naphthoquinones and Acute-Disease

Topics: Acute Disease; Adult; Coloring Agents; Dermatitis, Contact; Emergency Nursing; Female; Hair Dyes; Humans; Hypersensitivity; Male; Naphthoquinones; Phenylenediamines; Tattooing

To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.. Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.. The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (+/- SEM) oral clearance (Cl/F) estimates were 313+/-33 ml/h/kg and 1109+/-43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0+/-1.3 l/kg and 22.9+/-1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.. Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.

Topics: Acute Disease; Antimalarials; Artemisinins; Artesunate; Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Naphthoquinones; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Proguanil; Sesquiterpenes; Thailand

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; AIDS-Related Opportunistic Infections; Animals; Antiprotozoal Agents; Atovaquone; Drug Therapy, Combination; Encephalitis; Female; Follow-Up Studies; Humans; Male; Naphthoquinones; Pyrimethamine; Sulfadiazine; Time Factors; Toxoplasma; Treatment Outcome

The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P < 0.002). The atovaquone/proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in < 10% of the patients in either group, with the exception of increased vomiting found in the atovaquone/proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Atovaquone; Drug Combinations; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Naphthoquinones; Proguanil; Thailand; Treatment Outcome

Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria.. This open label, randomized trial compared atovaquone and proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment.. Both regimens were effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and proguanil hydrochloride (73).. In Kenyan children the combination of atovaquone and proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.

Topics: Acute Disease; Animals; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Therapy, Combination; Feces; Female; Humans; Malaria, Falciparum; Male; Naphthoquinones; Phenanthrenes; Plasmodium falciparum; Proguanil; Treatment Outcome

The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of atovaquone and proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambaréné, Gabon.. 142 adults were randomly allocated either a combination treatment of atovaquone 1000 mg daily and proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence.. In the atovaquone plus proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0.022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with atovaquone plus proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%).. Atovaquone and proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon.

Topics: Acute Disease; Adult; Amodiaquine; Antimalarials; Atovaquone; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Gabon; Humans; Malaria, Falciparum; Male; Naphthoquinones; Proguanil; Time Factors; Treatment Outcome

1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children (< or = 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimalarials; Atovaquone; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones; Proguanil

Clinical studies have shown atovaquone (ATQ), a new blood schizontocidal drug, in combination with proguanil (PROG) to be very effective in the treatment of acute multidrug-resistant falciparum malaria. The multiple dose pharmacokinetics of PROG were determined in Thai patients with acute falciparum malaria given PROG alone (200 mg PROG twice a day for 3 days, n = 4) and concurrently PROG and ATQ (200 mg PROG and 500 mg ATQ twice a day for 3 days, n = 12). There were no statistical differences (p > 0.05) in the area under the plasma drug concentration-time curve (AUC), apparent oral clearance (CL/F) and elimination half-life (t1/2) of PROG between patients given PROG alone and PROG/ ATQ. The median (range) kinetic values of PROG in patients given PROG alone and PROG/ATQ were respectively: CL/F = 1.25 l/h/kg (0.99-1.45) and 0.95 (0.73-1.32) l/h/kg, and t1/2 = 14.2 hours (9.3-16.8) and 13.6 hours (9.1-17.6). The CL/F and t1/2 of PROG in the Thai patients treated with the 2 treatment regimens were also comparable to values reported in healthy Thai volunteers given a standard prophylactic dose (200 mg PROG). The results of this preliminary study suggest that ATQ is unlikely to affect the pharmacokinetics of PROG to a clinically important extent at an ATQ dosage of 500 mg twice a day for 3 days in malaria infected patients.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Atovaquone; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Humans; Intestinal Absorption; Malaria, Falciparum; Male; Metabolic Clearance Rate; Naphthoquinones; Proguanil

The clinical experience of human immunodeficiency virus (HIV) + patients treated with oral atovaquone for acute Pneumocytstis carinii pneumonia (PCP) under a Treatment Investigational New Drug (IND) protocol (mild or moderate PCP) and an Open-Label Study protocol (severe PCP) was evaluated. A total of 940 patients intolerant of or unresponsive to trimethoprimsulfamethoxazole were enrolled from private practices, clinics, and institutional HIV treatment centers in the United States. Demographics data and the history and severity of PCP were collected at enrollment. The number of therapy days, adverse experiences, clinical response to therapy, and mortality were collected at day 21. Reporting of serious, unexpected adverse experiences attributable to therapy was required. Of the 760 (96%) patients with mild to moderate disease for whom follow-up observation was complete, 591 (78%) responded clinically to treatment, 177 patients (23%) discontinued treatment prematurely, and 50 patients (7%) died. Of the 140 patients (95%) with severe PCP with follow-up data, 79 (56%) responded to treatment, 45 (32%) discontinued treatment early, and 53 patients (38%) died. Adverse events that resulted in temporary or permanent discontinuation of therapy included diarrhea, vomiting, elevated liver enzyme levels, nausea, and fever. No serious unexpected adverse events attributable to the drug were reported. The treatment IND mechanism enabled a large number of patients with acute PCP to be treated with this experimental therapy while the drug was under regulatory view.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; Atovaquone; Child; Child, Preschool; Drugs, Investigational; Female; Follow-Up Studies; HIV Seropositivity; Humans; Infant; Male; Middle Aged; Naphthoquinones; Pneumonia, Pneumocystis

Although studies in oncology have well explored the pharmacological effects of

Topics: Acute Disease; Animals; Apoptosis; Caspase 3; Graft Rejection; Heart Transplantation; Imidazoles; Interferon-gamma; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Naphthoquinones; Survivin; T-Lymphocytes; Transplantation, Heterotopic

Chagas disease, which is caused by the protozoan Trypanosoma cruzi, is endemic to Latin America and mainly affects low-income populations. Chemotherapy is based on two nitrocompounds, but their reduced efficacy encourages the continuous search for alternative drugs. Our group has characterised the trypanocidal effect of naphthoquinones and their derivatives, with naphthoimidazoles derived from β-lapachone (N1, N2 and N3) being the most active in vitro.. In the present work, the effects of N1, N2 and N3 on acutely infected mice were investigated.. in vivo activity of the compounds was assessed by parasitological, biochemical, histopathological, immunophenotypical, electrocardiographic (ECG) and behavioral analyses.. Naphthoimidazoles led to a decrease in parasitaemia (8 dpi) by reducing the number of bloodstream trypomastigotes by 25-50% but not by reducing mortality. N1 protected mice from heart injury (15 dpi) by decreasing inflammation. Bradycardia was also partially reversed after treatment with N1 and N2. Furthermore, the three compounds did not reverse hepatic and renal lesions or promote the improvement of other evaluated parameters.. N1 showed moderate trypanocidal and promising immunomodulatory activities, and its use in combination with benznidazole and/or anti-arrhythmic drugs as well as the efficacy of its alternative formulations must be investigated in the near future.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Chagas Disease; Disease Models, Animal; Electrocardiography; Male; Mice; Naphthoquinones; Nitroimidazoles; Parasitemia; Time Factors; Trypanocidal Agents

ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy.. Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells. The overall protein expression alteration resulting from shikonin treatment was investigated using proteomics methods. Western blotting was performed to quantify the alteration in protein expression in HL-60 after shikonin treatment. Silencing and overexpression studies were carried out to highlight the therapeutic role of ERP57 in shikonin effect on AML cells.. Shikonin induces apoptosis in HL-60 cells without significant effect on Primary cells from healthy volunteers. The apoptotic effect was dose and time dependent and was accompanied by strong alteration in cell proteome. Among the proteins targeted by shikonin, ERP57 was significantly downregulated in HL-60 after treatment. Compared to healthy control ERP57 was found to be highly expressed in AML cell line HL60 and was downregulated after shikonin treatment. Overexpression of ERP57 protected HL-60 from shikonin induced apoptosis, whereas knockdown of ERP57 expression resulted in increase in shikonin induced apoptosis.. Our results demonstrate that ERP57 plays a crucial role in resistance towards shikonin induced apoptosis in AML cells. Targeting of ERP57 might offer a new therapeutic option for the treatment of acute myeloid leukemia.

Topics: Acute Disease; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Survival; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Electrophoresis, Gel, Two-Dimensional; Endoplasmic Reticulum Stress; Flow Cytometry; HL-60 Cells; Humans; Leukemia, Myeloid; Molecular Structure; Naphthoquinones; Protein Disulfide-Isomerases; Proteome; Proteomics; RNA Interference; Time Factors; Tunicamycin

The efficacy of lawsone against L-arginine induced acute pancreatitis was determined at 24 h by determination of serum levels of amylase, lipase and proinflammatory cytokines [tumor necrosis factor (TNF)-alpha, C-reactive proteins and interleukin (IL)], pancreatic myeloperoxidase (MPO) activity, lipid peroxidation (thiobarbituric acid reactive substances (TBARS)], nitrate/nitrite levels, and the wet weight/body weight ratio. Lawsone and methylprednisolone treatments significantly attenuated the L-arginine- induced increases in pancreatic wet weight/body weight ratio, and decreased the serum levels of amylase and lipase, and TNF-alpha and IL-6 and significantly lowered pancreatic levels of MPO, TBARS, and nitrate/nitrite. The histoimmunological findings further proved the amelioration of pancreatic injury by lawsone and further proved anti-inflammatory and antioxidant agent property of lawsone.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Arginine; C-Reactive Protein; Cytokines; Enzyme Inhibitors; Interleukin-6; Interleukins; Male; Naphthoquinones; Neutrophils; Oxidative Stress; Pancreas; Pancreatitis; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Topics: Acute Disease; Allergens; Child; Dermatitis, Allergic Contact; Humans; Male; Naphthoquinones; Phenylenediamines; Tattooing

The role of erythrocytes in realization of interrelation of the immunomodulating effects of lysozyme and naphthoquinones in normal and under conditions of acute hemorrhage was studied. Interaction of lysozyme and menadione at the level of intact erythrocytes and their stroma resulted in formation of highly efficient immunomodulating factors. The effect of such factors under conditions of acute hemorrhage was mediated by cytokines of the spleen macrophagael cells.

Topics: Acute Disease; Adjuvants, Immunologic; Animals; Drug Synergism; Erythrocytes; Hemorrhage; Leukocytes; Muramidase; Naphthoquinones; Rats; Rats, Wistar; Spleen; Vitamin K 1; Vitamin K 3

The efficacy of atovaquone (ATO) combined with clindamycin (CLI) against Toxoplasma gondii was examined in murine models of infection with a mouse-non-virulent (Me49) strain. Swiss-Webster mice inoculated by mouth with 10 or 20 cysts were treated with ATO and CLI alone or combined at dosages of ATO 5-100 and CLI 25-400 mg/kg/day for 2-4 weeks. Drug treatment was initiated (i) day 4 post-infection (acute infection), (ii) 3 months post-infection (chronic infection) and (iii) following a 2-3 week course of treatment with dexamethasone (DXM) alone or combined with cortisone-acetate (CA) introduced 3 months post-infection (reactivated toxoplasmosis). In acute infection, whereas treatment with any drug or drug combination significantly enhanced survival and reduced the brain cyst burden, in mice treated with ATO alone or combined with CLI, the cyst counts were significantly lower than in mice treated with CLI alone. In chronic infection, the decrease in the cyst burden observed 2 weeks after treatment with either drug alone was significant only in mice treated with the combined drugs. Most importantly, in reactivated toxoplasmosis, whereas an effect for the combined drugs was shown in mice suppressed with both DXM alone and combined with CA, in mice pre-treated with DXM a 3 week course of ATO > or = 25 and CLI 50 mg/kg/day significantly increased survival and markedly decreased the cyst burden. The latter effect was long-term, since the cyst burdens in treated mice continued to decrease up to 3 months later, whereas they increased in the untreated mice. The results warrant clinical evaluation of the combination of ATO and CLI in the treatment of toxoplasmosis in both immunocompetent and, more importantly, immunosuppressed patients.

Topics: Acute Disease; Animals; Atovaquone; Brain; Clindamycin; Cysts; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Naphthoquinones; Toxoplasma; Toxoplasmosis, Animal

Haemolytic crisis in glucose-6-phosphate dehydrogenase deficient individuals following topical application of henna occurred in four children: a female neonate (haemoglobin 50 g/l, serum bilirubin 700 micromol/l), who recovered after exchange transfusion; a male infant (haemoglobin 28 g/l) who died despite transfusion; and two preschool children (haemoglobin 40 and 41 g/l respectively).

Topics: Acute Disease; Child, Preschool; Coloring Agents; Fatal Outcome; Female; Glycogen Storage Disease Type I; Hemolysis; Humans; Infant; Infant, Newborn; Male; Naphthoquinones

The hydroxynaphthoquinone, atovaquone (Wellvone, Glaxo-Wellcome Ltd.) was found to have significant activity against Babesia microti, the main cause of human babesiosis in the U.S.A. This activity compares well with that of the most effective babesicide currently available for use in animals, imidocarb dipropionate, that unlike atovaquone is not licensed for use in humans. Treatment with well tolerated doses of atovaquone results in a rapid reduction in parasitemias and an early disappearance of parasites from blood smears. However, in common with all the other babesicides tested, atovaquone did not sterilize gerbils of infection, even at very high daily doses administered for up to 10 days. A combination of atovaquone and clindamycin was more effective than atovaquone alone in the treatment of both acute and chronic infections but failed to eliminate parasites completely.

Topics: Acute Disease; Animals; Antiprotozoal Agents; Atovaquone; Babesiosis; Chronic Disease; Clindamycin; Diminazene; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Gerbillinae; Humans; Imidocarb; Naphthoquinones; Pentamidine; Recurrence

The effect of clindamycin (CLI) combined with autovaquone (ATO) was examined in a murine model of acute toxoplasmosis. Swiss Webster mice intraperitoneally infected with 10(2) or 10(4) tachyzoites of the RH strain of Toxoplasma gondii were perorally treated with either drug alone (for ATO, 5, 25, 50, or 100 mg/kg of body weight/day; for CLI, 25, 50, or 400 mg/kg/day) or both combined (for ATO plus CLI, respectively, 5 plus 25, 25 plus 25, 25 plus 50, 50 plus 50, or 100 plus 400 mg/kg/day) starting with day 1 for 14 days. Survival was monitored during 7 weeks. Residual infection was assessed by a bioassay of representative 4-week survivors and by parasite DNA detection by PCR for representative 7-week survivors. An effect of treatment was shown in all treatment groups compared to untreated control mice (P = 0.0000). Among mice infected with 10(2) parasites, ATO and CLI at any dose combination protected significantly more animals than ATO alone (P = 0.0000), but compared to CLI alone, given its good effect, the combined drugs were no more effective (P > 0.05). For mice infected with 10(4) parasites, the drugs combined at the lowest and highest doses (5 plus 25 and 100 plus 400 mg/kg/day) were, similarly, more effective than ATO alone (P = 0.035 and 0.000, respectively) but not than CLI alone (P > 0. 05). However, treatment with ATO plus CLI at 25 plus 25, 25 plus 50, and 50 plus 50 mg/kg/day protected 20, 33, and 78% of mice, respectively, compared to virtually no survivals among those treated with either drug alone (P < 0.0005), thus demonstrating a significant synergistic effect of ATO and CLI against T. gondii. Furthermore, the dose of ATO at a given dose of CLI was shown to be critical to the effect. Moreover, the absence of residual infection in some survivors shows the potential of this drug combination to eliminate the parasite.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Antiprotozoal Agents; Atovaquone; Brain; Clindamycin; Dose-Response Relationship, Drug; Drug Synergism; Female; Lung; Mice; Naphthoquinones; Polymerase Chain Reaction; Toxoplasma; Toxoplasmosis, Animal

To evaluate the effects of drug therapy on the clinical course of acute acquired Toxoplasma retinochoroiditis and on the number of Toxoplasma cysts present in the brain and ocular tissues in the hamster animal model.. The Syrian golden hamster animal model of Toxoplasma retinochoroiditis was used. In acute disease, systemically administered atovaquone was compared with conventional therapies (pyrimethamine combined with sulfadiazine; clindamycin; and spiramycin). The clinical course of the ocular disease was determined with retinal examination and photography of the fundus. The number of Toxoplasma cysts remaining after treatment was evaluated in aliquots of brain homogenate and in retinal tissue. The effect of atovaquone on cerebral Toxoplasma cyst count was also studied in chronic disease.. None of the drugs administered altered the course of the acute disease, judged by clinical examination. Atovaquone alone significantly reduced the number of cerebral Toxoplasma cysts after acute disease. Atovaquone also significantly reduced the cerebral Toxoplasma cyst count in chronic disease.. Tissue cysts are believed to be responsible for reactivation of Toxoplasma retinochoroiditis. Atovaquone has the potential to reduce the risk of recurrent disease.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Antiprotozoal Agents; Atovaquone; Brain; Chorioretinitis; Chronic Disease; Cricetinae; Disease Models, Animal; Drug Therapy, Combination; Female; Mesocricetus; Naphthoquinones; Retina; Toxoplasma; Toxoplasmosis, Cerebral; Toxoplasmosis, Ocular

The aim of this work was to develop a new pharmaceutical form of atovaquone and to study its activity against Toxoplasma gondii in vitro and in vivo. Nanocapsules were chosen as the oral dosage form of administration. An analytical method was developed to determine the drug content in nanocapsules. The stability of these nanocapsules were assessed by following drug content, size, pH and osmolarity for a period of six months. The in vitro activity of atovaquone-loaded nanocapsules against tachyzoites of T. gondii (RH stain) was comparable to its suspension form. In vivo studies were carried out in murine models of acute and chronic toxoplasmosis. Mice acutely infected with the virulent RH strain were orally treated with a dose regimen of 15 mg/kg/day for 10 days, starting from day 1 post-infection. 75% of the mice receiving atovaquone-loaded nanocapsules survived 30 days post-infection, compared to none of untreated controls and none of mice treated with the suspension with the same dose regimen. In mice chronically infected by the COUL or the ME49 strain (Type II strains), then treated for six weeks, treatment with atovaquone (15 mg/kg/d, nanoparticles or suspension) resulted in a decrease of brain parasitic burden, which was significantly more pronounced in ME49-infected mice and in those treated with drug-loaded nanocapsules. These results show that the sensibility of T. gondii to atovaquone is different according to the strains and that the activity of atovaquone in the treatment of toxoplasmosis is enhanced when administered in nanoparticular form.

Topics: Acute Disease; Administration, Oral; Animals; Antiprotozoal Agents; Atovaquone; Brain; Capsules; Chronic Disease; Colloids; Disease Models, Animal; Drug Carriers; Drug Stability; Female; Lung; Mice; Naphthoquinones; Parasitemia; Solubility; Survival Rate; Suspensions; Temperature; Toxoplasma; Toxoplasmosis, Animal

This study demonstrates the activity of the hydroxynaphthoquinone (HNQ), atovaquone, against Babesia divergens, the cause of a rare but lethal form of human babesiosis. In vitro studies showed that unlike other anti-malarial drugs, the HNQs studied have a high level of anti-babesial activity and atovaquone was more active than imidocarb, the most effective compound used so far for human B. divergens babesiosis and also used routinely for the treatment of bovine babesiosis. Atovaquone also proved to be extremely active against B. divergens in gerbils (Meriones unguiculatus). Acute fulminating infections were effectively treated with as little as 1.0 mg/kg with increasing effectiveness up to 10 mg/kg, which compares well with the activity of imidocarb. Although immunosuppression with dexamethasone slowed the decline of parasitemias after treatment with atovaquone, gerbil survival was unaffected. Pretreatment of gerbils with 4 daily low doses of atovaquone did not have any effect on the development of subsequent infections. However, if treatment was continued after infection, daily doses as low as 0.5 mg/kg effectively suppressed the parasites.

Topics: Acute Disease; Animals; Antiprotozoal Agents; Atovaquone; Babesia; Babesiosis; Cattle; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Erythrocytes; Gerbillinae; Hemoglobinuria; Humans; Naphthoquinones; Parasitemia; Regression Analysis

Current therapy for toxoplasmosis with a synergistic combination of pyrimethamine plus sulfadiazine or pyrimethamine plus clindamycin is not always efficacious and is frequently discontinued due to intolerable toxic effects in immunocompromised individuals, particularly those with AIDS. Trovafloxacin, a new fluoroquinolone with potent activity against Toxoplasma gondii, was examined for potential synergistic activity when combined with other drugs used for treatment of human toxoplasmosis. Combinations of trovafloxacin with clarithromycin, pyrimethamine, or sulfadiazine demonstrated significantly enhanced activities compared to those observed with each drug alone. Our results suggest that combinations of trovafloxacin and other anti-toxoplasma drugs should be further explored for treatment of toxoplasmosis in humans.

Topics: Acute Disease; Administration, Oral; Animals; Anti-Infective Agents; Antiprotozoal Agents; Area Under Curve; Atovaquone; Clarithromycin; Drug Synergism; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Naphthoquinones; Naphthyridines; Rifabutin; Tissue Distribution; Toxoplasmosis, Animal

Topics: Acute Disease; Adenosine Triphosphate; Adult; Antioxidants; Humans; Myocardial Ischemia; Myocardium; Naphthoquinones

The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimalarials; Atovaquone; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Naphthoquinones

Transcription of type 1 human immunodeficiency virus (HIV-1) provirus is governed by the viral long terminal repeat (LTR). Drugs can block HIV-1 replication by inhibiting activity of its LTR. We report that topotecan, beta-lapachone, and curcumin are potent and selective inhibitors of HIV-1 LTR-directed gene expression, at concentrations that have minor effects on cells. At these concentrations, each drug inhibited p24 antigen production in cells either acutely or chronically infected with HIV-1. Their target is transcriptional function of the LTR.

Topics: Acute Disease; Antiviral Agents; Camptothecin; Cells, Cultured; Chronic Disease; Curcumin; Gene Expression Regulation, Viral; HIV Infections; HIV Long Terminal Repeat; HIV-1; In Vitro Techniques; Naphthoquinones; RNA, Viral; Topotecan; Virus Replication

We evaluated the efficacy of buparvaquone in eliminating infection with Babesia equi of European origin in carrier horses and in splenectomized horses with experimentally induced acute infection. When administered at the rate of 5 mg/kg of body weight, IV, 4 times at 48-hour intervals, buparvaquone prompted rapid abatement of parasitemia. However, secondary and tertiary recrudescent parasitemias invariably returned with establishment of the carrier state. Buparvaquone, at the dosage evaluated, had transitory therapeutic efficacy against acute B equi infection in splenectomized horses, but was unable alone to clear carrier infection.

Topics: Acute Disease; Animals; Antibodies, Protozoan; Antiprotozoal Agents; Babesia; Babesiosis; Carrier State; Complement Fixation Tests; Female; Fluorescent Antibody Technique; Horse Diseases; Horses; Injections, Intravenous; Male; Naphthoquinones; Splenectomy

Twenty cross-bred (Bos taurus X Bos indicus) calves, 7-21 days old, were infected by a ground-up tick supernate of Hyalomma anatolicum anatolicum infected with the Hisar isolate of Theileria annulata. Six calves acted as untreated controls and they all died of theileriosis within 17 days of infection. The remaining 14 calves were divided into Group A and B, each consisting of seven calves. All the calves of Groups A and B were treated intramuscularly with buparvaquone (BW 720C) on Day 11 post-infection, when clinical signs of theileriosis were apparent. Each calf received 2.5 mg BW 720 C kg-1 body weight as a single injection. In addition, each calf of Group B was given proprietary haematinics by intramuscular injection, daily for 12 days. In Group A, two calves died of cerebral theileriosis and five were clinically cured. However, four of these five calves later died of anaemia. In Group B, all the calves were clinically cured and none died during the observation period of 1 month. The parasitaemia declined to less than 1% within a fortnight of treatment. The initial declines in haemoglobin concentration and packed cell volume were halted and preinfection values were soon restored. No toxic signs attributable to treatment with buparvaquone were observed.

Topics: Acute Disease; Animals; Antiprotozoal Agents; Body Temperature; Cattle; Erythrocytes; Hematocrit; Hemoglobins; Injections, Intramuscular; Lymph Nodes; Naphthoquinones; Random Allocation; Theileriasis; Ticks

The general background of the role of mycotoxins in human disease is briefly reviewed. The acute effects of the ingestion of the aflatoxins and the role that long term exposure may play in human disease are examined in detail. The necessity for co-operation between chemists, veterinarians, physicians and mycologists in the elucidation of the role of the mycotoxins in human disease is stressed.

Topics: Acute Disease; Aflatoxins; Fusarium; Health; Humans; Mycotoxins; Naphthoquinones; Penicillium; Poisoning