[Spironolactone: renaissance of anti-aldosterone therapy in heart failure?]. / Spironolacton: Renaissance der Antialdosterontherapie bei Herzinsuffizienz?

Mortality of patients with severe congestive heart failure (CHF) is still high despite combined treatment with angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digitalis. Further therapeutic regimens are needed which include reversal of adverse myocardial remodeling and subsequent ventricular dysfunction. One third of all patients with CHF have diastolic left ventricular (LV) dysfunction with preserved systolic function. In these patients myocardial collagen matrix is the major determinant of myocardial stiffness and therefore diastolic function. Cardiac fibroblasts, expressing mRNA for types I and III collagens which are the major fibrillar proteins of the myocardial collagen network and for matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation, are controlled by the renin-angiotensin-aldosterone (RAAS) system irrespective of hemodynamics and cardiac myocyte growth. In the rat with primary or secondary hyperaldosteronism, myocardial fibrosis occurs in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophic right ventricle. In contrast, no fibrosis is found in either ventricle of rats with infrarenal aortic banding, when the RAAS is not activated, despite comparable systemic hypertension and LV hypertrophy. In cultured cardiac fibroblasts, either effector hormone of the RAAS, angiotensin (Ang) II and aldosterone (Aldo) stimulate collagen synthesis measured by 3H-proline incorporation under serum-free conditions. Aldo is able to stimulate collagen synthesis normalized per total protein synthesis in a dose-dependent manner and at concentrations (10(-9) M) which are comparable to stimulated states in vivo (e.g., CHF). While Aldo does not affect collagen degradation AngII significantly inhibits, MMP 1 activity that would lead to further accumulation of collagen in the myocardium. Specific AngII type I or Aldo receptor antagonists are able to abolish the AngII or Aldo-mediated increase in collagen synthesis, respectively. In vivo in rats with primary or secondary hyperaldosteronism, the Aldo antagonist spironolactone has been shown to prevent myocardial fibrosis in both ventricles irrespective of the development of LV hypertrophy and hypertension. Thus, in vivo and in vitro evidence could be provided that the mineralocorticoid. Aldo, plays a pivotal role in promoting myocardial fibrosis and can be antagonized by its competitive receptor blocker, spironolactone. This may be of particular clinical relevance in treating patients with CHF where the RAAS is activated leading to myocardial fibrosis with subsequent deterioration of myocardial function. Clinical trials are needed to confirm these experimental data. If the ongoing RALES mortality study will prove that survival and/or morbidity of patients with CHF are improved by combined ACE inhibitor/spironolactone treatment a renaissance of anti-aldosterone therapy in patients with CHF would occur.

Toxicological profile of praziquantel, a new drug against cestode and schistosome infections, as compared to some other schistosomicides.

2-Cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a] isoquinolin-4-one (praziquantel, EMBAY 8440, Biltricide), a new anthelminthic drug with activity against all species of schistosomes pathogenic to man, and against a wide range of cestodes, did not reveal any undesired pharmacodynamic effects. After oral administration praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a variety of metabolites predominantly via the kidneys by all species tested, including man. Its acute toxicity tested in rats, mice, rabbits and dogs is very low as compared with other schistosomicidal drugs. After repeated oral administration rats tolerated daily doses of up to 1000 mg/kg for four weeks, and dogs up to 180 mg/kg for thirteen weeks without any organ damage. In contrast to some other schistosomicidal drugs praziquantel did not disturb the whole reproductive process (up to F2-generation) in rats, nor did it reveal teratogenic effects in mice, rats and rabbits. In extensive mutagenicity trials performed in different European laboratories in a variety of test systems no induction of point mutations, nor of gene conversion, nor of DNA-repair, nor of sister chromatid exchanges (SCEs), nor of X-linked recessive lethals was detected. Besides, Salmonella tests with urines of praziquantel-treated mice, rats, healthy and Schistosoma-infected persons gave no indication of a mutagenic effect. In different in vivo mammalian assays praziquantel was not mutagenic either. In contrast to these findings other schistosomicidal drugs demonstrated mutagenic potential, in bacterial tests at least. According to the results available so far from carcinogenicity studies with oral doses of 100 and 250 mg praziquantel/kg, given once weekly to Syrian hamsters for 80 weeks and to rats for 104 weeks, there is no hint of a carcinogenic potential of praziquantel in small rodents, while hycanthone had cancerogenic effects in mice and niridazole was carcinogenic in mice, rats and Syrian hamsters.

Chromosome analysis of bone marrow in mammals after treatment with isoniazid.

Cytogenetic investigations in bone marrow from animals treated with isoniazid (INH) were performed in seven different laboratories according to a standard protocol. The experiments were carried out in the Chinese hamster, the mouse, and the rat. In short-term studies INH was administered twice at an interval of 24 h in doses of 5, 25, and 125 mg/kg, and the animals were sacrificed 6, 12, 24, and 48 h after the second dose. In long-term studies doses of 25 and 125 mg/kg were administered thrice weekly for 12 weeks. As a rule, each group consisted of at least four animals, and 100 metaphases per animal were counted. Statistical analysis of the data showed that the incidence of chromosomal aberrations including gaps lay in the critical range for two groups in one laboratory and was significantly higher than in the control in three groups in another of the seven laboratories. From the results of both the short-term and the long-term studies in all laboratories, however, it may be concluded, that isoniazid does not induce gross chromosomal aberrations.

In vivo cytogenetic investigations in bone marrow cells of rats, Chinese hamsters and mice treated with 6-mercaptopurine.

The chromosome-damaging effect of 6-mercaptopurine (6-MP) was investigated in bone marrow cells of rats, Chinese hamsters, and mice after single intraperitoneal injections of doses from 3.125 to 250 mg/kg, and after multiple applications of 10, 25, 50, and 125 mg/kg. The optimal time of investigation after single administration in these studies was 48 hrs after treatment for all 3 species. A nearly linear dose-response relationship with a low quadratic component was observed. The "critical dose" for all 3 species was 12.5 mg 6-MP/kg. However, mice generally demonstrated the highest sensitivity to the "clastogenic" effect of 6-MP. In agreement with results of acute toxicity studies, Chinese hamsters generally were less (and rats least) sensitive than the mouse to chromosomal damage induced by higher doses of 6-MP. After repeated treatment with low doses, the chromosome-damaging effect of 6-MP was less pronounced than after one single administration of a large dose equaling the total amount of substance applied in chronic treatment.