Validated liquid chromatography-tandem mass spectrometry method for simultaneous determination of clopamide, reserpine and dihydroergotoxine: Application to pharmacokinetics in human plasma.

A simple, sensitive and rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the simultaneous quantitation of clopamide, reserpine and dihydroergotoxine (ergoloid mesylates) in human plasma. Under basic conditions, liquid-liquid extraction using ethyl acetate was efficiently used for extraction of the analytes from plasma samples in presence of indapamide as internal standard (IS). The analytes were separated with isocratic elution on Phenomenex(®) Synergi Fusion-RP 80A column (50×4.6mm, 4µm). With positive ion electrospray ionization (ESI), the analytes were quantified and monitored on a triple quadrupole mass spectrometer using Multiple Reaction Monitoring (MRM) scanning mode. Satisfactory results regarding linearity, recovery, stability, accuracy and precision of the analytes were obtained. The method was linear in the concentration range of 0.04-30.00ng/mL for reserpine, 1-96.00ng/mL for clopamide, and 0.05-40.00ng/mL for dihydroergotoxine alkaloids, respectively. For all analytes, the high sensitivity of HPLC-MS/MS method revealed sufficient lower limit of quantification (LLOQ) ranged from 0.04-1ng/mL using 1mL of plasma. The recoveries from spiked control samples were ≥86.16% for all analytes and IS. The intra- and inter-day precision variations were lower than 13.03% while the accuracy values ranged from 91.76% to 111.50%. The developed method was successfully applied to pharmacokinetic study of fixed dose combination of clopamide, reserpine and dihydroergotoxine in healthy male volunteers.

The Incidence of Antihypertensive Drug-induced Side Effects in Patients with Diabetes Mellitus Type 2 and Hypertension.

OBJECTIVE: To determine types and frequency of side effects of antihypertensive drugs in patients with diabetes mellitus (DM) type 2 and hypertension. SUBJECTS AND METHODS: We performed a prospective study of 79 patients with DM type 2 and hypertension, randomly selected by systematic sampling, who were followed over a period of six months. Patients were assessed at baseline and once a month measuring following parameters: types of used antihypertensive drugs and frequency of side effects, the values (mmHg) of systolic (SBP) and diastolic blood pressure (DBP). RESULTS: Out of 79 patients, 48/79 (60.8%) were males and 31/79 (39.2%) were females. The median age in males was 53 years (IQR=48 to 55 years), in females was 53 years (IQR=49 to 56 years). There was no statistically significant difference in median age between males and females (P=0.368). There is a statistically significant difference in the values of SBP [χ2(5)=312.296, P<0.001] and DBP [χ2(5)=216.051, P<0.001] over a period of six months follow-up. The drug side effects were noted in 9/79 (11.4%) patients between 1-2 months, in 6/79 (7.6%) between 2-3 months, in 1/79 (1,3%) between 3-4 months. The most common side effect was cough (11/79 or 13.9%) associated with the combination of ACE inhibitor and thiazide diuretics. In 5/79 (6.3%) patients there were reports of: flushing, palpitations, headache, dizziness and leg edema associated with Ca blockers. CONCLUSION: The most common side effect of antihypertensive treatment was cough (13.9%) associated with the combination of ACE inhibitor and thiazide diuretic.

Diuretics prime plant immunity in Arabidopsis thaliana.

Plant activators are agrochemicals that activate the plant immune system, thereby enhancing disease resistance. Due to their prophylactic and durable effects on a wide spectrum of diseases, plant activators can provide synergistic crop protection when used in combination with traditional pest controls. Although plant activators have achieved great success in wet-rice farming practices in Asia, their use is still limited. To isolate novel plant activators applicable to other crops, we screened a chemical library using a method that can selectively identify immune-priming compounds. Here, we report the isolation and characterization of three diuretics, bumetanide, bendroflumethiazide and clopamide, as immune-priming compounds. These drugs upregulate the immunity-related cell death of Arabidopsis suspension-cultured cells induced with an avirulent strain of Pseudomonas syringae pv. tomato in a concentration-dependent manner. The application of these compounds to Arabidopsis plants confers disease resistance to not only the avirulent but also a virulent strain of the pathogen. Unlike salicylic acid, an endogenous phytohormone that governs disease resistance in response to biotrophic pathogens, the three diuretic compounds analyzed here do not induce PR1 or inhibit plant growth, showing potential as lead compounds in a practical application.

Automatic analysis of EMG during clonus.

Clonus can disrupt daily activities after spinal cord injury. Here an algorithm was developed to automatically detect contractions during clonus in 24h electromyographic (EMG) records. Filters were created by non-linearly scaling a Mother (Morlet) wavelet to envelope the EMG using different frequency bands. The envelope for the intermediate band followed the EMG best (74.8-193.9 Hz). Threshold and time constraints were used to reduce the envelope peaks to one per contraction. Energy in the EMG was measured 50 ms either side of each envelope (contraction) peak. Energy values at 5% and 95% maximal defined EMG start and end time, respectively. The algorithm was as good as a person at identifying contractions during clonus (p=0.946, n=31 spasms, 7 subjects with cervical spinal cord injury), and marking start and end times to determine clonus frequency (intra class correlation coefficient, α: 0.949), contraction intensity using root mean square EMG (α: 0.997) and EMG duration (α: 0.852). On average the algorithm was 574 times faster than manual analysis performed independently by two people (p ≤ 0.001). This algorithm is an important tool for characterization of clonus in long-term EMG records.

Development of a liquid chromatography tandem mass spectrometry method for simultaneous determination of eight adulterants in slimming functional foods.

A method for simultaneous determination of eight adulterants including two appetite suppressants, two energy expenditure-enhancing drugs, one diuretic and three cathartics in slimming functional foods by high performance liquid chromatography with electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) was established. After samples were ultrasonically extracted with 70% (v/v) methanol aqueous solution and centrifuged, the components of ephedrine, norpseudoephedrine, fenfluramine, sibutramine, clopamide, emodin, rhein, and chrysophanol in sample solution were separated by a Hypersil Gold column (2.1 mm × 150 mm, 5 µm) using a programmed gradient elution. A mobile phase consisting of 0.02% (v/v) formic acid-ammonium formate buffer solution (pH=3.50) and methanol was used for elution with a flow rate set at 250 µL/min and column temperature of 25 °C. Qualitative determination was based on characteristic ion pairs and retention time of the targeted compounds using SRM (selective reaction monitoring) mode. Clenbuterol and ibuprofen were internal standards in positive and negative ionization mode, respectively. The internal standard curves were used for quantification measurement. The average recoveries of three different concentrations were from 80.2% to 94.5%. The limits of detection (LODs) were from 0.03 to 0.66 mg/kg (except chrysophanol 1.6 mg/kg). The linear dynamic range covered from 1 to 500 µg/L (except chrysophanol 50-5000 µg/L) for the twelve samples analyzed. Adulterants in four different kinds of slimming functional foods were determined by this developed method, and satisfactory results were obtained. These experimental results showed that, adulteration of sibutramine or/and fenfluramine were the major adulterating components with contents varying from 6.1 to 1.3×10(3) mg/kg and 1.9 to 9.7×10(3) mg/kg, respectively. In addition, three cathartic compounds were detected in six of those tested samples, and ephedrine, norpseudoephedrine and clopamide were not detected in all samples.

[Simultaneous determination of five illegal drugs in weight control foods with solid phase extraction-high performance liquid chromatography].

OBJECTIVE: To develop a method for simultaneous determination of hydrochlorothiazide, furosemide, clopamide, bumetanide and sibutramine hydrochloride in weight control foods with solid phase extraction-high performance liquid chromatography. METHODS: The analytes in the samples were extracted with 2% phosphoric acid-methanol (1:1, V/V) solution ultrasonically and centrifuged. The extracts were clean-up with Osis MCX SPE columns, concentrated under weak N2 stream, and reconstituted with 2% phosphoric acid-methanol (1:1, V/V) solution, vortex mixing and centrifugation at 12,000 r/min. The high performance liquid chromatography was performed with Phenomenex C18 (250 x 4.60 mm, 5 microm) as separation column, 0.02 mol/L acetonitrile potassium dihydrogen phosphate buffer as mobile phase, gradient elution of 1.0 mL/min for the flow rate, and 40 degrees C for the column temperature. The standard curve method was used for the quantitative analysis. RESULTS: A good linear range appeared for the five analytes from 0.25 to 100 microg/mL (r > or = 0.999). The detection limits were 5.2-108 microg/kg. The average recoveries were 86.5%-113.1%, with the relative standard deviations of 1.6%-8.9%. CONCLUSION: The proposed method is a reliable method with high selectivity and high sensitivity for the detection of the five illegal chemicals in the weight control foods.

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.

[Erythrocyte-induced "torsade de pointes" ventricular tachycardia]. / Erythromycin által elöidézett "torsades de pointes" kamrai tachycardia.

A case of erythromycin-induced acquired long QT syndrome and "torsades de pointes" ventricular tachycardia is reported. The peculiar ventricular tachyarrhythmia was evoked by orally administered erythromycin (1.5 g/die) in the presence of diuretic (clopamide)-induced hypokalaemia. The pause-dependent "torsades de pointes" was preceded by prolonged QTU interval (560 ms), "particular bigeminy" and "short-long-short" RR interval sequence. The recurrent ventricular tachycardia causing syncopal attacks was abolished by the discontinuation of erythromycin treatment, K+/Mg(2+)-supplementation and oral mexiletine therapy. It is emphasized that the macrolide antibiotic/prokinetic erythromycin, applied in therapeutic dosages, blocks the rapidly activating delayed rectifier potassium current (IKr), and as such, prolongs ventricular repolarization and may be "torsadogenic".

Different concepts in first-line treatment of essential hypertension. Comparison of a low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group.

Low-dose combination therapy has been proposed as a rational first-line approach to hypertension treatment. We compared the efficacy and tolerability of the fixed combination of reserpine (0.1 mg) plus the thiazide clopamid (5 mg) with its single components and the calcium-antagonist nitrendipine (20 mg) in a randomized, double-blind, parallel study of 273 hypertensive patients with diastolic blood pressure (BP) between 100 and 114 mm Hg. The four groups did not differ regarding baseline characteristics (mean age, 58 years; 51% men; mean BP after a 2-week placebo period, 158 to 160/103 to 104 mm Hg). After 6 weeks of treatment with one capsule daily, mean reductions in sitting BP from baseline at 24 hours after dosing in the reserpine-clopamid combination, reserpine, clopamid, and nitrendipine groups were -23.0/-17.1, -14.0/-11.7, -13.6/-11.9, and -11.6/-12.3 mm Hg, respectively (2P < .01). The corresponding normalization rates (diastolic BP < 90 mm Hg) were 55%, 40%, 36%, and 33% (2P = .11). All patients whose BP had not been normalized at this point received two capsules of the respective medication once daily from weeks 7 to 12. At week 12, mean BP reductions were -25.7/-18.1, -14.6/-12.2, -17.7/-13.4, and -14.9/-15.3 mm Hg in the four groups, respectively (2P < .01). The respective normalization rates were 69%, 35%, 39%, and 45% (2P < .0001). Linear regression modeling indicated that reserpine and clopamid combined acted more than additively. As regards tolerability, adverse experiences were observed in 27%, 28%, 29%, and 48% of patients, respectively (2P < .05). The respective rates of premature discontinuation because of adverse effects were 3%, 3%, 7%, and 13% (2P = .06). In conclusion, a low-dose combination of reserpine and clopamid lowered BP significantly more than both the components alone and nitrendipine. Moreover, the combination was tolerated as well as its components and significantly better than nitrendipine. Thus, the use of this low-dose reserpine-thiazide combination appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.

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)

Simultaneous determination of clopamide-pindolol combination in tablets by zero-crossing derivative spectrophotometry.

A first-derivative spectrophotometric method, using a 'zero-crossing' technique of measurement has been used for determining clopamide-pindolol mixture in tablets. In the first-derivative mode the zero-crossing points of clopamide and pindolol occur at 272.6 and 262.4 nm, respectively. The relative ease offered by this technique for the quantification of these drugs with closely overlapping bands was demonstrated. The linearity of the calibration curves was satisfactory (r = 0.9998) and the precision (RSD%) better than 1.89. Detection limits were 0.50 and 0.44 micrograms ml-1 for pindolol and clopamide, respectively. No spectral interferences from tablet excipients were found. Applications are given for the assay of commercial tablets and content uniformity test. The procedures proved to be suitable for rapid and reliable quality control.

Clinicopharmacological reappraisal of the potency of diuretics.

From a clinicopharmacological standpoint, the urinary excretory potency of diuretics should be assessed comparatively on the basis of the changes in 24-hour natriuresis, with respect to 24-hour natriuresis after placebo, caused by single oral doses administered to healthy adult subjects who are in habitual and steady-state external sodium balance. The potency of various formulations of loop (e.g., furosemide), of early distal tubular (e.g., the thiazides), and of potassium-retaining diuretics, as well as of several combinations of diuretics, has been evaluated in a series of studies. Two formulations of loop diuretics (muzolimine 20 mg and torasemide 2.5 mg) are definitely nondiuretic. The majority of the other formulations of loop diuretics studied are, in general, comparatively less potent than most of the common formulations of early distal tubular diuretics studied. As a general rule, most common formulations of early distal tubular diuretics are at least not less potent than the majority of common formulations of loop diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar potencies. Loop diuretics increase mean renal sodium output strikingly within the first few (0-6) hours after dosing, but this forced excretion is followed by a rebound with respect to postplacebo mean urinary sodium flow; the rebound usually takes place between 6 and 24 hours after dosing. However, no rebound in mean urinary sodium flow occurs during the 24 hours following a single dose of a distal tubular diuretic; these substances increase urinary sodium excretion with lower maximal intensity but more protractedly than loop diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)

[The principles of left-right hemispheric interactions of pharmacological preparations exemplified by Brinaldix]. / Nekotorye printsipy levo-pravopolusharnykh vzaimodeistvii farmakologicheskikh preparatov na primere brinal'diksa.

The effect of 4-chlor-N-(cys-2,6-dimethyl peridine)-3-sulfomoin-benzamide as an anti-hypertensive drug on left-to-right hemisphere interactions was studied on experimental animals. Its effect on hemispheres was shown to be asymmetrical. The most effective action of the drug was demonstrated on the left hemisphere of rats differing in their trends of interhemispheric interactions.

Sensitive high-performance liquid chromatographic determination of famotidine in plasma. Application to pharmacokinetic study.

A sensitive high-performance liquid chromatographic (HPLC) method for the quantitation of famotidine in human plasma is described. Clopamide was used as the internal standard. Plasma samples were extracted with diethyl ether to eliminate endogenous interferences. Plasma samples were then extracted at alkaline pH with ethyl acetate. Famotidine and the internal standard were readily extracted into the organic solvent. After evaporation of ethyl acetate, the residue was analysed by HPLC. The chromatographic separation was accomplished with an isocratic mobile phase consisting of acetonitrile-water (12:88, v/v) containing 20 mM disodium hydrogenphosphate and 50 mM sodium dodecyl sulphate, adjusted to pH 3. The HPLC microbore column was packed with 5 microns ODS Hypersil. Using ultraviolet detection at 267 nm, the detection limit for plasma famotidine was 5 ng/ml. The calibration curve was linear over the concentration range 5-500 ng/ml. The inter- and intra-assay coefficients of variation were found to be less than 10%. Applicability of the method was demonstrated by a bioavailability/pharmacokinetic study in normal volunteers who received 80 mg famotidine orally.

[Combined uni- and multicenter double-blind studies in hypertensive patients. Comparison of blood pressure measurements]. / Kombinierte uni- und multizentrische Doppelblindstudie bei Hypertonikern. Vergleich der Blutdruckmessungen.

In a double-blind study to investigate the antihypertensive effect of a fixed triple combination with 0.05 mg reserpine, 2.5 mg clopamide and 0.4 mg dihydroergocristine in comparison to a fixed double combination with 0.05 mg reserpine and 2.5 mg clopamide, a patient subgroup of 34 patients followed a unicenter (central unit, 'institute') as well as a multicenter (established physicians) study design. The patients visited both investigation units on the day of admission to the study (week 0), after four weeks and after eight weeks of therapy (after the morning intake of the drugs). The paper in hand looks at the results of this subgroup with respect to the conformity of blood pressure values in the two investigative units. The analyses confirm the already published results of the entire study: Both combinations proved to be highly effective antihypertensive drugs. The triple combination showed therapeutical advantages for systolic blood pressure after four weeks, for diastolic pressure after eight weeks of therapy at the 'institute' as well as, although less distinct, in the medical offices. A comparison of the individual values did not show a convincing coherence of the measurements between institute and offices. All investigated possible systematic sources of error (different methods of measurement, days or times of measurement) could be excluded by correlation statistics as a reason for the divergences. The results show the necessity--particularly in multicenter studies--of a careful documentation of all accompanying data (e.g. method or time of measurement) as well as a greatest possible standardization of investigation (e.g. identical measuring apparatus and investigator.)

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.

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.

[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.

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.