BackgroundA recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.MethodsThis randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg.Findings42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively).ConclusionData suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.Trial RegistrationClinicalTrials.gov NCT00255567

Introduction 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. Methods 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. Results Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h -1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUC τ,SS ) for 15 mg/kg/day (median [interquartile range]) was higher in and .2]) compared with ). ConclusionThe 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.

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Background: Hair dye is commonly used in the Kingdom of Saudi Arabia (KSA). Poisoning occurs when someone swallows dye or tint used to color hair and is considered one of the most significant causes of intentional self-harm. Commercial hair dye may contain varying amounts of paraphenylenediamine and even undeclared chemical ingredients. Therefore, the aim of this study was to evaluate the organ toxicity of commercial hair dye in rats. Acute toxicity study: The commercial hair dye X was orally administered to the rats at a dose of 50 mg/kg and was observed for 24 h for mortality or behavioral changes. Sub-chronic toxicity: The commercial hair dye X was administered to rats orally for 8 days in doses of 2.5 and 5 mg/kg, then the heart, liver, kidney, and testis were dissected out of the animals and kept in formalin for histopathological examinations using H-E stain. Results: In this study, the commercial hair dye X at the dose of 50 mg/kg single dose has not shown any mortality in rats. On the other hand, the commercial hair dye X administered to rats orally for 8 days at doses of 2.5 and 5 mg/kg caused toxicological effects manifested by some histopathological changes in the heart, liver, kidney, and testis in rats compared to the control group. Conclusion: The current study showed that the commercial hair dye X at doses of 2.5 and 5 mg/kg produced toxic effects on the heart, liver, kidney, and testis in rats. Therefore, it is important to raise the public awareness about the potential toxicity of the hair dyes.

In Kingdom of Saudi Arabia Achillea fragrantissima is a fragrant, perennial herb has long been used medicinally for its analgesic properties among Rafha residents. The present study concluded that Achillea fragrantissima (Gaisoom) possess a potent anticonvulsant activity against PTZ induced seizures which may be due to GABAA agonistic activity and /or antioxidant activity. The results of the current study showed that the ethanolic extract of Gaisoom at doses of 300 mg/kg and 600 mg/kg has anticonvulsant activity in pentylenetetrazole and maximum electroshock induced seizures models on mice. The Hexane extract have protected the mice against pentylenetetrazole -induced seizures with 100% protection rate and 100% animal survival similar to the anticonvulsant drug phenobarbital. HPLC-DAD fingerprints of different fractions were also carried out to find the pharmacological active compound. The studies are in progress to isolate the compounds by HPLC technique. Supplementary studies are required to explain the exact mechanism of action by which Gaisoom act as an anticonvulsant agent.

Many patients may administered medications like captopril (ACE inhibitor) for treatment of chronic diseases and may also take Paracetamol as an Over The Counter (OTC) drug which may interact with captopril. Therefore, the aim of this study is to evaluate of the hepatoprotective effect of captopril on liver toxicity induced by low and high dose of paracetamol in rats. This study was conducted in two phases: first study for low dose of paracetamol (300 mg/kg); animals were divided into 4 groups of 6 rats each (n = 6); all groups were treated orally either 0.9 % Normal Saline (NS), captopril 20 mg/kg, paracetamol 300 mg/kg or captopril 20 mg/kg plus paracetamol 300 mg/kg for 10 consecutive days. Second study for single high dose of paracetamol (3000 mg/kg); animals were divided into 4 groups of 6 rats each (n = 6); all groups were pretreated orally either 0.9 % Normal Saline (NS) or captopril 20 mg/kg for 7 consecutive days followed by single oral administration of Paracetamol 3000 mg/kg or normal saline. The administration of Paracetamol or normal saline was performed 24 hours after the last administration of captopril. After 48 hours of hepatic injury induction, the animals were then sacrificed and the liver was removed for histopathological studies. Low dose (300 mg/kg) for 10 days and high single dose (3000 mg/kg) of paracetamol produced hepatotoxic effects. While captopril 20 mg/kg showed marked protection against changes induced by low and high dose of paracetamol on the liver.

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Background: Diabetes Mellitus is a chronic metabolic disease characterized by hyperglycemia due to impaired insulin secretion or insulin resistance. It has been increasing at a high rate in the last decades, affecting males and females at reproductive age. Therefore, the current study aimed to assess the safety of some oral hypoglycemic drugs and their combinations on normal male rats' fertility. Methods: Ninety-six male rats were included in this experiment, and it consisted of two phases. The subchronic phase for 30 days and the chronic phase for 90 days. Each phase contained 48 rats, which were divided into 8 groups (n=6) including the control group and the test groups (metformin 500 mg/kg, glibenclamide 5 mg/kg, sitagliptin 50 mg/kg, metformin 500 mg/kg plus glibenclamide 5 mg/kg, metformin 500 mg/kg plus sitagliptin 50 mg/kg, glibenclamide 5 mg/kg plus sitagliptin 50 mg/kg and the last group was a combination of the three mentioned drugs). The drugs were administered orally. After the completion of the experiment period for both phases, hormonal analysis and sperm parameters were measured. Results: The results of the subchronic and chronic phases revealed that metformin and sitagliptin and their combination affected hormonal and sperm parameters negatively as they reduced testosterone level, sperm count and sperm motility. In comparison, glibenclamide didn't show any significant effect. Conclusion: This study concludes that metformin exhibits testicular dysfunction. The results of the combination of metformin and glibenclamide in chronic use are encouraging because glibenclamide reduced the testicular dysfunction effect of metformin.