Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine.

Accepted clinical evidence suggests superior efficacy of novel antipsychotics in the treatment of cognitive symptoms in schizophrenia. Whether this constitutes a primary drug effect or a secondary effect due to easing extrapyramidal side-effects or improving positive symptoms when converting from a first- to a second-generation neuroleptic is still open to debate. Long-term efficacy as well as differential drug effects on cognitive performance are also poorly documented. We therefore compared cognitive performance of olanzapine vs. clozapine treatment in a controlled, randomized, double-blind trial. Fifty-four patients were assessed following a 2- to 9-day washout and again after 4 and 26 wk of neuroleptic treatment. Patients were rated on the PANSS for psychopathological changes, extrapyramidal side-effects were assessed on the Simpson-Angus Scale, and cognitive performance was assessed with the Stroop, Wisconsin Card Sorting and the Tower of London tests. Schizophrenia symptoms, extrapyramidal side-effects and cognitive performance improved significantly in the course of either drug treatment. Stroop test performance and Tower of London planning time improved significantly over 26 wk compared to baseline and 4-wk follow-up assessment while Wisconsin Card Sorting and Tower of London execution time improved significantly after 4 wk with no further improvement after 26 wk. Improved executive function was not related to improving positive symptoms and easing extrapyramidal side-effects, thus indicative of a primary treatment effect of either antipsychotic. However, Stroop reaction time improved with olanzapine while clozapine had a stronger effect on improving negative symptoms, thus suggestive of a differential drug effect.

Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor.

The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated. A total of 127 adult outpatients with diastolic blood pressure between 100 and 114 mmHg were randomized into this double-blind, parallel group study. After a 2-week wash-out period and a subsequent 2-week placebo run-in period, they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide (R/C), or 5 mg enalapril. If diastolic blood pressure was not normalized after 3 weeks of therapy (i.e. DBP < 90 mmHg), the dosage was doubled from week 4 to 6. The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure (DBP/SBP) after 3 weeks of therapy. Secondary variables included the change in DBP and SBP after 6 weeks of therapy, the BP normalization rates at 3 and 6 weeks and, concerning tolerability, the rates of adverse events after 6 weeks of therapy. An intent-to-treat analysis was performed. The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics (mean age 57 or 58 years, respectively; 63% or 56% males, respectively; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups). After 3 weeks of treatment with one capsule daily, mean SBP/DBP reduction from baseline (24 h after last medication intake) in the R/C combination group was -19.6/ -17.0 mmHg, in the enalapril group -6.1/ -9.5 mmHg (between-group comparison: 2p < 0.01 for both parameters). The normalization rates for DBP (< 90 mmHg) were 64.1% (R/C) and 28.6% (enalapril) (2p < 0.01). Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients (17.2%) in the R/C group and in 9 patients (14.3%) in the enalapril group (NS). Two patients in the enalapril group discontinued the study prematurely due to adverse events (cough; skin eruption). In the treatment of mild-to-moderate hypertension, a low-dose combination of reserpine and clopamide once a day is considerably more effective than, and as tolerable as, 5-10 mg of enalapril once a day. These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension. Besides, the "old" reserpine-diuretic regimen also in these days appears to be a rational alternative to "modern" monotherapies.

Changes in urinary enzyme levels following the use of antihypertensive agents in patients with essential hypertension.

When choosing antihypertensive agents for the treatment of hypertension, it is necessary to consider the predisposition of individuals to renal damage, which may be associated with the long-term effect of such agents. In this respect, this study examined the effect of two commonly used antihypertensive drugs (Brinerdin and Minizide) on renal function over 24 months in patients diagnosed as having essential hypertension. We utilized urinary enzyme studies, which are indicators of subtle renal dysfunction. Other parameters of glomerular and tubular function were also determined in the pretreatment period, as well as during and at the end of treatment of 28 patients (16 males and 12 females) with therapeutic doses of Brinerdin and 22 patients (12 males and 10 females) with conventional doses of Minizide. During the follow-up period, blood pressure (BP) fell from a mean of 160/108 +/- 9/4 (SD) mmHg to 130/90 +/- 7/4 on Brinerdin and from a mean of 160/106 +/- 5/2 (SD) mmHg to 130/90 +/- 8/5 on Minizide. There was no significant difference in the levels of BP between the patients taking Minizide and those taking Brinerdin before, during, and at the end of treatment. Significant elevation (p < 0.05) of the levels of urinary protein, lactate dehydrogenase (LDH), and N-acetyl-B-D-glycosaminidase (NAG) was observed in patients on Minizide during treatment, and these levels remained elevated during the latter part of the study. Normotensive, untreated, age- and sex-matched control subjects showed no such urinary parameter changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of clopamide, a thiazide diuretic, on copper and zinc levels in hypertensive patients.

Thiazide diuretics, which are often prescribed to treat mild to moderate hypertension, commonly cause an increase in urinary zinc (Zn) excretion. Metabolic interrelationships between Zn and copper (Cu) are known to exist; consequently, Zn might influence Cu levels. This study aims to determine whether or not Cu and Zn levels in hypertensive patients were influenced by treatment with clopamide, a thiazide diuretic. Eight male patients, aged 36-59 and with an average supine diastolic pressure of 95-115 mm Hg, were treated with single daily doses of clopamide 5 mg as monotherapy for 16 weeks. Plasma, erythrocyte (RBC), and mononuclear leukocyte (WBC) levels of Cu and Zn were determined immediately before therapy (week 0) and again at weeks 8 and 16. There was a significant fall in Cu in mononuclear WBCs from 13.25 (SEM = 0.86) to 1.9 fg/cell (SEM = 0.56) (p less than 0.001) and an increase in Zn from 33.87 (SEM = 3.7) to 70.8 fg/cell (SEM = 11.7) (p less than 0.001), with no change in either cell count or measurable cell volume. Plasma Cu levels increased significantly (p less than 0.001), but the Zn levels decreased only slightly (p less than 0.03). Changes in RBC Cu levels during the treatment period were not significantly altered (p less than 0.1). Zn levels in RBCs were significantly (p less than 0.04) lower. It is concluded that treatment with clopamide may induce some changes in Cu and Zn levels in normal hypertensives, particularly in WBCs. Further investigation is needed to determine the extent of this influence.

[Evaluation of hemodynamic changes in patients with primary arterial hypertension after treatment with a combination of pindolol and clopamide (Viskaldix)]. / Ocena zmian w dynamice krazenia u chorych z pierwotnym nadcisnieniem tetniczym po leczeniu trwalym polaczeniem pindololu z klopamidem (Viskaldix).

In 35 patients with mild essential hypertension the influence of 9 week Viskaldix therapy on hemodynamics was evaluated. Twelve of them underwent repeated hemodynamic examinations after mean 13 months treatment. Viskaldix therapy lowered total peripheral resistance --TPR and there was no significant influence on the heart rate, stroke volume, and cardiac output. It was demonstrated that decrease of total peripheral resistance after treatment with Viskaldix was directly proportional to the initial values of TPR.

Well-being and its measurement in hypertension. A randomized, double-blind cross-over comparison of 5 mg clopamide with 25 mg hydrochlorothiazide. Hunter Hypertension Research Group.

We conducted a randomized, double-blind, cross-over comparison of six weeks' treatment with 5 mg clopamide or with 25 mg hydrochlorothiazide in 17 hypertensive patients (average age 62 years). No significant differences were found between the two treatments in blood pressure control, plasma biochemical values, body weight or response to a comprehensive "quality of life" questionnaire. Despite the apparently identical performance of both drugs, significantly (x2 = 4.76; P less than 0.05) more patients expressed a preference for clopamide (12) than for hydrochlorothiazide (3). Two had no preference. Current quality of life assessments are relatively insensitive and patient preference remains a valid discriminator between otherwise comparable medications.

Combination of a thiazide, a vasodilator and reserpine compared with methyldopa plus hydrochlorothiazide in the treatment of hypertension in Zimbabwe.

Brinerdin (Sandoz), a combination of a diuretic (clopamide 5 mg), a vasodilator (dihydro-ergocristine 0.5 mg) and reserpine (0.1 mg) (CDR) was compared with methyldopa (MD) plus hydrochlorothiazide (HCT) for antihypertensive effect, adverse reactions, compliance and patient preference in an open cross-over trial. Eighteen patients completed both arms of the trial and 5 patients who completed the CDR arm were withdrawn while on the MD arm because of adverse effects in 4 and poor control in 1. On HCT 50 mg daily the mean baseline systolic blood pressure was 163.9 +/- 16.3 mmHg and the diastolic blood pressure was 105.9 +/- 6.7 mmHg. On CDR these were reduced to systolic blood pressure 140.3 +/- 15.1 mmHg and diastolic blood pressure 87.8 +/- 9.3 mmHg. On MD + HCT the systolic blood pressure was reduced to 138.5 +/- 16.9 mmHg and the diastolic blood pressure to 88.9 +/- 10.3 mmHg. The differences between the two treatment periods in systolic blood pressure (1.8 mmHg; 95% confidence interval (CI) - 4.1 + 7.7 mmHg) and diastolic blood pressure (1.1 mmHg; 95% CI - 4.6 + 2.4 mmHg) were not significant with P values of 0.6 and 0.7 respectively. Compliance was 98.2% for CDR and 94.7% for MD + HCT (P = 0.02). Unusual sleepiness occurred more frequently in the MD arm (P less than 0.01). Thirteen patients chose to continue on CDR, 2 on MD + HCT and 3 had no preference (P = 0.005). CDR is similar in antihypertensive effect to MD + HCT but is better tolerated with fewer withdrawals, fewer adverse effects, better compliance and has more patients electing to continue taking it.

Effects of pindolol, or a pindolol/clopamide combination preparation, on plasma lipid levels in essential hypertension. Hunter Hypertension Research Group.

In an open study that was conducted in general practice, 22 patients with previously-untreated mild hypertension received an average daily dose of 11.7 mg of pindolol over a 50-week study period. The total cholesterol, high-density lipoprotein fraction and plasma triglyceride levels showed no significant change from baseline values at the conclusion of this period. A separate group of 18 patients were treated with 10 mg of pindolol a day for 12 weeks, to which regimen was added 5 mg of clopamide for the succeeding 38 weeks. A small rise in total plasma cholesterol levels in this group of patients at both 12 and 50 weeks did not achieve statistical significance, and no change was observed in either the high-density lipoprotein fraction or the plasma triglyceride levels. These results which were obtained in general practice and over a prolonged period of time accord with the general view that the treatment of hypertension with pindolol, a beta-receptor blocking drug with partial agonist activity, is not associated with either the increases in total plasma cholesterol levels or the falls in the high-density lipoprotein fraction that have been reported with other beta-blocking compounds.

[The Kristepin and obzidan treatment of patients with hypertension]. / Lechenie kristepinom i obzidanom bol'nykh gipertonicheskoi bolezn'iu.

A study is presented of 67 patients with hypertensive disease (stage II) at the age from 35 to 60 years. Three types of central hemodynamics were singled out: hyperkinetic, hypokinetic and eukinetic. The optimal effect was observed with associated use of Kristepin and obsidan in patients with the hyperkinetic type of hemodynamics. Concentrations of plasma renin and aldosterone cannot be used as criteria for the choice of hypotensive treatment in the above categories of patients.

[Hemodynamic effects of hydrochlorothiazide, propranolol and a combination of pindolol and clopamide in patients with essential hypertension]. / Efectos hemodinámicos de la hidroclorotiacida, el propranolol y la asociación pindolol-clopamida en hipertensos esenciales.

To characterize the haemodynamic effects of diuretics, betablockers and the association of both, 24 hypertensive patients, stages I-II WHO criteria, were studied. Two haemodynamic studies were performed, before under placebo and after two month of active drug therapy. Seven patients received propranolol (PPL) (160-240 mg/day); 7 patients, hydrochlorothiazide (HCT) (150-100 mg/day), and 10 a combined fixed dose of pindolol (PDL) and clopamide (CLP): PDL 10 mg, CLP 5 mg per tablet, each patient receiving one to three tablets according blood pressure response. The haemodynamic study was performed with percutaneous intravenous flow-directed. Swan-Ganz catheter, associated with direct puncture of femoral artery and measuring cardiac output by thermodilution. Arterial pressure was significantly reduced on PPL (p less than 0.05) and PDL-CLP (p less than 0.01) groups, but not in the HCT group. The cardiac index was reduced by PPL (p less than 0.05) but not by HCT and PDL-CLP. The systemic vascular resistance was only reduced in the PDL-CLP group (p less than 0.05). The use of a betablocker with intrinsic sympathetic activity (ISA) (pindolol) in association with a thiazide diuretic (clopamide) seems to induce a favourable change in systemic resistance without a deleterious change in cardiac output as occurred with propranolol.

Pindolol-clopamida en hipertensión arterial / Pindol-clopamide in arterial hypertension

Se estudiaron 20 pacientes de ambos sexos que cursaban con hipertensión-obsidad. El estudio fue realizado en la Clínica de Hipertensión Arterial del Hospital de Apoyo Hipólito Unanue, Perú. Se aplicó una combinación de pindolol-clopamida, con la supresión de todo tratamiento anterior de asociaciones de betabloqueadores y diuréticos. El curso del estudio comprendió dos fases: lavado farmacológico y fase activa. Se confirmó la eficacia terapéutica de la combinación pindolol-clopamida, logrando una reducción de 22.4 y 21.6% para las presiones sistólica y diastólica respectivamente

Effects of pindolol and clopamide on blood lipids in arterial hypertensive patients.

The effects of clopamide, pindolol and its combination on plasma lipids in 49 hypertensive patients (WHO I-II), divided into three parallel randomized groups, were studied over a 6 months period. Total cholesterol, triglycerides, HDL and LDL cholesterol fractions were determined twice during an initial 4-week washout phase, and after a 1-, 3- and 6-month active hypotensive drug phase. Patients were instructed to maintain their usual dietary habits. Daily drug doses were adjusted progressively to attain optimal hypotensive effects. In the clopamide monotherapy group, total cholesterol increased significantly (p less than 0.05); triglycerides and LDL showed a tendency to increase while for HDL a tendency to decrease was observed. In the pindolol monotherapy group, a significant reduction of triglycerides (p less than 0.01) and a significant increase of HDL cholesterol (p less than 0.05) were recorded. No significant changes in total cholesterol or LDL fraction were observed. Combined pindolol-clopamide therapy decreased total triglycerides (NS), increased HDL significantly (p less than 0.05) and did not influence total cholesterol and LDL fraction. It is concluded that pindolol does not negatively influence blood lipids as the thiazide-type diuretic clopamide does, and that when both drugs are used together, the beta-blocker can probably counterbalance the diuretic-induced negative effects on blood lipids. Accordingly, it is suggested that pindolol could be a more favorable beta-blocker drug to be used on hypertensive subjects with metabolic coronary risk factors.