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1. The pharmacokinetics and pharmacodynamics of prochlorperazine (PCZ) have been studied in healthy young males following single 12.5 mg i.v. and 50 mg oral doses, and during repeated doses (25 mg twice daily) for 14 days. 2. Oral bioavailability was low and an N-desmethyl metabolite was detected. Plasma clearance was high (0.98 1 kg-1 h) and the volume of distribution was large (12.9 1 kg-1) after i.v. dosing. 3. The terminal elimination half-life of PCZ was 9 +/- 1 h and 8 +/- 2 h after i.v. and single oral dosing, respectively. The urinary recoveries of drug and metabolite were low. 4. Accumulation of PCZ and its metabolite occurred following repeated dosing. The half-life at the end of 14 days therapy was 18 +/- 4 h. 5. Postural tachycardia, decreased salivary flow, impaired psychomotor function and a diminished level of arousal were observed after intravenous PCZ. Similar effects, but of lower magnitude were observed after single oral doses. During chronic dosing postural tachycardia and antihistaminic effects were observed, the latter not being observed after single doses. 6. After single intravenous dosing the maximal drug effects occurred 2-4 h after peak plasma drug concentrations for all measures except for plasma prolactin and self-scored restlessness 7. An antagonist action at dopamine (D2), muscarinic-cholinergic and alpha-adrenoceptors is postulated after single doses, with antihistaminic effects during chronic dosing, possibly indicating the presence of an active metabolite. [ABSTRACT FROM AUTHOR]

1. Benorylate (4-acetamido phenyl-O-acetylsalicylate) hydrolysis in vitro by human plasma and by human liver microsomes and cytosol has been investigated. 2. Benorylate was hydrolysed by a route involving initial hydrolysis of the acetyl group to yield phenetsal followed by hydrolysis to paracetamol and salicylate. Hydrolysis via acetylsalicylate was minor. 3. Benorylate was more actively hydrolysed by liver cytosol than microsomes and about 10 times faster than plasma. 4. Following a single oral dose benorylate (4 g) to volunteers only salicylate and paracetamol were detected in the plasma. 5. The therapeutic effects of benorylate appear to be mediated by salicylate and paracetamol. [ABSTRACT FROM AUTHOR]

1. To test the hypothesis that angiotensin converting enzyme (ACE) inhibitors potentiate the tissue effects of bradykinin, the thickness of weals produced by intradermal injections of bradykinin was measured in 17 hypertensive subjects whose antihypertensive regimen included an ACE inhibitor, and in 12 whose treatment did not. 2. Weal thickness increased linearly with the logarithm of the bradykinin dose in both groups (P less than 0.0001). 3. The patients receiving ACE inhibitors showed a mean response of 1.18 +/- 0.08 mm (mean +/- s.e. mean), compared with a mean response of 0.75 +/- 0.08 mm for patients not receiving an ACE inhibitor (P = 0.002). Mean weal response (1.08 +/- 0.9 mm) was not significantly different in patients taking captopril (n = 11) compared with that (1.29 +/- 0.12 mm) in patients taking enalapril (n = 9). 4. Facial flushing during the experiment occurred in six patients taking ACE inhibitors but none who were not. 5. Dermal responses to bradykinin are enhanced in patients taking ACE inhibitors as routine antihypertensive therapy. This study supports the hypothesis that bradykinin may be responsible for some of the adverse effects of these drugs. [ABSTRACT FROM AUTHOR]

1. In 1986 the CSM received 15,527 yellow cards. This was the highest number received in any one year since the scheme started in 1964. Much of the increase was due to the use by doctors of the yellow cards now included in the British National Formulary and NHS prescription pads. 2. The overall profile of reports of serious reaction, in 1986, was broadly similar to that of the previous years. The most commonly reported serious suspected adverse reactions involved the gastro- intestinal tract (801 reports), the skin (539 reports), the central nervous system (535 reports), and the blood (505 reports). 3. Of the drugs introduced between 1984 and 1986 appreciable numbers of reports of serious reactions were received in association with the use of diltiazem (33 reports), mitozantrone (30 reports), enalapril (173 reports) and etodolac (27 reports). [ABSTRACT FROM AUTHOR]

1. The rate of onset and magnitude of the effect of levocabastine, a potent H1-receptor antagonist, in reversing histamine-induced bronchoconstriction were determined in a double-blind cross-over trial against saline placebo. Histamine was administered by nebuliser so that forced expiratory volume in 1 second (FEV1) was reduced to 80-75% of baseline FEV1 in 10 men with mildly or moderately responsive airways and the effects of intravenous injection of saline or saline + 200 micrograms levocabastine were studied. 2. The maximum rate of recovery of FEV1 was 7[2-10]% min-1 (median [range]) in the first 5 min after levocabastine injection, but only 4[1-7]% min-1 after saline alone (P less than 0.05). 3. The median area under the recovery curve of FEV1 from 0 to 30 min after injection was 405 [228-498]% basal FEV1 X min after levocabastine and 301[98-502]% basal FEV1 X min after saline alone (P less than 0.002). 4. FEV1 returned to 90% of baseline within 30 min in all subjects after levocabastine, but not after saline alone (P less than 0.002). 5. Histamine-induced bronchoconstriction was relieved more quickly by levocabastine than saline alone. This model may have application to the study of drugs used in the treatment of anaphylaxis. [ABSTRACT FROM AUTHOR]

As a substrate for human liver microsomes, ethoxyresorufin appears to be metabolised by a group of cytochrome P450 isoenzymes which are inducible by cigarette smoking. Kinetic studies in microsomes from four human livers indicate that only one enzyme component is involved over the full substrate range. Ethoxyresorufin O-deethylation activity at both high and low substrate concentrations correlated with the high affinity component of ethoxycoumarin O-deethylation and of diphenyloxazole metabolism. [ABSTRACT FROM AUTHOR]

The potential interaction between ketanserin and propranolol has been investigated in eight healthy volunteers. Volunteers received single doses of placebo, propranolol (80 mg), ketanserin (20 mg), and propranolol (80 mg) plus ketanserin (20 mg) following a randomised double-blind regimen. A single dose of ketanserin had little effect on resting heart rate and blood pressure and the effects of propranolol and ketanserin in combination were similar to those of propranolol alone. The inhibition of exercise induced tachycardia by propranolol was not affected by ketanserin. The pharmacokinetics of propranolol elimination were not influenced by the concurrent administration of ketanserin, nor the pharmacokinetics of ketanserin by propranolol. [ABSTRACT FROM AUTHOR]

Using 7-ethoxycoumarin as a probe substrate, microsomal monoxygenase activity has been measured in liver tissue from patients with primary biliary cirrhosis (PBC) of varying histological severity, and in histologically normal control tissue. Interindividual variation in enzyme activity was considerable, and in no histological category was the activity significantly different to control. We conclude that: (a) in PBC, hepatic microsomal monoxygenase activity is determined primarily by factors other than the histological severity of the liver disease, and (b) studies of xenobiotic metabolism in patients with liver disease should specify the nature of the underlying disease process. [ABSTRACT FROM AUTHOR]

Aspirin 1200 mg was compared with placebo in a randomised, double- blind, crossover study in 15 patients with postoperative pain after removal of impacted lower third molars. Over a 5 h investigation period, patients reported significantly less pain (P less than 0.01) after treatment with aspirin, than after treatment with placebo. Peak concentrations of aspirin occurred at 15 min after dosage. Significant negative correlations were observed between plasma aspirin esterase activity and both AUC aspirin (r = −0.904, P less than 0.001) and AUC analgesia (r = −0.91, P less than 0.001). Similarly, a significant correlation was observed between AUC aspirin and AUC analgesia (r = 0.96, P less than 0.001). Evidence from this study would suggest that an individual's pain relief in postoperative dental pain is determined by the rate of aspirin hydrolysis to salicylate. [ABSTRACT FROM AUTHOR]

The effects of acute and chronic (3 months) dosing with astemizole on indocyanine green kinetics have been investigated in normal volunteers and patients. A single dose of astemizole 40 mg produced significant reduction in indocyanine green clearance (P less than 0.02) and volume of distribution (P less than 0.02) when assessed at 48 h, but not at 24 h. In six volunteers who did not receive astemizole there was no significant change in indocyanine green kinetics over a 48 h period. In seven patients on chronic treatment with astemizole there was no significant change in indocyanine green kinetics when these were measured at 1 month and 3 months and compared to pre-treatment values. The change in indocyanine green clearance and volume of distribution following acute astemizole treatment did not correlate with H1-receptor antagonism. Change in indocyanine green clearance following acute drug administration may not be due to changes in liver blood flow and should therefore be interpreted with caution. [ABSTRACT FROM AUTHOR]

Activities of the microsomal mono-oxygenases 7-ethoxycoumarin O-de- ethylase (EOC) and aldrin epoxidase (AE), together with microsomal epoxide hydrolase (EH) activity and concentrations of reduced glutathione (GSH) have been measured in liver from patients with alcoholic cirrhosis and in normals. Activities of both mono-oxygenases were significantly reduced in alcoholic cirrhosis. EOC activity (pmol 7- OH coumarin formed/mg microsomal protein/min) was 108.0 +/- 10.6 (n = 8) in normals and 60.9 +/- 11.6 (n = 8) in alcoholic cirrhosis (P less than 0.01). AE activity (pmol dieldrin formed/mg microsomal protein/min) was 58.9 +/- 9.5 (n = 11) in normal liver biopsies and 29.9 +/- 8.6 (n = 9) in alcoholic cirrhosis (P less than 0.05). Microsomal EH activity (nmol styrene glycol formed/mg microsomal protein/min) was similar in normals (39.2 +/- 4.4, n = 11) and alcoholic cirrhosis (40.5 +/- 9.1, n = 6). GSH concentrations (microgram GSH/g liver tissue) were lower (P less than 0.01) in alcoholic cirrhosis (792 +/- 73, n = 10) compared to normals (1182 +/- 76, n = 6). [ABSTRACT FROM AUTHOR]

1 Soluble aspirin, 600 mg and 1200 mg, and placebo were compared in a double-blind, cross-over study in 12 patients with post-operative pain following removal of impacted lower third molars. 2 Significant analgesia after 600 mg aspirin occurred only at 45 min after administration, whereas significant analgesia after 1200 mg aspirin occurred from 45 to 240 min. The 1200 mg dose produced greater analgesia than the 600 mg dose and is to be recommended in clinical practice. 3 Plasma concentrations of salicylate and acetylsalicylate were measured after both doses. A significant correlation (rs = 0.876, P less than 0.01) was observed between analgesia and plasma salicylate concentration after 1200 mg aspirin. [ABSTRACT FROM AUTHOR]

1 Antipyrine clearance has been measured from serial saliva samples in 36 healthy adult Indo-Pakistani immigrants to Britain, to assess the effect of dietary differences within this population. 2 Clearance (mean +/- s.e. mean) was significantly slower in 16 lactovegetarians (0.54 +/- 0.06 ml min −1 kg −1) than in the subjects who ate meat regularly (0.91 +/-0.07 ml min −1 kg −1). 3 The absence of meat from the diet was associated with a significantly smaller daily intake of dietary protein, which was abnormally low by Western standards. 4 It is likely that the contrast in daily protein intake between the dietary subgroups was largely responsible for the differences observed in antipyrine clearance. [ABSTRACT FROM AUTHOR]

1 Epoxide hydrolase (EH) activity was measured in biopsied skin (n = 42) using 7-[H3]-styrene oxide as substrate, and separation of the products by high performance liquid chromatography. 2 EH activity (mean +/- s.d.) was present in separated epidermis (139 +/- 105 pmol glycol formed mg-1 min-1) and dermis (165 +/- 120 pmol glycol formed mg-1 microsomal protein min-1). 3 Whole skin EH activity (mean +/- s.d.) varied widely (433 +/- 254 pmol glycol formed mg-1 microsomal protein min-1) 4 No significant difference in EH activity was observed in skin from breast, penis and leg. 5 Skin EH activity does not appear to contribute significantly to the systemic metabolism of epoxide, but may be important in determining the effects of epoxides formed within the epidermis. [ABSTRACT FROM AUTHOR]

Br J Clin Pharmacol 1980 Aug;10(2):121-6 1 beta-Adrenoceptor blockade, plasma labetalol concentrations and anti- hypertensive actions were investigated at 2 hourly intervals during the interdose period of chronic oral therapy in six hypertensive patients. 2 beta-adrenoceptor blockade varied during the inter-dose period and was maximal 2 and 4 h after the oral dose (P > 0.05). 3 Systolic pressure rose during the interdose period (P > 0.05). A significant correlation was found between the degree of beta-adrenoceptor blockade and the change in systolic pressure at 2 h after the oral dose. 4 Efficacy of labetalol as a beta-adrenoceptor antagonist and anti- hypertensive drug was assessed 2 h after an oral dose during chronic eight hourly dosage in sixteen hypertensive patients. Pharmacokinetics of labetalol were studied in the same patients. 5 Peak plasma labetalol concentration occurred 2 h after the oral dose and subsequently the plasma concentration declined monoexponentially. 6 The steady state concentration (CSS) of labetalol was correlated significantly with the daily oral dose in mg kg-1, the mid point labetalol concentration (Cmax+Cmin) divided by 2 and the isoprenaline dose ratio-1 at 2 h after the oral dose. 7 No correlation was found between the antihypertensive effect and the CSS ng ml-1 labetalol or between the isoprenaline dose ratio-1 and the CSS labetalol ng ml-1. [ABSTRACT FROM AUTHOR]

1 In a multicentre open trial, labetalol was given to 128 patients in ten centres. Forty-three patients had not previously received antihypertensive therapy; the remainder (85 patients) had been on antihypertensive therapy with either unsatisfactory BP control or troublesome side-effects. 2 Thirty-two patients were withdrawn from the trial in the first 6 months of therapy, 24 (19% of the total) because of side-effects. 3 Control of BP was generally satisfactory or considerably improved. Other drugs (usually a diuretic) had to be added in 23 patients. 4 There was an abnormality of liver function in one patient; otherwise there were no biochemical or haematological problems. [ABSTRACT FROM AUTHOR]

The concentration of alpha 1-acid glycoprotein (AAG) was measured in plasma from 200 healthy subjects belonging to 78 family units. The AAG concentration varied markedly between individuals (mean 0.77, range 0.36-1.46 g 1(-1]. When the genetic contribution to the variability was assessed, the only significant correlation observed was that between husband and wife and this was weak. We conclude that in addition to the known effects of age and gender, environmental (rather than genetic) factors largely determine the variance of AAG concentrations. [ABSTRACT FROM AUTHOR]

Antipyrine clearance was determined in 41 psoriatics and age-sex matched controls, using sequential measurements of salivary concentration. Antipyrine clearance and elimination rate constant were less in psoriatics (P less than 0.05) and apparent volumes of distribution were similar. These differences were greater between female psoriatics and controls (P less than 0.025; P less than 0.05) and the differences between male psoriatics and controls were not significant. Correlation of simultaneous measurements of saliva and plasma antipyrine concentration in six psoriatics and age-sex matched controls showed no differences between the two groups. We conclude that antipyrine clearance is reduced in psoriasis but the underlying mechanism is unclear. [ABSTRACT FROM AUTHOR]

Sodium salicylate, 537 mg and 1074 mg were compared in a double-blind cross-over study in 24 patients with post-operative pain following removal of impacted lower third molars. No significant analgesic effect was observed after either dose of sodium salicylate, either overall or at any time point during the 5 h investigation period. Peak plasma concentrations of salicylate after 537 mg were observed at 30 min after dosage, whereas peak plasma salicylate concentrations after 1074 mg sodium salicylate occurred at 45 min after dosage. [ABSTRACT FROM AUTHOR]

The activity of aryl hydrocarbon hydroxylase (AHH) in monocytes from 13 healthy control subjects and in 16 patients with discoid psoriasis was measured. The mean basal monocyte AHH activities of the control and psoriatic groups were 3.4 +/- 0.47 and 4.46 +/- 0.55 respectively (pmol 3-OHBP h-1 10(-6) cells). This difference was not significant. The mean induced monocyte AHH activities in the control and psoriatic groups were 56.4 +/- 10.8 and 77.8 +/- 16.0 pmol 3-OHBP h-1 10(-6) cells respectively but this difference was not significant. The mean induction ratios in the control and psoriatic groups were 16.5 +/- 1.8 and 20.4 +/- 3.6 respectively. Again, this difference was not significant. We conclude therefore, that monocyte aryl hydrocarbon hydroxylase activity is not reduced in psoriasis. [ABSTRACT FROM AUTHOR]

1 Apparent Vmax and Km for phenytoin were estimated in 40 children (aged 8-33 months) and 21 adults (aged 18-66 years). 2 The derived values of Vmax and Km were used to predict the plasma and salivary concentrations of phenytoin following a change in dose. There was a highly significant correlation between observed and predicted steady- state concentration in both children and adults (P less than 0.001). 3 The apparent Km was similar in children (7.5 +/- 1.2 mg/l) and adults (9.4 +/- 2.3 mg/l). 4 Vmax differed significantly (P less than 0.001) between children (20.4 +/- 2.1 mg kg-1 day-1) and adults (8.7 +/- 0.7 mg kg-1 day-1). 5 After correction for differences in the ratio of liver weight to body weight in children and adults, Vmax was similar in the two groups. [ABSTRACT FROM AUTHOR]

1 The pharmacological and therapeutic effects of labetalol were investigated during an 8 h interdose period of chronic oral therapy in six patients with essential hypertension. 2 Peak plasma labetalol concentrations were observed 2 h after the morning oral dose, and subsequent decline was mono exponential. 3 Beta-adrenoceptor blockade paralleled the changes in labetalol concentration and was maximal 2 and 4 h after the oral dose. 4 Resting supine systolic BP rose significantly during the interdose period, but no change occurred in diastolic BP. 5 Ambulatory intra-arterial BP studies in a further six patients with essential hypertension controlled with labetalol did not confirm the increase in BP during an 8 h interdose period. [ABSTRACT FROM AUTHOR]

1 Twenty patients with essential hypertension completed a double-blind, dose-tritrated, cross-over comparison of methyldopa and labetalol. 2 Average lying BPs (systolic/diastolic) were reduced by 28/15 mmHg with methyldopa and by 23/15 mmHg with labetalol. 3 Average standing BPs (systolic/diastolic) were reduced by 29/14 mmHg with methyldopa and by 29/15 mmHg with labetalol. 4 Both lying and standing heart rates were reduced with labetalol. 5 It is concluded that the antihypertensive properties of labetalol and methyldopa are similar but that larger patient populations are needed to study the relative incidence of subjective adverse effects. [ABSTRACT FROM AUTHOR]

1 Mean steady-state plasma concentrations of labetalol (labetalol Css) in 17 hypertensive patients undergoing chronic treatment with this drug, have been examined in relation to dose, fall in BP, and beta- blockade. 2 A significant relationship (rs = 0.81, P less than 0.001) was observed between labetalol Css and daily dose. 3 No correlation was found between labetalol Css and antihypertensive response. 4 In thirteen patients, there seemed to be significant relationship between labetalol Css and beta-blockade (rs = 0.72, P less than 0.005). In three patients, the degree of beta-blockade was disproportionate to the drug concentration. [ABSTRACT FROM AUTHOR]