The isolation and determination of structure of some plant procyanidins in their free phenolic forms are described. The distribution of procyanidins in the tissues of twenty-nine plant species has been examined and the biogenetic implications of this study are briefly discussed.
Clinical pharmacology studies were undertaken in young healthy volunteers, in a small number of elderly subjects and in migraine subjects during and between attacks. Absorption after subcutaneous and oral administration was rapid. Bioavailability was nearly 100% after subcutaneous administration and averaged 14% after oral administration. Elimination was predominantly by metabolism to a non-active indoleacetic acid analogue. The plasma half-lives of sumatriptan and the metabolite were about 2 h. Pharmacokinetic and pharmacodynamic variables were similar in all groups studied and were not altered by the presence of food, alcohol, dihydroergotamine or prophylactic migraine treatments. Sumatriptan produced a number of minor adverse events, but had no clinically significant effect on routine haematological or biochemical investigations using the intravenous, subcutaneous or oral routes. Transient rises in blood pressure were observed which were no greater than those that would be anticipated during moderate exercise. The physician-administered subcutaneous injection resulted in transient stinging at the site of injection in many subjects; administration using the auto-injector was better tolerated.
Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT1 receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan’s precise clinical mode of action have focused on the human meningeal circulation and should lead to a better understanding of the pathogenesis of migraine. Administering [14C]sumatriptan, drug-related material was shown to be well absorbed. Following absorption there was some first-pass metabolism resulting in oral bioavailabilities of 37, 58 and 23% in rat, dog and rabbit, respectively. In all species, circulating sumatriptan was cleared rapidly by metabolic and renal clearance with a half-life of 1–2 h. The indoleacetic acid metabolite is the primary metabolic product; however, rats, mice and rabbits also N-demethylate the methylaminosulphonylmethyl side-chain. The passage of sumatriptan and its metabolites across the blood-brain barrier appeared to be very limited, although some drug could be detected in the cerebrospinal fluid after administration of high intravenous doses. Safety studies in various animal species showed that sumatriptan produced few adverse pharmacodynamic effects when administered acutely, except at high doses, although it was less well tolerated in dogs. No findings of toxicological significance were observed in rats and dogs after chronic dosing for 1 year or more. The highest doses used in both acute and chronic toxicology studies were limited by behavioural effects but there were no pathological changes. In rats and rabbits sumatriptan had no adverse effects on reproduction and there was no evidence of genotoxicity. Long-term exposure did not induce any treatment-related increase in the incidence of tumours in mice or rats.
A 4 mg dose of beclomethasone‐17,21‐dipropionate‐16,16a‐3H(BP2‐16‐3H) has been given orally in a capsule to 4 subiects, and 2 further subjects as a micrafine suspension. The plasma levels of radioactivity reached a peak at 3 to 5 hours equivalent to 9.6 to 15.2 ng BP2‐16‐3H per milliliter in the capsule‐treated subjects, and 20 ng BP‐16‐3H per milliliter in the subjects given the suspension. Ten to fifteen per cent of the administered dose of radioactivity was excreted in the urine as both unidentified conjugated and free metabolites of the steroid. Fram radiochemical and chromatographie analyses of the feces it was estimated that 90% of the drug in the microfine suspension was absorbed compared with 61 % to 76% of that in the capsule formulation. In vitra BP2‐16‐3H was hydrolyzed by tissue and fecal esterases to beclomethasone‐17‐ propionate‐16,16a‐3H and beclomethasone‐16,16a‐3H. This study has shown that the swallowed portion of an aerosol of beclomethasone dipropionate would be absorbed fram the gastraintestinal tract, and that the lack of suppressive activity on the hypothalamo‐pituitary‐adrenal (HPA) axis of patients on therapeutic doses of the aerosolized steroid is not due to malabsorption of the drug.
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