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1 Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276-Ba, which has been shown to have antidepressant activity. 2 In five normal volunteers tested before and during treatment with Ciba 34276-Ba, no abnormalities of resting or post-exercise electrocardiographs occurred. A three-fold reduction in tyramine-responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276-Ba whilst on long-term treatment with bethanidine showed loss of blood pressure control. 3 The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276-Ba.

1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 μg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient. 2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time. 3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K(m)) corresponding with 50% saturation was 3.8 μg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 μg/ml was 345-400 mg/day. 4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 μg/ml it is then appropriate to adjust dose by small steps of about 25 mg.

1 Urine was collected over 24 h from 40 patients with advanced malignant disease who had received a known four-hourly oral dose of either diamorphine or morphine in an elixir or of diamorphine by injection for at least 3 days. 2 Samples were assayed for total urinary morphine (free and conjugated) by gas-liquid chromatography. 3 The percentage of the administered dose recovered as morphine was: (a) diamorphine hydrochloride by injection: 70% (s.d. 25) (b) diamorphine hydrochloride by mouth: 77% (s.d. 27) (c) morphine sulphate by mouth: 56% (s.d. 21) 4 It is suggested that diamorphine hydrochloride is completely absorbed by the gastro-intestinal tract but that morphine sulphate is only some two-thirds absorbed.

1 The administration of 0.5 mg glyceryl trinitrate by chewing and keeping under the tongue increased heart rate in normal subjects in the supine and erect posture. 2 There was no significant difference between the responses in the same subject on repeated administration of glyceryl trinitrate on different days but there was a significant difference between the responses in different subjects. 3 The oral administration of practolol and propranolol reduced the responses to glyceryl trinitrate. The two drugs progressively reduced the increase in heart rate produced by glyceryl trinitrate; there was no significant difference between their effects. Propranolol produced a significantly greater reduction than practolol in the maximum heart rate that was produced by glyceryl trinitrate. 4 The administration of practolol (300 mg) twice daily by mouth to patients after an acute episode of ischaemic heart disease significantly reduced the increases in heart rate produced by standing and by glyceryl trinitrate in comparison to the responses in similar patients receiving a placebo.

1 The half-life of hydrocortisone (cortisol) has been measured in six patients before and after a three-week course of prednisone given for asthma. 2 There was considerable variation in peak plasma level of cortisol both within and between patients, but on both occasions the plasma half-lives were the same. 3 It was concluded that short courses of prednisone have no effect on the handling of hydrocortisone.

1 The effects of oral doses of the bronchodilator drugs, salbutamol (4 and 8 mg) and terbutaline (5 and 10 mg), on physiological tremor, bronchial tone, heart rate and blood pressure were studied in six normal subjects. 2 Both drugs produced a significant increase in physiological tremor, compared with placebo. Terbutaline, but not salbutamol, produced a dose related response. No significant differences were observed between drugs. 3 Terbutaline (5 and 10 mg) and salbutamol (8 mg) produced a significant bronchodilatation compared with placebo. Dose related responses were obtained with both drugs, although this reached significance only with terbutaline. 4 Both doses of each drug produced a tachycardia, although this was only statistically significant with the high doses. 5 No significant change in blood pressure was observed with either drug. 6 Peak effects of salbutamol occurred between 1 and 3 h and terbutaline between 1 and 4 hours. Both drugs were still active at 6 hours.

1 Fifteen patients with diastolic blood pressures between 90 and 120 mmHg were admitted to a trial comparing placebo with practolol at doses up to 500 mg 12 hourly. 2 The trial was a double blind cross over study. Treatments were allocated at random and each treatment block lasted 12 weeks. 3 Ten patients completed the trial, and none of those who withdrew experienced serious unwanted effects. 4 Practolol caused significant falls in standing systolic and diastolic pressures and the supine diastolic pressure.

1 Intravenous propranolol and practolol both reduced resting supine heart rate in patients with hyperthyroidism. Propranolol produced a significantly greater reduction than practolol, which did not have a dose-dependent effect. 2 The effect of these drugs on resting heart rate was much less than their effect on the tachycardias produced both by severe exercise and by standing upright in hyperthyroid patients. Propranolol again produced a significantly greater reduction than practolol in each situation, but practolol did have a dose dependent effect on exercise heart rate. 3 The percentage reduction of standing tachycardia produced by the two drugs appeared to parallel closely the reduction in exercise tachycardia. 4 It is concluded that a simple and convenient way of assessing the activity of β-adrenoceptor blocking drugs in hyperthyroid patients would be to measure their effect on the tachycardia induced by standing. Their effect on resting heart rate should not be used. 5 Practolol may be useful in the management of hyperthyroidism in patients in whom propranolol and similar non-selective β-adrenoceptor blocking drugs are contraindicated.

1 Δ(1)-trans-tetrahydrocannabinol (Δ(1)-THC; 10 mg) or a placebo was given orally on 7 days to two groups of six patients on a cross-over pattern with 7 days rest between. 2 The patients were hospitalized, suffering from inoperable bronchogenic carcinoma, subjected to radiation therapy, and anxious. 3 Self-rating mood scales were filled in before, and 2 and 6 h after ingestion on the first and seventh day of medication. 4 Records of sleep, pain, general well-being, temperature, cardiovascular and gastrointestinal parameters were kept. 5 Δ(1)-THC caused drowsiness and improved night sleep, reduced pain, increased fatigue and confusion and reduced elation and vigour; it caused slight tachycardia and hypotension as also did placebo. 6 The effects of Δ(1)-THC were stronger after 2 h than 6 h and no tolerance had developed at 7 days. 7 The management of stressful patients was considered to have been improved by the drug.

1 ST-91, 2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride produces in animal experiments bradycardia, and in larger doses, also hypertension, due to α-sympathomimetic activity and probable central sympathetic inhibition. 2 The effects of ST-91, after oral administration, were studied in 10 healthy volunteers. A dose-dependent, significant decrease of the heart rate was observed. On average the resting heart rate was reduced by 11-19 beats/min (15-29%). During exercise the decrease of the heart rate was less pronounced. After the largest dose there was a fall of the systolic blood pressure during exercise averaging at 14-15 mmHg (11-12%). Otherwise the blood pressure remained unchanged. 3 Eight out of the 10 test-subjects complained of hair-raising and goose-flesh after all doses, due to the α-sympathomimetic effect of the drug. No toxic effects were observed.

1 A controlled trial of charcoal haemoperfusion as an early treatment for paracetamol overdose showed no benefit. 2 The plasma clearances of paracetamol by the charcoal column were variable and disappointingly small (range 4-119 ml/minute). The cumulative amounts removed were also low, mean 1.4 g (range 0.2-5.2 g). 3 No clinical problems were encountered with the technique of haemoperfusion and in particular the drop in blood platelet counts was small (mean fall 16%).

1 A double blind cross-over study was carried out on patients with reversible airways disease attending an out-patient clinic. 2 Twenty patients were given either salbutamol (200 μg) or propellant by aerosol for two week periods and in another study twelve patients were given identical tablets containing either salbutamol (4 mg) or placebo for four week periods. Both forms of therapy were taken four times per day but stopped the evening before attending the clinic. 3 The improvement in FEV1 10 min following salbutamol (200 μg) by aerosol was measured after previous treatment with either salbutamol or placebo administered by aerosol and orally and the results were compared statistically. This failed to show a significant difference and suggests that regular treatment with salbutamol does not lead to a decreased response.

1 Twelve chronically anxious psychiatric out-patients, comprising six with somatic anxiety and six with psychic anxiety, were treated with (±)-propranolol, diazepam and placebo for one week each in flexible dosage using a balanced cross-over experimental design. 2 After each treatment, in addition to ratings completed by patient and psychiatrist, finger tremor, EEG, averaged auditory evoked response, skin conductance, heart and respiratory rate were measured. 3 Diazepam significantly increased the amount of fast activity (13.5-26 Hz) in the EEG but produced few peripheral effects apart from a reduction in finger tremor. 4 Propranolol had no central physiological effects but reduced both pulse rate and finger tremor. 5 The physiological effects of propranolol in chronic anxiety are different from those of diazepam and therapeutic benefit appears to be due to a direct effect on certain somatic symptoms.

1 The effect of acetylsalicylic acid (1 g), indomethacin (50 mg), and phenylbutazone (200 mg) on psychomotor skills was examined double blind on 180 volunteer students. Ninety students received ethyl alcohol (0.5 g/kg) and 90 subjects an equal volume of placebo drink in combination with the drugs. 2 Psychomotor skills were measured with a choice reaction test, two co-ordination tests, and a divided attention test, having correlation with traffic behaviour. The subjects assessed their feelings of performance by means of a rating scale. The tests were done 30, 90 and 150 min after the administration of the agents. 3 Acetylsalicylic acid proved inactive whereas both indomethacin and phenylbutazone impaired eye-hand co-ordination and divided attention. Acetylsalicylic acid did not interact with alcohol to a measurable extent whereas indomethacin in combination with alcohol proved less harmful than without it. The deleterious effects of phenylbutazone and alcohol were additive. 4 An impairment of psychomotor skills related to driving by indomethacin and phenylbutazone should be considered when prescribing these drugs to active out-patients.

1 The effect of repeated administration of phenobarbitone on the plasma disposition of fenoprofen (±-2-(3-phenoxyphenyl) propionic acid) was investigated in rats and man. 2 The plasma elimination rate constants increased significantly and the rats excreted proportionately more metabolized fenoprofen in the urine. These findings are consistent with an increase in the rate of metabolism of fenoprofen. 3 This interaction between phenobarbitone (and presumably other inducers of drug metabolizing enzymes) and fenoprofen should be considered when evaluating the clinical usefulness of fenoprofen.

1 Ko 1313 competitively inhibited the increases in heart rate produced by isoprenaline in anaesthetized dogs. 2 Ko 1313 was 35 times more active than propranolol in blocking an isoprenaline induced tachycardia in anaesthetized dogs but only three times more active in blocking the increase in femoral blood flow produced by the injection of isoprenaline into the femoral artery. These observations suggest that Ko 1313 may have some cardio-selective activity. 3 When a series of doses of Ko 1313 was injected intravenously into anaesthetized dogs, the lower doses decreased heart rate while the larger doses increased heart rate. The same doses of propranolol reduced heart rate. 4 In lightly anaesthetized dogs, a series of doses of Ko 1313 progressively increased heart rate while propranolol produced little change. These observations indicate that Ko 1313 has slight intrinsic sympathomimetic activity. 5 The oral administration of Ko 1313 and propranolol had no effect on resting heart rate in man but reduced the increases produced by head-up tilt, standing and exercise.

1 A specific gas-chromatographic method was developed for determination of N-acetylprocaine amide in plasma and urine, using 4-amino-N-(2-piperidinoethyl)benzamide as an internal standard. The investigation was performed in 50 cardiac patients who had reached steady-state plasma concentrations of procaine amide. 2 The plasma concentrations of the acetylated metabolite varied between 1.0 and 15.0 μg/ml and were thus of the same order of magnitude as those of the parent drug. Especially high plasma levels of the metabolite were seen in patients with poor kidney function. 3 The urinary excretion of the metabolite varied markedly between individuals and ranged between 6 and 52% of the administered daily dose. There was a clear tendency towards higher rates of acetylation of procaine amide in patients with short plasma half-lives of isoniazid, i.e. the phenotype rapid acetylators. Because of coexisting therapy with other drugs and impaired renal function in some patients studies are required in healthy human volunteers to ascertain whether the acetylation of procaine amide and isoniazid are mediated by the same enzyme system.

1 The metabolites of thiopurinol have been investigated in intact human and pig erythrocytes using [6-(14)C]-thiopurinol, high voltage electrophoresis and automated cation exchange chromatography. 2 Pre-incubation of human erythrocytes in vitro with thiopurinol increased the formation of hypoxanthine from [8-(14)C]-inosine and simultaneously reduced IMP synthesis. 3 Reduced inosine formation, following one week of thiopurinol therapy, has also been observed in vitro using the intact red cells from three patients suffering from gout. 4 Binding of thiopurinol, and to lesser extents of 6-mercaptopurine, uric acid, oxipurinol and allopurinol, has been demonstrated electrophoretically to human and pig serum proteins. 5 Thiopurinol is shown to have a greater binding capacity for purified human serum albumin than uric acid or 6-mercaptopurine at varying substrate and albumin concentrations covering the physiological range. Under these conditions the binding of uric acid is reduced in the presence of thiopurinol. 6 A comparison of the distribution of thiopurinol, 6-mercaptopurine, allopurinol and oxipurinol in whole blood has revealed that allopurinol and oxipurinol are not irreversibly bound to cellular proteins; whereas 30% and 13% of the total cellular uptake was irreversibly bound in the case of thiopurinol and 6-mercaptopurine respectively at substrate levels of 1 nmol per μl blood.

1 Adriamycin was administered as a single intravenous dose. The plasma concentration in man and rat decayed as a double exponential function of time. 2 A two compartment model was used to predict plasma and tissue concentrations in man and the rat. The validity of the tissue concentration predictions was confirmed experimentally in the rat. 3 Tissue components had a high capacity for the drug. There was evidence in the rat of preferential accumulation in the liver, spleen and bone marrow. 4 The large tissue capacity and the prolonged half time for elimination predispose to accumulation. This may be responsible for the greater toxicity of treatment schedules with short intervals between consecutive doses.

1 A new β-adrenoceptor blocking agent, Ro 3-4787, was administered orally to resting subjects. Peak levels of 106.2 ± 15.5 ng/ml were reached after 20 mg given in the fasting state. After intravenous administration, an inverse rectilinear relationship was shown between the log dose (2 mg-20 mg) and the heart rate during vigorous exercise on a bicycle ergometer. 2 A double-blind study in five normal subjects using 0.03 mg/kg and 0.15 mg/kg showed that propranolol and Ro 3-4787 were equally effective in reducing the exercise heart rate. There was an inverse correlation between the log plasma level before exercise and the heart rate during exercise for both drugs over the range studied.

1 The absorption and metabolism of [3H]-salbutamol have been studied to assess whether intermittent positive pressure breathing (IPPB) or a particular nebulizer have any advantages in delivering bronchodilator drugs to asthmatic patients. 2 [3H]-salbutamol (10 mg) was given to asthmatic patients from either the Bird Mark 7 ventilator without intermittent positive pressure, the Bird micronebulizer attached to an electric air compressor, or the Wright's nebulizer attached to the same compressor. 3 All patients showed a high early plasma level of radioactivity due mainly to free salbutamol. This pattern suggests absorption from the lung and is similar to that seen after giving the drug from the Bird nebulizer using IPPB. 4 In all cases less than 20% of the original dose was absorbed by the patient. 5 Improvement in forced expiratory volume in one second (FEV1) was seen with all three treatments.

1 The plasma elimination half-life of mexiletine was measured in four subjects when the urine was rendered (a) acidic and (b) alkaline. 2 Urinary acidification (pH 5.0) was associated with a plasma elimination half-life of 2.8 h and 57.5% of the intravenous dose was excreted in the urine within 48 hours. When the urine was alkaline (pH 8.0) the half-life increased to 8.6 h with negligible amounts of drug appearing in the urine. 3 Urinary pH varies widely in cardiac patients and should be controlled or monitored to provide better therapeutic precision with mexiletine.

1 The effect of RX 72601, neostigmine plus atropine, or saline on neuromuscular blockade with (+)-tubocurarine was studied in a double blind trial in four healthy male volunteers. 2 The methods used to assess neuromuscular function were voluntary grip strength and indirectly evoked muscle twitches. The muscarinic action was assessed by measuring intestinal motility with a pressure sensitive radio pill, and auscultation of the abdomen. Blood pressure and pulse rate were also recorded. The degree of acetylcholinesterase inhibition achieved in whole blood was determined before and at intervals after the administration of the anticholinesterases. 3 Both RX 72601 (0.66-0.83 mg) and neostigmine (2.5 mg) completely reversed the neuromuscular blockade produced by tubocurarine, but the time course of reversal differed. RX 72601 (0.66-0.83 mg) produced similar inhibition of acetylcholinesterase in whole blood to neostigmine (2.5 mg). The doses of RX 72601 used caused minimal stimulation at muscarinic sites as evidenced by the limited effect on pulse rate and intestinal activity. 4 It was concluded that RX 72601 could be safely used to reverse the effects of neuromuscular blockade without the need for premedication with atropine.

1 Intestinal absorption of digoxin was assessed by determination of peak plasma concentrations, areas under plasma concentration curves over 80 h, and 10 day urinary excretion. Absorption was equal after ingestion of single doses of standard Lanoxin (Wellcome) tablets, tablets and capsules of ultra-rapid dissolution rate material, or an oral solution of digoxin in water. 2 Mean plasma concentrations and dosage-interval urinary excretion were highly similar during 14 day courses of either Lanoxin or ultra-rapid dissolution tablets. Increased bioavailability does not result from encapsulation of solid dosage presentations, nor from increasing tablet dissolution rate beyond 75% in 15 minutes. 3 Fourteen day courses of tablets of slow dissolution rate produced lower and less consistent mean plasma concentrations and urinary excretion. Slow dissolution rates are associated with greater individual variability in absorption.