Acute effects of neuroleptics on unmedicated schizophrenic patients and controls.

Acute administration of haloperidol (0.2 mg/kg) produced many more side effects in normal controls than in unmedicated schizophrenic patients. Prior to the neuroleptic challenge, both groups were on the peripheral monoamine oxidase inhibitor, debrisoquin, for at least 1 week, in order to enhance the relative contribution of CNS catecholamine metabolites to those measured in both plasma and urine. The patient group had higher plasma levels of methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) and higher urinary MHPG output than controls, but there were no effects of haloperidol challenge, compared to placebo challenge. In both groups there were significant declines in plasma HVA levels from 8:30 AM to 12 NOON. These declines were unaffected by the haloperidol challenge. Explanations for the marked differences in behavioral effects of haloperidol on patients and controls include the possibility that dopamine receptor numbers were increased in the brains of the schizophrenic patients.

Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions.

To evaluate the role of defective drug oxidation as a predisposing factor for neuroleptic-induced dystonic reactions, 26 patients who developed the reaction and 53 with no history of dystonia were phenotyped by the debrisoquine hydroxylation test. The percentage of poor debrisoquine metabolizers was similar in patients with dystonic reactions (11.5%) and in the control group (9.4%). These results suggest that there is no association between the individual's drug oxidative status and the occurrence of neuroleptic-induced dystonia.

Scleroderma is associated with differences in individual routes of drug metabolism: a study with dapsone, debrisoquin, and mephenytoin.

Exposure to certain environmental agents may induce a scleroderma-like syndrome in a small proportion of individuals. Differences in susceptibility could involve metabolic activation of a protoxin, with affected patients having a greater converting ability. This possibility was investigated in 84 patients with scleroderma and 108 control subjects with in vivo probes of specific pathways of metabolism. Scleroderma was associated with reduced hydroxylating activity for dapsone and S-mephenytoin, whereas the ability to hydroxylate debrisoquin and N-acetyl dapsone was similar in both groups. Logistic regression confirmed these associations based on the shift in frequency distribution. Individuals who were poor metabolizers for mephenytoin and only modest N-hydroxylators of dapsone had a tenfold increased risk of scleroderma (p = 0.008). Thus this combined metabolic impairment may be causally involved in the development of scleroderma or, alternatively, the disease may produce inhibition of selected metabolizing enzymes in a subset of patients.

Psychiatric side effects of antihypertensive drugs other than reserpine.

The psychiatric side effects of the major antihypertensive drugs other than reserpine are reviewed, including centrally acting drugs such as methyldopa and clonidine, peripheral adrenergic drugs such as guanethidine, beta-adrenoceptor blockers such as propranolol, and diuretics. Problems with differential diagnosis and with the interpretation of case reports make assessment of psychiatric side effects difficult. Sedation and sleep disturbances are the most common side effects, occurring with methyldopa, clonidine, and propranolol. Only methyldopa is clearly associated with depression. Other reported effects are toxic confusional states and psychotic reactions. These are rare, however, and no clear patterns of development have been recognized.

An evaluation of debrisoquine and mefruside in the treatment of hypertension in African and Indian patients.

A double-blind, crossover trial was carried out in 20 hypertensive patients (9 African and 11 Indian) to compare the effectiveness and tolerance of treatment with debrisoquin, mefruside, and a fixed-dose combination of the two drugs with placebo. Patients were treated initially with placebo for 2 weeks before being crossed-over to treatment for 4 weeks with each of the other regimens. Maximum daily dosages of the active drugs were 20 mg debrisoquin and 25 mg mefruside. Satisfactory hypotensive control, i.e. diastolic blood pressure less than or equal to 90 mmHg, was not achieved in any of the treatment periods. The best hypotensive response was obtained in African patients on mefruside. The combination of debrisoquin and mefruside did not produce the expected synergistic response. Few side-effects were reported. The failure of an adequate hypotensive response to debrisoquin in African and Indian patients could be due to a genetic difference in the hydroxylation of debrisoquin.

Patterns of blood-pressure during chronic administration of postganglionic sympathetic blocking drugs for hypertension.

Continuous recording of intra-arterial blood pressure in 11 ambulant patients taking postganglionic blocking drugs for the treatment of hypertension has shown an alternating pattern of high pressures at rest and very low pressures associated with exertion during normal daily activities. In 4 patients there was evidence of decreased cerebral or myocardial blood-flow during hypotensive episodes. It is suggested that these agents may predispose towards cerebral and myocardial infarction.

Exertional hypotension due to postganglionic sympathetic blocking drugs.

Debrisoquine, guanethidine and bethanidine may produce troublesome hypotensive symtoms related to exertion. Thirteen patients with such symptoms were exercised on a treadmill and the response of blood pressure and heart rate was compared to that of thirty patients without these symptoms, who were exercised to the same extent. There was a slight drop of systolic and diastolic pressures on standing in both groups, but after exertion there was a significantly greater drop of systolic pressure in the group with symptoms than in the asymptomatic group. The diastolic pressure after exertion was significantly lower in the group with symptoms. It was impossible to predict from the standing blood pressure levels at rest which patients would develop hypotensive symptoms after exertion. All three drugs had a similar negative chronotropic effect at rest and on exercise. It is suggested that patients are exercised during control of hypertension in order to identify those prone to exertional hypotension. Patients with such hypotension should be exercised on each attendance before the blood pressure is measured. Treatment other than postganglionic sympathetic blocking drugs should be employed whenever possible in patients with milder hypertension.

A comparison of debrisoquine and methyldopa in hypertension.

Debrisoquine, an antihypertensive agent, was compared with methyldopa in a double-blind trial in the treatment of hypertension in 20 patients. The cross-over method was used to treat each patient with first one and then the other drug for two periods of six weeks each. Two placebo periods of two weeks each were also included, one before the trial, and the other between the two therapy periods. The maximum daily dose was 3 X 10 mg debrisoquine compared with 3 X 250 mg methyldopa. Hydrochlorothiazide, 50 mg daily, was added in all cases for the entire trial. Both preparations lowered blood pressure statistically significantly (p less than 0.005). Tablet for tablet, debrisoquine had a slightly more pronounced effect than methyldopa, but the difference was not statistically significant. Both drugs were well tolerated and in no case had treatment to be interrupted because of side effects. Debrisoquine produced less sedation and dizziness than methyldopa. The conclusion was that both drugs were equally effective in the doses studied and well tolerated and that debrisoquine is of value in the treatment of moderate hypertension.

Factors predisposing to postural hypotensive symptoms in the treatment of high blood pressure.

Symptoms due to orthostatic and exertional hypotension occurred in 23-4 per cent of 448 hypertensive patients treated with guanethidine, debrisoquine, or bethanidine. Symptoms were significantly more frequent in patients treated with guanethidine than in those treated with bethanidine or debrisoquine. Women rather than men and patients with radiological evidence of cardiomegaly, electrocardiographic evidence of left ventricular hypertrophy, or ST/T wave changes, developed these symptoms significantly more often than other patients. A raised blood urea was found more frequently in patients with postural hypotensive symptoms. Characteristically guanethidine produced early morning postural hypotensive symptoms, wheras hypotensive symptoms caused by bethanidine and debrisoquine occurred at other times of the day and particularly one to two hours after tablet ingestion. Debrisoquine and guanethidine had a significantly greater negative chronotropic effect than bethanidine. It is suggested that negative chronotropic effects of these drugs may potentiate hypotensive symptoms in patients with cardiovascular, renal, or cerebrovascular disease. It should be possible to minimize symptoms of postural hypotension by attention to predisposing factors and selection of treatment accordingly.