Toxicological effect of Artemisinin-Based Combination Therapies plus Paracetamol in malaria patients.

BACKGROUND: Following the paucity of safety reports in the use of Artemisinin-Based Combination Therapies (ACTs) plus paracetamol, the study assessed safety potential of artemether-lumefantrine (ALP), artesunate-amodiaquine (AAP), artesunate-mefloquine (AMP), artesunate-sulphadoxine-pyrimethamine (ASPP) and dihydroartemisinin-piperaquine (DHPP) combination with paracetamol in malaria patients. METHODS: ACTs and paracetamol were administered concomitantly in conventional doses/regimen to randomly selected patients. Blood samples were collected from the ante-cubital vein before and after completion of therapies. Toxicity markers such as weights, glucose, lipids, renal electrolytes, liver enzymes and haematological indices were assessed using standard protocols. RESULTS: The total numbers of participants were 57 patients. Male to female ratio was 1:1.1. Mean body weight and ages were 59.19 ± 1.39 kg and 42.86 ± 1.32 years respectively. The mean temperatures prior to and after therapy were 37.49 ± 1.02 °C and 37.50 ± 0.17 °C respectively. Mean parasitaemia before the commencement of therapy was 6282 ± 21.01 parasites/µl. Out of thirty-seven toxicological indices evaluated, twenty-four were significantly altered by ACTs plus paracetamol (P < 0.05). Increased serum toxicity markers due to the drug combinations were glucose (AAP, AMP), urea (ALP, ASPP), bicarbonate ion (ALP, AAP, AMP, ASPP), chloride ion (ALP, AAP, AMP), creatinine (ALP, AAP, AMP, ASPP), alkaline phosphatase (ALP, AAP), aspartate aminotransferase and alanine aminotransferase (ALP, AAP, AMP, ASPP, DHPP), total protein (AMP, DHPP) and albumin (AMP, DHPP). Decreased serum toxicity markers due to the drugs were glucose (ALP, ASPP, DHPP), urea (AMP), bicarbonate ion (DHPP), chloride ion (ASPP, DHPP), creatinine (DHPP), alkaline phosphatase (AMP, ASPP, DHPP), total protein (ALP, AAP, and ASPP) and albumin (ALP, AAP, ASPP). Altered haematological indices were white blood cells, red blood cells, mean cell haemoglobin and platelets. CONCLUSION: Since ACTs plus paracetamol altered human system, discrete selection is essential in managing uncomplicated malaria most especially in patients with co-morbid conditions.

Antihypertensive properties of Allium sativum (garlic) on normotensive and two kidney one clip hypertensive rats.

Allium sativum (garlic) is reported to act as an antihypertensive amidst an inconsistency of evidence. In this study, we investigated the cardiovascular effects of aqueous garlic extracts (AGE) on normotensive and hypertensive rats using the two-kidney one-clip (2K1C) model. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in normotensive and 2K1C rat models anesthetized with thiopentone sodium (50 mg/kg body weight i.p.) through the left common carotid artery connected to a recording apparatus. The jugular vein was cannulated for administration of drugs. Intravenous injection of AGE (5-20 mg/kg) caused a significant (p<0.05) decrease in both MAP and HR in a dose-dependent manner in both the normotensive and 2K1C models, with more effects on normotensive than 2K1C rat model. The dose of 20mg/kg of AGE significantly (p<0.05) reduced systolic (16.7 ± 2.0%), diastolic (26.7 ± 5.2%), MAP (23.1 ± 3.6%) and HR (38.4 ± 4.3%) in normotensive rats. In 2K1C group, it significantly reduced systolic (22.2 ± 2.1 %), diastolic (30.6 ± 3.2%), MAP (28.2 ± 3.1%) and HR (45.2 ± 3.5%) from basal levels. Pulse pressure was significantly elevated (33.3 ±5.1%) in the 2K1C group. Pretreatment of the animals with muscarinic receptor antagonist, atropine (2 mg/kg, i.v.), did not affect the hypotensive and the negative chronotropic activities of the extract. AGE caused a decrease in blood pressure and bradycardia by direct mechanism not involving the cholinergic pathway in both normotensive and 2K1C rats, suggesting a likely involvement of peripheral mechanism for hypotension.

In vitro determination of the uterine stimulatory effect of the aqueous leaf extract of Ficus exasperata.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Ficus exasperata Vahl (Moraceae) are used by traditional healers in Southern Nigeria to arrest pre-term contractions and are also used as an abortifacient in some parts of Africa. AIM OF STUDY: An earlier study on the aqueous leaf extract of Ficus exasperata (AET) showed that the extract at lower concentrations inhibited oxytocin-induced uterine contractions and at higher concentrations, stimulated uterine contraction. This study thus aims to determine, the possible mechanisms by which AET stimulates uterine contraction in vitro. MATERIALS AND METHODS: The contractile effect of AET (5.0 x 10(-2) to 100 x 10(-2)mg/ml) and oxytocin (which was used as a reference drug) were examined in the presence of the following antagonists: atropine (1.18 and 11.91 nM); indomethacin (1.42 and 14.25 nM); verapamil (2.03 and 20.35 nM); phentolamine (4.09 and 40.91 nM), or diphenhydramine (4.45 and 44.47 nM). The EC(50) and E(max) were determined and statistically analyzed using one-way ANOVA and Dunnett post hoc test. RESULTS: There was no significant difference in the EC(50) and E(max) of AET and oxytocin in the presence of atropine. Diphenhydramine and phentolamine significantly inhibited (p<0.01) the extract but both drugs had no effect on oxytocin. However, significant differences (p<0.01) were observed in the EC(50) and E(max) of AET and oxytocin in the presence of verapamil and indomethacin. CONCLUSIONS: These results suggest that the stimulation of uterine contractility by AET may arise from the activation of histamine H(1)- and/or alpha-adrenergic receptors, interference with calcium channels and/or stimulation of prostaglandin synthesis in utero.

Antiinflammatory Activity of Aqueous Extract of Stereospermum kunthianum (Cham, Sandrine Petit) Stem Bark in Rats.

Stereospermum kunthianum, Cham, Sandrine Petit (family: Bignoniaceae) is used in traditional medicine to treat bronchitis, pneumonia and coughs, gastritis, wounds, rheumatic arthritis, ulcers, dysentery, leprosy and venereal diseases in humans. The antiinflammatory activity of the aqueous extract of the stem bark was investigated with experimental animal models using the carrageenan-induced paw oedema, leucocytes migration and granuloma air pouch tests in rats. The extract (100, 200 or 400 mg/kg) at 3 h post-treatment caused a significant (p<0.05) reduction in the paw oedema in rats. The effect of the extract was most pronounced at the dose of 400 mg/kg and was higher than that of indomethacin (10 mg/kg). The extract (400 mg/kg) caused a significant (p<0.05) reduction in the number of recruited leucocytes and it's inhibition of peritoneal exudate formation was comparable to that of indomethacin at a dose of 10 mg/kg. The exudate formation inhibited by 400 mg/kg of the extract in the granuloma air pouch test was comparatively less to that of indomethacin at a dose of 10 mg/kg. The findings of the study indicate that the aqueous extract of Stereospermum kunthianum stem bark possesses antiinflammatory activity which is probably related to the inhibition of prostaglandin synthesis. This is a possible rationale for its folkloric use as an antiinflammatory agent.

Effects of potassium adaptation on blood pressure and pressor responses in normotensive and renal hypertensive Wistar rats.

Potassium adaptation reduces blood pressure (BP) in hypertensive humans and animals but its effects on normotensive BP and the nature of pressor responses to vasoactive drugs are not known. We measured directly, the mean arterial pressure (MAP) of normotensive control, normotensive potassium-adapted (given 0.75% potassium chloride solution for 5 weeks), renal hypertensive (RHP), and renal hypertensive Wistar rats later adapted to potassium. The maximum percentage change, the ED25, and recovery times after bolus injections of noradrenaline (NA), angiotensin II (Ang. II), sodium nitroprusside (SNP), and acetylcholine (ACh) were compared. The MAP of normotensive potassium-adapted rats was significantly lower than that of the normotensive controls (95.6+/-5.0 vs. 110.8+/-2.8 mmHg, p<0.05). The potassium-adapted hypertensive rats (RHP-A) also had significantly lower MAP values than the non-adapted hypertensive ones (116.0+/-4.4 vs. 138.2+/-4.1 mmHg, p<0.01). Potassium adaptation significantly blunted responses to NA and augmented responses to SNP but while the duration of action of Ang. II was significantly shortened, that of SNP was significantly increased. We conclude that potassium adaptation reduces BP in the normotensive and hypertensive rats and may influence both the degree and duration of action of vasoactive drugs given as bolus injections.

Haematological influences of potassium adaptation in normotensive and renally-hypertensive Wistar rats.

Dietary potassium is known to cause reduction in blood pressure in several models of hypertension in human and animal studies but its haematological effects are not known. Here, experiments are designed to study the haematological effects of potassium adaptation (achieved by administering 0.75% KCl solution in drinking water for five weeks) in Wistar rats. The animals are divided into four groups comprising controls, potassium-adapted, renal hypertensive, and renal hypertensive with later adaptation to potassium. Packed cell volume (PCV) and platelet count (PC), whole blood and plasma viscosities, and platelet aggregation in the presence of sodium nitroprusside, levcromakalim, and glibenclamide, are studied. Results showed comparable PCV and PC in all groups. While relative whole blood viscosity was significantly higher (P<0.05) in the hypertensive group, relative plasma viscosity was similar in all groups. Adaptation significantly reduced (P<0.05) the tendency of platelets to aggregate to collagen. Sodium nitroprusside significantly reduced (P<0.05) the pro-aggregatory effects of collagen only in the control group. Neither of the potassium-channel modulators (levcromakalim, glibenclamide) caused any significant alteration in platelet response to collagen at the concentrations studied. Although these results suggest that potassium adaptation may not affect haemorheology, the reduced ability of platelets to aggregate--by mechanisms not clearly understood--has implications for reduced thromboembolism and the attendant cardiovascular sequelae.

Some studies on the rodenticidal action of indomethacin.

The oral LD50 of indomethacin for a seven-day observation was found to be 12.58 +/- 1.15 mg/kg. At LD10 of 6.61 mg/kg, a dose to weight ratio of 28 was obtained for a 240 g rat, while at a maximum single dose of 3 mg/kg in man it is only 0.04. Neither diazepam nor phenobarbital influenced death at the doses of both drugs used. However, cholestyramine 2 g/kg/day was found to protect by 50% from the LD100 of indomethacin. Gross pathological studies showed dose-dependent ulceration and perforation (P < 0.001, 12 vs 24 mg/kg) and such lesions occurred in starved rats, were low in bile duct-ligated compared to sham-operated rats (P < 0.001) and were also low in cholestyramine-treated rats. Indomethacin-induced lethality in rats was found to be dose-dependent.