Toxicity assessment of sub-acute and sub-chronic oral administration and diuretic potential of aqueous extract of Hibiscus sabdariffa calyces.

BACKGROUND: Food and herbal usage of Hibiscus sabdariffa (HS) is attaining improved global relevance and acceptance without recourse to its potential toxic effects. This study investigated the safety profile of acute, sub-acute, sub-chronic administrations and diuretic potential of aqueous extract of Hibiscus sabdariffa calyces (AEHSC). METHOD: Acute oral toxicity, sub-acute and sub-chronic toxicity as well as diuretic studies were carried out on HS. A total of 20 Wistar rats were used for each toxicity study and assigned into four groups of five rats. The extract was administered as a single daily dose of 125, 250 and 500 mg/kg body weight (bwt) for 28 and 90 days respectively. To evaluate diuretic activity, 25 rats were divided into five groups of five rats and administered normal saline, hydrochlorothiazide 10 mg/kg, AEHSC 67.5, 125 and 250 mg/kg via the oral route. Urine sample was collected after 18 h, volume measured and concentration of electrolytes analyzed. The hematological and biochemical parameters were evaluated as well as the histopathology of kidney and liver. RESULTS: The acute oral toxicity was found to be >2000 mg/kg. AEHSC did not alter concentration of WBC, MCV, MCHC, lymphocyte as well as total and direct bilirubin in the sub-acute study. However, AEHSC significantly (p < 0.05) increased total protein, albumin, globulin, Na+, Cl-, HCO3 - and platelet levels, while levels of uric acid, creatinine, K+, RBC, Hb, total cholesterol, triglycerides, LDL-C, HDL-C and atherogenic index were decreased significantly (p < 0.05). In the sub-chronic study, AEHSC significantly (p < 0.05) increased the levels of globulin, urea, creatinine, MCH and atherogenic index. The concentrations of uric acid, WBC, platelets and HDL-C were significantly (p < 0.05) decreased. In both the sub-acute and sub-chronic studies, activities of ALP, ALT, AST, GGT and LDH in selected organs were altered without significant increase (P < 0.05) in activity of these enzymes in the serum. The AEHSC at all the doses showed remarkable diuretic activity during 18 h period comparable to hydrochlorothiazide. The extract also showed a non-dose-dependent increase in excretion of electrolytes. Histological analysis of sections of the liver and kidney for both sub-acute and sub-chronic studies showed normal histology comparable to the control group. CONCLUSION: This study revealed AEHSC has some toxic effects in rats on sub-chronic administration. In addition, the extracts produced a significant diuretic activity. Hence, prolonged oral consumption of the extract may not be recommended.

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).

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.

Effect of Nigerian meals on the pharmacokinetics of chlorpropamide in type II diabetic patients.

Food-drug interactions are best evaluated on an individual drug basis, in a group of subjects in a population at risk. This is due to their complex nature, which is a function of type and size of meal, the physical and chemical form of the drug and the time lapse between food intake and drug administration. This work was aimed at investigating the effect of three different Nigerian meals, which are regularly consumed by the three major tribes in Nigeria, on the pharmacokinetics of chlorpropamide, a drug commonly used to treat Type II diabetes in this country. Meal A (maize flour meal) was composed of 81% carbohydrate, 3% protein and 11% fat; meal B (cassava flour meal) was composed of 76% carbohydrate, 3% protein and 15% fat; while meal C (browned yam flour meal) was composed of 85% carbohydrate, 2% protein and 8% fat. The effects of the three meals were investigated by administering each of the meals alone, without the medicinal drug (Treatment I); in Treatment II each meal was administered 30 min following the administration of 250 mg chlorpropamide; in Treatment III the drug was administered together with each of the standard meals. Analysis of the plasma levels of chlorpropamide was performed by high performance liquid chromatography (HPLC). Ingestion of the meal alone (Treatment I) resulted in a significant difference in postprandial plasma glucose levels. The time to maximum plasma chlorpropamide concentration was significantly increased in Treatment III (P < 0.05), while all pharmacokinetic parameters and plasma glucose levels were not significantly altered in Treatment II. Analysis of the results demonstrated a better glycaemic response with meals A and C compared with meal B.