1 Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. 2 Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. 3 After intravenous infusion of nicardipine at 5 mg-' for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. 4 With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. 5 Steady-state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10-40 mg three times daily. 6 Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.

1. Ketorolac is an investigational non‐opioid analgesic. Buprenorphine, an opioid compound and diclofenac, a non‐steroidal anti‐inflammatory, are analgesics used in clinical practise. 2. The psychomotor effects of ketorolac (30 mg), buprenorphine (0.3 mg), diclofenac (50 mg) and placebo all administered i.m., were examined in 12 healthy male volunteers (age 19‐38 years), up to 8 h post‐dose. 3. Creatine phosphokinase (CPK) was measured up to 24 h post‐dose, providing an indication of local tissue damage following injection. 4. Buprenorphine caused significant psychomotor impairment in seven out of eight psychomotor tests. The effects consistently peaked 4 h post‐dose and were still apparent in many cases 8 h post‐dose. These psychomotor effects were supported by marked symptoms in all volunteers. 5. Ketorolac and diclofenac had no clinically significant effects on psychomotor tests and only minimal symptoms were reported. 6. Diclofenac caused a marked increased in CPK (mean Cmax 298 iu l‐1) compared with ketorolac (mean Cmax 70 iu l‐1) and buprenorphine (mean Cmax 68 iu l‐1). 7. These results suggest that ketorolac and diclofenac are suitable for administration following day case surgery.

Summary Ten adult male patients with long‐standing atopic eczema took part in a double‐blind randomized cross‐over trial of compound LN2974. This is a new potent selective H1‐receptor antagonist, unrelated to other antihistamines and devoid of H2‐reccptor antagonist activity. It has little or no sedative action. No significant suppression of scratching, as measured by limb movement meters, or of itching, recorded on visual analogue scales, could be demonstrated.

Four human volunteers given a 30 mg oral dose of nicardipine hydrochloride containing 40 microCi of the 14C-labelled material achieved peak plasma levels of compound-related radioactivity within one hour of dosing. Parent compound comprised only a minor fraction of the circulating radioactivity indicating rapid first-pass metabolism. Plasma radioactivity declined to background levels within 96 h and was excreted both in the urine and faeces. Urinary excretion was the favoured route comprising about 60% of the dosed radioactivity. Mean total recovered radioactivity amounted to 94.8%. Both 1,4-dihydropyridine and pyridine metabolites of nicardipine hydrochloride were excreted in the urine. The major urinary metabolites, comprising some 36% of the radioactivity excreted in the 0-8 h post-dose period, were the glucuronide conjugates of +/- 2-hydroxyethyl methyl-1,4-dihydro-2,6-dimethyl-4(m-nitrophenyl)-3,5-pyridine dicarboxylate and its pyridine from 2-hydroxyethyl methyl-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine dicarboxylate.

1. The biotransformation of nafimidone, an imidazole-substituted anticonvulsant, has been studied by characterization of urinary metabolites in dogs, cynomolgus monkeys, baboons and man. 2. The biotransformation of nafimidone in these laboratory animals and man is initially very similar, in each case proceeding by reduction to the aliphatic alcohol metabolite, nafimidone alcohol or 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole. 3. Further transformation of this metabolite involves oxidation in the naphthyl and imidazole functions, and/or conjugation. 4. The dog differs from the higher primates in that no metabolic modification of the naphthyl group takes place, the major metabolite in the dog being the O-beta-glucuronide of nafimidone alcohol. 5. In higher primates and man two isomers involving dihydroxylation in the naphthyl ring--1-[2-hydroxy-2-(5,6- or 7,8-dihydroxydihydro-2-naphthyl)ethyl]imidazole--were tentatively identified. These species alone showed evidence of an imidazole linked N-glucuronide of nafimidone alcohol. 6. The possible occurrence of stereoselective metabolism by the introduction of a chiral centre at C-9 in nafimidone alcohol was indicated in human urine by the presence of both epimers of the O-beta-glucuronide of nafimidone alcohol in a 2:1 ratio.