Postmarketing in vitro/in vivo assessment of fixed dose combination products of first line antiretrovirals.

The purpose of this study was to evaluate the postmarket pharmaceutical equivalence, stability and bioequivalence of generic and innovator fixed dose combination products of lamivudine (3TC) and zidovudine (AZT) 150/300 mg tablets available in Nigeria. An isocratic HPLC-UV method was developed and validated for the quantitative determination of 3TC and AZT in human plasma and pharmaceutical samples. The model independent f(2) similarity factor was used to compare the dissolution profiles of the two products stored at accelerated and long-term stability conditions for 6 months. The f(2) values for 3TC and AZT in both products were found to be greater than 51. Also, the tablets were stable according to the USP potency and drug dissolution criteria with more than 80% of drug dissolution in 30 min indicating the pharmaceutical equivalence of the two products. The 90% confidence interval for the ratios of generic/innovator pharmacokinetic parameters for 3TC/AZT were 73.5-112.6/63.4-95.8 (C(max)); 68.5-105.6/68.0-114.8 (AUC(0-t)); and 64.2-106.2/80.1-120.3 (AUC(0-infinity)) respectively. The pharmacokinetic parameters failed to fully demonstrate bioequivalence between the products. The results underscored the importance of assessing the quality of the combination drug products that would ensure the safety and efficacy of the generic drug products available in the market.

The influence of Nifadin, Niprisan and Niprd/92/001/1-1 (AM-1) on the pharmacokinetics of metronidazole in rats.

The single oral dose pharmacokinetics of metronidazole was studied alone and after co-administration with phytomedicines, Nifadin, Niprisan and Niprd/92/001/1-1 (AM-1), in rats. Plasma metronidazole concentrations were measured using high-performance liquid chromatography method developed earlier in our laboratory. The data were fitted into a WinNonlin standard non-compartmental programme. The co-administration of the herbal medicines with metronidazole produced an increase in the serum concentration of metronidazole at each sampling time. The highest increase of 184% occurring at the time of peak concentration (1 h) was obtained with AM-1, followed by 145% with Niprisan, the least was 131% with Nifadin. Significant increase was also observed in some other parameters, such as area under the serum concentration-time curve (AUC0-24) and maximum serum concentration (Cmax), while the apparent volume of distribution (Vd) and plasma clearance (C1) reduced significantly (P < 0.05). It was concluded that the gastric presence of the herbal medicines impaired the absorption and elimination Niadin alone) of metronidazole in rats significantly (P < 0.05).

Physicochemical Analysis of the Aqueous Extracts of Six Nigerian Medicinal Plants

Purpose: Extracts of Picralima nitida seeds; Detarium microcarpum stem bark; Aframomum melagueta seeds; Terminalia catappa leaves; Acacia nilotica pods; and Morinda lucida stem bark; are under consideration for development into suitable dosage forms for treating diabetes mellitus; sickle cell anemia and malaria. This study aimed at evaluating the extracts for features that would influence decisions on them in the course of the project. Methods: Physicochemical determinations; including proximate analysis; were done by sensory examination; and gravimetric and electrochemical techniques. Thin layer chromatography was carried out with normal silica plates using various solvent systems. Metallic content analyses were carried out by atomic absorption spectroscopy. Results: The extracts were dry but hygroscopic; with a loss on drying range of 0.26 - 12.00w/w. The pH of the 5 - 10solutions ranged 5 - 7. No harsh sensory effects; such as lacrimation; were detected in any of the extracts. Total ash ranged from 3.79 - 20.68w/w; while acid insoluble ash values were below detection. The extracts yielded reproducible chromatograms on normal silica plates developed with various solvent systems. Copper; present at 0.16 - 0.58 mg/100g; was the lowest occurring microelement while calcium content was highest; at 41 - 216 mg/100g. The level of lead; a heavy metal; was 0.05 - 0.22 mg/100g. Conclusion: The results confirm that the extracts require no special handling; possess characteristics that would allow their possible development into solid dosage forms; and that their lead contents complied with official limits

Effect of phytomedicines, AM-1, niprisan and nifadin on the pharmacokinetics of chloroquine in rats.

The single oral dose pharmacokinetics of chloroquine was studied alone and after coadministration with phytomedicines NIPRID\92\001\1-1 (AM-1), Niprisan, and Nifadin in rats. Plasma chloroquine concentrations were measured using High performance liquid chromatography (HPLC) method developed earlier in our laboratory. The data were fitted into a WinNonlin standard non-compartmental programme. The co-administration of the herbal medicines with chloroquine produced decrease in the serum concentration of chloroquine at each sampling time. The highest decrease of 85% occurring at the time of peak concentration (1 h) was recorded with Nifadin, followed by 75% with Niprisan the least was 50% with AM-1. Significant reduction was also observed in some other parameters, such as area under the serum concentration- time curve (AUC(0-24)) and maximum serum concentration (Cmax) while the apparent volume of distribution (Vd) and elimination half-life (t 1/2beta) increased significantly (P< 0.05). It was concluded that the gastric presence of the herbal medicines significantly impaired the absorption of chloroquine in rats.

The influence of lamivudine, stavudine and nevirapine on the pharmacokinetics of chlorpropamide in human subjects.

Diabetic patients tend to be prone to infections, and multiple drug therapy cannot be ruled out in the management of diabetes. The effect of three routinely prescribed antiretroviral (ARV) drugs on the pharmacokinetic profile of an antidiabetic drug, chlorpropamide, was investigated in 18 human subjects, who had recently been diagnosed positive for human immunodeficiency virus (HIV) infection. The volunteers, aged 22-44 years and weighing 59-66 kg, were randomized into three groups with six subjects in each group. The study was carried out in two phases; in the first phase, all the subjects received chlorpropamide (250 mg) in a fasting state. In the second phase, the subjects received 250 mg of chlorpropamide together with lamivudine (150 mg) or stavudine (40 mg) or nevirapine (200 mg) in a fasting state. Chlorpropamide concentrations in the plasma were determined using a high performance liquid chromatography (HPLC) method developed earlier in our laboratory, while plasma glucose levels were determined using the standard glucose oxidase method. Lamivudine and stavudine decreased significantly (P < 0.05) the mean maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curve (AUC(0-168h)) of chlorpropamide, while both drugs significantly increased the absorption half-life (t(1/2ab)) and elimination half-life (t(1/2el). the apparent volume of distribution (Vd) and the plasma clearance rate (Cl) of chlorpropamide (P < 0.05). The plasma glucose levels were also significantly increased between 0.5 - 4 h post dose (P < 0.05). However, it was found that the pharmacokinetic parameters of chlorpropamide and the blood glucose levels were not significantly altered by the co-administration with nevirapine.

Alteration of oral salivary pharmacokinetics of paracetamol by an investigational anti-malarial phytomedicine, in healthy human volunteers.

Effect of an investigational anti-malarial phytomedicine (AM1) on the salivary pharmacokinetics of paracetamol (PCM), in healthy human volunteers was examined. The drug salivary level of paracetamol was determined using spectrophotometric method. Lower concentrations of PCM was observed in concomitant administration of 1000mg PCM tablets with 250mg AM1 capsule compared with administration of 1000mg paracetamol tablets alone (control). The area under the curve (AUC), time for maximum concentration (t(max)), maximum concentration (Cmax) were generated using the GRAPHPAD PRISM software version 2.0. The pharmacokinetic parameters were calculated from the semi-logarithmic plots of concentration-time data for PCM. The absorption kinetics parameters kab, lag-time, t1/2ab for both test (0.03min(-1), 9min, 18min.) and control (0.03min(-1), 9min, 22.8min.) were identical. There were statistically significant reductions in the bioavailability parameters AUC, Cmax, between control (1856microg/ml/min, 8.08microg/ml) and test (847.87microg/ml/min, 4.59microg/ml/) experiments. There were also insignificant but definite alterations in the elimination phase kinetic parameters kel, t1/2el, between control (0.1172min(-1), 69min.) and test (0.01027min(-1), 75min). The study shows that the botanical anti-malarial remedy (AM1) reduced the systemic availability of PCM when used concomitantly.

Concentrations of copper, iron, and zinc in the major organs of the wistar albino and wild black rats: a comparative study.

The concentrations of copper, iron, and zinc in the major organs of Wistar albino (Rattus norvegicus) and wild black rats (Rattus rattus) were measured by means of atomic absorption spectroscopy. The copper levels in the kidneys and liver of the Wistar albino rats (WARs) were significantly higher (p<0.05) than in the wild black rats (WBRs). There were no significant differences in the concentrations of zinc in the liver, lungs, kidneys, and brain between the two study groups, but zinc was significantly higher in the spleen (p<0.05) and lower in the heart (p<0.05) of WAR, compared to WBRs. Iron was significantly higher (p<0.05) in the heart and spleen of WBRs, compared to WARs. There were no extreme differences in the organ concentrations of trace elements between the two species, but, cumulatively, the WARs tend to have higher metallic concentrations in their system than the WBRs. The potential of these differences on the experimental results should not be overlooked and will serve as basis to further consider the complex interrelationships of these animals in their microenvironments and macroenvironments.

Effect of the aqueous extract of African mistletoe, Tapinanthus sessilifolius (P. Beauv) van Tiegh leaf on gastrointestinal muscle activity.

Effects of the aqueous extract of T. sessilifolius on the gastrointestinal muscle were investigated on smooth muscle preparations isolated from rabbit jejunum, guinea pig ileum and on gastrointestinal transit in mice. Elemental analysis of the extract was also carried out. The aqueous extract of T. sessilifolius evoked a concentration dependent contraction of the rabbit jejunum and guinea pig ileum. The contractions evoked by the extract were not attenuated either by atropine or mepyramine, but they were completely blocked by verapamil. The elemental analysis revealed the presence of Mg, Zn, Fe, Cu, and very high concentration of Ca. The intraperitoneal LD50 in mice was found to be 1500 mg/kg. The aqueous extract of T. sessilifoliius possesses active components that may be mediating the observed biological activity through calcium mobilization.

Double-blind, placebo-controlled, randomised cross-over clinical trial of NIPRISAN in patients with Sickle Cell Disorder.

The study was undertaken to determine the safety and efficacy of NIPRISAN, a phytomedicine, developed for the management of patients with Sickle Cell Disorder (SCD). The study design is a placebo-controlled double blind cross-over trial. Eighty-two (82) patients with SCD were recruited and randomised into two groups. An initial 4 month pre-trial study was undertaken to determine the similarity of the groups. The main study was conducted over a twelve-month period with crossover at six months. Safety of the drug was assessed clinically and biochemically. NIPRISAN significantly (P < 0.01) reduced the frequency of SCD crisis associated with severe pains. Acute toxicity to the liver assessed by the activities of liver enzymes, indicate that NIPRISAN is safe. Renal function assessed by the serum levels of creatinine and blood urea nitrogen remained normal. Both the clinical and laboratory results of the present phase IIB (pivot) clinical study suggest that NIPRISAN is a safe and efficacious phytomedicine for the management of patients with Sickle Cell Disorder.

Effect of activated charcoal on the disposition of sulphadoxine.

Studies were conducted to examine the effect of activated charcoal on the disposition kinetics of sulphadoxine after Fansidar administration. Activated charcoal caused a significant reduction in ka, half-life and AUC0-48hr from 1.4 to 0.7 hr, 256 to 117 hr and 2533 to 1346 mg/l/hr, respectively. Activated charcoal absorbed sulphadoxine effectively in vitro. Sulphadoxine, at a simulated highly toxic dose of 5 mg/ml, showed adsorption percentages of 23.06, 28.66, 41.24, 64 and 100 to amounts of activated charcoal of 12.5, 25, 50, 100 and 250 mg, respectively. The results show that activated charcoal effectively adsorbs sulphadoxine both in vitro and in vivo.