Placebo-controlled comparison of the efficacy and tolerability of once-daily moxonidine and enalapril in mild-to-moderate essential hypertension.

OBJECTIVES: To compare the antihypertensive efficacy and tolerability of the imidazoline I1 receptor agonist moxonidine, a centrally acting antihypertensive, with the angiotensin converting enzyme inhibitor enalapril. DESIGN: An 8-week, double-blind, randomized, placebo-controlled study involving 140 outpatients with mild-to-moderate essential hypertension. METHODS: Outpatients with WHO stage I or II hypertension were enrolled in the study. After a 4-week placebo-controlled stabilization phase patients were allocated randomly to placebo, 0.2 mg moxonidine once a day or 5 mg enalapril once a day for 2 weeks. Dosages were then doubled to 0.4 mg moxonidine once a day or 10 mg enalapril once a day for a further 6 weeks. Blood pressure responses to therapy were measured by conventional office techniques and by 24 h ambulatory blood pressure monitoring. RESULTS: The mean reduction in sitting blood pressure with moxonidine was similar to that with enalapril (19.5 +/- 16.0/12.3 +/- 8.7 versus 18.9 +/- 13.7/11.8 +/- 8.0 mmHg) and significantly superior to that with placebo (-4.6 +/- 12.3/-4.7 +/- 6.8 mmHg, P< 0.001). In addition to reducing blood pressure during conventional measurements, moxonidine administration reduced blood pressure throughout 24 h ambulatory measurements. The trough:peak ratio for moxonidine was 0.7. Both moxonidine and enalapril were tolerated well. CONCLUSIONS: Moxonidine is an effective and well-tolerated antihypertensive, at least as good as other established forms of antihypertensive medication. The trough:peak ratio of 0.7 indicates that the drug will be effective administered once a day.

Measurement of renal clearance of inulin and PAH in the steady state without urine collection.

Two different methods of inulin and PAH clearance were tested in 25 patients with normal and impaired renal function. The clearance calculated from the infusion rate and the serum levels was equal to the classical clearance calculated from serum levels and urinary excretion. The advantages of the clearance method without urine sampling are: a) catheterization of the bladder can be omitted, b) less analytical work and, c) exact timing serum and urine samples is unneccessary.

Anion packing density: a universal quantity for both dense and porous crystalline inorganic phases.

To compare densities of inorganic high-pressure phases their molal volumes or specific gravities are usually employed, whereas for zeolites and other microporous materials the so-called framework density, FD, is applied. The definition of FD, which refers only to phases with three-dimensional tetrahedron frameworks, is extended to a 'generalized framework density' d(f), which is independent of the dimensionality of the framework and the coordination number(s) of the framework cations. In this paper the anion packing density, d(ap), is introduced as a new quantity which is not only applicable to any inorganic phase but, in contrast to FD and d(f), also allows quantitative comparisons to be made for crystalline inorganic phases of any kind. The anion packing density can readily be calculated if the volume and content of the unit cell and the radii of the anions of a phase are known. From d(ap) values calculated for high-pressure silica polymorphs studied under very high pressure, it is concluded that Shannon-Prewitt effective ionic radii do not sufficiently take into account the compressibility of the anions.

Changes of electrolyte excretion, renin activity, angiotensin-II and aldosterone concentrations during administration of 3-amino-1-(3,4-dichloro-a-methyl-benzyl)-2-pyrazolin-5-one (Bay g 2821).

After the administration of 40 mg Bay g 2821, a new potent diuretic substance, a significant increase of sodium and water diuresis occurred. There was only a short rise in potassium excretion. In contrast to the sodium and water diuresis no significant increase of renin-activity, angiotensin-II or aldosterone concentration was seen. In spite of the insignificant stimulation of the renin-angiotensin-aldosterone system, a significant increase of correlation occurred between the three components of the renin-angiotensin-aldosterone system.

[The value of stimulation of the renin-angiotensin-aldosterone system as a screening test for hypertension (author's transl)]. / Aussagefähigkeit der Stimulation des Renin-Angiotensin-Aldosteron-Systems als Suchtest auf Hypertonie.

Renin activity, angiotensin-II concentration and venous aldosterone concentration were measured in 20 healthy subjects and 18 hypertensives before and after stimulation of the renin-angiotensin-aldosterone system. The test did not distinguish between the two groups: in the individual case there was no relationship between renin-activity, angiotensin-II concentration and aldosterone concentration in peripheral venous blood. Stimulation of the system without sodium balance is not a reliable screening test for hypertension.

[Haemodialysis in diabetics with terminal renal failure]. / Hämodialyse bei Diabetikern mit terminaler Niereninsuffizienz.

Long-term dialysis treatment of diabetics with terminal renal failure is beset with severe complications. In 19 unselected diabetics in terminal renal failure (13 juvenile diabetics and 6 maturity-onset diabetics) the clinical course during long-term dialysis was observed. A total of 1377 dialyses during 167 months of treatment were performed. Diabetic angiopathy, hypertension, and hyperhydration were the most prominent complications. The interval between the onset of diabetes and the beginning of dialysis treatment was 21,5 years in the juvenile diabetics and 5,2 years in maturity-onset diabetes. The survival time during dialysis was on average 13,2 months for the juvenile diabetics and 0,6 months for maturity-onset diabetics. The patients died chiefly from cardiovascular complications.

Transdermal delivery of bupranolol: pharmacodynamics and beta-adrenoceptor occupancy.

Bupranolol is a non-selective beta-adrenoceptor antagonist with a Ki-value of 6-15 nmol/l (equivalent to 1.5-4 ng/ml in plasma) at beta 1- (rat salivary gland) and beta 2-adrenoceptors (rat reticulocytes) in receptor binding studies with 3H-CGP 12177 in the presence of human plasma. After oral administration of 200 mg bupranolol to healthy volunteers, the maximal plasma concentration was observed within 1.2 h but it only reached a level close to the Ki-value. Elimination from plasma was rapid (t 1/2 = 2.0 h). Administration of 30 mg bupranolol in a transdermal delivery system (TTS) every 24 h to 6 healthy volunteers for 72 h yielded steady state plasma concentrations 4- to 5-times above the Ki-value as shown by in vitro inhibition of beta-adrenoceptor binding by plasma samples. The pharmacodynamic effect, measured as the reduction in exercise tachycardia, showed a stable inhibitory effect; antagonism of a bolus injection of isoprenaline indicated a 10- to 15-fold right shift of the dose-response curve during the observation period of 72 h. It is concluded that steady-state plasma concentrations and effect of the elsewise rapidly eliminated beta-blocker bupranolol can be achieved by a transdermal delivery system applied each day.

Clearance and dialysance of 3H-aldosterone in vitro.

Using an "in vitro dialysis" with different dialyzers, a significant decrease in 3H-aldosterone concentration was seen. From the decrease of 3H aldosterone elimination parameters were calculated. Half time of elimination was 21,5 min, the mean clearance of all dialyzers averaged 32.2 ml/min. The dialysances of 3H aldosterone evaluated with dialyzers of different surface areas were correlated with the surface areas of the dialyzers. From the results can be concluded, that besides individual influences of regulation, haemodialysis influences aldosterone concentration in plasma by physical factors.

[Plasma aldosterone during haemodialysis in patients with terminal renal failure]. / Verhalten des Plasma-Aldosterons während der Hämodialyse bei terminal niereninsuffizienten Patienten

In 14 patients with terminal renal failure who underwent dialysis with a solution containing potassium in a concentration of 2 mmol/l, the aldosterone concentration in plasma decreased significantly during haemodialysis. On the other hand a clear increase of plasma aldosterone was observed during haemodialysis in two patients who were dialysed with a solution containing potassium in a concentration of 4 mmol/l. This observation demonstrates the importance of plasma potassium for the regulation of plasma aldosterone concentration during haemodialysis. It suggests that the renin-angiotensin system has no major role in the regulation of aldosterone despite sodium and fluid losses.

Moxonidine and hydrochlorothiazide in combination: a synergistic antihypertensive effect.

This study was designed as a multicenter, double-blind, placebo-controlled, parallel-group, prospectively randomized study comparing, after a 4-week placebo run-in phase, moxonidine 0.4 mg once daily (o.d.), hydrochlorothiazide 25 mg o.d., and the combination of the two with placebo. A total of 160 patients were analyzed in an intent-to-treat analysis. Moxonidine 0.4 mg o.d. was effective in significantly lowering blood pressure in this group of mild-to-moderate hypertensive patients in comparison with placebo. The efficacy and the side-effect profile of moxonidine were comparable to those of the first-line antihypertensive agent hydrochlorothiazide. The combination of moxonidine and hydrochlorothiazide in the same dosage as a monotherapy improves efficacy significantly without additive effects on the safety profile. Response rate after monotherapies was calculated with 70.3 and 70.0%, respectively, after combination treatment in 87.8% of all patients in the treatment group. The trial gives support to a recommended dosage regimen of moxonidine 0.4 mg o.d. This profile of moxonidine is highly comparable to a standard first-line antihypertensive drug such as hydrochlorothiazide, without sacrificing tolerance and safety for increased efficacy, in combination with hydrochlorothiazide.

Moxonidine and cognitive function: interactions with moclobemide and lorazepam.

OBJECTIVE: Moxonidine represents a new generation of centrally acting antihypertensive drugs. It binds to I1-imidazoline receptors and exerts its antihypertensive activity through a reduction in systemic vascular resistance, while cardiac output remains unchanged or even increases slightly. Moxonidine is prescribed for the treatment of mild to moderate hypertension. Typical doses are 0.4 to 2.0 mg given as one dose in the morning or as divided doses in the morning and evening. METHODS: The effects of moxonidine 0.4 mg once daily in combination with moclobemide or lorazepam were investigated in two, double-blind, randomised, placebo-controlled, two-way crossover studies in a total of 48 healthy volunteers. Safety assessments were made in each study and included pre- and post-study measurement of blood pressure, heart rate, ECG, haematology, blood biochemistry, and urinalysis, and recording of adverse events. RESULTS: In the first study, moxonidine alone was found to produce small but statistically significant impairments of vigilance detection speed at 4 h and 6 h. Lowering of subjective alertness was also observed. Repeat dosing with moxonidine produced an impairment of memory scanning performance. These findings were not reproduced in the second study, in which moxonidine alone produced an improvement in immediate word recall at 4 h and 6 h. No interactions were observed when moxonidine was co-administered with moclobemide. Moxonidine, when co-administered with lorazepam, produced interactions with three tasks requiring high levels of attention: choice, simple reaction time and digit vigilance performance; memory tasks; immediate word recall, delayed word recall accuracy; and visual tracking. A total of 47 adverse events were reported in study 1. Moxonidine produced a slight decrease of systolic and diastolic blood pressure. In study 2, a total of 55 adverse events were reported. In both trials, the most frequently reported events were tiredness and dryness of mouth, the latter occurring only under the moxonidine treatment. There were no clinically relevant changes observed in blood pressure, pulse rate, and laboratory tests in either study, nor was there any evidence of any interaction between moxonidine and either moclobemide or lorazepam. CONCLUSION: Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is codosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg.

[Differential therapy of thrombotic-thrombopenic purpura. Administration of fresh plasma versus plasma separation]. / Differentialtherapie der thrombotisch-thrombozytopenischen Purpura. Frischplasmagabe versus Plasmaseparation.

In a 29-year-old man with primary thrombotic-thrombocytopenic purpura a significantly increased plasma concentration of platelet-specific proteins was demonstrated as an expression of increased intravascular platelet activation and destruction during the acute phase of the disease. There was also abnormally elevated IgG loading of platelets. During administration of fresh plasma alone (total of six litres over one week) the clinical state deteriorated further into coma and failure of spontaneous ventilation. The marked thrombocytopenia and microangiopathic haemolytic anaemia remained unchanged. Only after repeated plasmapheresis was it possible to break through the acute disease process. Remission (restoration of vital functions, normalization of platelet count and haemolysis signs) was achieved after five courses of plasmapheresis with a total exchange volume of 20 litres. At least in this case, the therapeutic success of plasmapheresis argues for an immunological-toxic genesis of thrombotic-thrombocytopenic purpura.