Biotransformation of benzamidine and benzamidoxime in vivo.

After administration of benzamidine (1) or benzamidoxime (2), respectively, to rats and rabbits, plasma from rats and rabbits as well as urine from rats were examined for the presence of benzamidoxime (2) or benzamidine (1). Some of the samples were worked-up directly and the others after enzymatic pretreatment with beta-glucuronidase or arylsulfatase, respectively. HPLC analysis was employed for the detection of the metabolites. After administration of 1, an in vivo N-hydroxylation of an amidine to an amidoxime was demonstrated for the first time. The metabolite 2 could only be detected after enzymatic cleavage of the glucuronide or sulfate, respectively, and only in plasma at a low concentration. After administration of benzamidoxime (2), on the other hand, benzamidine (1) was detected in very high concentrations in all biological samples. Benzamidine was present in the free state but indications for glucuronidization and sulfatation were also detectable. These investigations suggest that the benzamidoxime (2) formed by an in vivo N-hydroxylation undergoes ready retro-reduction but that further transformations of the metabolite 2, such as conjugation to a glucuronide or a sulfate, respectively, prevent complete back reaction. Furthermore, benzamide (3) could be detected as a transformation product in urine after administration of either 1 or 2.

Influence of pentamidine and two new trypanocidal agents (DAPI, DIPI) on liver metabolism of mice.

The effects of equimolar doses (65.5 mumol/kg intraperitoneally) of three trypanocidal compounds, i.e., pentamidine, 6-amidino-2-(amidinophenyl)indole (DAPI), and 6-imidazolino-2-(imidazolinophenyl)indole (DIPI) on some parameters of liver carbohydrate, lipid and energy metabolism have been assessed in male NMRI mice. Most prominent effects were an initial increase of the blood glucose and fatty acid levels followed by long lasting increases of the hepatic triglyceride and glycogen contents which were accompanied by decreases of the liver pyruvate and lactate and ATP contents. These effects which can be interpreted as results of a transient lipolytic and glycogenolytic effect and a longer lasting inhibition of the energy yielding carbohydrate metabolism were most pronounced after DAPI and DIPI and less marked after pentamidine.

Investigations on mutagenicity and genotoxicity of pentamidine and some related trypanocidal diamidines.

Pentamidine, DAPI and some related compounds (DAI, 6-Br-AI, DPTN, DIPI, 3-Am-DAI, DiaPBF) were investigated in 2 different screening test systems for their potential mutagenic and cytotoxic effects, in the light of their binding to DNA. In the Ames test using Salmonella typhimurium strains TA98 and TA100 with and without metabolic activation no mutagenic effects could be observed. All diamidines tested, except DAI, were toxic at concentrations of 0.5 and 1.0 mumole/plate. In the sister-chromatid exchange (SCE) assay with human peripheral lymphocytes all compounds tested were growth-retarding particularly in the G0 phase. A significant induction of SCEs could only be seen after treatment with the monoamidino compound 6-Br-AI at a concentration of 100 mumole/l. It is concluded from the data obtained that pentamidine and related diamidines in the 2 assays tested show no mutagenic or genotoxic effects, in spite of their tight binding to DNA.

Effects of naftidrofuryl on the indocyanine green clearance and cardiovascular function of rats with liver cirrhosis.

The influence of intrahepatically infused naftidrofuryl (Dusodril) on indocyanine green (ICG) clearance was measured in healthy rats and rats with liver cirrhosis. In control rats naftidrofuryl reduced the ICG clearance from 0.043 to 0.029 mumol/min/g liver. Plasma half-life of ICG was prolonged significantly from 3.07 to 4.25 min. This was probably due to a depression of the cardiovascular function (blood pressure, heart-rate). In cirrhotic rats, the removal rate of ICG (0.050 mumol/min/g liver) was significantly lower and its half-life (7.61 min) longer than in normal rats. Probably the extraction rate for ICG was so low that naftidrofuryl did not further impair the reduced ICG clearance and half-life inspite of reduced diastolic blood pressure and heart rate.

[Forms of reactive arthritis]. / Formen der reaktiven Arthritis.

This review describes the term reactive arthritis and Reiter syndrome. We enumerate all our patients with reactive arthritis in the years 1980 to 1985.

Hemodynamic side effects of trypanocidal diamidines in rats. Studies on possible antagonisms.

The influence of the alpha-receptor agonist oxymetazoline, the antihistaminics mepyramine and cimetidine and of cromoglicic acid disodium salt (disodium cromoglycate, DSCG) on the hypotension produced by the trypanocidal diamidines pentamidine, diamidinophenylindole (DAPI) and diimidazolinophenylindole (DIPI) was investigated. 75-100 nmol/kg oxymetazoline were effective only in DAPI-treated animals and diminished the drop of the systolic blood pressure by 25-49%. Pretreatment with DSCG was ineffective in all groups under the conditions used. Preapplication of a combination of 5 mumol/kg mepyramine and 10 mumol/kg cimetidine was effective only in pentamidine-treated animals and reduced the drop of the systolic pressure by 57%.

Phospholipase A2 induced diffuse alveolar damage--effect of indomethacin and dexamethasone upon morphology and plasma-histamine level.

Phospholipase A2, injected as a bolus into the jugular vein of adult male Wistar rats was investigated with respect to its action upon lung morphology and blood- plasma- histamine. In comparison with the injection of saline, phospholipase A2 causes hyperemia of the lungs, sequestration of granulocytes and intraalveolar pulmonary edema; the histamine level is increased to the sixfold. Pretreatment of the animals with indomethacin diminishes the toxic effect of phospholipase A2 upon the lungs and the histamine level.

Amelioration of the hypotensive effect of trypanocidal diamidines by use of heavy soluble salts.

The influence of a heavy soluble dicaprylate salt preparation of a new trypanocidal diamidine (DiaPBF) on systolic and diastolic blood pressure and heart rate of rats has been compared with the effects of the easily soluble DiaPBF-dihydrochloride (DiaPBF-diHCl). After the dicaprylate the drop of the systolic blood pressure was 50% smaller than after an equimolar doses of DiaPBF-diHCl.

Plasma histamine levels in rats treated with trypanocidal diamidines.

The histamine levels in rat plasma treated with various new trypanocidal diamidines and diimidazolines were evaluated by HPLC and fluorometric detection. Equimolar doses (10 mumol/kg) of the new compounds raised the plasma histamine level to a much smaller degree than pentamidine or diminazene.

Alpha-adrenoceptor-blocking properties of some trypanocidal diamidines.

A series of trypanocidal diamidines and diimidazolines known to cause severe hypotension were tested for their alpha-adrenoceptor blocking properties in vitro. At the postsynaptic alpha 1-receptor of the guinea-pig aorta in vitro all compounds at doses of 0.5 to 50 mumol/l showed weak antagonistic effects against noradrenaline. Similar results were obtained at the presynaptic alpha 2-receptor of the rat vas deferens.

Changes in serum transaminases, SDH and liver morphology after treatment with trypanocidal diamidines in mice.

The effects of 2 recently developed trypanocidal agents, Diamidinophenylindol (DAPI) and Diimidazolinophenylindol (DIPI) at doses of 10-30 micrograms/g intraperitoneally (i.p.) on serum GOT, GPT and sorbitol dehydrogenase (SDH) levels and on liver morphology have been investigated in mice. Pentamidine served as reference drug. Both agents caused dose-dependent increases in serum transaminases and SDH, and discrete morphological changes of the liver, e.g., fatty degenerations, azinoperipheral vacuolisation and alterations of the nuclei, at least at the higher dosage.

[Lung changes after organ transplantation]. / Lungenveränderungen nach Organtransplantation

The morphological pulmonary alterations in renal transplant recipients have been investigated in the light of 62 autopsies. Apart from the predominant pulmonary edema of septic, uremic or circulatory origin, pneumonic opportunistic infections were prominent. The most important agents proved to be bacteria, cytomegalovirus and fungi. In most cases, mixed infections were observed. At autopsy, pneumocystis carinii infections appeared to be of little importance. The pathology of the pulmonary changes reflects the reduced defense inevitably following on immunosuppressive medication, which in turn is indispensable for successful transplantation.