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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.

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.

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)

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.

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.

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.

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.

The therapeutic efficacy of combined and separate application of a diuretic (brinaldix) and beta-adrenoblocker (visken) was compared in the treatment of 69 patients with essential hypertension running a stable course; the patients were kept on a low-sodium diet (4-6 g NaCl daily) and given a potassium substitute for NaCl.

The case is reported of a 16 year-old girl with arterial hypertension, generalized neurofibromatosis, coarctation of the abdominal aorta, bilateral renal artery stenosis, occlusion of the coeliac artery and superior mesenteric artery and kyphoscoliosis.

After a two week washout period 25 patients with moderate to severe essential hypertension were treated with pindolol. In 12 patients the reduction in blood pressure was excellent and treatment with pindolol was continued. In 13 patients treatment was supplemented subsequently with clopamide and 12 patients had a satisfactory result. Side-effects were few and mild.

A large, open, multi-centre study was carried out in general practice to evaluate the effectiveness and tolerance of a combination of 10 mg pindolol plus 5 mg clopamide, in single tablet form, in the treatment of patients with essential hypertension. Computer analysis of the records of 8989 patients who completed the 8-weeks' study period showed that treatment with the combination product, in a dosage of 1 tablet daily in 83% of the patients, resulted in excellent blood pressure control in the majority (75%) of cases, irrespective of age or previous antihypertensive treatment, and was particularly effective in those with mild to moderate hypertension who had previously not received any therapy. Side-effects were generally not troublesome and only 8.3% of patients stopped treatment for this reason. The most commonly reported side-effects were dizziness, nausea, tiredness and headache.

40 patients with essential hypertension were subjected to an analysis of efficacy and safety of the three-component-combination Briserin (Reserpine, Clopamide, Dihydroergocristine). After double-blind and randomized allocation, one group received the two constituents Reserpine/Clopamide, another the full combination Briserin and a third first Reserpine/Clopamide and Briserin afterwards. Both types of treatment proved equi-effective in terms of blood pressure reduction with the blood pressure values falling below 150/90 mm Hg within one week. The most important finding resided in the improved orthostatic tolerance due to Briserin. Maximal systolic pressure drop during standing and the tachycardia associated were significantly reduced by Briserin, i.e. by the influence of Dihydroergocristine. In addition, there was a corresponding difference in terms of subjective complaints due to orthostasis. The same held true for general symptoms related to hypertension such as headache, dizziness, undue tiredness and sleeplessness. Patients preferred treatment with Briserin as compared to the other regimen. The discussion deals with the clinical-pharmacological impact of the orthostatic regulation quality within the framework of antihypertensive treatment.

Viskaldix, a combination of Pindolol (Visken)--10 mg with Clopamide--5 mg, was administered to 15 patients with arterial hypertension. The follow up of the patients was according to a previous plan, the preparation administered according, to a schedule. In the determination of the stage of the disease, consideration was mainly given to the values of the diastolic pressure, measured in a lying position. The patients examined were of the following age: to 40--I patient; to 50-7 patients; to 60--7 patients. Seven patients were at the stage I, 4 patients--stage OII and 4 patients--stage III. Reduction of systolic and diastolic pressure with more than 1.33 kPa (10 mm Hg column) both in a lying and standing position were recorded in 2/3 of the patients with the treatment carried out. The effect on the blood pressure, was noticed to develop in 1/3 of the patients with the administration of 2 tablets daily. The blood pressure of only one patient failed to respond to the treatment.

Body fluid spaces: total body fluid volume, extracellular fluid volume, circulating plasma volume, intracellular and interstitial fluid volumes were studied in 60 patients with essential hypertension, stage IIB. The studies were performed prior and following a two-week treatment with diuretics ( furosemid , oxodolin , hydrochlorothiazide, brinaldix ). The patients were divided into 3 groups. I--patients whose total body fluid volume was considerably increased due to intracellular fluid. They had the highest blood pressure level. Treatment with diuretics was the most effective in this group and was accompanied by intracellular fluid reduction and slight circulating plasma volume decrease. II--patients whose fluid spaces did not differ from those of normal subjects. Treatment with diuretics was effective and accompanied by simultaneous reduction in intracellular and interstitial fluid volumes. III--patients with reduced interstitial fluid volume and raised circulating plasma/interstitial fluid ratio. Treatment with diuretics was ineffective and accompanied by intracellular fluid level reduction and fluid passage from the vascular bed into the interstitial space. Furosemid and oxodolin were most effective decreasing intracellular fluid volume, hydrochlorothizide --reducing interstitial fluid volume and brinaldix was equally effective decreasing both fluid volumes.

Two male patients with severe reversible muscle weakness and excessive potassium deficiency associated with alkalosis during treatment with diuretics are presented. The case reports are further illustrated by the morphologic changes as seen in light and electron microscopic examination of muscle biopsies. Hypokalemia and muscle dysfunction are discussed in relation to other investigations of altered potassium metabolism and myopathy during treatment with certain diuretics.

1 We have assessed the efficacy of Viskaldix, a combination of pindolol 10 mg and clopamide 5 mg using continuous intra-arterial ambulatory blood pressure monitoring. 2 Fourteen of the sixteen patients entered were studied on no therapy and following a minimum of 6 weeks at a constant dosage of Viskaldix. 3 Viskaldix produced a marked and consistent reduction of the blood pressure over the 24 h. The diurnal variation in the heart rate was decreased. 4 The results were compared with those of a similar study with once-daily pindolol where there was control during the day but not in the early morning when the blood pressures rose rapidly.

30 hypertensive patients aged over 60 years underwent an antihypertensive treatment for a time of 3 months with Viskaldix . There was an excellent hypotensive effect in supine and standing position and no bradycardia or orthostatic dysregulation occurred. Metabolic parameters were not influenced, and this is of great importance in elderly patients. It seems notable that elderly patients may benefit from a beta-blocker therapy, as there is clinical or subclinical coronary heart disease.

The possibility of treating resistant forms of cardiac insufficiency by a combination of furosemide and brinaldix was studied. The efficacy of the diuretics was appraised with reference to diurnal diuresis, sodium-potassium- and chloruresis on the days of taking the diuretics. In making investigations the method of dispersion analysis (permutation trial test) was used. The final results show that the proposed combination (80 mg of furosemide and 40 mg of brinaldix) is effective and warranted in dealing with patients resistant to many diuretics including furosemide. The action of this combination continues for a long time in the presence of signs of cardiac incompetence and is not accompanied by the development of a marked hypokalemia.

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.

The anti-hypertensive effect of propranolol is studied in 35 essential permanent hypertensive patients. The decrease in blood pressure in higher in the presence (p is less than 0.01) than in the absence of diuretic therapy. The anti-hypertensive effect is higher in severe than in moderate hypertension. No side effect was observed except the decrease in heart rate (p is less than 0.001). Dihydralazine was added in 4 severe hypertensive patients and induced in 2 of them anginal attacks.