6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities.

This paper reports on the synthesis and pharmacological activity of 6-aryl-4,5-dihydro-3(2H)-pyridazinone derivatives. The compounds exhibit an aggregation inhibiting action on human platelets in vitro and on rat platelets under ex vivo conditions, as well as a hypotensive action on rats. The strongest pharmacological effects were found with dihydropyridazinones, which have a 6-[p-[(chloroalkanoyl)amino]phenyl] substituent, together with a methyl group in the 5-position. The antiaggregation activity of compounds of this type is in vitro up to 16000 times and ex vivo up to 370 times greater than that of acetylsalicylic acid; the hypotensive action is up to 40 times as great as that of the comparative substance dihydralazine.

Investigation of dialysis membranes with atomic force microscopy.

AFM was used to investigate dialysis membranes made of regenerated cellulose by the cuoxam process. The membranes were either Cuprophan or experimental samples, modified with different amounts of diethylaminoethylcellulose (DEAE). Atomic force microscopes with optical-lever detection systems were used to image the dry membranes in air as received from the manufacturer as well as wet membranes in a swollen state under water. Differences could be observed between modified and unmodified as well as between dry and wet membranes.

The puzzle of Alzheimer's disease (AD).

A compromised defensive system of brain cells against aluminium, together with local defects in glucose metabolism, causes AD. Lack of citrate is a driving force and free cis-aconitate or glutamate are potential carriers, which enable the exotoxin to cross lipid membranes. Only a few aluminium ions replace magnesium in key positions. They block the reversibility of phosphorylation reactions, which are important for short term memory: sensitization of the insulin receptor and protein phosphorylations. Due to disturbed phosphorylation of the cytoskeleton, protein synthesis runs out of balance. Efforts to restore the disturbed reactions result in AD specific deposits. Aluminium ions are the common cause for the induction of AD pathogenesis in patients with genetic defects, with mechanical brain lesions or with minor infarcts, as well as with changes in the relation between numbers of neurons and neuron nursing glia cells due to age.

[Involvement of the urogenital system in non-Hodgkin lymphoma (primary and secondary involvement)]. / Die Beteiligung des Urogenitalsystems am non-Hodgkin-Lymphom (Primär- und Sekundärbefall).

According to the literature the non-Hodgkin-lymphoma is involving the kidney and its capsule, the hilus of the kidney and the retroperitoneal space in some instances. Today one assumes that the disease is originating unifocally therefore one can achieve a healing or complete remission by radical surgery when one or both kidneys or a testicle are involved. Prior to this generalised disease must be ruled out. Two cases are reported where one or both kidneys were involved showing long survival time or cure. The prognosis, however, is very poor when the urogenital system is included in systemic forms of non-Hodgkin-lymphoma.

[Paravesical angiofollicular hyperplasia of the lymph nodes (so-called Castleman tumor). A contribution to differential diagnosis of benign retroperitoneal space-occupying lesions]. / Paravesikale angiofollikuläre Lymphknotenhyperplasie (sog. Castleman-Tumor). Ein Beitrag zur Differentialdiagnose benigner retroperitonealer Raumforderungen.

Clinical and pathological presentation of a benign so-called "Castleman Tumour", is very rare in the urological literature. It caused impression of the bladder and displacement of the right ureter in a 47-year-old male patient with a six-year case history. Detailed description of the two types of tumours is presented differing both histologically and clinically. This adds to the differential diagnosis in cases of space occupying lesions in the retroperitoneal cavity.

[Fibrosarcoma in onocytoma (author's transl)]. / Fibrosarkom in einem onkozytären Adenom der Niere.

In a 69-year-old male patient a leftsided renal tumor was found. The patient who initially refused an operation, was treated surgically 3 1/2 years later, when loss of strength and weight as well as pain in the upper abdomen were noted. The tumorweight was 920 g and represented histologically, besides a oncocytic adenoma, a fibrous sarcoma. Both tumors were intermingled. We assume that the malignant growth originated in degenerated areas of the benign adenoma.

[So-called glomera in the region of the prostate]. / Sog. Glomera im Bereich der Prostata.

In three cases prostate biopsies revealed structures which showed the histological characteristics of so called glomera (chemodectomas), one within the prostatic tissue, the others in the area of the capsule. Clinicians and pathologists to avoid misinterpretation have to be aware of the fact that this wellknown structure can occur in biopsy material.

[Evaluation of anti-arrhythmia agents in the animal model]. / Bewertung von Antiarrhythmika im Tiermodell.

In view of the results of CAST, researchers working in the field of experimental arrhythmia have been increasingly focusing on the quest for new anti-arrhythmic modes of action and ways of detecting pro-arrhythmic properties of antiarrhythmic drugs at an early stage. Here, the experimental methods available play a particularly important role. While trying to assess anti-arrhythmic effects without investigating electro-physiological parameters in isolated tissue would be inconceivable, the degree to which the results of in vitro studies can be transferred to the intact organism is limited because of the complex nature of the arrhythmias. Of the various existing in vivo models, the most commonly employed are those in which arrhythmia is induced after experimental surgical interventions causing ischemia and infarction, followed by reperfusion. This shows that researchers are striving to "create" pathophysiologically-defined conditions and, as far as possible, a pathophysiological situation which is similar to that in the patient. Guidelines were laid down for this model complex in the Lambeth Conventions (1988) in order to improve uniformity of the methods and better comparability of the results generated by different investigators. Of the existing arrhythmia models, the ventricular re-entry arrhythmia model after myocardial infarction triggered by programmed stimulation, which was devised by Spear/Moore (1983), has proven to be particularly useful in the assessment of antiarrhythmics and is used by many researchers. Class II and III antiarrhythmics can be identified reliably by this method, whereas class I antiarrhythmics are mostly inconspicuous.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic interaction of gallopamil and propranolol in the conscious dog.

The interaction of gallopamil (Procorum) and propranolol was studied in conscious trained dogs by injecting gallopamil intravenously (consecutive injection of 0.0464, 0.1 and 0.215 mg/kg at 30-min intervals) with and without propranolol pre-medication (0.464 mg/kg i.v., 10 min before the first injection of gallopamil). An intraindividual comparison of the cardiovascular effects was made. The interaction was mostly minor and occurred only with the highest dose of gallopamil. It was noticeable most in the influence on myocardial contractility which was more pronounced than the influence on electrophysiological parameters. A shift in threshold doses was not observed. Much more pronounced effects of the gallopamil-propranolol interaction become apparent when the animals were at the same time subjected to vagal blockade (methylatropine). In this situation, combined administration of gallopamil and propranolol led to a greater reduction of contractility, increase of AV block and occurrence of asystole. As regards the latter, a shift in the threshold dose occurred. The differences in the intensity of the interaction between gallopamil and propranolol in animals with or without vagal blockade are therefore a consequence of the presence or absence of reflex regulation. The findings explain, and relativize, the clear-cut interaction in the anaesthetized dog demonstrated by other authors, i.e. experimental conditions matching an autonomic blockade.

[Kidney tumors in the elderly patient over 75]. / Der Nierentumor des alten Menschen über 75 Jahre.

35 patients (17 females, 18 males), ranging from 75 to 92 years of age, underwent nephrectomy because they suffered from renal tumours, which in 12 cases had preoperatively a total blockage of the renal artery after angiography. A total of 27 retroperitoneal and 8 transperitoneal operations were performed. Indications as well as post-operative complications and long-term effects are dealt with. Except suppurative pyelonephritis of the residual kidney neither temporary nor permanent renal insufficiency could be observed. Even in patients of advanced age, nephrectomy will yield satisfactory longterm results and prevent the formation of metastases.

[Effect of plant glycosides on resistance and capacitance vessels]. / Zur Wirkung pflanzlicher Glykoside auf Widerstandsgefässe und Kapazitätsgefässe.

In the anaesthetized cat, SCOA ( Miroton ), a product which contains extracts from Scilla , Convallaria , Oleander and Adonis , displays not only its well-known positive inotropic effect but has also constrictor effects on veins when applied in intravenous doses of 21.5-100 GPU /kg ( GPU = guinea-pig units, i.e. cardiotoxic equivalents related to 1 g body weight of guinea-pigs). The latter effect differs in that it is somewhat more prolonged. With intraduodenal administration the doses required to achieve equal peak effects as with intravenous injection are about 4 times larger and this suggests a relatively good enteral availability in the cat. SCOA constricts not only veins but also arteries. However, this latter effect is comparatively small and occurs only after intraarterial infusion of high doses (9.1 and 91 GPU /min, respectively).--The cardiac glycosides contained in the drug product primarily account for its vasoactive qualities. The venous constrictor effect correlates with the guinea-pig units. In qualitative respects, the pure glycosides cymarin , convallatoxin , proscillaridin , and scillaren exert equal effects. There is, however, evidence that the correlation between the effect on veins and on the heart differs for the glycosides tested. Based on equal guinea-pig units, the adonis extract, for instance, acts on capacitance vessels about twice as much as scilla , oleander and convallaria extracts. Cymarin , too, has a stronger effect on veins than would be expected from its cardiotoxic effect. The action on arteries and veins are based on different mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by the combined Ca2+ and 5-HT2 receptor antagonist nexopamil (LU 49938) of intracoronary thrombus formation in a canine model of arterial stenosis and intimal damage.

We investigated the effects of nexopamil, a combined Ca2+/5-HT2 antagonist on thrombus formation in vivo and on platelet aggregation in vitro. In anesthetized mongrel dogs, cyclic flow reductions (CFRs) in the left anterior descending coronary artery (LAD) were induced by implanting a constrictor after the endothelium was injured mechanically. The CFRs were due to intracoronary thrombus formation. After CFRs were recorded for 1 h, the test compounds were injected intravenously (i.v.) for 2 min. Measurements were made for another hour. Nexopamil (0.05 mg/kg) completely abolished CFRs during the first 30 min after application without significantly altering hemodynamics. The same effect was noted with 0.02 mg/kg ketanserin (5-HT2/alpha 1 antagonist). The Ca2+ antagonist gallopamil reduced CFRs only in the highest hemodynamically tolerable dose by 40%. Serotonin-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro was most potently inhibited by ketanserin (IC50 0.55 x 10(-8) M), followed by nexopamil (IC50) 0.81 x 10(-7) M) and gallopamil (IC50 1.76 x 10(-6) M). Because serotonin is an important pathophysiologic mediator in unstable angina, 5-HT2 receptor antagonism should be of considerable benefit by preventing platelet activation and aggregation. The combination with calcium-antagonistic activity leads to an increase in coronary blood flow (CBF) and a decrease in cardiac oxygen demand. Therefore, the effects noted with nexopamil should be of importance in treating patients with coronary artery disease.

How to catch urea? Considerations on urea removal from hemofiltrate.

Hemofiltration imitates the first step in the natural function of the kidney. After separation from corpuscular and high molecular weight blood components, a filtrate remains which contains urea together with electrolytes and other low molecular weight metabolites. To use a hemofilter in a recirculating closed-loop system, a big quantity of urea must be eliminated. A survey of published attempts to solve this problem is presented. Reasons are given for the difficulty to eliminate urea directly from dilute aqueous solutions. Explanations for ambiguous results of some reactions proposed for urea removal are discussed. The concept of hard and soft acids and bases is used to develop demands to the structure of a reagent which reacts preferentially with urea in aqueous solution. On monomeric model substances-activated aldehydes-this hypothesis is proven in vitro. In spite of the given technical possibility of urea removal, the authors doubt whether solving the problem of urea removal will enable a closed-loop system for alternative simpler or more economic ways of treating renal failure.

[New beta-sympatholytic agents. Synthesis and pharmacological activity of isomeric benzthiazole and benzoxazole derivates (author's transl)]. / Neue beta-Sympatholytika: Synthesen und pharmakologische Wirkung isomerer Benzthiazol- und Benzoxazol-Derivate.

The synthesis and comparative pharmacological studies concerning structure-activity relationship of new benzothiazole, benzisothiazole, benzoxazole, and benisoxazole derivatives with beta-sympatholytic activity are reported. Most of the 4-benzisothiazole derivatives studied strongly act on cardiac beta 1-receptors in rats in situ (2.6-8.3 times propranolol). On the other hand derivatives of 4-benzisoxazole and 5-benzisothiazole are less potent. A strong decrease in activity was observed going from the benzisothiazoles and benzisoxazoles to the isomeric benzthiazoles and benzoxazoles. The active substances also block vascular beta 2-receptors. In the most cases they have little intrinsic adrenergic activity. The observed tendency concerning beta 1-selectivity in rats could not be confirmed in cats. The most potent 4-benzisothiazole derivatives in rats show also - beside some minor differences - very good beta-sympatholytic activity in cats after i.v. as well as after i.d. administration. Similar to the results in rats and cats the 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole (LU 24329) was found to possess a high activity in conscious dogs by oral or i.v. application. Both in dogs (i.v.) and in isolated perfused guinea pig hearts LU 24329 is eleven times more active than propranolol in blocking beta 1-receptors. A negative inotropic effect as an expression of non-specific membrane-stabilizing action of LU 24329 is also demonstrated in guinea pig hearts. The effective concentration is 4650 times higher than that effective on beta 1-adrenoceptors. The active compounds have a moderate acute toxicity. The LD50 values in mice after i.p. administration are ranging from 55-174% of the propranolol toxicity.

[Pharmacology of N-(2-imidazolin-2-yl)-N-(4-indanyl)amino (indanazoline), a new vasoconstrictive imidazoline compound]. / Zur Pharmakologie von N-(2-Imidazoline-2-yl)-N-(4-indanyl)amin (Indanazolin), einer neuen vasokonstriktorisch wirksamen Imidazolinverbindung.

In animal experiments the new imidazoline derivative N-(2-imidazolin-2-yl)-N-(4-indanyl)amine (indanazoline, E-VA-16, as monohydrochloride active substance of Farial) is characterized by a pronounced vasoconstrictive action after local or intravenous application. This is due to a direct action of the compound on alpha-adrenergic receptors. When applied systemically E-VA-16 being a peripherally acting alpha-sympathomimetic induces a rise in blood pressure and a reduction of heart rate and exerts antiphlogistic, spasmolytic, hyperglycemic and diuretic actions. When given by the intranasal route the substance influences blood pressure and heart rate only at concentrations considerably higher than those intended for use in therapy. After enteral administration the effective doses also markedly exceed the single therapeutic doses. There was no evidence of side-effects restricting the use of the drug as compared to other imidazoline derivatives. Studies on the isolated perfused rabbit ear, however, indicated a broader therapeutic range in local application.

Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate.

Ninety-five patients with prostatic carcinoma, stages A-D and of all histological grades were randomized between a continuous and an intermittent treatment regimen of Estracyt (estramustine phosphate). 77 patients were evaluated (46 with continuous and 31 with intermittent therapy). Remissions were seen in 13 (28%) and (13%), respectively. Stable disease was recorded in 30 (65%) and 24 (77%), respectively. Progression experienced 3 (6%) and 3 (10%) respectively. 19% were unable to continue therapy due to intolerable gastrointestinal side effects (7 patients receiving continuous and 8 patients receiving intermittent therapy).

Regeneration of hemofiltrate by anodic oxidation of urea.

Urea can be oxidized electrochemically in a chloride solution to carbon dioxide, water, and nitrogen. The microkinetics of this hypochlorite-mediated urea oxidation are elucidated. Based on this kinetic information, the optimal conditions and construction principles for an electrochemical reactor are deduced. The construction of a cheap, disposable oxidation cell and necessary auxiliary equipment are described. In vitro data are reported for urea removal. A 36-L volume was used to simulate a 60-kg patient; 18 L was recirculated through a 0.12-m2 oxidation cell. Within 3 h, 35 g urea could be removed from the system. The technical and economic possibilities as well as safety requirements for hemofiltrate regeneration to a reinfusable substitution solution by anodic urea oxidation are discussed critically. Although the process does not appear to be economically practical for discontinuous hemofiltration, it might be desirable for continuous (24 h/day) treatment.