Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia.

WHAT IS KNOWN AND OBJECTIVE: Imatinib mesylate is the first-line drug for the treatment of Philadelphia/bcr-abl positive chronic myeloid leukaemia (CML). It is known to be metabolized mostly by CYP3A4 and CYP3A5 isoforms while its efflux is mediated by the transporters ABCB1 and ABCG2. Genetic polymorphism of some of these enzymes and transporters have been linked with inter-individual variations in the pharmacokinetics of the drug. This study, therefore, investigated the influence of CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T genetic polymorphism on the clinical outcome and steady-state trough plasma concentration (TPC) of imatinib in Nigerians with CML. METHODS: A total of 110 Nigerians with CML each of whom had been receiving a 400 mg daily dose of imatinib for at least 1 month were genotyped for CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T. The TPC of all the patients were determined by a validated HPLC method and possible relationships between genotypes, age, clinical outcome, sex, TPC and ethnicity were analysed. RESULTS AND DISCUSSION: Subjects of TT genotype of ABCB1 C3435T had higher frequencies of complete haematological response (CHR), complete cytogenetic response (CCR) and major molecular response (MMR) but these were not statistically significant (P < 0·05). No genetic polymorphism in ABCG2 421C>A was observed. However, significant associations were observed between TPC and various genotypes in both CYP3A5*3 (P < 0·001) and ABCB1 C3435T (P < 0·001). The GG and TT genotypes in CYP3A5*3 and ABCB1 C3435T, respectively, were linked with higher TPC. WHAT IS NEW AND CONCLUSION: This is the first pharmacogenetics study of CML patients in the Nigerian population with ethnic differences in the distribution of ABCB1 C3435T. Genetic polymorphisms in CYP3A5*3 and ABCB1 C3435T are associated with TPC in CML patients in this population.

Distribution of iridiod glucosides and anti-oxidant compounds in Spathodea campanulata parts.

The antioxidant principles isolated from the various parts of the plant are verminoside (leaf, stem bark and flowers; EC(50) = 2.04 µg/ml), Specioside (flowers; EC(50) = 17.44 µg/ml), Kampeferol diglucoside (leaf; EC(50) = 8.87 µg/ml) and Caffeic acid (leaf and fruits). The non anti-oxidant components isolated in the study include ajugol (stem bark and fruits) and phytol (leaf).

Antinociceptive and antiinflammatory effects of essential oil of Dennettia tripetala G.Baker (Annonaceae) in rodents.

In this study we evaluated the analgesic and anti-inflammatory activities of the essential oil (EO) of the fruits of Dennettia tripetala in rodents. The plant is a tropical African plant and the fruits are commonly eaten as spices and consumed as a stimulant, and its various parts are used in the treatment of fever, cough and as anti-emetics.The analgesic effects of the oil was assessed in mice using the hot plate, acetic acid-induced writhings and formalin test, while carrageenan-induced paw oedema was used to study the antiinflammatory effects in rats. The EO at 25-50 mg/kg exhibited significant (p<0.05) antinociceptive effects comparable to a potent opioid agonist, morphine (10 mg/kg) and non-steroidal anti-inflammatory drugs such as, aspirin (100 mg/kg) and indomethacin (80 mg/kg). The antinociceptive effect of the EO was also blocked by naloxone (2 mg/kg) in all the models used. The EO demonstrated significant (p<0.05) anti-inflammatory effect in the carrageenan-induced paw oedema model of inflammation that is also comparable to dexamethasone (1 mg/kg) The results showed that the essential oil of D. tripetala possesses significant antinociceptive and antiinflammatory effects in the animal models used. The results also suggest that the analgesic effects may be mediated both centrally as well as peripherally, while the antiinflammatory activity may be effective in both early and late phases of inflammation. The results obtained may therefore be used to rationalize the use of the plant in the treatment of pain and fever in traditional medicine.

Antinociceptive and antiinflammatory effects of essential oil of Dennettia Tripetala G. Baker (annonaceae) in Rodents

In this study we evaluated the analgesic and anti- inflammatory activities of the essential oil (EO) of the fruits of Dennettia tripetala in rodents. The plant is a tropical African plant and the fruits are commonly eaten as spices and consumed as a stimulant, and its various parts are used in the treatment of fever, cough and as anti-emetics. The analgesic effects of the oil was assessed in mice using the hot plate, acetic acid-induced writhings and formalin test, while carrageenan-induced paw oedema was used to study the antiinflammatory effects in rats. The EO at 25-50 mg/kg exhibited significant (p0.05) antinociceptive effects comparable to a potent opioid agonist, morphine (10 mg/kg) and non-steroidal anti-inflammatory drugs such as, aspirin (100 mg/kg) and indomethacin (80 mg/kg). The antinociceptive effect of the EO was also blocked by naloxone (2 mg/kg) in all the models used. The EO demonstrated significant (p0.05) anti-inflammatory effect in the carrageenan-induced paw oedema model of inflammation that is also comparable to dexamethasone (1 mg/kg) The results showed that the essential oil of D.tripetala possesses significant antinociceptive and antiinflammatory effects in the animal models used. The results also suggest that the analgesic effects may be mediated both centrally as well as peripherally, while the antiinflammatory activity may be effective in both early and late phases of inflammation. The results obtained may therefore be used to rationalize the use of the plant in the treatment of pain and fever in traditional medicine

Clinical evaluation of Acalypha ointment in the treatment of superficial fungal skin diseases.

In an open non-comparative study to evaluate the efficacy and safety of Acalypha wilkesiana ointment in superficial fungal skin diseases, 32 Nigerian patients with clinical and mycological evidence of superficial mycoses were recruited. Twelve patients defaulted and were lost to follow up, while one patient withdrew because of intolerable excoriation at the site of the lesion. Of the 19 patients that completed the trial, clinical cure was achieved in 73.3% of the patients. The ointment was very efficacious in the treatment of Tinea pedis, Pityriasis versicolor and Candida intetrigo where the cure rate was 100% in each condition. It is recommended that Acalypha ointment can be used for the treatment of these superficial mycoses.

Prieurianoside, a protolimonoid glucoside from the leaves of Trichilia prieuriana.

The ubiquitous glycolipid 1,2-dilinolenoyl-3-galactopyranosylglycerol and a new protolimonoid glucoside, named prieurianoside, were isolated from the leaves of Trichilia prieuriana. The structure of the latter was established, by spectroscopic techniques, as 12beta,21-diacetoxy-29-beta-D-glucopyranosyloxy-23zeta -hydroxytirucalla-7,24-dien-3-one.

Antimicrobial constituents of the leaves of Acalypha wilkesiana and Aacalypha hispida.

An activity directed fractionation of a 50% aqueous ethanol extract of A. wilkesiana and A. hispida leaves resulted in the isolation of gallic acid, corilagin and geraniin as the compounds responsible for the observed antimicrobial activity. Quercetin 3-O-rutinoside and kaempferol 3-O-rutinoside were also isolated from the inactive fraction of A. hispida. The structures were established by permethylation, 2D - NMR ((1)H and (13)C) and MS data.

Petersaponins III and IV, triterpenoid saponins from Petersianthus macrocarpus.

Two new triterpenoid saponins, petersaponins III and IV (1 and 2), were isolated from an n-butanol extract of the bark of Petersianthus macrocarpus. They possess 21-O-benzoyl-22-O-acetylbarringtogenol C and 21-O-2-furoxyl-22-O-tigloylbarringtogenol C as the aglycon, respectively. For both 1 and 2, the trisaccharide moiety linked to C-3 of the aglycon consists of D-glucuronic acid, D-xylose, and D-galactose, while a L-rhamnose unit is linked to C-28. The structures of 1 and 2 were elucidated by extensive NMR experiments including (1)H-(1)H (COSY, HOHAHA, NOESY) and (1)H-(13)C (HMQC and HMBC) spectroscopy and by chemical evidence.

New amides from Zanthoxylum lemairie pericarps.

Two new aromatic amides were isolated from the pericarps of Zanthoxylum lemairie. The structures were elucidated by spectroscopic methods and confirmed by synthesis. A known aromatic amide, zanthosinamide, and four dibenzylbutyrol-actone lignans were isolated.

Pharmacokinetics and bioavailability of drotaverine in humans.

The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.