leishimania donovani Kenya strain. After treatment, review would be after two months, six months and twelve months periods. Splenic aspirates were routinely done weekly and on the last day of each treatment. The drugs administered for varying periods included intravenous sodium stibogluconate 20 mg/kg daily, P20 in combination with allopurinol 21 mg/kg three times daily, and Pentamidine 4 mg/kg three times weekly and antituberculous drugs. The presence of abundant extra cellular leishmania donovani bodies in the bone marrow and possible pulmonary tuberculosis might have precipitated the frequent relapses. It is not clear which of the drugs effected the cure. It was observed that inspite of prolonged antileishmanial drug administration no side effects were noted.

Topics: Allopurinol; Animals; Antimetabolites; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Pentamidine; Recurrence

We report on 4 cases of post-kala-azar dermal leishmaniasis (PKDL). History of kala-azar was available in all 4 patients. Slit-skin smears (SSS) for leishmania donovani (LD) bodies were negative in all 4. In 3 patients hypopigmented lesions were present over the face. Papules and nodules over his lips, tongue, scrotum and dactylitis were some unusual features observed in 1 patient. Histopathological examination showed LD bodies in 2 patients; histopathology was nonspecific in the other 2. All the patients were treated with sodium stibogluconate, 20 mg/kg/day. Infiltrated papules and nodules had subsided by 3 months, while hypopigmented macules took longer to improve. In 3 patients there had previously been a misdiagnosis as leprosy sufferers and they had been treated with antileprosy drugs. Clinical and histopathological differences between PKDL and leprosy are discussed.

Topics: Adult; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Diagnosis, Differential; Female; Humans; Leishmania donovani; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Leprosy; Male

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Hemorrhage; Humans; Leishmaniasis, Visceral

To determine the utility of the serum concentrations of interleukin 6 (IL-6) as a marker of disease activity and therapeutic efficacy in visceral leishmaniasis (VL), IL-6 levels were measured in 19 patients with active VL from Sudan before and after treatment. IL-6 levels were 30 +/- 6 pg/ml during the active phase of the disease, decreased to levels around the detection limit of the assay (2 pg/ml) directly after successful antimony therapy, and remained low or undetectable for up to 6 months in persistently cured patients (P < 0.005 versus baseline). In 2 patients who had a relapse of VL, IL-6 was elevated at the time the relapse was diagnosed. Two patients with post-kala-azar dermal leishmaniasis did not have detectable IL-6 in their circulation. Sequential measurements of serum IL-6 levels may be useful for monitoring therapeutic efficacy in patients with VL.

Topics: Acute Disease; Adolescent; Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Biomarkers; Child; Child, Preschool; Female; Humans; Interleukin-6; Leishmaniasis, Visceral; Male; Middle Aged

The aminoglycoside, aminosidine exhibited ED50S of between 1 and 5 microM against the amastigotes of Leishmania major and Leishmania tropica in mouse peritoneal macrophages whereas other strains causing New World cutaneous leishmaniasis such as Leishmania braziliensis were more refractory. Aminosidine was also active against all but one of the Leishmania donovani strains tested and when combined with sodium stibogluconate, the drug showed marked potentiation against the amastigotes of L. donovani in vitro and an additive effect in experimentally infected BALB/c mice.

Topics: Animals; Antimony Sodium Gluconate; Cells, Cultured; Cricetinae; Drug Combinations; Drug Interactions; Female; Leishmania; Leishmania donovani; Leishmaniasis, Visceral; Macrophages, Peritoneal; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Microbial Sensitivity Tests; Paromomycin

Visceral leishmaniasis was detected incidentally in a patient with acute lymphoblastic leukaemia in remission, during maintenance therapy. Absence of fever, a normal haemogram, normal serum globulins, a negative serology and testicular involvement were the hallmarks of the case. Treatment with sodium stibogluconate (20 mg/kg for 55 days) failed. Subsequent therapy with pentamidine resulted in complete parasite clearance. Prolonged therapy with pentavalent antimony compounds or a higher dose of second line drugs such as pentamidine are recommended for complete clearance.

Topics: Antimony Sodium Gluconate; Child, Preschool; Humans; India; Leishmaniasis, Visceral; Male; Pentamidine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Testicular Diseases; Time Factors

Five non-ionic surfactants (Surfactants V-IX) were screened for their ability to produce vesicles for the delivery of sodium stibogluconate. Mean vesicle diameter and antimony content were determined prior to in vivo assessment of antiparasitic activity in a mouse model of acute visceral leishmaniasis. V/D suspensions (i.e. stibogluconate loaded vesicles kept in the hydrating drug solution) were more effective against spleen, liver and bone marrow parasites than drug loaded vesicle suspensions that had unentrapped drug removed. A Surfactant IX V/D suspension was the most active antileishmanial preparation causing 74 +/- 10%, 99 +/- 1% and 38 +/- 8% suppression of liver, spleen and bone marrow parasite burdens respectively. Contrary to previous findings, a reduction in splenic and bone marrow parasite burdens was achieved using large vesicles (mean diameter > 800nm). The significance of these results is discussed.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Bone Marrow; Drug Carriers; Female; Leishmaniasis, Visceral; Liver; Male; Mice; Mice, Inbred BALB C; Microspheres; Particle Size; Spleen; Surface-Active Agents

The inhibition of carbocyclic inosine (C-Ino), 3'-deoxyinosine (3'-dI), and 3'-fluoroinosine (3'-FI) to Leishmania donovani amastigotes was examined. J774.1 cells (a mouse macrophage line) were cultured in GIT medium with lipopolysaccharide and hemin and infected with the parasite. C-Ino (3 microM) completely inhibited and 3'-dI (30 microM) reduced to 40% the infection rate on Day 6 after infection. Pentostam (30 microM) resulted in a 38% infection rate. The therapeutic efficacies of nonentrapped free and liposome-entrapped inosine analogs were tested in mice infected with L. donovani. The mice were injected intravenously five times on alternate days, beginning 2 days after infection. Treatment with the nonentrapped free inosine analog of C-Ino (100 mg/kg), 3'-dI (100 mg/kg), or 3'-FI (50 mg/kg) resulted in an LDU that was 94, 68, or 73% lower, respectively, than the control values. Treatment with the corresponding entrapped inosine analog (10 mg/kg) caused decreases of 90, 69, or 68% LDU, respectively. The entrapped inosine analogs were inhibitory at doses one-fifth to one-tenth of the nonentrapped free inosine analogs. C-Ino had the strongest inhibitory effect among the three analogs tested in vitro and in vivo. Liposome-entrapped C-Ino had no severe side effects, although spleen weight increased. The agent may be useful as an anti-leishmanial drug.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Line; Drug Carriers; Inosine; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Male; Mice; Mice, Inbred BALB C; Pilot Projects; Random Allocation

Acute pancreatitis is an adverse effect of the treatment with antimonial drugs which is infrequently described in patients with HIV infection and visceral leishmaniasis (VL). Twenty-two percent of the patients having this treatment had acute pancreatitis (7 cases) in the authors' center. In all the cases, severe immunosuppression was present with pancreatitis appearing following the administration of 3,400 to 15,300 mg of stibogluconate. The pancreatitis was slight in the 7 cases with no complications of note and with no symptoms observed in three cases. The maximum values of amylasemia ranged from 976 to 2,568 U/l, from 1,055 to 5,860 U/l for lipasemia, and from 1,970 to 25,520 U/l for trypsinemia. These values returned to normal from 15 days to 2 months after suppression of the drug. Stibogluconate was readministered in three patients due to VL recurrence with a further acute pancreatitis being observed. The authors conclude that acute pancreatitis is a relatively infrequent complication of antimonial treatment for VL in patients with HIV infection and believe that a maximum dose of 850 mg/day should not be surpassed.

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Antimony Sodium Gluconate; Antiprotozoal Agents; Clinical Enzyme Tests; Female; HIV-1; Humans; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Pancreatitis; Recurrence

Topics: Amphotericin B; Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; HIV Seropositivity; Humans; India; Leishmania donovani; Leishmaniasis, Visceral

Topics: Acute Disease; Adult; Amphotericin B; Antimony Sodium Gluconate; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Pancreatitis

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Child; Drug Administration Schedule; Drug Carriers; Drug Resistance; Humans; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Male

Serum concentrations of soluble receptors for tumor necrosis factor (sTNFRs) were measured before and after antimony therapy in 25 Sudanese patients with active visceral leishmaniasis (VL). Both sTNFR types I and II were significantly elevated in patients with VL compared with healthy controls from the same region and from the Netherlands (P < .01). In all 23 patients who initially responded to therapy, both sTNFR types decreased sharply, reaching and remaining at levels similar to those found in normal controls; 2 relapsed after an initial response to therapy, and their sTNFR concentrations had increased at the time of relapse. The 2 patients who did not respond to therapy had persistently elevated sTNFR levels. Tumor necrosis factor was detectable in only 16% of patients with VL. Hence, the serum concentrations of sTNFRs may be useful for monitoring therapeutic efficacy in patients with VL.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Biomarkers; Child; Child, Preschool; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Solubility; Treatment Outcome

Neurologic changes in visceral leishmaniasis (VL) are rarely reported. From January 1992 to April 1993, 111 patients with VL were seen at Soba University Hospital in Khartoum, Sudan. Fifty-two (46%) patients had neurologic symptoms or signs; the most common symptom was a sensation of burning feet. Four patients had foot drop. Five patients had deafness and one patient had multiple cranial nerves palsies. None of our patients had vitamin deficiency or any of the other known causes of neuropathy. Nerve conduction studies in 15 patients showed evidence of axonal degeneration and demyelination, which were confirmed by histopathology and electron microscopy of nerve biopsies. There was no direct parasitic infection of the nerve and there was no neuritis. In most patients, the sensory symptoms disappeared within two weeks in most of our patients after specific anti-leishmanial treatment. Motor recovery was much slower. Audiographic studies in five patients with deafness showed it to be sensory-neural. Hearing returned to normal after treatment with sodium stibogluconate. Further studies are needed to define the etiology of the nerve pathology in patients with VL.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Biopsy; Child; Cranial Nerve Diseases; Demyelinating Diseases; Female; Hearing Loss, Sensorineural; Humans; Hyperesthesia; Leishmaniasis, Visceral; Male; Microscopy, Electron; Nerve Degeneration; Nervous System Diseases; Neural Conduction; Paresthesia; Sural Nerve

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Amylases; Animals; Antimony Sodium Gluconate; Humans; Leishmania infantum; Leishmaniasis, Visceral; Male; Necrosis; Pancreas; Pancreatitis

Resurgence of Kala-Azar in India has posed many problems. Apart from patients from endemic areas, cases are being reported from non-endemic areas also. In the present series, four out of 26 patients were from non-endemic areas. Other than diagnostic difficulties, resistance to stibogluconate and relapse are common problems which were seen in eight patients. The clinical profile of cases, their management, and how the problem of resistance was tackled are described.

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Drug Resistance, Microbial; Female; Humans; Incidence; India; Infant; Leishmaniasis, Visceral; Male

The recombinant product (rK39) of the 39 amino acid repeats encoded by a kinesin-like gene of visceral Leishmania spp. was further evaluated by enzyme-linked immunosorbent assay (ELISA) for its diagnostic potential in Indian kala-azar (VL) and post kala-azar dermal leishmaniasis (PKDL). Anti-rK39 antibodies were highly positive in 20 symptomatic cases, including 6 resistant to single or double chemotherapy, but became negligible or absent in 9 recently cured patients. Endpoint titration of samples from the 20 active cases showed that the anti-rK39 IgG titers fell within a wide range of 10(-2) to > 10(-6), and that their mean was > 1 order of magnitude higher than in VL reported previously. The anti-rK39 IgG titers were correlated with parasite burden found in the patients and remained undiminished in those refractory to chemotherapy. These results indicate that: (1) the K39 epitope is conserved in Indian strains of Leishmania donovani, (2) the extremely high levels of K39 antibodies in both VL and PKDL suggest the application of rK39 for sensitive and specific serodiagnosis, and (3) rK39 ELISA is also valuable for prognostic evaluation of both diseases.

Topics: Adolescent; Adult; Antigens, Protozoan; Antimony Sodium Gluconate; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leishmaniasis, Visceral; Male; Pentamidine; Predictive Value of Tests; Protozoan Proteins; Recombinant Proteins; Trypanocidal Agents

128 untreated cases of Kala-azar were divided in 4 equal groups of 32, Group A was treated with Sodium Stibogluconate (SSG) in the dose of 20 mg/kg/body wt. for 30 days. Group B was treated SSG plus allopurinol in the dose of 20 mg/kg/body wt. orally in divided dosage for 30 days. Group C received SSG plus Ketoconazole 600 mg orally in divided dosage for 30 days. Group D in addition to SSG also received levamisole in single oral daily dose of 13 mg/kg/body wt. for 30 days. Response of Group B, C and D was compared to Group A. Results from this study revealed combination of allopurinol with SSG to be statistically not superior to SSG alone.

Topics: Adult; Allopurinol; Antimony Sodium Gluconate; Antiprotozoal Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Ketoconazole; Leishmaniasis, Visceral; Levamisole; Male

Topics: Adult; Animals; Antifungal Agents; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance; Female; Humans; India; Ketoconazole; Leishmania donovani; Leishmaniasis, Visceral; Male; Treatment Outcome

The diagnosis and management of childhood visceral leishmaniasis were studied in 51 parasitologically proven cases from Abha, Saudi Arabia. Bone marrow aspiration was positive in 40 of 47 cases (85%). Splenic aspiration, though rarely used because of perceived dangers, was not associated with complications and revealed the parasite in all 12 cases in which it was used. There was prompt response to sodium stibogluconate, with defervescence in 93% and decrease of hepatosplenomegaly in 67% of patients within 1 week of commencing chemotherapy. A dose of 20 mg/kg/day for at least 3 weeks was generally safe and effective in achieving cure and preventing relapse. Two children with persistent massive splenomegaly after the first course responded to prolonged chemotherapy. Bronchopneumonia and severe cytopenia were common complications. Disseminated intravascular coagulation and hepatitis were associated with a poor outcome. The four patients who died had a progressive course with multiple complications. Early detection and appropriate management of complications may help to reduce morbidity and mortality in childhood visceral leishmaniasis.

Topics: Antimony Sodium Gluconate; Bone Marrow Examination; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Injections, Intramuscular; Leishmaniasis, Visceral; Male; Retrospective Studies; Saudi Arabia; Spleen

Pentavalent antimony (Sbv), formulated as sodium stibogluconate or meglumine antimoniate, is the standard treatment for the leishmaniases. In 16 of 17 consecutive, prospectively observed patients in Washington D.C., serum levels of amylase and lipase rose to abnormal values after therapy with sodium stibogluconate was started; 12 of 17 had symptoms of pancreatitis. Sbv therapy was continued to completion in 7 of 17 patients and interrupted in 10 of 17. Pancreatitis improved in every patient after Sbv therapy was stopped. Sbv treatment was resumed after brief interruptions in 6 of 10 patients. All six of these patients had flares of pancreatitis, but each completed therapy. Subsequently, we measured amylase and lipase levels in stored sera from 32 patients treated in Peru with either sodium stibogluconate or meglumine antimoniate for mucosal leishmaniasis. In all 32 Peruvian patients, serum amylase and lipase rose to abnormal levels during Sbv therapy; 11 of 32 had symptoms of pancreatitis. Standard Sbv regimens induce pancreatitis in almost all patients, but continued therapy is often tolerated; pancreatitis subsides when therapy is stopped, and rechallenge may be tolerated after a brief halt in treatment.

Topics: Adult; Amylases; Antimony Sodium Gluconate; Antiprotozoal Agents; District of Columbia; Humans; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral; Lipase; Male; Meglumine; Meglumine Antimoniate; Middle Aged; Organometallic Compounds; Pancreatitis; Peru; Prospective Studies

Sixty-five patients, 51 males and 14 females, with clinical and parasitological evidence of visceral leishmaniasis were initially treated as follows: 44.6% were on intravenous sodium stibogluconate (pentostam) 20 mg/kg/d for 30 days, 35.4% was on a combination of pentostam as above and allopurinol 21 mg/kg/d in three divided doses for 30 days while 20% was on pentostam 10 mg/kg thrice/d intravenously for 10 days. All patients were parasitologically negative by the end of their respective treatment regimen. All patients were reviewed at 2 months, 6 months, and 12 months periods in order to evaluate the relapse rates and optimal follow-up period. Thirteen patients (20%) relapsed at 2 months and one patient (1.5%) relapsed at 6 months follow-up periods respectively. There was no relapse between 6 months and 12 months follow-up period. The mean liver and spleen sizes in responders showed a dramatic reduction at 2 months follow-up and thereafter a gradual reduction occurred in the next 10 months. Weight gain continued throughout the year. Apart from platelet count which showed a sustained high level from discharge to 12 months follow-up, the peripheral blood indices stabilized from 2 months follow-up. Relapses were retreated until parasitologically negative twice and then followed up, for a period of 12 months. At follow-up the liver and spleen sizes reduced gradually in the next 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aftercare; Allopurinol; Antimony Sodium Gluconate; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leishmaniasis, Visceral; Male; Middle Aged; Recurrence; Treatment Outcome

We studied 27 patients presenting with renal dysfunction after Stibamate therapy. Eighteen patients were proved cases of Kala Azar, others of PUO. Out of 10 cases in whom Kidney biopsy was done, 6 had tubular necrosis, one had mild mesangial proliferation and 3 had normal picture.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Blood Urea Nitrogen; Creatinine; Female; Fever of Unknown Origin; Glomerular Mesangium; Glomerulonephritis; Humans; Kidney Diseases; Kidney Tubular Necrosis, Acute; Leishmaniasis, Visceral; Male; Middle Aged; Proteinuria; Sodium

A total of 17 Leishmania isolates, 6 of them isolated from antimony-resistant patients, were collected in the Sudan and tested for their sensitivity to sodium stibogluconate (Pentostam) as promastigotes. Six of those isolates were tested as amastigotes infecting a murine macrophage cell line. The results indicated that the conventional promastigote screening assay did not correlate with the clinical picture, whereas the amastigote/macrophage system produced results that pertained to the in vivo responses to the drug. A laboratory-generated resistant strain of L. major was adapted to grow at a high concentration of Pentostam (1000 micrograms/ml) as promastigotes but was quite sensitive to the drug at much lower concentrations in the amastigote/(macrophage system (20 micrograms/ml), thus suggesting that Pentostam's inhibitory action is mediated through the macrophage rather than through a direct toxic effect exerted on the parasite.

Topics: Animals; Antimony Sodium Gluconate; Cell Line; Drug Resistance; Humans; Leishmania donovani; Leishmania major; Leishmaniasis; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Macrophages; Mice; Sudan

Topics: Antimony Sodium Gluconate; Drug Resistance; HIV Infections; Humans; Incidence; India; Leishmaniasis, Visceral

Topics: Acute Kidney Injury; Adult; Antimony Sodium Gluconate; Cranial Nerve Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Glossopharyngeal Nerve; Humans; Injections, Intramuscular; Leishmaniasis, Visceral; Male; Paralysis; Vagus Nerve

Although cases of visceral leishmaniasis in Libya have been reported for over 80 years, all these reports were from the northern coastal areas near Tripoli and the Green Mountain area. Since 1985, there have been new cases of the disease from the southern part of Libya in the Saharan and sub-Saharan areas, an area 250 km to the south-west of Sabha. This southern area has recently undergone much agricultural organization with increasing water supply and other environmental changes, which may be partially responsible for the establishment of these new foci. Twenty patients with hepatosplenomegaly and fever were referred from that area to the El-Fateh Children's Hospital in Benghazi for investigation. All had the clinical features and laboratory data indicative of the Mediterranean type of the disease. All were treated with sodium stibogluconate (10 mg kg-1 day-1), and responded well to this regime.

Topics: Anti-Bacterial Agents; Antimony Sodium Gluconate; Bronchopneumonia; Child, Preschool; Diarrhea; Female; Follow-Up Studies; Humans; Hypersplenism; Incidence; Infant; Leishmaniasis, Visceral; Libya; Male; Pilot Projects; Retrospective Studies; Splenectomy

Relapse after chemotherapy using the pentavalent antimonials, sodium stibogluconate and meglumine antimoniate, was assessed in 135 patients diagnosed in the Aba Roba focus of south western Ethiopia during the period 1982-1991. Ten cases relapsed with a mean of 15.6 +/- 16.3 months following treatment. A 15-day course of 10 mg Sbv/kg b.wt. sodium stibogluconate used in 1982/1983 had a better outcome than a 15-day course of 17 mg Sbv/kg b.wt. of meglumine antimoniate used in 1990/1991. The relapse rate among patients treated with sodium stibogluconate 16-20 mg Sbv/kg b.wt. for 20 days in 1985-1990 was comparable to the relapse rate in patients treated with meglumine antimoniate 16-20 mg Sbv/kg b.wt. for 20 days in 1990/1991. Findings are discussed.

Topics: Adolescent; Adult; Age Factors; Antimony Sodium Gluconate; Antiprotozoal Agents; Child; Child, Preschool; Ethiopia; Female; Follow-Up Studies; Humans; Infant; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Recurrence; Sex Factors; Treatment Outcome

Indigenous people have been trained to provide a culturally appropriate kala-azar control programme for the tribal population of Sahibganj, Bihar, India. Cultural resistance to modern medicine has been overcome and the influence of village witch-doctors has been countered.. In the district of Sahibganj, Bihar, India, there were 23,670 new cases of kala-azar between 1985 and 1990. The Social Development Centre, Dumka, drafted an emergency plan as a solution. 30 village health workers attended a 3-day training course regarding how to administer sodium stibogluconate intramuscularly, spray DDT, conduct door-to-door surveys, and refer affected persons to health centers. Kala-azar awareness programs in the villages imparted information on the treatment and control of the disease explaining that the disease could not be controlled by witch-doctors. DDT was sprayed during January/February and May/June on the inner walls of houses and covered cowsheds in order to eradicate sandfly prevalence. Persons who had had fever for more than 3 weeks underwent examinations for total and differential counts of white blood cells, haemoglobin concentration, aldehyde test, and thick and thin blood smears for the detection of malaria parasites. Treatment consisted of sodium stibogluconate given intramuscularly at 20 mg per kg body weight daily for 20 days in new cases and for 40 days in relapsed patients, with a maximum of 850 mg. Clinical cure was achieved if patients became afebrile and their spleens returned to normal size. If no relapse occurred in 6 months, the patients were regarded as definitively cured. Of the 1640 treated patients, 1592 were cured, and of the 48 patients who relapsed and were treated again with a 40-day course of sodium stibogluconate, 8 relapsed a second time. 44 patients became unresponsive to sodium stibogluconate and were sent to hospitals for treatment. The spraying performed by the village health workers reduced the incidence of kala-azar and malaria in 3 villages, while increased numbers of cases were recorded in 1 village. Remote tribal areas need educative, preventive, and curative programs backed up by mobile hospitals carrying diagnostic and spraying equipment.

Topics: Animals; Antimony Sodium Gluconate; Community Health Workers; Ethnicity; Female; Humans; India; Insect Control; Leishmaniasis, Visceral; Male; Medically Underserved Area; Medicine, Traditional; Primary Prevention; Psychodidae

We report the case of a 30-years old HIV-infected woman who suffered from recurrent fever up to 41 degrees C, loss of appetite, loss of 8 kg body weight and swelling of the cervical and inguinal lymph nodes. The diagnostic work-up revealed infection with leishmania in gastric and duodenal biopsies. The parasites were also found in the inguinal lymph nodes and in the bone marrow of the patient. According to patient's history the infection was acquired on a holiday in southern spain. The patient was treated with pentavalent antimony in combination with interferon gamma. Visceral leishmaniosis in immuno-suppressed patients is discussed and therapeutic approaches are described.

Topics: Adult; AIDS-Related Opportunistic Infections; Antimony Sodium Gluconate; Biopsy; Combined Modality Therapy; Female; Gastric Mucosa; Humans; Interferon-gamma; Intestinal Diseases, Parasitic; Intestinal Mucosa; Leishmaniasis, Visceral

Visceral leishmaniasis (VL) is endemic in several areas in the Sudan. The disease is associated with depressed cellular immunity. Tinea versicolor is a normal commensal of the skin which can become pathogenic particularly in patients with depressed cell-mediated immunity. Patients with VL have a high prevalence of tinea versicolor.. One hundred and thirty patients with parasitologic confirmation of VL were screened for tinea versicolor infection. In the suspected cases the diagnosis was made by demonstrating the fungal hyphae and spores in skin scrapings. All patients were treated with sodium stibogluconate.. Of the 130 patients with VL, 10.8% were found to have severe tinea versicolor. The fungal infection developed or became worse with the start of VL. After successful treatment of VL, the tinea lesions disappeared completely or decreased in severity.. Depressed cell-mediated immunity that is a feature of VL is the probable underlying cause for fungal infection. Tinea infection during the course of VL is to be distinguished from lesions of post-kala-azar dermal leishmaniasis.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Diagnosis, Differential; Facial Dermatoses; Female; Follow-Up Studies; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Opportunistic Infections; Remission Induction; Sudan; Time Factors; Tinea Versicolor

Fifteen Indian patients with relapsing or drug-refractory visceral leishmaniasis were retreated for 30 days with antimony plus interferon-gamma (IFN-gamma). All 15 had failure of an initial course of antimony and at least one additional course of antimony or pentamidine; 7 patients had failure of three or four prior courses of therapy. During the study, treatment was discontinued in 2 patients because of anemia and congestive heart failure in 1 and intractable vomiting in the other; both subsequently died. In the remaining 13 patients, IFN-gamma plus antimony treatment was associated with daily fever but no other adverse reactions. After 30 days of therapy, 9 (69%) of the 13 patients were apparently cured. Six months after treatment, all 9 were healthy, had parasite-free bone marrow aspirate smears, and were considered cured. None have relapsed during a mean follow-up of 15.9 +/- 1.7 months. These results support the use of antimony plus IFN-gamma as an immunochemotherapeutic alternative for kala-azar patients who have repeated failures of conventional treatment.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Combined Modality Therapy; Death; Drug Administration Schedule; Female; Follow-Up Studies; Humans; India; Interferon-gamma; Leishmaniasis, Visceral; Male; Pentamidine; Recombinant Proteins; Time Factors

Topics: Antimony Sodium Gluconate; Dose-Response Relationship, Drug; Drug Resistance; Humans; India; Leishmaniasis, Visceral

The influence of host genetic background on the response of Leishmania donovani-infected mice to chemotherapy was studied using the H-2d and H-2b haplotypes on a BALB or a B10 genetic background. Animals were treated with free or liposomal sodium stibogluconate and parasite burdens in the liver, spleen and bone marrow were assessed. In all the mouse strains and their congenic derivatives examined, the liver responded best to therapy regardless of drug formulation, whilst the spleen and the bone marrow respectively were increasingly less responsive to chemotherapy. Treatment with free drug was more effective in congenic mice carrying the H-2b haplotype than in those carrying the H-2d haplotype and in mice carrying the same H-2 haplotype, animals from a BALB background were better responders than those from a B10 genetic background. Liposomal drug was more effective than free drug treatment in all four mouse strains and produced a similar significant suppression (> 99%, P < 0.001) in liver parasite burdens to that obtained using a six times greater free drug dose. This liposomal drug dose was more effective than free drug in reducing bone marrow parasite burdens in all four mouse strains and equally (BALB/c mice) or more effective (P < 0.01, BALB/B, B10 and B10.D2 strains) in reducing spleen parasite numbers. Liposomal dependent influences apparent using free sodium stibogluconate. These results are discussed in relation to the genetic factors which are known to control the course of L. donovani infection in mice.

Topics: Animals; Antimony Sodium Gluconate; Bone Marrow; Drug Carriers; Female; Genes, MHC Class I; H-2 Antigens; Haploidy; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred BALB C; Spleen

Topics: Alanine Transaminase; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Liver; Serum Albumin

A case of a renal transplant recipient who developed pancreatitis during stibogluconate treatment for visceral leishmaniasis and who was successfully treated with a combination of allopurinol and ketoconazole is reported. The features of this case are compared with those of the three previously reported cases of pancreatitis during stibogluconate treatment. Complete cure was achieved during the follow-up period of 15 months. If stibogluconate is used for treatment of renal transplant recipients, we advise extreme caution with close observation and combination therapy to be considered instead.

Topics: Adult; Allopurinol; Antimony Sodium Gluconate; Drug Therapy, Combination; Female; Humans; Ketoconazole; Kidney Transplantation; Leishmaniasis, Visceral; Pancreatitis

We examined the antileishmanial activity of DL-alpha-difluoromethylornithine (DFMO) and a bis(benzyl)polyamine analogue (MDL 27695; N,N'-bis (3-[(phenyl-methyl)amino] propyl) 1,7-diaminoheptane) in L. donovani infected golden hamsters. DFMO, an enzyme activated irreversible inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine biosynthesis, has potent antileishmanial activity. When given as a 2% solution in drinking water 2 days after infection and continued for 4 days, it suppressed liver parasites by 90% and spleen parasites by 99%. Liver parasites were suppressed by 50% and spleen parasites by 77% in L. donovani infected hamsters when treated three times per day for 4 days with a total dose of 60 mg kg-1 body weight of MDL 27695. The polyamine content of the liver and spleen of hamsters was determined after 8 days of L. donovani infection and also after treatment with these drugs. Putrescine and spermidine levels increased significantly in both liver and spleen after Leishmania infection of golden hamsters. Treatment with drugs that inhibit the growth of Leishmania mastigotes in the liver and spleen of golden hamsters also reduced polyamine levels of previously infected golden hamsters. There is a close correlation between the therapeutic activity of the drugs and the polyamine content.

Topics: Animals; Antimony Sodium Gluconate; Biogenic Polyamines; Cricetinae; Eflornithine; Leishmania donovani; Leishmaniasis, Visceral; Mesocricetus; Polyamines

A one-year-old Swedish boy developed kala-azar six months after a holiday in Spain. Upon visiting the hospital after one week of illness he demonstrated clinical and laboratory findings of fever, splenomegaly and cytopenia. A fine-needle aspiration biopsy of the spleen revealed hemophagocytosis and he had increased serum levels of the cytokines tumor necrosis factor-alpha and interferon-gamma. Initially, a diagnosis of hemophagocytic lymphohistiocytosis was made. Re-evaluation of the spleen smears and of the bone marrow aspiration revealed Leishmania parasites and subsequent therapy with sodium stibogluconate was successful. This patient illustrates the interesting similarities between these two disorders involving the mononuclear phagocyte system as well as the problems involved in differential diagnosis. This case also reminds us of the possibility of contracting visceral leishmaniasis in Mediterranean countries.

Topics: Animals; Antimony Sodium Gluconate; Bone Marrow; Cytokines; Diagnosis, Differential; Histiocytosis, Non-Langerhans-Cell; Humans; Infant; Leishmania; Leishmaniasis, Visceral; Male; Spain; Spleen

We previously reported the effectiveness of trans-aconitic acid (TAA) as an antileishmanial compound. Inhibitory effects of TAA along with other antileishmanial compounds on transformation and in vitro multiplication in macrophage cultures of Leishmania donovani have been assessed. The efficacy of TAA in combined chemotherapy of experimental visceral leishmaniasis has also been evaluated along with those of commonly used antileishmanial compounds such as sodium stibogluconate, pentamidine, and allopurinol. TAA (2 mM) inhibited transformation of L. donovani amastigotes to promastigotes by 95.2%, whereas in combination with pentamidine (5 micrograms/ml), allopurinol (10 micrograms/ml), and sodium stibogluconate (50 micrograms of Sb per ml), it inhibited transformation by about 100, 99, and 98.5%, respectively. Sodium stibogluconate (20 micrograms of Sb per ml), pentamidine (2 micrograms/ml), and allopurinol (5 micrograms/ml) suppressed the amastigote burden in peritoneal macrophage cultures from BALB/c mice by 32.6, 56.1, and 46.3%, respectively. When these three drugs were used along with TAA (5 mM), the parasite loads were reduced by 100, 100, and 88.1%, respectively. TAA (5 mM) alone suppressed the amastigote burden by 59.5%. In experimental visceral leishmaniasis in hamsters (1-month model), TAA at a dose of 200 mg/kg of body weight per day suppressed the spleen parasite load by 73.5%, and TAA in combination with sodium stibogluconate (50 mg of Sb per kg per day), pentamidine (8 mg/kg/day), and allopurinol (15 mg/kg/day) inhibited the spleen parasite load by 98, 98.9, and 97%, respectively. Individually, these three drugs inhibited the parasite load by 35, 20, and 22%, respectively. TAA (400 mg/kg/day) inhibited the spleen parasite load by 99.8%, but an inhibitory effect of approximately 100% was noted when TAA was supplemented with an antileishmanial drug. TAA was administered in experimental animals through oral, intraperitoneal, and intramuscular routes; the intramuscular route was most effective.

Topics: Aconitic Acid; Allopurinol; Animals; Antimony Sodium Gluconate; Cells, Cultured; Cricetinae; Drug Therapy, Combination; In Vitro Techniques; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages; Mesocricetus; Mice; Mice, Inbred BALB C; Pentamidine; Spleen; Stereoisomerism

Topics: Antimony Sodium Gluconate; Child, Preschool; Humans; Leishmaniasis, Visceral; Male; Recurrence; Thrombocytopenia

Post-kala-azar dermal leishmaniasis is a condition peculiarly confined to the Indian subcontinent.. The clinical features and investigations in 18 patients of post-kala-azar dermal leishmaniasis were studied.. There was a polymorphic picture from hypopigmented macules to nodules and plaques. Mucous membranes were affected in five, the lips and glans penis being the most frequent sites. Histopathologically, a rich dermal infiltrate was seen in indurated lesions and in macules; it was confined to perivascular foci in the upper dermis. Leishman-Donovan bodies were seen in 16.. The lesions cleared in 4 to 5 months after treatment with sodium antimony gluconate intramuscularly 20 mg/kg/day up to a maximum of 1 g/day. The drug was well tolerated.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Biopsy; Child; Diagnostic Tests, Routine; Female; Follow-Up Studies; Humans; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Skin

Topics: Adult; Antimony Sodium Gluconate; Female; Humans; India; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral

Described are the susceptibility of the Indian langur (Presbytis entellus) to Leishmania donovani and the consequent haematological and serum biochemical changes. The host response to antileishmanial chemotherapy and the immunological profile were also examined. Each langur was inoculated intravenously with 1 x 10(8) amastigotes; a spleen biopsy carried out on day 35 post-infection (p.i.) revealed 10-13 L. donovani bodies per 500 cell nuclei, which reached a maximum of 130-195 at death (day 105-110 p.i.). The infected monkeys lost body weight, developed severe anaemia, lymphocytosis, hyperproteinaemia, hypergammaglobulinaemia, hypoalbuminaemia and an increase in the level of alkaline phosphatase and alanine aminotransferase (AAT). Treatment with sodium stibogluconate (60 mg Sb5+ per kg body weight intramuscularly for 10 days) reduced the number of spleen parasites (0-1 amastigotes per 500 cell nuclei) but after the therapy the parasites appeared in the skin, which had previously been free of infection. Relapse occurred on day 30 post-treatment (10-24 amastigotes per 500 cell nuclei) and the parasites were resistant to repeat intensive therapy (120 mg Sb5+ per kg per day x 30 days). The stibogluconate treatment caused a proportionate reduction in the haematological and biochemical parameters to normal values except for alkaline phosphatase and AAT, which remained elevated. The level of IgG antibodies, which rose during the infection, rapidly fell to the pretreatment value following the first therapeutic schedule and then increased a second time coinciding with relapse. Our findings suggest that langurs could serve as acceptable models for human visceral leishmaniasis.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Cercopithecidae; Disease Models, Animal; Leishmania donovani; Leishmaniasis, Visceral; Male; Recurrence; Skin; Spleen

The epidemiology, clinicopathological features, and response to therapy of 63 Saudi patients with visceral leishmaniasis are described. The clinical features in our cases were similar to those described from Asir province, India, and Ethiopia, except for the presence of lymphadenopathy. Fever, hepatosplenomegaly, pancytopenia, and liver dysfunction were common findings. The unusual feature is the seasonal variation in the distribution of the disease. The response to sodium stibogluconate was excellent and the mortality rate was low (less than 1 per cent).

Topics: Antimony Sodium Gluconate; Bone Marrow Examination; Child; Child, Preschool; Female; Hematologic Tests; Humans; Infant; Leishmaniasis, Visceral; Male; Retrospective Studies; Saudi Arabia

The clinical presentation of kala-azar in 43 children and 45 adults was compared. In both groups fever, left upper quadrant abdominal pain and swelling, and weight loss were equally the most common presenting symptoms. Lymphadenopathy was observed in 86 per cent of children and 76 per cent of adults. Splenomegaly was absent in 2 per cent of children and 7 per cent of adults. No significant difference was found in frequency distribution of symptoms and signs between children and adults. Haematological indices were compared in both children and adults with kala-azar and their control groups. In both children and adults with kala-azar, haemoglobin concentration, total white cell count, and platelet count were significantly lower before than after treatment. Only haemoglobin concentration was lower in children with kala-azar as compared with adults with the disease. Children in the control group had lower haemoglobin and higher total white cell count than adult controls. Response to therapy was evaluated in 693 patients. Two-hundred-and-fifty children and 373 adults were treated with sodium stibogluconate 10 mg/kg for 30 days; in both groups 12 per cent deaths and 4 per cent relapses occurred. Thirty children and 40 adults were treated with sodium stibogluconate 2 x 10 mg/kg for 15 days. In children, 3 per cent deaths and 7 per cent relapses were noted; in adults there were 8 per cent deaths and 5 per cent relapses. No significant difference in death rate or relapse rate was found between children and adults in both regimens. Both regimens performed equally well in children and adults with regard to death rate and relapse rate.

Topics: Adolescent; Adult; Age Factors; Antimony Sodium Gluconate; Child; Child, Preschool; Hemoglobins; Humans; Infant; Infant, Newborn; Leishmaniasis, Visceral; Middle Aged; Sudan; Treatment Outcome

BALB/c mice with an acute or chronic Leishmania donovani infection were treated with intravenous sodium stibogluconate solution and the parasite suppressions determined in the spleen, liver and femur bone marrow. Antimony concentrations in these and other tissues were determined by hydride generation-atomic absorption spectrophotometry. There was little correlation between tissue antimony levels one hour after treatment and drug efficacy. It would appear that the peak tissue antimony concentration achieved soon after dosing, rather than the lower concentrations which are readily sustained in most tissues, is the most important factor in the antileishmanial activity of stibogluconate. A high peak antimony concentration occurred in the liver, where parasites were significantly suppressed, and was not observed in the two other sites of infection, where the parasites were apparently less susceptible to stibogluconate therapy.

Topics: Acute Disease; Animals; Antimony; Antimony Sodium Gluconate; Chronic Disease; Female; Leishmania donovani; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C

The in vitro antileishmanial activity of sodium stibogluconate (SSG) and pentamidine in peritoneal macrophages from three different groups of animals (i.e. normal, Leishmania donovani-infected and drug-treated BALB/c mice) is reported. Peritoneal macrophages were extracted from all these animals and infected in vitro with L. donovani promastigotes. After 24 h, the infected macrophages (with amastigotes) were exposed to various concentrations of SSG (10-90 micrograms/mL) and pentamidine (0.1-5.0 micrograms/mL). The in vitro infection could be cured readily with 80 micrograms/mL of SSG and 4 micrograms/mL of pentamidine in macrophages from normal animals. But even higher dosages of these drugs added in vitro could not reduce the amastigote loads in macrophages from infected animals. In contrast, incubation in vitro of infected macrophages with very low dosages of these drugs (40 micrograms/mL of SSG and 1.0 mu/mL of pentamidine) could eliminate the parasites present within macrophages obtained from drug-treated animals. This was probably because the macrophages from drug-treated animals tackled the parasites themselves by their microbicidal mechanisms and the in vitro infection was tackled by the drug in vitro. This implies that a well-developed specific immunity in leishmaniasis helps in the antileishmanial activity of these drugs.

Topics: Animals; Antimony Sodium Gluconate; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred BALB C; Pentamidine; Peritoneal Cavity

Mucosal leishmaniasis as an oral disease in the form of chronic periodontitis with involvement of the oral mucosa is described. Leishmania parasites were isolated from the oral lesions, lymph nodes, and bone marrow. The patient had a low-grade fever and hepatosplenomegaly that regressed along with the oral lesions after treatment with stibogluconate sodium.

Topics: Antimony Sodium Gluconate; Chronic Disease; Humans; Injections, Intravenous; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral; Male; Middle Aged; Periodontitis

Hexadecylphosphocholine (He-PC), a novel phospholipid derivative, was tested against Leishmania donovani and Leishmania infantum, the causative agents of visceral leishmaniasis. In vitro, promastigotes were highly susceptible to He-PC; the 50% inhibitory concentrations were between 0.89 and 2.25 micrograms/ml for the different leishmanial strains. In vivo, a marked antileishmanial activity in infected BALB/c mice could be demonstrated after oral administration of He-PC. Whereas parasite suppression and killing in the liver were comparable after 5 days of treatment with He-PC (10 or 20 mg/kg of body weight per day administered orally) and sodium stibogluconate (120 mg of pentavalent antimonal agent per kg/day administered subcutaneously), a superior reduction in the parasite load in the spleen and bone marrow was observed after oral treatment with He-PC. After a 4-week treatment period, parasite suppression in the spleen was better than that observed with standard sodium stibogluconate therapy by a factor of more than 600.

Topics: Administration, Oral; Animals; Antimony Sodium Gluconate; Bone Marrow; Female; Leishmania; Leishmania donovani; Leishmaniasis, Visceral; Liver; Mice; Mice, Inbred BALB C; Phosphorylcholine; Spleen

Antileishmanial chemotherapy is hampered by the location of the parasite within the phagolysosome of the macrophage, which restricts the bioavailability of many potentially useful antileishmanial drugs. In this study, the possibility of using antileishmanial drugs targeted to the infected macrophages by means of a chemical linkage to a neutral mannose-substituted poly-L-lysine carrier molecule was explored. The study was performed in an in vitro model with Leishmania donovani-infected murine macrophages. The antileishmanial activities of various synthetic constructs were compared with those of the free drugs and the pentavalent antimonial Pentostam, which was used as the positive control. The 50% effective dose of allopurinol riboside linked to the mannosylated poly-L-lysine was below 7.5 x 10(-6) M, while it was up to 3 x 10(-4) M for the free drug, indicating that the drug bound to the polymer was 50 times more active than the free drug. Control experiments with other constructs (e.g., allopurinol riboside linked to the mannose-free polymer) confirmed that the enhancement of activity was indeed achieved by means of the mannose homing device.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Membrane; Drug Carriers; Glycosylation; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Mice; Polymers; Rats

Topics: Ampicillin; Animals; Antimony Sodium Gluconate; Bone Marrow; Child; Child, Preschool; Female; Gentamicins; Hepatomegaly; Humans; Injections, Intramuscular; Leishmania donovani; Leishmaniasis, Visceral; Male; Splenomegaly

We have adapted the simple and sensitive McAb-antigen spot test (AST) for evaluating the efficacy of anti-Leishmania chemotherapy. Serum samples from 37 kala-azar patients were tested by McAb-AST, and all showed definite positive reactions before treatment. After a course of antimony treatment, 20 turned negative, coupled with the disappearance of clinical symptoms; another 12 cases responded with weak positivity accompanied by an improvement of clinical manifestations; and the remaining 5 antimony-resistant patients showed strong positive reactions, with their conditions gradually worsening. Furthermore, all 6 cases in which the diagnosis was missed by the bone marrow smear method turned McAb-AST negative after chemotherapy. These results suggest that McAb-AST can be used to evaluate the efficacy of chemotherapy as well as to avoid missed diagnosis by the bone marrow smear method.

Topics: Adolescent; Adult; Animals; Antibodies, Monoclonal; Antigens, Protozoan; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male

Six weeks after his return from a two-week vacation in Croatia a 52 year-old janitor from Graz complained of loss of appetite, fever, headache, and a 9-kg weight loss. The spleen was enlarged to 16cm as measured by sonography. Laboratory tests revealed pancytopenia, a prolonged prothrombin time and elevation of serum LDH concentration. While repeated bone marrow biopsy showed no signs of leishmaniasis, high antibody titers against leishmania antigen led to the diagnosis of kala-azar. The indirect immunofluorescent antibody test (1:128) and a haemagglutination-inhibition test (1:512) showed diagnostic elevations of titers. Therapy with pentostam led to prompt defervescence and resulted in a full recovery of the patient. After six weeks a marked decrease of antibody titers in the haemagglutination-inhibition test (1:16) could be observed. Leishmaniasis has to be considered in patients with fever of unknown origin who return from Mediterranean countries. Despite a negative bone marrow biopsy a diagnosis is possible on the basis of serological tests. This is important because effective therapy is available as illustrated by this patient and because of the fact that the disease runs a lethal course if the diagnosis is missed.

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Croatia; Diagnosis, Differential; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Middle Aged; Travel

Visceral leishmaniasis is an important public health problem in Libya, but its exact prevalence is not known. Prompted by the paucity of information in the literature relevant to Libyan children, we reviewed the records of 21 children treated at El-Fatah Children's Hospital, Benghazi between March 1982 and May 1990. Visceral leishmaniasis was diagnosed on the basis of the history, physical findings and confirmatory laboratory tests including examination of bone marrow. The duration of illness before seeking medical advice ranged from 3 months to 1.5 years. The commonest presenting features were fever, abdominal distension, anorexia with weight loss, hepatosplenomegaly and pallor. The consistent laboratory findings were anaemia with reticulocytosis and normal serum iron, neutropenia, thrombocytopenia, high ESR and hyperglobulinaemia. The bone marrow was positive for L. donovani in 86% of cases and the indirect haemagglutination test was positive in all patients. Bronchopneumonia was the most common complication and responded rapidly to antibiotics. All patients were treated with sodium stibogluconate 10 mg/kg/day. There were no major side-effects or complications of drug therapy. The relative paucity of cases and their late presentation may reflect a lack of awareness of the occurrence of visceral leishmaniasis by doctors in the community.

Topics: Antimony Sodium Gluconate; Bronchopneumonia; Child, Preschool; Humans; Infant; Leishmaniasis, Visceral; Libya; Pentamidine

In a prospective study conducted in Mymensingh district of Bangladesh, 1, 273 patients were assessed for the presence of visceral leishmaniasis (VL). Sodium antimony gluconate (SAG) was successfully administered to 715 patients with parasitologically confirmed infection. In the remaining 558, although there was clinical indication of VL, Leishmania donovani parasites could not be demonstrated. Administration of SAG in this group was on the grounds of the prevailing symptoms, exclusion of malaria and a positive direct agglutination test (DAT). Significant improvements in the clinical and hematological parameters were observed in 547 (98%) of the unconfirmed VL cases. On the basis of the parasitological findings or positive response to specific anti-Leishmania chemotherapy, the sensitivity and specificity of the DAT were 99.6% and 97.7% respectively. The results supported the reliability of DAT for diagnosis of VL at levels below that of parasitological detection.

Topics: Agglutination Tests; Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Enzyme-Linked Immunosorbent Assay; Hemagglutination Tests; Humans; Leishmania donovani; Leishmaniasis, Visceral; Prospective Studies

An adult man with post-kala-azar dermal leishmaniasis who had lessons distributed in a manner strikingly similar to lepromatous leprosy is described. He was mistakenly treated with multidrug therapy as recommended by the WHO Expert Committee on leprosy. All investigations including slit-skin smears, histopathology, culture for Leishmania donovani and an indirect fluorescent antibody test to confirm post-kala-azar dermal leishmaniasis proved futile. The diagnosis was ultimately based on the previous history of kala-azar, the absence of other disorders which were ruled out by relevant laboratory tests and the good therapeutic response to sodium antimony gluconate. The epidemiological significance of this case and the salient points to distinguish this condition from leprosy are discussed.

Topics: Animals; Antimony Sodium Gluconate; Diagnostic Errors; Humans; Leishmaniasis, Visceral; Leprosy, Lepromatous; Male; Middle Aged; Skin

In a young man who had a prolonged fever of unknown origin, hepatosplenomegaly, and progressive pancytopenia, stained smears, blood-agar cultures of bone marrow, and serologic testing for antileishmanial antibodies were negative. Biopsies from liver and bone marrow were uninformative. Visceral leishmaniasis was diagnosed only after splenectomy, when amastigotes were finally cultured from the spleen. The parasite was shown to be an unusual leishmanial parasite, possessing a mixture of intrinsic biochemical and serologic characteristics displayed independently by Leishmania tropica and Leishmania donovani sensu lato, the latter being the usual cause of visceral leishmaniasis. After splenectomy, parasites were also demonstrated in stained bone marrow aspirate smears. Recovery was uneventful after treatment with antimony for 28 days. Visceral leishmaniasis can be a cause of fever of unknown origin and should be considered in its differential diagnosis in endemic areas.

Topics: Adult; Animals; Antimony Sodium Gluconate; Diagnosis, Differential; Humans; Injections, Intravenous; Leishmania donovani; Leishmania tropica; Leishmaniasis, Visceral; Male; Spleen; Splenectomy; Splenomegaly

The fine structure of Leishmania donovani amastigotes has been studied in bone marrow aspirates from a 4-year-old girl with visceral leishmaniasis before and during treatment with sodium stibogluconate. Free amastigotes in the bone marrow were forming junctions with previously undescribed cytoplasmic buddings of macrophages prior to engulfment; these buddings were suggested to be transient parasitophorous vacuoles. Three stages of infection within macrophage parasitophorous vacuoles were identified: early stage in which the vacuole membrane was closely apposed to entire surface of the amastigote; advanced stage in which the vacuole became slightly distended and contained single amastigote; the late stage in which the vacuole was greatly distended and was occupied by several amastigotes. Prior to treatment, degeneration of parasites has appeared as a partial loss of the pellicle and a low dense perinuclear space and seems to be under digestive lysosomal effects of the host cell. The most consistent effects of treatment on the amastigotes were a reduction on average size and moderate increase in the electron-density of the cytoplasm which was associated with a greater concentration of ribosomes. This may occur in addition to degeneration seen before treatment which dramatically increased during treatment. It is suggested that the parasite, during treatment, is under double actions; the drug may function to lyse the parasite intracellularly, while the macrophage lysosomes act to digest the membrane of the parasitophorous vacuole and its vacuolar contents extracellularly.

Topics: Animals; Antimony Sodium Gluconate; Biopsy, Needle; Bone Marrow; Child, Preschool; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Microscopy, Electron

An ultrastructure study was carried out on the effect of a standard drug sodium stibogluconate and a newly identified active CDRI compound 87/305 [1,2-dimethyl-3-methoxy carbonyl-4-(2-nitro-4,5-dimethoxyphenyl) pyrrole] on amastigotes of Leishmania donovani in macrophage cells of spleen of infected hamsters. While Na-stibogluconate exerted its effect by activating the digestion capacity of host macrophages, compound 87/305 was directly lethal to the parasites without, exerting any effect on the host cells.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cricetinae; Leishmania donovani; Leishmaniasis, Visceral; Male; Microscopy, Electron; Pyrroles; Spleen

Sixty-seven cases of visceral leishmaniasis managed at the Rabat Hospital for Children from 1979 through 1988 were studied retrospectively. Mode of onset and outcome were analyzed. Clinical manifestations included enlargement of the spleen (60 cases), fever (45 cases), enlargement of the liver (38 cases), and weight loss (53 cases). Six patients had misleading onset manifestations including one case each of pigmentary lithiasis, severe marasmus without enlargement of the spleen, nephrotic syndrome, evidence of portal hypertension, jaundice, and an abdominal mass. Diagnosis was established by the bone marrow study (positive in 58 of 66 patients) or by indirect immunofluorescence (positive in 21 of 24 patients, including 6 with a negative bone marrow study). In one patient, the parasite was recovered from a jejunal biopsy specimen. Drugs used included N-methyl-glucamine in 86 cases, pentamidine in 26 cases, and sodium gluconate stibio in one case. Complete recovery was achieved in 24 patients. Seven patients failed to respond to therapy. There were 8 deaths, including 4 prior to initiation of therapy; among these four deaths, three were due to acute anemia. Another patient died after leaving the hospital despite the physician's advice to the contrary. The 3 remaining deaths were caused by toxicity of the drugs used. Thirty-one patients were lost to follow-up after initial improvement. The severity of this disease and cost of management make earlier diagnosis and faultless management imperative.

Topics: Adolescent; Age Factors; Antimony Sodium Gluconate; Bone Marrow Examination; Child; Child, Preschool; Diagnosis, Differential; Drug Therapy, Combination; Female; Fluorescent Antibody Technique; Hospitals, Pediatric; Humans; Infant; Leishmaniasis, Visceral; Male; Meglumine; Morocco; Pentamidine; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Acidosis, Renal Tubular; Antimony Sodium Gluconate; Female; Humans; Leishmaniasis, Visceral; Middle Aged

We present the first case of visceral leishmaniasis (VL) in a Spanish patient with HIV infection living in Belgium. After four weeks of stibogluconate and zidovudine treatment, the initially low CD4 count improved, and the splenomegaly regressed. VL is becoming frequently reported in association with HIV infection, especially in countries where leishmaniasis is endemic. The apparent effect of VL on the CD4 count may cause problems in the staging of HIV infections.

Topics: Adult; Antimony Sodium Gluconate; Female; HIV Infections; Humans; Leishmaniasis, Visceral; Zidovudine

We report the case of 43-year-old homosexual patient with HIV infection and a history of travel to the Far East in whom visceral leishmaniasis was the first infectious complication. Symptoms were fever, malaise, weight loss, hepatosplenomegaly, generalized lymphadenopathy, and oral thrush. Laboratory abnormalities included a slight elevation of liver enzymes, impairment of liver function tests, leukocytopenia, anemia, hypergammaglobulinemia, and markedly depressed CD4(+)-cell counts. Despite initially successful treatment with pentavalent antimony, a relapse of leishmaniasis occurred after 7 months. Eradication of the infection was not achieved. Treatment was continued as a palliative chronic suppressive treatment with fortnightly pentamidine infusions. The clinical course was complicated by legionella pneumonia and the development of rapidly progressing Kaposi's sarcoma. The case is presented in detail, and the influence of HIV infection on the course of leishmaniasis is discussed.

Topics: Adult; AIDS Serodiagnosis; Antimony Sodium Gluconate; CD4-CD8 Ratio; HIV Infections; HIV-1; Humans; Leishmaniasis, Visceral; Leukocyte Count; Macrophages; Male; Opportunistic Infections; Pentamidine

A sixth autochthonous case of visceral leishmaniasis is reported in Bolivia. It is also the fourth case detected in the Yungas Valley (Department of La Paz) confirming the long-term existence of the disease in this area where cases of canine leishmaniasis and natural infestation of the phlebotomine sandfly, Lutzomyia longipalpis, were previously reported.

Topics: Antimony Sodium Gluconate; Bolivia; Child; Humans; Leishmaniasis, Visceral; Male

One hundred twenty-nine cases of visceral leishmaniasis (kala-azar) seen over a thirteen year period in a nonendemic area at a referral medical center in north India are described. The epidemiological, clinical and therapeutic features of these patients are presented. A large number of patients came from nonendemic areas and showed some unusual clinical and laboratory features. Use of sodium antimony gluconate led to relapse in approximately 34 percent of cases. Lack of awareness of the occurrence in a nonendemic area and the unusual manifestations may cause considerable difficulties in establishing the diagnosis.

Topics: Adolescent; Adult; Age Factors; Aged; Antimony Sodium Gluconate; Child; Child, Preschool; Humans; India; Infant; Leishmaniasis, Visceral; Middle Aged

Post kala-azar dermal leishmaniasis (PKDL) occurs occasionally after successful cure of visceral leishmaniasis. Twelve patients with diagnosis consistent with PKDL were seen at Clinical Research Centre from 1981 to 1985. Clinical presentation ranged from macular hypopigmented lesion to generalized nodular lesions. All lesions cleared either by self-cure or by treatment with sodium stibogluconate.

Topics: Antimony Sodium Gluconate; Female; Humans; Kenya; Leishmaniasis, Cutaneous; Leishmaniasis, Visceral; Male; Time Factors

We describe a case of blepharo-conjunctivitis due to Leishmania donovani in association with nodules of post kala azar dermal leishmaniasis (PKDL) on the chin. The diagnosis was confirmed by isolation of the parasite in culture. Direct implantation of the parasite by contaminated fingers from the chin nodules to the eye is suggested as the mode of spread. The role of cell-mediated immunity, (CMI) in restricting the skin lesions on the chin for 37 years at the same site, was suspected. This is only the second report of ocular involvement in L. donovani infection from India.

Topics: Agglutination Tests; Antimony Sodium Gluconate; Blepharitis; Conjunctivitis; Fluorescent Antibody Technique; Humans; Immunity, Cellular; Leishmaniasis, Visceral; Male; Middle Aged; Recurrence

A fatal disease epidemic affected the Bentiu area in southern Sudan and led to a mass migration of the Nuer tribe searching for treatment. The initially available information revealed a high mortality rate due to a possible occurrence of tuberculosis, malaria, enteric fever or visceral leishmaniasis (VL). Serological screening of 53 of the most severely affected patients in an enzyme-linked immunosorbent assay (ELISA) or an improved direct agglutination test (DAT) revealed positivity for VL. In 39 of those patients, diagnosis was confirmed by identification of Leishmania donovani amastigotes in lymph node or bone-marrow aspirates. In a total of 2714 patients observed, 1195 (44.0%) had clinical symptoms suggesting VL: DAT positive titers (1:3200-greater than or equal to 1:12800) were obtained in 654 (24.1%), of whom 325 were confirmed parasitologically. Forty-two VL cases died before or during treatment, giving a mortality rate of 6.4%. Among the intercurrent infections diagnosed in the VL population (654), respiratory involvements (31.7%) and malaria (10.7%) were most prevalent. With the exception of four (0.6%), all other VL patients (509) responded readily to sodium stibogluconate. The factors initiating the outbreak are discussed. Malnutrition and nomadic movements to potential VL endemic areas appeared to be the most important. HIV infection as a possible predisposition seemed remote considering the clinical and epidemiological similarity to VL occurring in East Africa, adequate humoral response in DAT, and immediate positive response to specific anti-Leishmania chemotherapy.

Topics: Adolescent; Adult; Age Factors; Agglutination Tests; Antimony Sodium Gluconate; Child; Disease Outbreaks; Enzyme-Linked Immunosorbent Assay; Female; Humans; Incidence; Leishmaniasis, Visceral; Male; Prevalence; Sex Factors; Sudan

Topics: Adolescent; Antimony Sodium Gluconate; Cardiomyopathy, Dilated; Electrocardiography; Female; Heart; Humans; Leishmaniasis, Visceral

In experimental visceral leishmaniasis, intermittently administered interferon-gamma (IFN-gamma) induces antileishmanial activity, which is primarily microbistatic. To determine if the efficacy of IFN-gamma immunotherapy could be enhanced by continuous delivery, Leishmania donovani-infected mice were treated using a subcutaneous osmotic pump. Once-daily intraperitoneal injections of 10(5) or 10(6) units of IFN-gamma inhibited the replication of L. donovani within liver macrophages but overall did not reduce liver parasite burdens. In contrast, a comparable dose of IFN-gamma (2.4 x 10(5) units/day) administered continuously induced an enhanced effect and reduced liver burdens by almost 50%. Although pump delivery did not similarly increase the efficacy of antimony chemotherapy in infected mice, continuous treatment with IFN-gamma plus antimony produced an additive antileishmanial effect. These results suggest that continuous infusions of macrophage-activating lymphokines such as IFN-gamma (used alone or in combination with chemotherapy) may be required to optimize in vivo antimicrobial effects.

Topics: Animals; Antimony Sodium Gluconate; Combined Modality Therapy; Female; Immunotherapy; Infusion Pumps, Implantable; Injections, Intraperitoneal; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages; Mice; Mice, Inbred BALB C

Fifty three (30 male and 23 female), previously untreated, patients with post kala-azar dermal leishmaniasis (PKDL) were treated with sodium stibogluconate, at the dose of 20 mg/kg/bw/d/im/(with a maximum of 8.5 ml) for 120 days (or more, if necessary). All the patients were followed up for 12 months. The patients were assessed after 40 days and thereafter at an interval of 20 days. The mean age of onset was 24 yr, maximum number of patients developed the disease within 3 yr of apparent cure of kala-azar. Maximum number of patients sought treatment within 5 yr of the onset of PKDL. The disease affected the face (98%), trunk (83%), upper limb (72%), lower limb (40%), genetalia (6%), and mucus membrane of the tongue 40%. The lesions observed were nodules (19%), papules (30%), and hypopigmented (45%) and reddish macules (7%). The parasites could be demonstrated in the nodules (100%), papules (69%) and macules (59%). The response to treatment started in 72 per cent of patients in the first 20 days and in 40 days in all patients. All the nodules and papules disappeared in 120 days, and the macules within 200 days. The side effects of treatment noted were changes in S T and T in electrocardiogram (7%), arthralgia (11%), allergic rash (7%), swelling at the site of injection (5%), neuralgia (4%) and metalic taste (6%). The S T and T changes reverted to normal when the drug was discontinued for 20 days. Arthralgia improved with indomethacin. The higher dosages and longer course of treatment were well tolerated and resulted in a cure in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Gluconates; Humans; Infant; Leishmaniasis; Leishmaniasis, Visceral; Male; Middle Aged

In a Dutch infant, aged 10 months, with fever of unknown origin for 5 weeks and a relatively good clinical condition splenomegaly was present. Visceral leishmaniasis was diagnosed. The parasite is found in (sub)tropical regions and had in this case been acquired in Southern Spain. Epidemiology, clinical symptoms, diagnostic procedures and therapy are discussed.

Topics: Animals; Antimony Sodium Gluconate; Bone Marrow; Female; Fever of Unknown Origin; Humans; Infant; Leishmania; Leishmaniasis, Visceral

We report the occurrence of two side effects, pancreatitis and palindromic arthropathy with effusions, associated with injections of sodium stibogluconate used in the treatment of kala-azar. No clear mechanism to account for the problems was identified despite extensive investigation. We suggest that when abdominal pain is experienced during treatment with antimonial drugs pancreatitis should be borne in mind as a possible cause.

Topics: Adult; Animals; Antimony Sodium Gluconate; Cyclosporins; Gluconates; Humans; Immune Tolerance; Joint Diseases; Leishmania donovani; Leishmaniasis, Visceral; Male; Malta; Pancreatitis

Topics: Adult; Anemia, Aplastic; Antimony Sodium Gluconate; Bone Marrow; Gluconates; Humans; Leishmaniasis, Visceral; Leukopenia; Male

Sodium stibogluconate, did not bring about significant increase in the production of IL-1, when both specific leishmanial antigen, or non specific Staphylococcus epidermidis was used as stimulus in normal uninfected animals. However, Staph. epidermidis was found to be a better stimulus as it brought about a significant increase (P less than 0.001) in IL-1 production when compared with leishmania antigen. In BALB/c mice infected with L. donovani there was a significant reduction (P less than 0.001) in IL-1 levels on various post infection days irrespective whether Staph. epidermidis or leishmanial antigen was used as stimulus when compared with controls. IL-1 levels were significantly increased (P less than 0.05) when L. donovani infected animals were treated with SSG, after 14 days post infection, irrespective of the stimuli used.

Topics: Animals; Antimony Sodium Gluconate; Female; Interleukin-1; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C; Staphylococcus epidermidis

The efficacy of sodium stibogluconate against Leishmania donovani infections was markedly enhanced by encapsulating this drug in tuftsin-bearing liposomes. Also, pretreatment of the animals with these liposomes (free of drug) rendered them resistant to this infection, possibly by activating the host's macrophages. These results demonstrate that tuftsin-bearing liposomes besides delivering the drug to the target cells could also enhance the nonspecific resistance against infections, thus offering an additional advantage over the use of tuftsin-free liposomes as drug carriers in leishmania therapy.

Topics: Adjuvants, Immunologic; Animals; Antimony Sodium Gluconate; Cricetinae; Drug Carriers; Gluconates; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Macrophages; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Tuftsin

Although directly microbicidal, pentavalent antimony has failed as treatment for visceral leishmaniasis in patients who also have AIDS or are receiving immunosuppressive therapy. To define the role of T cells in the successful host response to chemotherapy, we examined the efficacy of pentavalent antimony (sodium stibogluconate, Pentostam) in normal and T cell-deficient BALB/c mice infected with Leishmania donovani. In euthymic (nu/+) mice, single injections of 250 and 500 mg/kg of Pentostam induced the killing of 67% and 89% of intracellular liver amastigotes, respectively. In contrast, in athymic nude (nu/nu) mice, up to three injections of 500 mg/kg achieved no L. donovani killing and did not retard visceral parasite replication. Once nude mice were reconstituted with nu/+ spleen cells, however, Pentostam exerted strong leishmanicidal activity, an effect that appeared to be transferred by either L3T4+ or Lyt-2+ cells. Responsiveness to chemotherapy could also be induced by providing nude mice with either interferon-gamma or interleukin 2 alone. The absence of this T cell- and probably lymphokine-dependent mechanism is a likely explanation for treatment failures in immunocompromised patients infected with L. donovani and perhaps other systemic intracellular pathogens as well.

Topics: Adjuvants, Immunologic; Animals; Antigens, Differentiation, T-Lymphocyte; Antigens, Ly; Antimony Sodium Gluconate; Body Fluids; Female; Gluconates; Immunity, Innate; Interferon-gamma; Interleukin-2; Intracellular Fluid; Leishmaniasis, Visceral; Mice; Mice, Inbred BALB C; Mice, Nude; Phenotype; Recombinant Proteins; T-Lymphocytes

The ability of BALB/c mice to resist reinfection with Leishmania donovani following chemotherapy was studied. BALB/c mice, infected with L. donovani, were treated on Days 7 and 8 postinfection with free, niosomal, or liposomal sodium stibogluconate. It was found that all three drug treatments caused a dramatic reduction in liver parasite burdens as measured on Days 6 and 29 post-treatment. On Day 6 postdrug treatment infection with L. donovani amastigotes, of mice from infected, drug-treated groups, along with age- and sex-matched uninfected controls, showed that at 23 days later, significantly fewer parasites were recovered from the livers of reinfected animals compared with controls given their first infection. Treatment of mice with sodium stibogluconate 6 days prior to a primary infection significantly reduced the number of parasites recovered 14 days later, especially using the carrier form of the drug. In vivo macrophage activity in the liver, as measured by the uptake of radiolabeled horseradish peroxidase immune complex, was significantly raised following stibogluconate treatment of infected but not uninfected mice. These results suggest that a state of resistance persists in the liver of infected mice following chemotherapy which may in part be due to local macrophage activation but also to an unsuspected persistance of the drug.

Topics: Animals; Antimony Sodium Gluconate; Bone Marrow; Drug Carriers; Female; Gluconates; Leishmania donovani; Leishmaniasis, Visceral; Liver; Macrophages; Mice; Mice, Inbred BALB C; Phagocytosis; Recurrence; Spleen

A four-year-old Danish boy developed kala-azar 18 months after a holiday in Malta. Splenectomy, with liver biopsy, was performed six months after onset of symptoms because of hypersplenism, and the diagnosis of kala-azar was only made four months later, when the histopathological specimens were reviewed. Previous bone marrow biopsies did not show Leishmania. Treatment with sodium stibogluconate was successful. The development of kala-azar after one week's stay in an endemic area stresses the importance of including this potentially fatal disease in the differential diagnosis of cases presenting with fever, splenomegaly, and pancytopenia.

Topics: Antimony Sodium Gluconate; Child, Preschool; Denmark; Humans; Leishmaniasis, Visceral; Male; Malta

We report the characterization of 6 Leishmania tropica isolates from 2 patients with visceral leishmaniasis who were unresponsive to treatment with sodium stibogluconate. The Leishmania isolates, MHOM/KE/81/NLB-029A, -029XIB, and -029XIC and MHOM/KE/81/NLB-030I, -030B, and -030XXA, all from splenic aspirates, were characterized by cellulose acetate electrophoresis using 11 enzymes: malate dehydrogenase, malic enzyme, phosphogluconate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutamate-oxaloacetate transaminase, adenylate kinase, nucleoside hydrolase, mannose phosphate isomerase, glucose phosphate isomerase, and phosphoglucomutase. Isozyme migration patterns were indistinguishable from those of 2 WHO reference strains of Leishmania tropica (MHOM/SU/60/LRC-L39, NLB-305 and MHOM/IQ/OO/LRC-L36, NLB-067). These are the first reported cases of visceral leishmaniasis (kala-azar) caused by L. tropica in Africa; these cases were refractory to sodium stibogluconate.

Topics: Animals; Antimony Sodium Gluconate; Child; Child, Preschool; Drug Resistance; Electrophoresis, Cellulose Acetate; Female; Gluconates; Humans; Isoenzymes; Kenya; Leishmania tropica; Leishmaniasis, Visceral; Male; Spleen

The resident peritoneal macrophages from untreated mice develop potent microbicidal activity against amastigotes of Leishmania major and Leishmania donovani after in vitro exposure to lymphokines (LK) from mitogen stimulated spleen cells. However, to the best of our knowledge, the response of L. donovani infected peritoneal macrophages from already infected/treated animals to LK has not been investigated. Therefore in the present study, the effect of LK on infected macrophages from BALB/c mice following specific infection and subsequent treatment with sodium stibogluconate has been investigated. As the infection progressed, a decrease in percent microbicidal activity was noticed. An attempt was also made to treat the animals on different post infection days and reinfect them in vitro. Infection could not be produced in vitro in late treatment groups when the treatment was given on 14 days and 21 days post infection. Whereas, macrophages obtained from animals treated on 7 days post infection (early treatment) could be infected in vitro. However, only 50% of the cells got infection. This infection was eliminated when the cells were exposed to LK for 72 hours.

Topics: Animals; Antimony Sodium Gluconate; Cells, Cultured; Leishmania donovani; Leishmaniasis, Visceral; Lymphokines; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Peritoneal Cavity

A 53-year-old man developed a septic fever up to 40 degrees C, pancytopenia and hepatosplenomegaly after a holiday in Spain. Administration of piperacillin and amikacin was ineffective, but the fever subsided and partial haematological remission occurred when 1 mg/kg methylprednisolone daily was added. After six months his general condition worsened and pancytopenia with typical inclusion bodies in bone-marrow macrophages was noted, leading to the diagnosis of visceral leishmaniasis (Kala-Azar). The diagnosis was confirmed by serological tests. The causative organism was eliminated and the abnormal findings regressed during treatment with sodium stibogluconate, at first 600 mg/d for two weeks, then 850 mg/d over 16 days, interrupted for 14 days because of side effects.

Topics: Antimony Sodium Gluconate; Diagnosis, Differential; Hepatomegaly; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Pancytopenia; Splenomegaly; Travel

The efficacy of various sodium stibogluconate formulations against Leishmania donovani has been investigated using a BALB/c mouse model of visceral leishmaniasis. Only one therapy, multiple dosing with drug loaded sonicated vesicles, liposomes or niosomes, was found to be effective against parasites in the liver, spleen and bone marrow. Other treatments significantly reduced parasite liver burdens but either failed to effect spleen and bone marrow parasites, or were effective but toxic. Prophylactic treatment with sodium stibogluconate preparations, six days before infection, reduced parasite multiplication in the liver (free, niosomal and liposomal drug) and the spleen (sonicated, drug loaded niosomes only), but had no suppressive effect on bone marrow parasite burdens compared with controls. These results indicate that in-vivo sodium stibogluconate persists in some compartments at parasiticidal concentrations and that failure to reach this concentration at some sites of infection such as bone marrow, is the cause of treatment failure and relapse.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Antimony Sodium Gluconate; Bone Marrow; Chemistry, Pharmaceutical; Female; Gluconates; Leishmaniasis, Visceral; Liver; Mice; Mice, Inbred BALB C; Spleen

Topics: Antimony Sodium Gluconate; Diagnosis, Differential; Female; Humans; Infant; Leishmaniasis, Visceral; Scotland

We report three cases of combined anemia, neutropenia and thrombocytopenia in patients with visceral leishmaniasis (kala-azar). Using immunofluorescence techniques and the common antiglobulin (Coombs') test, we showed membrane-associated antiplatelet, antineutrophil and antierythrocytic IgG antibodies in all three cases. Treatment with sodium stibogluconate raised the patients' platelet, neutrophil and erythrocyte count. At that time no antibodies were detected on peripheral blood cells. Immunological studies performed on these patients did not show marked abnormalities except for reduced T-helper cells and elevated OKM1-positive cells, which normalized after recovery. As bone marrow suppression was not found, it is suggested that pancytopenia resulted from rapid destruction of antibody-coated blood cells. Whether these antibodies are specific is not clear.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Autoantibodies; Blood Cell Count; Child, Preschool; Coombs Test; Female; Fluorescent Antibody Technique; Humans; Immunodiffusion; Immunoglobulin G; Leishmaniasis, Visceral; Male; Pancytopenia

To determine if the macrophage-activating T cell lymphokine gamma interferon (IFN-gamma) can enhance the effect of conventional chemotherapy against intracellular Leishmania donovani, we treated human macrophages in vitro with both recombinant (r) IFN-gamma and sodium stibogluconate (Pentostam). After pretreatment with a nonactivating dose of rIFN-gamma (10 U/mL), ineffective concentrations of Pentostam (1 and 5 micrograms/mL) were converted to leishmanistatic concentrations, and a leishmanistatic dose (10 micrograms/mL) was converted to uptake of Pentostam. In a model of visceral leishmaniasis, infected mice were treated with ineffective concentrations of rIFN-gamma (10(4) U) plus suboptimal doses of Pentostam (10 or 50 mg/kg). With combination therapy, the doses of Pentostam required to achieve 50% inhibition or killing of visceral L. donovani were reduced by 10-fold and fourfold, respectively. These results suggest that IFN-gamma therapy may be a useful adjunct in visceral leishmaniasis and illustrate one potential role for IFN-gamma in the treatment of systemic intracellular infections.

Topics: Animals; Antimony Sodium Gluconate; Gluconates; Humans; Immunotherapy; Interferon-gamma; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred BALB C

Pentavalent antimony (Sb) is the classical treatment for visceral and cutaneous leishmaniasis. We investigated Sb levels in serum, liver, spleen, and skin of hamsters administered therapeutic dosages of Sb (600 and 300 mg Sb/kg). Single administration of Sb was more effective against hepatic parasites than dividing the same total dose into multiple administrations, which suggests that for elimination of hepatic parasites in vivo, peak Sb concentration is more important than total area-under-the-curve levels. Serum Sb declined with an initial half-life of 1 hr. Skin Sb levels (352 micrograms Sb/g 1 hr after 600 mg Sb/kg) were initially higher than liver levels (77 micrograms Sb/g) or splenic levels (156 micrograms Sb/g), but levels were comparable (7-24 micrograms Sb/g) in the three organs by 8 hr after dosing. The generally comparable levels of Sb in the skin and in the visceral organs support the present clinical practice of administering the same dosage of Sb for cutaneous and visceral leishmaniasis.

Topics: Animals; Antimony Sodium Gluconate; Cricetinae; Gluconates; Leishmaniasis, Visceral; Liver; Mesocricetus; Skin; Spleen; Tissue Distribution

Cell-mediated immune (CMI) response and the concurrent clinical events were studied longitudinally before, during and after treatment in 24 kala-azar (KA) and ten post-kala-azar dermal leishmaniasis (PKADL) patients for a period of six months. The status of specific CMI response was estimated by in vitro tests, viz. lymphocyte transformation and leucocyte migration inhibition in response to L. donovani antigen. The generalized CMI response was assessed by lymphocyte transformation in the presence of mitogen (phytohaemagglutinin) and quantitation of the circulatory T-lymphocyte population. To measure the drug response, the extent of clinical improvement following treatment was used as a yardstick. The results showed that suppression of the CMI response was both specific and generalized in nature during the active stage of KA; but in PKADL, unlike in KA, suppression of the CMI response was found to be associated only at the specific level. With administration of the drug (sodium antimony gluconate), the immunosuppression was gradually eliminated with concomitant clinical improvement in both KA and PKADL patients, although the latter took a longer period of time and a larger amount of drugs compared to the former.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Cell Migration Inhibition; Child; Female; Humans; Leishmaniasis; Leishmaniasis, Visceral; Leukocyte Count; Leukocytes; Lymphocyte Activation; Male; T-Lymphocytes

To facilitate studies on the effect of chemotherapeutic agents on the host-parasite interaction in leishmaniasis, we have developed an experimental model for infecting mouse peritoneal macrophages in culture with recently-isolated Leishmania donovani promastigotes. As the drug action is often dependent on concentration, the distribution of sodium stibogluconate, which is the commonly used drug for treatment of leishmaniasis, was studied in various parts of the macrophages by energy dispersive X-ray microanalysis. The drug was found to accumulate in secondary lysosomes. The ultrastructural examination, using TEM and SEM, of macrophages, whose secondary lysosomes had been preloaded with gold particles, showed that leishmania parasites are phagocytosed and finally located in secondary lysosomes. Using flameless atomic absorption spectrophotometry, the concentration of Mn, Fe and Cu in promastigotes of Leishmania donovani, Leishmania aethiopica, Leishmania crithidia, Leishmania major and their culture media was estimated. Of the three transition metals, the parasites accumulated only Mn from the medium, which they may use in a primitive defense mechanism against reactive oxygen metabolites produced by macrophages during the respiratory burst associated with phagocytosis.

Topics: Animals; Antimony Sodium Gluconate; Cells, Cultured; Disease Models, Animal; Electron Probe Microanalysis; Female; Gluconates; Gold; Leishmania; Leishmaniasis; Leishmaniasis, Visceral; Lysosomes; Macrophages; Male; Metals; Mice; Microscopy, Electron; Microscopy, Electron, Scanning; Specimen Handling; Spectrophotometry, Atomic

5 patients with visceral leishmaniasis were treated with sodium stibogluconate (2 patients) or meglumine antimoniate (3 patients) given intramuscularly at a dose of 10 mg antimony (Sb) per kg body weight daily for 30 d. Blood samples were obtained at intervals during treatment and blood Sb concentrations measured by anodic stripping voltametry. The pharmacokinetics of both drugs were remarkably similar, with peak concentrations of approximately 10 mg/litre occurring 2 h after the initial dose. Most of the Sb was eliminated rapidly, but nadir Sb concentrations increased gradually during treatment from 0.04-0.08 mg/litre 24 h after the first dose to 0.19-0.33 mg/litre 24 h after the 30th dose. For both drugs, the data were best described by a two compartment, three term pharmacokinetic model representing an initial absorption phase with a mean half-life of 0.85 h, a rapid elimination phase with a mean half-life of 2.02 h, and a slow elimination phase with a mean half-life of 76 h. The slow terminal elimination phase may be related to in vivo conversion of pentavalent Sb to trivalent Sb, which could contribute to the toxicity associated with long-term high dose therapy.

Topics: Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Gluconates; Humans; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Sorbitol

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Arrhythmias, Cardiac; Child; Electrocardiography; Gluconates; Humans; Leishmaniasis, Visceral

A 32-year-old homosexual with AIDS, who until 1985 was a frequent traveller to South America and mediterranean countries, had recurrent bouts of fever, splenomegaly, arthralgias as well as granulocytopenia and anaemia. Liver and bone-marrow punctures were performed to exclude malignant lymphoma and (or) a mycobacterial infection. Both biopsies revealed Leishmania donovani. During administration of sodium stibogluconate (Pentostam) the fever disappeared for a time and there was clinical improvement, but further treatment was limited because of thrombocytopenia. In patients with AIDS who have splenomegaly with nonspecific fever, visceral leishmaniasis must be considered in the differential diagnosis even outside of endemic regions.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antimony Sodium Gluconate; Diagnosis, Differential; Humans; Leishmaniasis, Visceral; Male; South America; Travel

A case of visceral leishmaniasis is presented, where a pre-existing polycythemia vera obscured signs of the infection.

Topics: Aged; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Male; Polycythemia Vera

Topics: Antimony Sodium Gluconate; Humans; India; Leishmaniasis, Visceral; Liver Diseases, Parasitic

Topics: Antimony Sodium Gluconate; Drug Resistance; Gluconates; Humans; India; Leishmaniasis, Visceral

Topics: Antimony Sodium Gluconate; Female; Humans; Infant; Leishmaniasis, Visceral; Male; Pregnancy; Pregnancy Complications, Infectious

Suppression of Leishmania donovani liver amastigotes by sodium stibogluconate has been determined in a murine model of experimental visceral leishmaniasis. Niosomal and liposomal drug formulations were equiactive and both increased drug efficacy by an order of magnitude compared with that of free drug. Niosomes containing 30 mol % cholesterol were prepared from three different non-ionic surfactants and no significant difference in activity was detected among the different drug-loaded niosomes. Both negatively charged and neutral vesicles were found to be equally effective. However, vesicle cholesterol content had a slight influence on the antiparasitic activity of the drug-loaded niosomes. Empty vesicles produced a dose-dependent parasite suppression for all vesicles studied. Studies of antimony distribution in the mouse using neutron activation analysis showed high liver levels after i.v. administration of the carrier forms of the drug.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Chemistry, Pharmaceutical; Female; Gluconates; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred BALB C; Spectrophotometry, Atomic

A study of the antileishmanial efficacy of sodium stibogluconate was carried out in BALB/c mice. The drug was administered to Leishmania donovani-infected animals on days 7 and 8 post-infection in one of three forms; free (40-50 mg Sbv Kg-1), liposomal, or niosomal (6.4-8.0 mg Sbv Kg-1) drug. On day 14 post-infection counts of the number of parasites present in the liver, spleen and bone marrow of treated and control animals showed that although all three drug preparations significantly reduced parasite numbers in the liver (approximately equal to 99% suppression) they had little effect on those residing in the spleen or bone marrow. The carrier forms of the drug were therefore significantly more effective than free drug in reducing liver parasite burdens. Increasing the concentration and the number of doses of free drug (maximum of 500 mg Sbv Kg-1), and reducing the size of the vesicles used to deliver the drug had a minimal effect on parasite numbers in the spleen and bone marrow. It is proposed that because of the resistance of spleen and bone marrow parasites to drug therapy, the BALB/c mouse infected with L. donovani provides an excellent model system for the study of drug delivery to these deeper tissue sites.

Topics: Animals; Antimony Sodium Gluconate; Female; Gluconates; Leishmaniasis, Visceral; Male; Mice; Mice, Inbred BALB C

Between May 1982 and September 1986 13 dogs with leishmaniosis received inpatient treatment with Pentostam at the I. Medical Department of the Veterinary Faculty, University of Munich. Predominant clinical signs of all animals were alterations of the skin and hair coat and additionally they showed a reduced general condition (4 dogs), loss of weight (3 dogs), diarrhea (5 dogs) and pain during movements. In the blood samples taken prior treatment in 9 dogs there was an increased total protein concentration. 5 dogs had changes in the red and 4 dogs in the white blood count. Thrombocytopenia occurred in 6 dogs. Leishmaniosis was diagnosed clinically and serologically (IFAT). Na-Stibogluconate (Pentostam) was used for the treatment at a dosage of 10 or 20 mg/kg on 10 or 14 consecutive days. Two dogs died during an early stage of therapy. 6 dogs were discharged as clinically cured after a single or repeated treatment course(s).

Topics: Animals; Antimony Sodium Gluconate; Blood Proteins; Dog Diseases; Dogs; Erythrocyte Count; Gluconates; Leishmaniasis, Visceral; Leukocyte Count

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Drug Resistance; Female; Gluconates; Humans; Leishmaniasis, Visceral; Pentamidine

We report the case of a laboratory worker who received close medical follow-up after accidently inoculating her hand with a needle containing a Humera strain of Leishmania donovani amastigotes. She developed a leishmanoma and histologic evidence of local lymphatic dissemination before being treated. The spectrum of disease caused by L. donovani is discussed.

Topics: Adult; Antimony Sodium Gluconate; Female; Humans; Laboratory Infection; Leishmaniasis, Visceral; Lymph Nodes

Topics: Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Hemagglutination Tests; Humans; Kinetics; Leishmania donovani; Leishmaniasis, Visceral

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Biotransformation; Cricetinae; Excipients; Female; Gluconates; Leishmania donovani; Leishmaniasis, Visceral; Liver; Mesocricetus; Mice; Mice, Inbred BALB C; Microspheres; Spectrophotometry, Atomic; Starch

Topics: Adult; Antimony Sodium Gluconate; Electrocardiography; Female; Gluconates; Humans; Leishmaniasis, Visceral; Tachycardia

Liver and serum concentrations of antimony in the mouse have been determined after administration of sodium stibogluconate in the free, liposomal and niosomal form. High liver and low serum values were attained by the use of both vesicular formulations. Niosomal sodium stibogluconate was shown to be more active than free drug against experimental murine visceral leishmaniasis, an effect apparently dependent on maintaining high drug levels in the infected reticuloendothelial system.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Gluconates; Kinetics; Leishmania donovani; Leishmaniasis, Visceral; Liver; Male; Mice; Mice, Inbred BALB C; Micelles; Pharmaceutical Vehicles; Surface-Active Agents; Tissue Distribution

The levels of immunoglobulin classes (IgG, IgM and IgA) along with B lymphocyte population size were estimated in 24 kala-azar (KA) patients and results were compared with those obtained from 30 controls. A marked increase in the level of IgG and to a lesser extent in that of IgM was noted in the sera of KA patients. But, no such difference could be noted in serum IgA level. Along with the increased levels of immunoglobulins the elevation of B lymphocyte population size was also observed. Follow-up studies during and after chemotherapy for the period of 8 months showed that clinical improvement in KA patients resulting from treatment had a positive correlation with the progressive decline in the B lymphocyte population and in the level of immunoglobulin though the latter, particularly IgG, took a longer time to return to normal.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; B-Lymphocytes; Child; Child, Preschool; Gluconates; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infant; Leishmaniasis, Visceral; Leukocyte Count

Two months after a vacation in Bosnia and at the Dalmatian coast, a 52-year-old Jugoslav male resident in Switzerland developed slowly progressive fever with arthralgia. Two months later his temperature became septic and his general condition deteriorated. After many wrong diagnostic tracks, six months after onset of the illness kala-azar was finally diagnosed. Treatment with Pentostam cured the disease completely.

Topics: Antimony Sodium Gluconate; Bone Marrow; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Switzerland; Travel; Yugoslavia

Topics: Antimony Sodium Gluconate; Diagnosis, Differential; Humans; Kenya; Leishmaniasis; Leishmaniasis, Visceral; Male; Middle Aged; Time Factors

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Female; Gluconates; Humans; Leishmaniasis, Visceral; Male; Time Factors

This paper reports on 164 cases of kala-azar observed in the Baringo District of Kenya between February 1981 and February 1983. All were confirmed serologically by enzyme-linked immunosorbent assay (ELISA) and all but 20 by parasitological examination as well. Following the standard treatment with a 30 day course of sodium stibogluconate (Pentostam) two non-responders and four relapses were observed. Children between 2 and 15 years old were found to be the most affected age group; male patients predominated slightly at 57%. All cases occurred in the semi-arid and arid parts of the district below 1500 m, where pastoralism predominates. Besides scattered cases, certain kala-azar foci could be identified. Two of these--Endao with 49 households, 228 inhabitants and 13 cases of kala-azar, and Koriema with 22 households, 93 inhabitants and 11 cases--were subject to a house to house survey. People were examined physically, their weight and height recorded and fingerprick blood collected on blotting paper for later serological testing. Each household was mapped and the relevant environmental factors recorded. A positive correlation could be demonstrated between kala-azar cases and the vicinity of their homesteads to seasonal rivers and also between kala-azar cases and people living in timber houses, rather than mud and wattle houses. Eroded termite hills were not found to be of epidemiological importance. No satisfying explanation could be found for the striking temporal and local clustering of cases. The homestead was identified as an important site of transmission with optimum conditions for transmission occurring during supper in the evening. Based on spleen rates, Endao was classified as hyperendemic for malaria and Koriema as mesoendemic. Diagnostic ELISA values above 0.2 were observed in all cases of active kala-azar. However, ELISA values above 0.04, taken as the borderline non-specific reaction, could be found in about half of the study areas population. Therefore we conclude that asymptomatic infection must be common. Observations demonstrated that spontaneous recovery may follow clinical illness and visceralization of the parasite. Comparison of parasitological and serological data suggest that this may be expected in more than 15% of cases.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Environment; Enzyme-Linked Immunosorbent Assay; Female; Geography; Health Surveys; Humans; Infant; Kenya; Leishmania donovani; Leishmaniasis, Visceral; Male; Nutritional Status; Socioeconomic Factors

We have studied the mechanism of a transfusion-dependent anaemia found in a two-year-old Maltese girl with visceral leishmaniasis that was resistant to multiple courses of antimonial therapy. Major factors contributing to the anaemia were haemolysis occurring in both the massively enlarged spleen and liver and haemodilution resulting from expansion of the plasma volume. There was no evidence of significant ineffective erythropoiesis, but a reduced plasma iron in the presence of greatly increased iron stores suggested that reticuloendothelial hyperplasia was accompanied by abnormal iron retention by macrophages typical of the 'anaemia of chronic disorders'. This may limit the erythropoietic response to anaemia in chronic visceral leishmaniasis.

Topics: Anemia; Antimony Sodium Gluconate; Erythrocyte Aging; Erythropoiesis; Female; Ferritins; Humans; Infant; Iron; Iron Radioisotopes; Leishmaniasis, Visceral; Pentamidine

Topics: Antimony Sodium Gluconate; Cardiomyopathies; Gluconates; Humans; India; Leishmaniasis, Visceral

Topics: Antimony Sodium Gluconate; Child, Preschool; Disease Outbreaks; Egypt; Female; Humans; Infant; Leishmaniasis, Visceral; Male

Topics: Animals; Antimony Sodium Gluconate; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Hemagglutination Tests; Leishmania; Leishmaniasis, Visceral

The case report is presented of a 18-year old patient, who was admitted to the Haematology Department of the Hanusch Hospital with septic fever, an enlarged spleen and suspected bone marrow failure. Since the patient reported a stay in Sicily prior to the onset of his disease, an infection with Leishmania was suspected. The serological test was highly positive and Leishmania was also isolated from the spleen aspirate. Chemotherapy with Pentostam was successful and the patient made an uneventful recovery. This paper deals with the epidemiology of the disease and discusses the diagnostic approaches.

Topics: Adolescent; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Male; Serologic Tests; Sicily; Splenomegaly; Travel

Topics: Antimony Sodium Gluconate; Antiprotozoal Agents; Bone Marrow; Child; Fluorescent Antibody Technique; Humans; Infant; Leishmaniasis, Visceral; Male; Switzerland

Topics: Adult; Antimony Sodium Gluconate; Antiprotozoal Agents; Diagnosis, Differential; Female; Humans; Leishmaniasis, Visceral; Male

Serial electrocardiograms (ECGs) were obtained during 65 courses of sodium stibogluconate treatment in 59 Kenyan patients with leishmaniasis (56 visceral and 3 cutaneous). ECG abnormalities developed during 54% of the treatment courses. The frequency with which abnormalities occurred was related to the total daily dose of antimony (Sb), increasing from 2/9 patients treated with 10 mg Sb/kg/d to 25/48 treated with 20-30 mg Sb/kg/d and 8/8 treated with 40-60 mg Sb/kg/d. The frequency with which ECG abnormalities developed was also related to the duration of treatment, increasing from 11/65 patients after 7 days to 18/44 after 15 days, 26/39 after 30 days and 11/12 after 60 days. ECG abnormalities were similar to those previously described during treatment with trivalent antimonial drugs, the most common being flattening and/or inversion of T waves. Prolongation of the corrected QT interval occurred in 13 patients, all of whom were treated for more than 30 days or with more than 20 mg Sb/kg/d. One patient died suddenly during the fourth week of treatment with 60 mg Sb/kg/d, and 2 patients died of measles after 9 or 10 days of treatment with 30 mg Sb/kg/d. QT prolongation and a concave ST segment developed in all 3 patients who died. We conclude that minor ECG abnormalities are common when sodium stibogluconate is used at doses above 20 mg Sb/kg/d for more than 15 days, and that life-threatening arrhythmias may occur if very high doses are used.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Arrhythmias, Cardiac; Child; Dose-Response Relationship, Drug; Electrocardiography; Gluconates; Heart Rate; Humans; Leishmaniasis; Leishmaniasis, Visceral; Male; Middle Aged

Topics: Antimony Sodium Gluconate; Gluconates; Humans; Leishmaniasis, Visceral

Studies were made of the ultrastructure of amastigotes of Leishmania donovani before and during treatment of patients with sodium stibogluconate. The most consistent effects of treatment on the amastigotes were a reduction in average size, greater irregularity of the cell outline, and a moderate increase in the electron density of the cytoplasm associated with a greater concentration of ribosomes. It is suggested that the drug affects active transport functions or permeability of the plasma membrane.

Topics: Adolescent; Antimony Sodium Gluconate; Child; Child, Preschool; Cytoplasm; Female; Gluconates; Humans; Leishmania donovani; Leishmaniasis, Visceral; Male; Microscopy, Electron; Ribosomes; Spleen; Vacuoles

Treatment of visceral and cutaneous leishmaniasis rests on pentavalent antimonial drugs. However, side effects are often a problem and resistance may emerge. N-methyl-glucamine given for kala-azar induced hematologic or hepatic toxicity in three patients and failed in two. Four patients with cutaneous leishmaniasis recovered but two exhibited adverse side effects. Sodium stibo-gluconate failed in one of three kala-azar patients and in one of two patients with cutaneous leishmaniasis. The effects of these two drugs are discussed, as well as indications of pentamidine and splenectomy.

Topics: Adolescent; Adult; Antimony; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Gluconates; Humans; Infant; Leishmaniasis; Leishmaniasis, Visceral; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Pentamidine; Splenectomy

The history of a Moroccan girl is described with splenomegaly, lymphadenopathy and pancytopenia after a holiday in her native country. Bone marrow smears were considered negative for Leishmaniasis in four different laboratories. All other diagnostic options could also not be confirmed. Reexamination of the bone marrow smears in a laboratory for tropical diseases revealed Leishmania donovani organisms. Treatment with sodium antimony gluconate was successful. Epidemiology, symptoms and diagnostic problems are discussed.

Topics: Antimony Sodium Gluconate; Bone Marrow; Child, Preschool; Female; Humans; Leishmania donovani; Leishmaniasis, Visceral; Splenomegaly

Ten Kenyan patients with visceral leishmaniasis, unresponsive to sodium stibogluconate at a dose of 16 to 20 mg Sb/kg/day given for 30 to 98 days, have been studied clinically and immunologically and compared with 57 antimony-responsive patients. Pulmonary tuberculosis and previous treatment with antimonial drugs were the only factors which were more common in unresponsive patients. The degree of immunosuppression and rate of recovery of immunoreactivity did not differ between antimony-responsive and -unresponsive patients. Only one patient had never been treated before (primary unresponsiveness). In the other nine patients secondary unresponsiveness occurred after one or more treatment courses, suggesting that the parasite developed resistance to antimony. Antimony-unresponsiveness in visceral leishmaniasis is a serious problem numerically, clinically and economically. A plea is made that the initial treatment of visceral leishmaniasis should be adequate in dose and duration.

Topics: Antimony Sodium Gluconate; Drug Resistance; Humans; Immune Tolerance; Leishmaniasis, Visceral; Skin Tests; Tuberculosis, Pulmonary

Ten Kenyan patients with visceral leishmaniasis unresponsive to sodium stibogluconate, at a dose of 16 to 20 mg Sb/kg body-weight/day given for 30 to 98 days, were treated with 20 mg Sb/kg bw given every eight hours. This regimen was modified or abandoned in six patients because of suspected toxicity, although toxicity was difficult to assess because of intercurrent illness. Toxic effects included lethargy, anorexia, vomiting, electrocardiographic changes, fall in haemoglobin and rise in liver enzymes. One patient died, probably from a cardiac arrhythmia. Two patients were cured, four responded partially and four showed no response. Pentamidine, at a dose of 4 mg/kg body-weight given one to 3 times per week for 5 to 39 weeks, was given as initial treatment in one patient and after failure of sodium stibogluconate in seven. Toxic effects included nephritis, hepatitis, transient diabetes and subcutaneous abscesses. Two patients were cured, two responded partially, three showed no response and one, after apparent cure, relapsed and was unresponsive to additional pentamidine treatment. Low-frequency, long-duration pentamidine was often useful in maintaining any improvement made during treatment with the less well tolerated high-dose, high frequency sodium stibogluconate. We observed the step-wise development of resistance to both sodium stibogluconate and pentamidine. The problems of managing patients with visceral leishmaniasis which is unresponsive to conventional doses of pentavalent antimonials are discussed and some tentative suggestions put forward.

Topics: Amidines; Antimony Sodium Gluconate; Child; Drug Resistance; Female; Gluconates; Humans; Leishmaniasis, Visceral; Male; Nephritis; Pentamidine; Spleen

Five patients with long-standing visceral leishmaniasis who were unresponsive to sodium stibogluconate, 20 mg antimony/kg body-weight once or twice daily, were treated for 14 to 54 days with a combination of sodium stibogluconate at the same dose plus allopurinol at a dose of 20 mg/kg body-weight per day in three divided doses. This combination was safe and effective. Negative splenic aspirate smears were obtained from all patients within 19 days, and none has relapsed in at least 12 months of follow-up.

Topics: Adolescent; Allopurinol; Antimony Sodium Gluconate; Child; Drug Resistance; Drug Therapy, Combination; Female; Gluconates; Humans; Leishmaniasis, Visceral; Male; Spleen

A better knowledge of the mechanisms of resistance of leishmanias to drugs, of their survival strategy and the investigation of the immune mechanisms developed by the host against these parasites would be of the highest importance in the therapeutic approach of the disease, for a better use of available drugs, to try to stop the infectious process and to develop and immunotherapy and an efficient protection against the disease.

Topics: Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents; Drug Resistance, Microbial; Humans; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Mice; Organometallic Compounds; Pentamidine

This study compared splenic and hepatic uptake of free and liposome-entrapped sodium antimony gluconate after i.v. administration to mice infected with Leishmania donovani. It was demonstrated that entrapment within liposomes greatly altered the kinetics of uptake of the drug. We were also able to show that liposomes composed of sphingomyelin, stearylamine and cholesterol were marginally better than any other preparation in delivering entrapped drug to liver and spleen. X-ray microanalytical studies on the uptake of liposomes by Kupffer cells infected with L. donovani have indicated that internalised liposomes probably fuse with parasitophorous vacuoles, transferring their contents into the immediate locality of the leishmanial parasites. It is proposed that this is the way in which liposome entrapped antileishmanial agents have an enhanced therapeutic effect over free drug therapy.

Topics: Animals; Antimony Sodium Gluconate; Gluconates; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred Strains; Microscopy, Electron; Phagocytes; Spectrophotometry, Atomic; Spleen; Vacuoles

This epidemic of kala-azar in Bihar, India, started from a small block and gradually spread to almost all of North Bihar. Vaishali was the district most affected, with the highest incidence rate of 5.9 per thousand in 1978. The epidemic spread more to the east than to the west. In 1977 there were 100,000 cases of kala-azar in Bihar and in Vaishali district the death rate was 28.7% of affected cases. It took five years to control the epidemic. 750 parasitologically confirmed cases of kala-azar were studied. The male:female ratio was 5.5:1. 63.4% of cases were aged 10 to 29 years. Clinical features were classical. Sodium stibogluconate, used as a first line drug, was effective in 92.6% of cases. By increasing the course of antimonial therapy from 10 to 20 days the relapse rate was reduced to 0.5% compared with 15% in the previous epidemic. Kala-azar patients who also had tuberculosis were treated with the antimonial and antituberculosis drugs concurrently and all cases recovered. 86 cases unresponsive to sodium stibogluconate were given pentamidine, which was effective in 93.4%. Side effects with sodium stibogluconate were minimal, but were common and serious with pentamidine. The need for a safer drug effective in cases which do not respond to antimony was very evident. 20 cases of post kala-azar dermal leishmaniasis (PKDL) were reviewed: two had no previous previous history of kala-azar. The relapse rate was higher in PKDL than in kala-azar.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Disease Outbreaks; Female; Humans; India; Infant; Infant, Newborn; Leishmaniasis; Leishmaniasis, Visceral; Male; Middle Aged; Pentamidine

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Drug Therapy, Combination; Female; Gluconates; Humans; Kenya; Leishmaniasis, Visceral; Male

Topics: Antimony Sodium Gluconate; Cell Division; Female; Gluconates; Humans; Leishmaniasis, Visceral; Lymphocyte Activation; Male; Phytohemagglutinins

A method has been defined for infecting primary mouse peritoneal macrophages with amastigotes of Leishmania donovani in vitro, and analysing the response of the infected macrophages to treatment with drugs. The growth of intracellular amastigotes was inhibited by all clinically used antileishmanial drugs. Toxic effects on macrophages were observed with some drugs. Other experimental antileishmanial compounds were active in this system. This test is proposed as an initial screening test for the discovery of novel antileishmanial compounds.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Culture Media; Gentamicins; Humans; Leishmania; Leishmaniasis, Visceral; Macrophages; Male; Mice

Topics: Allopurinol; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Pentamidine

Topics: Animals; Antimony Sodium Gluconate; Egypt; Gluconates; Leishmaniasis, Visceral; Male; Rats

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Drug Administration Schedule; Gluconates; Humans; Leishmaniasis, Visceral

The course of immunological parameters in a 2 year old patient with mediterranean kala-azar is reported. Plasma-fibronectin was reduced to 33% of the normal value at the time of diagnosis. When the clinical symptoms of the disease were most severe, a marked activation of complement without demonstrable circulating immune complexes was observed. Therapy with sodium-stibogluconate lead to improvement of the child's condition, normalization of complement reaction and fibronectin levels, and detection of circulating immune complexes. The activity of the disease seems to be well indicated by the level of C-reactive protein and the complement cleavage product C3 d. Incubation of living Leishmania donovani with normal human serum leads to activation of complement in vitro.

Topics: Antibodies; Antigen-Antibody Complex; Antimony Sodium Gluconate; C-Reactive Protein; Child, Preschool; Complement Activation; Complement C3; Complement C3d; Fibronectins; Humans; Leishmania; Leishmaniasis, Visceral; Male

Sixty four Kenyan patients with visceral leishmaniasis were treated with sodium stibogluconate (Pentostam) (40 patients) or various combinations of Pentostam and allopurinol (24 patients). Three patients, initially considered cured after Pentostam, relapsed but responded to further treatment. Sixty two were cured and two patients died. The treatment and the clinical, haematological and parasitological response to treatment are described in detail. If follow up is impossible or unlikely it is advised to continue treatment until parasitological cure is obtained. Prolonged courses of Pentostam, which were required in some patients, resulted in cures and apparently were non toxic. Consideration is to be given to extended treatment with Pentostam before more toxic drugs such as pentamidine and amphotericin B are given.

Topics: Adolescent; Allopurinol; Antimony Sodium Gluconate; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Gluconates; Humans; Kenya; Leishmaniasis, Visceral; Male; Middle Aged; Recurrence

Of 16 patients with kala-azar treated with sodium stibogluconate (0.1 ml/kg body weight a day), one died on the 12th day of treatment and nine were cured by a 30-day course, although two subsequently relapsed. Extending the course cured a further five patients, and in one patient allopurinol was used in addition before a cure was achieved. Clinical and hematological recovery began within a few days of the start of treatment, but parasites continued to be seen in splenic aspirates for 3 weeks or more.

Topics: Antimony Sodium Gluconate; Erythrocyte Indices; Female; Gluconates; Hemoglobins; Humans; Kenya; Leishmania; Leishmaniasis, Visceral; Leukocyte Count; Male; Spleen

Small-intestinal function was studied in 10 patients with visceral leishmaniasis. Vitamin-A absorption was impaired in 7 and d-xylose in 1. In 5 of the 10 patients Leishmania were demonstrated in biopsy specimens of intestinal mucosa. Parasitised macrophages were present in villous tips and less commonly in the lamina propria and submucosa; a moderate inflammatory infiltrate was composed of lymphocytes and plasma cells. 2 patients had partial villous atrophy. There was no correlation between intensity of parasitisation and severity of malabsorption. After treatment with sodium stibogluconate there was a significant improvement in absorption of vitamin A and d-xylose, and biopsy specimens became normal. In 1 patient visceral leishmaniasis was thought to be the cause of chronic diarrhoea.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Biopsy; Child; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Jejunum; Leishmaniasis, Visceral; Male; Middle Aged; Vitamin A; Xylose

A regimen of combined immunostimulation and chemotherapy for the elimination of Leishmania donovani amastigotes was evaluated. An in vitro experimental model utilized cultured peritoneal macrophages from C57B1/6 mice infected with L. donovani tissue forms. Partial or complete activation of macrophages as judged by killing of tumor cells significantly enhanced the efficacy of sodium antimony gluconate (Pentostam). The quantity of drug required for elimination of parasites from immunostimulated cells was considerably lower than that required to achieve comparable amastigote killing in thioglycolate-elicited macrophages. In contrast, amphotericin B cleared infected cells of amastigotes at comparable drug levels when tested with immunostimulated and unstimulated macrophages. Several drugs tested inhibited the conversion of amastigotes to promastigotes in vitro but were ineffective in killing of intracellular tissue forms. Allopurinol and difluoromethylornithine (DMFO) blocked amastigote conversion significantly. These drugs at high concentrations, however, exerted only minimal toxicity for amastigotes residing within macrophages. Efficacy of combined therapy was also demonstrated in vivo. Immunoenhancement of L. donovani-infected mice with Corynebacterium parvum vaccine combined with a regimen of sodium antimony gluconate was significantly more effective than was immunotherapy or drug therapy alone.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Female; Immunization; Leishmania; Leishmaniasis, Visceral; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL

Metronidazole has been claimed in several earlier reports to be active in human cases of leishmaniasis and trypanosomiasis. Its efficacy against the protozoa causing these diseases was tested in hamsters infected with Leishmania mexicana or L. donovani, and in mice infected with Trypanosoma brucei brucei. In separate experiments, hamsters were either inoculated intradermally into the nose with 5 million amastigotes of L. mexicana or intracardially with 10-30 million amastigotes of L. donovani, and mice were infected intraperitoneally with 30 million T. b. brucei. Metronidazole was administered in four oral doses on alternate days for a total of 375 mg/kg to hamsters and 500 mg/kg to mice. Sodium stibogluconate (Pentostam) served as a positive control. In hamsters the extent of infection was assessed by the appearance of flagellates in blood agar cultures of nose and spleen, by counting amastigotes in nose and liver impression smears, and by measuring the size of nose lesions. Ultrastructure of nose lesions before and after treatment with metronidazole or Pentostam was also evaluated. Infection in mice was assessed by the extent of parasitemia and/or survival to 30 days. In no case did metronidazole-treated animals differ from untreated controls. Metronidazole shows no activity against experimental infections of leishmaniasis or trypanosomiasis in these animal models.

Topics: Animals; Antimony Sodium Gluconate; Cricetinae; Leishmaniasis; Leishmaniasis, Visceral; Mesocricetus; Metronidazole; Mice; Microscopy, Electron; Nose; Pentamidine; Trypanosoma brucei brucei; Trypanosomiasis, African

In vitro lymphocyte blastogenesis stimulated by phytohaemagglutinin (PHA), streptococcal antigens (SKSD) and leishmanial antigens were used to assess T cell responsiveness in one patient with kala-azar before and after therapy. During the illness, responses to PHA and SKSD but not to leishmanial antigens could be detected. After treatment lymphocytes responded to all three stimuli when cells were cultured in convalescent plasma, but failed to respond to leishmanial antigens when cultured in plasma obtained before treatment. These observations suggest the presence of a circulating inhibitor of anti-leishmanial T cell responsiveness in kala-azar, and warrant further investigation.

Topics: Adult; Antimony Sodium Gluconate; Humans; Leishmania; Leishmaniasis, Visceral; Lymphocyte Activation; Male; T-Lymphocytes

Topics: Antimony Sodium Gluconate; Europe; Humans; Leishmaniasis, Visceral; Male; Middle Aged; Prognosis

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Kenya; Leishmaniasis, Visceral; Male

The therapeutic and prophylactic effect of dehydroemetine and pentostam on Leishmania donovani in experimentally infected golden hamsters (Mesocricetus auratus) have been investigated. The intracardially infected hamsters with L. donovani and treated with dehydroemetine showed significantly lower weights in liver and spleen, and less in spleen length than those treated with pentostam. Dehydroemetine and pentostam failed to provide these animals with any protection against experimental infection with L. donovani when the drugs were administered prophylactically.

Topics: Animals; Antimony Sodium Gluconate; Cricetinae; Emetine; Gluconates; Leishmaniasis, Visceral; Lethal Dose 50; Male; Mesocricetus

Topics: Adult; Anemia; Antimony Sodium Gluconate; Diagnosis, Differential; Fever of Unknown Origin; Hepatomegaly; Humans; Leishmaniasis, Visceral; Leukopenia; Male; Splenomegaly

Allopurinol was used in the treatment of 10 patients with kala-azar. Of six patients who had previously failed to respond satisfactorily to Pentostam, "cures" were achieved in four. However, it was necessary to add Pentostam to the allopurinol in one, and another relapsed after apparent "cure" but again responded to allopurinol. The response of four patients who had had no previous treatment for kala-azar was less satisfactory.

Topics: Adolescent; Adult; Allopurinol; Antimony Sodium Gluconate; Child; Child, Preschool; Female; Hemoglobins; Humans; Leishmaniasis, Visceral; Male; Spleen

Topics: Adult; Aged; Antimony Sodium Gluconate; Humans; Leishmaniasis, Visceral; Male; Mediterranean Islands; Middle Aged; Travel

Kenyan kala-azar is sometimes unresponsive to a standard course of sodium stibogluconate. The renal excretion of sodium stibogluconate was therefore studied in patients with kala azar and in volunteers; both urine and serum levels of sodium stibogluconate were measured. After intravenous injection sodium stibogluconate seemed to be distributed throughout the extracellular fluid and to have a renal clearance similar to that of inulin. At 6 h blood levels had fallen to less than 1% of peak values. After intramuscular injection, peak blood levels were lower and more sustained. However, more than 80% was excreted in the first 6 h, and blood levels fell to around 1% of peak values in 16 h. The dangers of cumulative toxicity may be exaggerated, and restriction of courses of sodium stibogluconate to 30 days or even to 10 days (in the U.S.A.) may not be necessary. If shorter courses are ineffective prolonged and continued courses may be given provided that renal function is assessed and the dosage is adjusted when indicated.

Topics: Antimony Sodium Gluconate; Gluconates; Humans; Injections, Intramuscular; Injections, Intravenous; Kenya; Kidney; Leishmaniasis, Visceral

A patient with a rare cause of fever of unknown origin, visceral leishmaniasis (kala-azar), is reported. The diagnosis was made by exploratory laparotomy and splenectomy after diagnostic studies had failed to reveal the cause of the fever. The patient was cured with a 6-day course of therapy with Pentostam (sodium antimony gluconate). Visceral leishmaniasis should be considered in the differential diagnosis of patients with obscure fever who have traveled in endemic areas.

Topics: Adult; Antimony Sodium Gluconate; Diagnosis, Differential; Fever of Unknown Origin; Humans; Leishmaniasis, Visceral; Male

A description is given of two methods for investigating the action of drugs against a viscerotropic Leishmania in mice. The parasite employed was isolated from a patient with kala-azar in Ethiopia. It is designated 'L. infantum LV9' and produces a visceral infection in NMRI mice. The biochemical typing characters of the parasite are described. In Method A, infected animals were treated from the 5th or 6th day after infection (D + 5 or D + 6) for five consecutive days. They were sacrificed 24 hours after the completion of drug treatment and an estimate was made of the amastigote load in the liver. A comparison of this with untreated controls gives an index of activity of a test drug, from 0 to 3. Method B is similar except that the ED50 and ED90 are determined by graphic analysis of data from graded drug doses. A comparison is made with sodium stibogluconate used as a positive drug control to yield a 'Pentostam Index'. The course of infection in BALB/c and NMRI mice is compared with that in random-bred Swiss mice in which 'L. infantum LV9' produces an inconsistent infection. An inoculum of 10(7) amastigotes produces a peak parasite intensity between D + 15 and D + 20. The ED50 and ED90 of sodium stibogluconate (Pentostam) (as Sbv) in Method B are 22 x 5 and 46 x 5 mg/kg sc daily x 5. (By Method A the single dose figures are 65 and 280 mg/kg.) For routine use a standard dose level of 120 mg/kg sc daily x 5 of Pentostam (Sbv) is used in Method B. The ED50 and ED90 of meglumine antimoniate (Glucantime) (as Sbv) in Method B are 11 x 6 and 66 x 7 mg/kg sc daily x 5. Data are given for other antimonials in Method A. Pentamidine and diminazene aceturate proved to have a slow action which was more readily demonstrated if the observation period was prolonged. Amphotericin B was moderately active but toxic to the host. The relevance of these models and a comparison of data found in the mouse and hamster are debated.

Topics: Amphotericin B; Animals; Antimony Sodium Gluconate; Disease Models, Animal; Drug Evaluation, Preclinical; Leishmania; Leishmaniasis, Visceral; Liver; Mice

A 22-year-old man with fever, hepato-splenomegaly and severe pancytopenia is described in whom the histologic features of the spleen, liver and lymph nodes were consistent with malignant histiocytosis. Characteristic Leishman-Donovan bodies were demonstrated on a bone marrow aspirate, and the diagnosis of visceral leishmaniasis was confirmed by culturing the flagellated forms of the pathogen, and by an excellent response to sodium stibogluconate. In view of the similarity in clinical and histologic appearance, visceral leishmaniasis must be considered in the differential diagnosis of malignant histiocytosis in geographic areas where leishmaniasis is still endemic.

Topics: Adult; Antimony Sodium Gluconate; Bone Marrow; Diagnosis, Differential; Histiocytes; Humans; Leishmaniasis, Visceral; Liver; Lymph Nodes; Lymphatic Diseases; Male; Spleen

Kala-azar, a parasitic disease caused by Leishmania donovani, is usually found in tropical areas but may occasionally occur in other regions such as the Mediterranean. A case of kala-azar in a women who had been on a holiday in Greece is reported. The parasite was demonstrated in lymph node biopsies and bone marrow smears and treatment with stibogluconate was begun. High levels of circulating immune complexes were demonstrable before and during the demonstration of parasites; the immune complexes were partially characterized. The diminution of complexes in serum paralleled the regression of clinical symptoms, suggesting a relationship between the clinical course and levels of circulating immune complexes. The disease may be a serum sickness-like syndrome induced by the parasite.

Topics: Adult; Antigen-Antibody Complex; Antimony Sodium Gluconate; England; Female; Greece; Humans; Leishmania; Leishmaniasis, Visceral; Lymph Nodes; Switzerland; Travel

The clinical and laboratory features, and the response to treatment of visceral leishmaniasis were studied in 18 hospitalized patients. Clinical and laboratory findings were similar to those in patients with kala-azar in the Sudan and East Africa. Fever, heptosplenomegaly, relative lymphocytosis, leukopenia, low platelet counts, and severe anemia were common findings. Pentostam (sodium stibogluconate) was used to treat 17 patients and Neostibosam (ethylstibamine) for one. Three patients died. Four out of the 18 patients had not visited any known endemic area but the significance of this finding has not been fully evaluated.

Topics: Adolescent; Adult; Antimony Sodium Gluconate; Child; Ethiopia; Female; Hospitals, General; Humans; Leishmaniasis, Visceral; Male

The article reports on a case of visceral leishmaniasis in a 3-year-old child of German residents in Rome who had passed two vacations on the isle of Ischia. Initial signs were intermittent temperatures, marked anorexia, hepatosplenomegaly and pancytopenia, with spontaneous recovery after three weeks. At that time, leishmania serology was already positive, whereas no leishmania were found in several bone marrow preparations despite a most thorough search. During the following eight weeks, the patient had chickenpox and mumps. During the mumps, relapse of the visceral leishmaniasis occurred, associated with a dramatic increase of the hepatosplenomegaly and recurring pancytopenia. It was only now that we could discover multiple leishmania infection of the bone marrow. Subsequent therapy with sodium stibogluconate (Pentostam) was effective without any complications, and eventually cured the patient.

Topics: Antimony Sodium Gluconate; Chickenpox; Child, Preschool; Hepatomegaly; Humans; Leishmaniasis, Visceral; Male; Mumps; Pancytopenia; Splenomegaly

Topics: Animals; Antimony; Antimony Potassium Tartrate; Antimony Sodium Gluconate; Dose-Response Relationship, Drug; Gluconates; Leishmaniasis, Visceral; Liposomes; Mice

The chemotherapeutic effect of a new diamidine, HOE 668, the p-(4-amidino-phenoxy)-benzaldehyde-p-amidino-phenylhydrazone dihydrochloride, was compared with that of known anti-leishmanial drugs in golden hamsters infected with Leishmania donovani. The effect of HOE 668 against visceral leishmaniasis proved superior to that of pentamidine isethionate and the pentavalent antimonial drugs, sodium stibogluconate and N-methylglucamine antimoniate. However, HOE 668 can be used only experimentally because of its toxicity. Its very good anti-leishmanial action qualifies HOE 668 as a standard compound in screening tests.

Topics: Amidines; Animals; Antimony; Antimony Sodium Gluconate; Cricetinae; Drug Evaluation, Preclinical; Leishmaniasis, Visceral; Liver; Meglumine; Mesocricetus; Pentamidine

Topics: Antimony Sodium Gluconate; Cell Division; Humans; Leishmania; Leishmaniasis; Leishmaniasis, Mucocutaneous; Leishmaniasis, Visceral

Reported is a case of visceral leishmaniasis acquired in Greece by a 3-year-old American child. Untreated, this protozoan infection causes a high mortality. Specific treatment is available, making early recognition of the illness important. This child's infection responded dramatically to a course of sodium antimony gluconate. Repeat bone marrow cultures demonstrated persistent organisms and a second course of treatment was required. Monitoring of his response to therapy suggested that serial bone marrow cultures and the neutrophil response may be sensitive means for following the course of this infection.

Topics: Antimony Sodium Gluconate; Child, Preschool; Greece; Humans; Leishmaniasis, Visceral; Male; United States

Topics: Antimony Sodium Gluconate; Child; Child, Preschool; Female; Humans; India; Leishmaniasis, Visceral; Male

Topics: Animals; Antimony Sodium Gluconate; Gluconates; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred C57BL

Topics: Antimony; Antimony Sodium Gluconate; Asian People; Humans; Leishmaniasis; Leishmaniasis, Visceral; Sodium

Topics: Antimony; Antimony Sodium Gluconate; Asian People; Humans; Leishmaniasis; Leishmaniasis, Visceral; Sodium

Topics: Antimony; Antimony Sodium Gluconate; Gluconates; Humans; Leishmaniasis; Leishmaniasis, Visceral; Sodium; Stomach