Various unexpected symptoms and signs were noted in the two groups of patients (including patients who were withdrawn). One patient in the cimetidine group developed pulmonary embolism, one oedema of fingers, one presbyopia, two diarrhoea, and one arterial hypertension. Three patients in the placebo group complained of impotence, headache, and fatigue respectively. Reduced libido was reported by one patient from each group. Laboratory screening tests showed no significantly abnormal findings. Mean blood-pressure values and results of laboratory investigations at the beginning and end of treatment (after completing one year's treatment or at the time of relapse or withdrawal) are shown in table III. During the study one of the departments was moved to another hospital, where different standards were used. This might partly explain the differences in pretrial and post-trial values. The differences between cimetidine and placebo groups, however, were not significant (Mann-Whitney U tests, P 0 05). DiscussionThe possibility that symptomless relapse occurred in some patients and that symptomatic relapse in others was unaccompanied by renewed ulceration cannot be excluded since no patient underwent duodenoscopy. Such possible discrepancies are, however, of limited practical consequence, and we decided that it was more important to choose a design that imitated so far as possible the conditions under which cimetidine may be used in daily clinical practice. Our findings agreed with those of a similar trial conducted by Bodemar and Walan6 in showing that maintenance treatment with cimetidine for one year is highly effective, but we also found that the treatment had no lasting effect. Soon after treatment was completed relapses occurred at about the same rate as in patients whose ulcers had healed spontaneously or during a short course of cimetidine. Wallace et al7 reported severe relapses after cimetidine treatment, but we observed no such incidents in the patients who had received cimetidine for one year or in the patients in the placebo group who had received a short course of cimetidine before entering the maintenance trial. No side effects directly attributable to cimetidine were observed during the trial.Our results suggest that maintenance treatment with cimetidine is a realistic alternative to elective surgery in patients subject to frequent relapses, but several points still need clarification. Firstly, the optimal duration of treatment is not known. Fry8 and Greibe et al9 have shown that duodenal ulcer disease often resolves after a few years, especially in patients diagnosed in general practice, but the average ulcer history of 13 5 years in our patients also shows that prolonged treatment is needed in some cases. It remains to be proved that such treatment is safe and that patients do not acquire tolerance to cimetidine with time, though limited experience in cases of the Zollinger-Ellison syndrome suggests that this is unlikely.10The study was supported by grants 512-6636, 512-8291, and 512-6648 four patie...
Physiologic and clinical effects of chlorpromazine and their relationship to plasma levelTen patients suffering from functional psychoses who had not received medication for one month were studied. After investigation before treatment, they received chlorpromazine in liquid form, 100 mg. every 8 hours for 5 to 6 weeks. Testing was carried out on Days 4,8,15,22,29, and 36 or 43 of treatment: (1) Blood samples were taken for chlorpromazine assessment at 0, 2, 4, and 6 hours after the morning dose; (2) blood pressure and pulse rate, pupil size, sweat gland activity, and electroencephalogram (EEG) were recorded at these times; (3) salivary secretion, EEG-evoked response, auditory reaction time, and handwriting tests were carried out at the 2 hour point; and (4) clinical ratings were made between 2 and 4 hours. Wide interpatient variation in plasma level was found; concentrations were maximal in the first 2 weeks, then consistently declined. Changes in the peripheral autonomic measures correlated with those in plasma level, but changes in the central measures were inconsistent. Plasma levels and clinical improvement were weakly related during the first 2 weeks of treatment only. Clinical improvement correlated with palmar skin conductance (sweating) and with some latencies of the electroencephalographic-evoked response. The determination of chlorpromazine plasma levels should be of use in investigating nonresponders and patients with severe autonomic effects.
Median WGTT after 120 mg significantly increased by 4.1 h relative to placebo, but at higher doses median changes relative to placebo were not significant due to wide increases in group variance. The EI t50% was delayed by 1.4 min when results from the two highest doses were combined and compared with placebo; this small difference was statistically significant but seems unlikely to achieve physiological or clinical significance. OCTT, visual accommodation and saliva flow were unaltered. Otilonium bromide was well tolerated at all doses, due mainly to low systemic absorption.
Summary Concentrations of total radioactivity in plasma of rats given intravenous and oral 35S‐chlorpromazine, were similar. Concentrations of unchanged drug, however, were lower after oral doses. Chlorpromazine circulated in solution through isolated loops of rat intestine was rapidly absorbed by the tissue. Measurements of glucose transport and histological examination indicated that the tissue was intact. In these in vitro experiments some of the chlorpromazine was converted to products, which together with unchanged drug, were partly retained in the intestinal wall and partly transferred to the serosal side of the tissue. Observations at three concentrations supported the hypothesis that transfer of unchanged drug occurred by passive diffusion. Conversion of chlorpromazine to metabolites in the intestine in vivo, would account for the differences in concentrations of chlorpromazine and total radioactivity in plasma after oral doses.
A radioimmunoassay has been developed for propranolol with a sensitivity of 2.37 nmol l-1 in unextracted plasma using a 50 microliter sample. Plasma concentration measurements were made on samples from volunteers for up to 8 h after they had been given 5, 10, or 40 mg of propranolol by mouth. Analysis of the results showed that mean elimination half-lives and total body clearances were similar following each of the doses and that the area under the curve was proportional to the dose. Steady-state propranolol concentrations in 17 patients on regular propranolol treatment were linearly related to the dose ver the range 20-640 mg d-1; the regression line extrapolated to the origin. These data indicate non-saturable kinetics for the hepatic metabolism of propranolol within the dose ranges investigated and lead us to believe that there is no 'oral-threshold' dose for propranolol. The radioimmunoassay may be useful in clinical practice for monitoring plasma propranolol concentrations and for detecting patient compliance.
S U M M A R Y1. The plasma disappearance and cerebral effects of chlorpromazine were studied in twenty-four patients with compensated cirrhosis and in matched controls using a sensitive gas-liquid chromatography (g.1.c.) technique to measure chlorpromazine. Plasma disappearance followed a double-exponential decay curve. No difference could be detected between cirrhotic and control groups, even when the effect of prior treatment with inducing drugs was considered, and only minor differences were observed when the elimination rate constants (k,,) were calculated.2. Chlorpromazine caused drowsiness in all subjects, together with slowing of EEG activity. The slowest activity, which was accompanied by impaired cerebration, occurred in those patients with a past history of encephalopathy in whom the value for the pretreatment skew mean-dominant-frequency was abnormally low.3. The susceptibility of some patients with cirrhosis to chlorpromazine is probably due to increased sensitivity of cerebral neurones, rather than impaired hepatic drug metabolism.
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