phenanthrenes and Acute-Disease

Topics: Acute Disease; Adult; Animals; Antimalarials; Child, Preschool; Drug Evaluation; Humans; Incidence; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Travel

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 continuing spread of multidrug resistance in Plasmodium falciparum malaria makes the search for alternative treatments ever more urgent. We have investigated the relative efficacy of halofantrine and mefloquine in two paired randomised trials on the Thai-Burmese border, a multidrug-resistant area. In the first trial, 198 patients with acute uncomplicated falciparum malaria were randomly assigned either the standard halofantrine regimen (24 mg/kg) or mefloquine (25 mg/kg). The cumulative failure rates by day 28 were 35% with halofantrine and 10% with mefloquine (p = 0.0002). In the second study of 437 patients, a higher dose of halofantrine (8 mg/kg every 8 h for 3 days = 72 mg/kg) was both more effective and better tolerated than mefloquine 25 mg/kg; the failure rates were 3% and 8% (p = 0.03), respectively, or 1% vs 6% after adjustment for possible reinfections (p = 0.009). The rate of failure was higher after retreatment than after primary treatment in all study groups. Halofantrine 72 mg/kg was especially effective in the retreatment of these recrudescent infections; the failure rate was 44% with mefloquine and 15% with high-dose halofantrine (relative risk 3.0 [95% CI 1.2-7.3], p = 0.008). Thus, high-dose halofantrine is better tolerated and more effective than mefloquine for the treatment of uncomplicated falciparum malaria in this area. However, evidence of possible cardiotoxicity will need to be investigated fully before a role can be established for halofantrine in the treatment of multidrug-resistant malaria.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Child; Child, Preschool; Drug Resistance; Female; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Myanmar; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Recurrence; Refugees; Thailand; Treatment Failure

The clinical efficacy and tolerability of halofantrine, a new antimalarial schizontocide, was studied in a multi-centre trial involving 268 patients ranging in age from 6 months to 58 years. The patients were suffering from acute uncomplicated malaria due to either P. vivax or P. falciparum. Patients were treated orally with 3 doses of halofantrine hydrochloride, 500 mg/6-hourly in adults or 8 mg/kg body weight 6-hourly in children. The overall cure rate was 96.9%. The mean fever clearance time for different species was as follows: P. vivax--39.1 hours, P. falciparum--43.2 hours, mixed infection--60.0 hours, and the mean parasitaemia clearance times were 47.7, 55.1 and 72.0 hours, respectively. Recrudescence was reported in 11 (4.1%) patients, although all of them were parasite-free on Day 7 post-treatment. No haematological or biochemical abnormalities were noted. The drug was very well tolerated and no significant side-effects were reported. Halofantrine was found to be highly effective in acute malaria and offers an important alternative to existing medications.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Antimalarials; Body Weight; Child; Child, Preschool; Female; Fever; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Recurrence; Time Factors; Treatment Outcome

Topics: Acute Disease; Adult; Animals; Antimalarials; Child, Preschool; Drug Evaluation; Humans; Incidence; Infant; Malaria; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Plasmodium falciparum; Prospective Studies; Travel

Halofantrine chlorhydrate 2 per cent suspension was given to 50 children (mean age 6.2 years in a dose of 8 mg/kg three times a day as a single day treatment. The children were born and lived in Gabon, where malaria transmission is continuous. They all had acute Plasmodium falciparum malaria. The children were kept in hospital for 5 days, and regularly followed over a 15-day period. The 50 children were cured and efficacy was evaluated as good in 44 cases, and excellent in six cases, as judged by improvement in their clinical signs and parasitaemia. Two criterias were considered in the evaluation of efficacy: clearance of parasitaemia (mean day 4), fever clearance (mean hour 24). There were two cases of persistences of parasites at day 15 with a very low parasitaemia rate. Tolerance to halofantrine was good from a clinical and biological point of view. Acceptability was excellent in all cases. Halofantrine 2 per cent suspension is a good alternative in the treatment of acute Plasmodium falciparum malaria in children, especially with the present situation of multidrug-resistant strains in Central Africa.

Topics: Acute Disease; Adolescent; Antimalarials; Child; Child, Preschool; Drug Administration Schedule; Female; Gabon; Humans; Infant; Malaria, Falciparum; Male; Phenanthrenes

A multicenter prospective trial was performed to investigate the efficacy and the tolerability of halofantrine in nonimmune patients with malaria imported from areas with drug-resistant falciparum parasites (mainly Africa). Forty-five of the 74 subjects were treated with a one-day regimen (3 x 500 mg) of halofantrine, and the other 29 received the same regimen with an additional treatment on day 7. In the second group, a 100% efficacy rate was demonstrated, but in the group receiving the one-day regimen, four recrudescences were observed in patients with falciparum malaria. Only five mild adverse reactions were seen, which disappeared spontaneously after the end of the treatment. We conclude that halofantrine is highly effective in curing malaria in nonimmune subjects. The treatment scheme for such persons should include an additional treatment on day 7 for nonimmune individuals. This drug was well tolerated in our patients, indicating that halofantrine will be useful in the treatment of multidrug-resistant malaria in nonimmune persons.

Topics: Acute Disease; Adult; Antimalarials; Drug Resistance; Drug Tolerance; Female; Follow-Up Studies; Humans; Malaria; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Phenanthrenes; Travel

Halofantrine has been given to 14 children and 15 adults suffering from an acute attack of P. falciparum malaria and living in Dakar (Senegal) to a total dose of 24 mg/kg/body weight for the first group and 1,500 mg for the second in 3 times at 6-hourly intervals. This treatment has allowed the fever to clear in all cases within 36.3 +/- 19.9 hours and headache to disappear at D3 in 93.1% of cases. A reduction by 93.6% of the average parasite density which amounted before treatment to 27,710 trophozoites/mm3 of blood has been recorded from the day following the beginning of treatment and the parasite clearance obtained in all the patients of whom had chloroquine-resistant P. falciparum strains in mean time of 58.0 +/- 14.7 hours. In 3 cases (10.7%) a recrudescence of parasitemia has been noticed in D14. Only 1 of them was treated again with halofantrine which proved efficient from D2. The only adverse reactions have been nausea, vomiting, a slight diarrhoea and dizziness which affected only 13.8% of the patients. No abnormality has been noticed at a biological level. These results confirm the efficacy and good tolerance of halofantrine and allow to list it among the resource drugs used for the treatment of chloroquine-resistant P. falciparum malaria in our area.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Child; Child, Preschool; Drug Tolerance; Humans; Malaria, Falciparum; Middle Aged; Phenanthrenes; Senegal

In an open clinical trial, thirty patients 14 to 44 years old and with acute uncomplicated falciparum malaria were given halofantrine hydrochloride 500 mg (2 tablets) 6-hourly for 3 doses, a total dose of 1500 mg. All 30 patients were cured, with a mean asexual parasite clearance time of 47.6 hours and mean fever clearance time of 36.6 hours. Post-dosing side-effects occurred in 6 patients consisting of mild to moderate headache, dizziness and abdominal muscle spasm. Drug-induced hemolysis did not occur in two G6PD deficient patients. Twenty-three out of 28 isolates tested (82%) were resistant to amodiaquine, 3 (11%) were resistant to the sulfadoxine-pyrimethamine combination, and all were sensitive to chloroquine, quinine and mefloquine by in vitro microtests. The study confirms the efficacy of halofantrine hydrochloride as a blood schizonticide in falciparum malaria.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Blood Cell Count; Blood Chemical Analysis; Drug Resistance; Hematocrit; Hemoglobins; Humans; Malaria, Falciparum; Parasite Egg Count; Phenanthrenes

The incidence and nature of pruritus induced by chloroquine and halofantrine were studied in 82 patients with acute malaria and in 40 healthy subjects, using a visual analogue scale for quantitating pruritus. Results showed that the proportion of patients with acute malaria manifesting itch to halofantrine was significantly lower than the proportion manifesting itch to chloroquine. Furthermore, the intensity and duration of halofantrine-induced pruritus were significantly lower than those of chloroquine-induced pruritus. The few patients who itched to halofantrine all had a history of itching to chloroquine. The incidence and intensity of chloroquine-induced pruritus were significantly higher in patients with malaria than in healthy subjects. By contrast, there was no significant difference between malaria patients and healthy subjects as regards halofantrine-induced pruritus. These results suggest that itchers to halofantrine may constitute a small group within the population of itchers to chloroquine. Malaria infection appears to enhance chloroquine-induced pruritus but not halofantrine-induced pruritus and this may be of therapeutic importance.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Chloroquine; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kinetics; Malaria; Male; Middle Aged; Pain Measurement; Phenanthrenes; Pruritus

Triptolide (TP), the main active ingredient of

Topics: Acute Disease; Animals; Antioxidants; Ceruletide; China; Disease Models, Animal; Diterpenes; Epoxy Compounds; Gene Expression Regulation; Hep G2 Cells; Humans; Inflammation; Male; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Pancreas; Pancreatitis; Phenanthrenes; Reactive Oxygen Species

Exacerbation of chronic obstructive pulmonary disease (COPD) is characterized by acute airway inflammation and mucus hypersecretion, which is by far the most costly aspect of its management. Thus, it is essential to develop therapeutics with low side effects for CODP exacerbation. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA isolated as the major active component of Chinese herbal medicine Danshen. Although it possesses anti-inflammatory, anti-oxidative and anti-apoptotic properties, it remains unknown whether STS protects against COPD exacerbation. In this study, we challenged cigarette smoke (CS)-exposed mice with lipopolysaccharide (LPS), and then treated these mice with STS. We found that STS significantly ameliorated pulmonary inflammatory responses, mucus hypersecretion and lung function decline in CS-exposed mice challenged with LPS. STS treatment also significantly attenuated increased IL-6 and IL-8 releases from cigarette smoke extract (CSE)-treated human bronchial epithelial cells (16HBE) challenged with LPS. Mechanistically, STS reduced activation of ERK1/2 and NF-κB in lungs of CS-exposed mice and CSE-treated 16HBE cells challenged with LPS. Taken together, STS protects against acute exacerbation of CS-induced lung injury, which provides a promising and potential therapeutic avenue to halt acute exacerbation of COPD.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cell Line; Cigarette Smoking; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal; Humans; Lung; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phenanthrenes; Pulmonary Disease, Chronic Obstructive; Signal Transduction

Triptolide (TP), the major active compound derived from the traditional Chinese medicine Tripterygium wilfordii Hook. F, possesses an excellent pharmacological profile of immunomodulatory and anti-tumor activities. However, the application of TP was restricted due to its narrow therapeutic window and side effects, especially its hepatotoxicity. This study was designed to investigate the role of inflammasome in TP-induced acute liver toxicity. After the administration of TP at the dose of 600 μg/kg for 12 h or 24 h, we examined the serum biochemical parameters, liver histopathological changes, the expression of liver inflammatory factors, and the activation of NLRP3 inflammasome. Mice treated with TP displayed liver injury with a time-dependent increase of serum transaminases and activation of NLRP3 inflammasome, accompanied by the elevation of neutrophils infiltration. Further results implied that the activation of TLR4-Myd88-NF-κB pathway and oxidative stress induced by a single dose of TP (600 μg/kg) might participate in the activation of NLRP3 inflammasome. To investigate whether the activation of inflammasome participates in the liver damage induced by TP, a single dose of Ac-Yvad-Cmk (Caspase-1 inhibitor) was injected before TP administration. Ac-Yvad-Cmk pretreatment effectively prevented the increase of Cleaved Caspase-1 and inhibited the maturity of IL-1β. Additional studies revealed that Ac-Yvad-Cmk pretreatment decreased the recruitment of neutrophils and inhibited the production of massive pro-inflammatory factors. Taken together, our results revealed that activation of inflammasome aggravated the acute liver toxicity induced by TP. Inhibition of inflammasome could serve as a novel therapeutic target for the amelioration of TP-induced hepatotoxicity.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Cytokines; Diterpenes; Epoxy Compounds; Female; Inflammasomes; Liver; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; NF-KappaB Inhibitor alpha; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phenanthrenes; Toll-Like Receptor 4

Triptolide is one of the most widely used and one of the most potent Chinese traditional herbal medicines. However, side effects, especially nephrotoxicity, limit the use of triptolide. It has been reported that oxidative stress is involved in drug-induced nephrotoxicity. In the present study, we focused on observing triptolide-induced acute nephrotoxicity in rats and investigating whether or not oxidative stress is involved in the pathogenesis of this process. The results showed that a single large dose peritoneal injection of triptolide caused severe oxidative stress characterized by significant decreases of renal SOD and GSH-Px activities, as well as significant increase of renal MDA content and also led to severe impairment of renal structure and function characterized by injury of renal tubules observed in HE-stained and TUNEL-stained slides and increases of Cre and BUN concentrations in a short time. However, pretreatment with the antioxidant vitamin C significantly ameliorated triptolide-induced depletion in renal SOD and GSH-Px activities, caused marked normalization of renal MDA content and also blunt the impairment of renal tubules and renal function. These results suggest that triptolide induces oxidative stress via impairing the antioxidant system, and oxidative stress contributes, at least in part, to the mechanism of triptolide-induced acute nephrotoxicity.

Topics: Acute Disease; Animals; Antioxidants; Apoptosis; Body Weight; Diterpenes; Drugs, Chinese Herbal; Epoxy Compounds; In Situ Nick-End Labeling; Kidney; Kidney Diseases; Kidney Function Tests; Male; Molecular Structure; Organ Size; Oxidative Stress; Phenanthrenes; Rats; Rats, Sprague-Dawley

Relieving pulmonary edema is the key of a successful treatment to seawater drowning. Sodium tanshinone IIA sulfonate (STS) has been observed to reduce lung edema from lipopolysaccharide (LPS)-induced lung injury. In this study the authors investigated whether STS attenuates seawater aspiration-induced acute pulmonary edema, and examined the effects of sodium-potassium adensosine triphosphatase (Na(+),K(+)-ATPase) on it. Seawater was instilled through an endotracheal tube. The anesthetized and spontaneously breathing rats received STS intraperitoneally after seawater aspiration. Pao(2), lung wet-to-dry weight ratio, and pulmonary microvascular permeability were tested. The authors explored the effects of STS on the expression and activity of Na(+),K(+)-ATPase in vivo and in vitro. Additionally, the authors investigated the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in the stimulation of Na(+),K(+)-ATPase by STS. The results showed that STS significantly improved hypoxemia, attenuated lung edema, and alleviated seawater-induced lung injury in vivo. Both in vivo and in vitro, it was observed that STS up-regulated the expression and activity of Na(+),K(+)-ATPase. ERK1/2 inhibitor partially blocked the effects of STS on Na(+),K(+)-ATPase activity in alveolar type II cells following seawater incubation. These results indicated that STS could improve seawater aspiration-induced acute pulmonary edema by up-regulating Na(+),K(+)-ATPase activity, and the ERK1/2 signaling pathway may be involved in it.

Topics: Acute Disease; Animals; Base Sequence; DNA Primers; Drugs, Chinese Herbal; MAP Kinase Signaling System; Phenanthrenes; Pneumonia, Aspiration; Pulmonary Edema; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seawater; Sodium-Potassium-Exchanging ATPase; Up-Regulation

The mortality associated with acute pancreatitis (AP) is largely attributable to abnormalities that occur in distant organs and supportive care remains the only treatment for patients with these complications. Recently, prophylactic pharmacological blockade of poly(ADP-ribose) polymerase (PARP) enzymes has been shown to attenuate the severity of the disease. However, the clinical relevance of PARP inhibitors administered after the onset of AP remains uncertain. The aim of the present study was to investigate the therapeutic effects of PARP inhibitors in established AP.. Mice were fed a choline/methionine-deficient/ethionine-supplemented (CMDE) diet to induce AP. PARP inhibitors were given at 36 h after the onset of CMDE diet. Severity of pancreatitis was assessed by measurements of serum amylase, lipase, IL-1beta and IL-6, and histological grading. Serum hepatic enzymes, myeloperoxidase (MPO) activity and morphological changes were measured as indicators of hepatic insult. Lung injury was evaluated by MPO activity and morphological changes. Survival rates of mice were monitored for 7 days.. CMDE diet administration resulted in a significant increase in serum amylase, lipase, IL-1beta, IL-6, alanine aminotransferase and aspartate aminotranferase levels, indicating AP and associated liver injury. Analysis of the histopathological changes in pancreas, liver and lung revealed extensive tissue damage. Treatment of mice with PARP-inhibitors after the onset of AP was associated with a reduction in the severity of AP and, accordingly, with a reduced mortality rate.. Our results support the therapeutic application of PARP inhibitors in the treatment of established AP.

Topics: Acute Disease; Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Choline; Dietary Supplements; Enzyme Inhibitors; Ethionine; Female; Interleukin-1beta; Interleukin-6; Lipase; Liver Diseases; Lung Diseases; Methionine; Mice; Mice, Inbred Strains; Pancreatitis; Peroxidase; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Severity of Illness Index; Time Factors; Treatment Outcome

The severity of acute pancreatitis results from the transmigration and activation of leukocytes within the pancreas and the local synthesis and release of proinflammatory-soluble mediators that transform a local injury into a systemic inflammatory response. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether the genetic deletion of PARP-1 or PARP-2 (a new member of the PARP family) genes, or pharmacological inhibition of PARP activity might affect the development and severity of acute pancreatitis and pancreatitis-associated lung injury. Secretagogue-induced acute pancreatitis was achieved by 12 hourly intraperitoneal injections of cerulein in mice deficient in PARP-1 or PARP-2 genes, and wild-type (WT) littermate mice untreated or treated with PARP activity inhibitors. The severity of pancreatitis was assessed by measurements of serum amylase, lipase, interleukin-1beta and IL-6, pancreatic water content, histologic grading and pancreas myeloperoxidase (MPO) activity. Lung injury was evaluated by quantifying MPO activity and morphological changes. We found that the severity of acute pancreatitis and pancreatitis-associated lung injury was significantly attenuated in mice lacking PARP-1, but not PARP-2, compared with WT mice. Interestingly, administration of PARP inhibitors, 3-aminobenzamide or PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethyacetamide HCl), in WT mice markedly decreased acute pancreatitis severity and pulmonary-associated injury in a larger extension than genetic deletion of PARP-1. Our results support the potential therapeutic application of PARP inhibitors in the development and severity of acute pancreatitis and associated lung injury.

Topics: Acute Disease; Amylases; Animals; Benzamides; Ceruletide; Interleukin-1; Interleukin-6; Lipase; Lung Diseases; Mice; Mice, Knockout; Neutrophils; Pancreatitis; Peroxidase; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

The high mortality of patients with severe acute pancreatitis (SAP) is due to multiorgan dysfunction. The mechanisms of SAP are still obscure. The aim of this study was to investigate the role of nuclear factor-kappa B (NF-kappaB) activation in rats with SAP associated with liver injury and the protection effect of triptolide against liver injury in rats with SAP.. Ninety Wistar rats were randomly divided into three groups (n=30 each group): severe acute pancreatitis (group P), treatment with triptolide (group T), and sham operation (group S). SAP models were induced by retrograde injection of 5% sodium taurocholate to the pancreatic duct. After the model was successfully established, no treatment was given to group P. In group T, triptolide (0.05 mg/ml) was injected intraperitoneally (0.2 mg/kg). In group S, the abdominal walls of rats were opened, sutured, but not treated. The rats were sacrificed after operation at 2, 6, and 12 hours, respectively. The serum levels of amylase (AMY), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined at three time points (10 rats for each time point). Liver tissues were obtained to detect the activity of NF-kappaB and to observe their pathological changes with light and electron microscopes.. The serum levels of AMY and ALT were higher in groups P and T than in group S. The serum AMY levels were significantly lower in group T than in group P at 12 hours after operation. The serum ALT levels were significantly lower in group T than in group P at 6, 12 hours after operation. At the three time points, the levels of TNF-alpha and IL-6 in groups P and T increased more significantly than in group S. In group T they were decreased more significantly than in group P at the three time points. In groups P and T, NF-kappaB activity in liver tissue increased more significantly than in group S at the three time points. The activity of NF-kappaB was higher in group P than in groups S and T at the three time points. Liver pathological damages were milder in group T than in group P under light and electron microscopes.. NF-kappaB plays an important role in the pathogenesis of liver injury in rats with SAP. Triptolide can reduce pathological damage to the liver. Its mechanism is to inhibit the activity of NF-kappaB and to decrease the release of inflammatory mediators.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Immunohistochemistry; Interleukin-6; Liver; Liver Diseases; Male; NF-kappa B; Pancreatitis; Phenanthrenes; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

We recently reported that (Lamiaceae) may alleviate CCl(4)-induced acute hepatotoxicity in rats, possibly blocking the formation of free radicals generated during CCl(4) metabolism. Carnosol, one of the main constituents of Rosmarinus, has been shown to have antioxidant and scavenging activities. Therefore, it is plausible to expect that carnosol may mediate some of the effects of Rosmarinus on oxidative stress consequences induced by CCl(4) in the liver.. We evaluated the effectiveness of carnosol to normalize biochemical and histological parameters of CCl(4)-induced acute liver injury.. Male Sprague Dawley rats (n = 5) injured by CCl(4) (oral dose 4 g/kg of body weight) were treated with a single intraperitoneal dose (5 mg/kg) of carnosol. Twenty-four hours later, the rats were anaesthetized deeply to obtain the liver and blood, and biochemical and histological parameters of liver injury were evaluated.. Carnosol normalized bilirubin plasma levels, reduced malondialdehyde (MDA) content in the liver by 69%, reduced alanine aminotransferase (ALT) activity in plasma by 50%, and partially prevented the fall of liver glycogen content and distortion of the liver parenchyma.. Carnosol prevents acute liver damage, possibly by improving the structural integrity of the hepatocytes. To achieve this, carnosol could scavenge free radicals induced by CCl(4), consequently avoiding the propagation of lipid peroxides. It is suggested that at least some of the beneficial properties of Rosmarinus officinalis are due to carnosol.

Topics: Abietanes; Acute Disease; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Hepatocytes; Liver; Liver Diseases; Male; Phenanthrenes; Rats; Rats, Sprague-Dawley

The aim of this study was 1) to assess the incidence of electrocardiographic changes after treatment with halofantrine and 2) to study the relationship between these changes and plasma levels of halofantrine and its main metabolite, N-desbutyl-halofantrine. Thirty-four male patients with uncomplicated falciparum malaria were enrolled in this study. Halofantrine was administered on two separate days at a total oral dosage of 24 mg/kg/day in three doses over a 12-hr period. The interval between the two treatments was seven days. Twelve-lead electrocardiography (ECG) was performed to measure the QT interval (QTc), ambulatory ECG monitoring was done to detect ventricular arrhythmia, signal-averaged ECG was performed to detect late ventricular potentials, and blood tests were performed to determine plasma concentrations of halofantrine and N-desbutyl-halofantrine. Maximum QTc was observed at 12 hr after both the first (P < 0.0002) and second treatments (P < 0.03). Signal-averaged ECG revealed late potentials in four cases (72 hr after the first treatment in one case and 24 hr after the second treatment in three cases). Ventricular arrhythmia was not observed. Significantly higher plasma concentrations of halofantrine were observed 2 hr after the second treatment. At this time, both the time effect and time interaction were significant (P < 0.008 and P < 0.02, respectively). The QTc interval was significantly correlated with the plasma halofantrine level (r = 0.41, P < 0.01) but not with the plasma N-desbutyl-halofantrine level (r = 0.30, not significant). In three cases, late ventricular potentials were associated with a maximum concentration of halofantrine. Our findings indicate that electrocardiographic changes are dose-dependent and that a second treatment at the same dosage may be hazardous.

Topics: Acute Disease; Adult; Antimalarials; Electrocardiography; Heart; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

50 patients (45 males + 5 females) suffering from acute uncomplicated attack of Plasmodium falciparum (Pf) malaria were treated with 1500 mg of halofantrine divided in three doses of 500 mg each given at an interval of 6 h. Results showed there were no primary treatment failures. Average Parasite Clearance Time (av. PCT) was 51.12 h and average Fever Clearance Time (av. FCT) was 31.25 h. Adverse Drug Reactions (ADR) were mild and self limiting. We conclude that halofantrine is a quite safe and effective new antimalarial agent in the treatment of Pf malaria cases.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Female; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Topics: Acute Disease; Antimalarials; Drug Resistance, Multiple; Humans; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes; Primaquine; Recurrence

Twenty-eight nonimmune patients with acute uncomplicated falciparum malaria returning from subSaharan Africa were treated with a micronized formulation of halofantrine hydrochloride (three doses of 250 mg at 6-hr intervals) to investigate the drug's efficacy, tolerance, and pharmacokinetics. In vitro drug susceptibility patterns were determined by the isotopic semimicrotest. Twenty-four of 28 patients were cured. Two of the four patients experiencing recrudescence were associated with low absorption of the drug and parasites susceptible in vitro to halofantrine. The other two patients had adequate plasma concentrations of halofantrine and its main human metabolite, N-desbutylhalofantrine, but the isolates were also resistant in vitro to the drugs, suggesting drug resistance as the cause of treatment failure. Only mild, transitory side effects were noted. A wide interindividual variation in plasma concentrations of halofantrine and its metabolite was observed. Pharmacokinetic studies suggested that the micronized formulation of halofantrine hydrochloride may not increase drug absorption considerably. Further studies using higher doses or longer treatment periods are needed to ensure that adequate plasma concentrations of the drug are used.

Topics: Acute Disease; Administration, Oral; Adult; Animals; Antimalarials; Chemistry, Pharmaceutical; Half-Life; Humans; Malaria, Falciparum; Middle Aged; Phenanthrenes; Plasmodium falciparum; Tablets; Treatment Outcome

Fifty patients suffering from acute malaria were treated with 'Halofantrine Hydrochloride'. They were observed for 4 weeks. Clinical, haematological and biochemical parameters were assessed for evaluation of halofantrine in acute malaria, with special reference to its effectiveness, tolerability and side effects.

Topics: Acute Disease; Adolescent; Adult; Antimalarials; Child; Female; Humans; Malaria; Male; Middle Aged; Phenanthrenes

Malaria treatment of children is particularly difficult because of the absence of palatable suspensions for young children. Halofantrine hydrochloride is available as a suspension which is both palatable and simple to administer, and has been studied in a number of trials in the past 5 years. Children (331) ranging from 4 months to 17 years of age (mean 4.7 years) were treated with the 5% suspension using various dose regimens and 364 children ranging from 4 months to 14 years of age (mean 5.7 years) were treated with the 2% suspension 6 hourly for 3 doses. Using the 3-dose regimen there were only 2/462 (0.4%) who failed to clear the initial parasitaemia. Recrudescence occurred in 28/367 (7.6%) children with evaluable follow up data. The mean parasite clearance time in this group was 57.1 h (n = 417) and the mean fever clearance time was 50.9 h (n = 325). Symptoms related to malaria cleared rapidly following treatment generally by 24-48 h post treatment. Side effects possibly related to treatment were uncommon but were similar to those reported in adults. The frequency of diarrhoea and abdominal pain was lower than that seen in adults and was also less frequent following multiple doses and the use of the more dilute suspension. Since there was evidence that the majority of recrudescences were seen in younger children or those living in areas with low or seasonal transmission it is recommended that a further course of treatment 7 days later is given to these patients to prevent recrudescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Antimalarials; Child; Child, Preschool; Drug Evaluation; Female; Follow-Up Studies; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Patient Acceptance of Health Care; Phenanthrenes; Recurrence; Safety; Suspensions; Treatment Outcome

Topics: Acute Disease; Adolescent; Animals; Antimalarials; Blackwater Fever; Blood; Central African Republic; Hemolysis; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Plasmodium falciparum; Renal Dialysis

Thirty two children with symptomatic malaria due to P. vivax and P. Falciparum infections were treated with three doses of Halofantrine hydrochloride 8 mg/kg body weight every 6 hours. Mean fever clearance was 30 hours (range 24-48 hours). No significant clinical or biochemical side effects were observed. Symptoms cleared rapidly. Halofantrine hydrochloride was found to be highly effective and appeared to have no side effects in children with acute malaria infections.

Topics: Acute Disease; Animals; Antimalarials; Child; Child, Preschool; Female; Humans; Infant; Malaria; Male; Phenanthrenes; Plasmodium falciparum; Plasmodium vivax; Safety

Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbutylhalofantrine (n = 12) were 1192 +/- 410 (mean +/- s.d.) and 397 +/- 160 ng ml-1 with tmax values of 16 +/- 2 and 55 +/- 26 h, respectively. AUC was 60.6 +/- 23.9 and 48.5 +/- 22.2 mg l-1 h, respectively, for halofantrine and its metabolite. Halofantrine cured 83% of the patients but in two patients a reduction only in asexual parasitaemia was seen and no overall parasite clearance occurred. One of these, however had relatively low plasma concentrations of both halofantrine and its desbutyl metabolite and it appeared to be a case of inadequate treatment rather than true resistance. We suggest that the large intersubject variability in plasma drug concentrations may relate in part to its poor and inconsistent bioavailability and this rather than true resistance might be responsible for some of the treatment failures.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Humans; Malaria; Middle Aged; Phenanthrenes; Plasmodium falciparum

Topics: Acute Disease; Ampicillin; Anti-Bacterial Agents; Child; Child, Preschool; Chloramphenicol; Clioquinol; Enterococcus faecalis; Erythromycin; Erythromycin Ethylsuccinate; Escherichia coli; Feces; Furazolidone; Gastroenteritis; Humans; Methicillin; Nalidixic Acid; Neomycin; Oleandomycin; Oxytetracycline; Penicillin G; Phenanthrenes; Polymyxins; Proteus; Staphylococcus; Streptomycin; Tetracycline; Tetracyclines