[Pharmacologic principles of drug prescribing in pregnancy]. / Pharmakologische Grundlagen der Arzneimittelverordnung in der Schwangerschaft.

The administration of drugs to pregnant women comprises special problems. This review gives an overlook on changes in the pharmacocinetics due to pregnancy and on the possible side effects of drugs on embryo and fetus. Finally, general rules for the prescription of drugs to pregnant women are given.

Failure of calcium antagonistic agents to prevent hepatotoxicity induced by diclofenac.

Diclofenac (0.5-2 mM) dose- and time-dependently reduces the viability of isolated hepatocytes. This effect cannot be counteracted by the calcium channel blockers diltiazem (0.05-0.1 mM) and verapamil (0.05-0.5 mM), the calmodulin antagonist calmidazolium (0.01 mM) or Quin 2-AM (0.1 mM), an intracellular calcium chelating agent. On the contrary, verapamil even accentuates the toxic effects of diclofenac. It is concluded from these results, that diclofenac causes cell damage by other mechanisms than calcium overload.

Protective effect of various calcium antagonists against an experimentally induced calcium overload in isolated hepatocytes.

The effect of the hepatotoxic substance diamidinothionaphthene (98/202) on cytosolic, mitochondrial and extra-mitochondrial calcium distribution was measured in isolated rat hepatocytes. The drastic disturbance of the intracellular calcium homeostasis caused by this substance (increase of the cytosolic and mitochondrial calcium contents and depletion of extra-mitochondrial calcium stores, which at last lead to cell death) gave rise to an investigation of the possible cytoprotective effect of calcium antagonists of various chemical classes: verapamil, diltiazem, and nifedipine on isolated hepatocytes. Our results show that all three calcium antagonists prevented cell death caused by 98/202. The 98/202-induced increase of cytosolic and mitochondrial calcium content was inhibited by all three calcium antagonists. However, only verapamil was able to inhibit the depletion of extra-mitochondrial calcium stores. Since 98/202-induced cell death occurs only in the presence of extracellular calcium, it is concluded that calcium antagonists are also able to inhibit the influx of extracellular calcium in liver cells, which leads to a calcium overload of the cytosol and mitochondria. The various ways of interfering with the calcium homeostasis of liver cells qualifies the hepatotoxic substance 98/202 as a suitable in vitro hepatotoxicity model for testing the hepatoprotective effect of different calcium antagonists.

High-performance liquid chromatographic method for the routine determination of diclofenac and its hydroxy and methoxy metabolites from in vitro systems.

A rapid and sensitive high-performance liquid chromatographic method is presented for the determination of diclofenac and its hydroxylated and methoxylated metabolites. The procedure describes extraction of diclofenac and its metabolites from acidified incubation medium into tert.-butylmethyl ether. Separation is achieved with a C18 reversed-phase column and quantification by UV detection at 280 nm. The method employs an internal standard resulting in good accuracy and precision. The limit of detection is 5 ng/ml for diclofenac and 10 ng/ml for its metabolites. One analysis requires no more than twelve minutes so that the assay is very suitable for the determination of a large number of samples.

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.

Evaluation of the hepatotoxic potential of minocycline.

Minocycline (25 to 100 micrograms/g) dose dependently increased serum glutamic oxalacetic transaminase, urea, and bilirubin levels, and the hepatic triglyceride content in mice. In animals pretreated with phenobarbital to enhance minocycline metabolism, the effects on liver triglycerides were attenuated, while the changes in serum glutamic oxalacetic transaminase, urea, and bilirubin were enhanced. It is concluded that part of the toxic effects of minocycline may be produced by a metabolite of minocycline.

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.

Comparative evaluation of hepatotoxic side effects of various new trypanocidal diamidines in rat hepatocytes and mice.

A series of new trypanocidal diamidines was tested for their hepatotoxic potential. At a concentration of 0.5 mmol/l almost all agents tested produced leakage of lactate dehydrogenase and reduced viability of isolated rat hepatocytes. In mice serum sorbitol dehydrogenase was raised by a single i.p. dose of 65.5 mumol/kg. Only two agents, compounds 261/115 and 313/40, were free of these effects at this dose or concentration.

Investigation into the combined effects of ethanol and cadmium on rat liver and kidneys.

To examine the combined hepatotoxic and nephrotoxic effects of cadmium and ethanol, rats maintained on an ethanol containing liquid diet (5% w/w) were given cadmium either acutely (3 x 1 mg/kg IP) or subacutely (about 14 mg/kg/day PO for 6 weeks). Parameters tested were cadmium, zinc and copper contents of blood and various organs, metallothionein (MT) contents, polysome profile of liver and kidneys, serum SDH and GPT levels and creatinine clearance. Ethanol reduced the hepatic MT contents without altering the polysome profile and the zinc and copper contents. Cadmium on the other hand raised the MT contents in liver and kidneys. This effect of cadmium predominated in the combined treatment. Morphological examination and functional tests (SDH, GPT, creatinine clearance) indicate that cadmium does not enhance the toxic effects of ethanol, and vice versa.

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%.

The influence of tetracyclines on the aggregation of free and membrane-bound polysomes and on the RNA content of the liver of mice.

Tetracycline (100 micrograms/g) and, to a lesser extent, doxycycline (50 and 100 micrograms/g) inhibited the aggregation of free but not of membrane-bound polysomes in the livers of female NMRI mice. In addition tetracycline decreased the RNA content of the fraction of membrane-bound polysomes probably due to detachment from their membrane sites.