Biomedical subjects
D N Bateman
Publications and source records attributed to D N Bateman.
Studies on the pharmacological control of gastric emptying in man.
Three compounds with differing pharmacological properties have been studied with respect to their effects on gastric emptying, BP, pulse rate and sedation in comparison with placebo in three groups of normal male volunteers. BRL 20627 (10 mg i.v.), a benzamide without dopamine antagonist activity, increased gastric emptying rate (t0.5 BRL 20627 8.3 +/- 0.87 min, placebo 13.8 +/- 2.29 min, P less than 0.005). Zetidoline (20 mg orally), a dopamine D2-receptor antagonist had no significant effect on gastric emptying parameters. BK 34/530 (50 and 100 mg orally) a compound with mixed dopamine agonist and alpha-adrenoceptor antagonist activity, impaired gastric adaptive relaxation as measured by the volume 5 min after the drink and at the higher dose delayed gastric emptying (placebo--5 min volume 256 +/- 44.3 ml, t0.5 15.3 +/- 1.32 min: 50 mg BK 34/530-5 min volume 247 +/- 38 ml, t0.5 14.2 +/- 1.94 min: 100 mg BK 34/530-5 min volume 228 +/- 43.7 ml, t0.5 21.1 +/- 3.82 min). All three drugs resulted in small but significant falls in blood pressure, and in the case of BK 34/530 the 100 mg dose caused significant tachycardia. These studies suggest that dopamine antagonist activity is not a prerequisite for 'gastrokinetic' effects in man, and that there is no inhibitory dopaminergic tone on gastric emptying in normal subjects.
Gastric emptying and small-bowel transit rate in the elderly.
Gastric emptying of liquid and small bowel transit in a group of elderly patients (mean age 79 years) was studied, with the elderly subjects compared to two groups of young controls. In 14 elderly patients, the initial rate of gastric emptying was significantly higher than in 14 young controls: the five-minute volume was 159 +/- 30 ml (mean +/- SEM) in the elderly patients and 294 +/- 22 ml in the young controls (p less than 0.005). The two groups' gastric emptying rates after five minutes were not significantly different. Small-bowel transit in 15 elderly patients was not significantly different from that found in 15 younger volunteers. These results suggest that gastric homeostatic mechanisms are impaired in the elderly.
Delayed gastric emptying with dothiepin.
Dothiepin induced symptoms of delayed gastric emptying in an elderly lady. Rechallenge studies were undertaken and demonstrated a delay in gastric emptying of liquid after re-administration of dothiepin at a time when plasma concentrations were 93 micrograms/l. Elderly patients may be more susceptible to the anticholinergic effects of tricyclic antidepressants on the gut.
Opiate-induced rhabdomyolysis.
Three patients with opiate self-poisoning developed acute muscle damage with elevated serum aspartate aminotransferase and creatine kinase activities, increased serum myoglobin concentrations, raised plasma creatinine concentrations, hypocalcaemia and hyperphosphataemia. These abnormalities gradually resolved over 7-10 days, but recovery was complicated due to the development of acute renal failure (requiring haemodialysis) in one patient. Plasma drug concentrations, shortly after admission, in the patients taking dihydrocodeine and morphine were grossly elevated (184 and 60 micrograms/l respectively). Clinical evidence of myopathy was minimal in all three patients and muscle biopsy of one patient was normal at 7 days.
Pharmacokinetics and clinical toxicity of quinine overdosage: lack of efficacy of techniques intended to enhance elimination.
We report clinical details in 16 cases of quinine poisoning. Plasma quinine concentrations above 15 mg/l were associated with increased risks of permanent visual damage and of cardiac arrhythmias from which one of our patients died. The rate of quinine elimination was not significantly altered by forced acid diuresis in five patients (t 1/2 25.1 +/- SEM 4.6 h) as compared to eight patients treated conservatively (t 1/2 26.5 +/- SEM 5.78 h). Neither urinary pH or flow rate correlated consistently with urinary quinine clearance. In three other patients charcoal column haemoperfusion, haemodialysis and exchange transfusion were performed. These were also ineffective in increasing quinine elimination. It is concluded that techniques advocated to increase quinine elimination are ineffective in the management of quinine poisoning.
Adverse reactions to N-acetylcysteine.
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Atenolol pharmacokinetics in patients on continuous ambulatory peritoneal dialysis.
The elimination of atenolol (20 mg i.v.) has been studied in seven patients with renal failure on continuous ambulatory peritoneal dialysis (CAPD). Although atenolol was eliminated in the peritoneal fluid, the amount recovered in 24 h was relatively low (1.2 +/- 0.15 mg). The calculated urinary (n = 4) and peritoneal (n = 7) clearance was 0.289 +/- 0.058 l/h and 0.152 +/- 0.018 l/h respectively. This was considerably less than calculated total body clearance (1.21 +/- 0.086 l/h). The kinetics of atenolol in CAPD are worthy of further study.
Pharmacokinetics and efficacy of high-dose metoclopramide given by continuous infusion for the control of cytotoxic drug-induced vomiting.
To avoid the accumulation of metoclopramide that occurs with repeated i.v. bolus doses, a new regimen for the administration of high-dose metoclopramide consisting of a loading dose followed by a continuous infusion was investigated to determine the pharmacokinetics and antiemetic efficacy of the drug when given in this manner. Nine patients with non-Hodgkin's lymphoma entered the study, of whom six completed the study, receiving each of three dosage schedules of metoclopramide during three consecutive courses of chemotherapy. In these six patients plasma metoclopramide half-life was 5.9 +/- 0.4 h (mean +/- s.e. mean) and plasma clearance was 25.4 +/- 4.8 l/h (mean +/- s.e. mean). Neither half-life nor clearance were dose-related. Steady-state was achieved during 9/18 infusions. Nausea and vomiting were completely controlled in 13/24 treatment courses (57%) and adverse effects were minimal. We conclude that steady-state plasma concentrations of metoclopramide can be achieved using a weight-related infusion regimen, though the optimum plasma concentration remains to be determined.
Adverse reactions to N-acetylcysteine.
Clinical details of seven patients who suffered adverse reactions to N-acetylcysteine as Parvolex are documented. Skin testing was carried out to diluted Parvolex, and its individual components N-acetylcysteine and ethylenediaminetetra-acetate, in five reacting patients and five patients who had received Parvolex with no ill-effects. Weal responses to high concentrations (20 mg/ml) of acetylcysteine as Parvolex were significantly greater (p less than 0.02) in reactors. There were no other significant differences between the groups. In two patients who reacted, the effects of intradermal Parvolex could be inhibited by prior therapy with the antihistamine terfenadine. These results suggest a 'pseudo-allergic' rather than an immunological aetiology for adverse reactions to Parvolex.
The effects of astemizole on histamine-induced weal and flare.
The effect of astemizole on the weal and flare response to intradermal histamine has been studied in normal volunteers after single dosing, and in patients with urticaria and pruritus after chronic dosing with the drug. Single doses of astemizole (40 mg) in normal volunteers significantly reduced histamine weal and flare at 24 and 48 h (p less than 0.001). Before treatment, there was a significantly greater response to intradermal histamine in patients with urticaria than pruritus (p less than 0.05). Chronic dosing with astemizole produced significant reduction in histamine-induced weal and flare in both patient groups which did not show evidence of tachyphalaxis over the period of the study. The effect of astemizole on histamine-induced weal and flare was accompanied by a significant increase in the rate of weal and flare disappearance in both patients (weal p less than 0.002, flare p less than 0.05) and volunteers (weal p less than 0.02, flare p less than 0.005); but there was no change in the rate of weal formation. The effects of astemizole on weal and flare kinetics may be a function of its high level of H1 antagonist activity.
Lack of effect of astemizole on ethanol dynamics or kinetics.
The effects of astemizole (10 mg daily for 7 days) on the kinetics and CNS depressant activity of ethanol have been examined in a double-blind cross-over study agonist placebo in 7 volunteers. There was no significant change in the elimination rate or AUC of the plasma ethanol concentration-time curve after astemizole. Central nervous system effects of ethanol as monitored by visual analogues of sedation, visual discrimination, pursuit rotor and reaction time were also unaffected by astemizole pretreatment.
Delta-9-tetrahydrocannabinol and gastric emptying.
The effects of delta-9-tetrahydrocannabinol (0.5 and 1 mg i.v.) on gastric emptying of liquid were investigated in seven normal volunteers and compared with placebo. Despite significant change in pulse rate and psychological parameters consistent with cannabis activity there was no significant effect on the pattern of gastric emptying. It is therefore suggested that an anti-emetic action of delta-9-tetrahydrocannabinol does not involve a change in gastric emptying.
Dystonic reactions and the pharmacokinetics of metoclopramide in children.
The pharmacokinetics of metoclopramide have been studied in nine children receiving the drug as prophylaxis for cytotoxic induced vomiting. Plasma concentrations of metoclopramide have also been studied in three children with dystonic reactions to the drug. The pharmacokinetics in children were similar to those reported in healthy adults. There was no difference in the plasma concentration of metoclopramide of children with dystonia when compared to those without this adverse effect. Kinetic differences in childhood do not explain the occurrence of dystonia, which in the individual appears to be related to factors other than plasma drug concentrations.
The acute and chronic effects of H1 receptor blockade with astemizole on indocyanine green clearance.
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.
High dose metoclopramide-preliminary pharmacokinetic studies.
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The effects of astemizole on antipyrine clearance.
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