4-Dimethylallyl-tryptophanDie Ergot-und Clavin-Alkaloide werden von Claviceps-Pilzen aus Tryptophan einerseits und Mevalonsaure andererseits gebildet, wobei letztere wahrscheinlich uber Isopentenylpyrophosphat und Dimethylallylpyrophosphat eingebaut wird 1). Fiir die weiteren Umwandlungen dieser Reaktionskomponenten lassen sich zwei ziemlich verschiedene Reaktionswege diskutieren, die im einzelnen besprochen werden sollen, wenn uber den Einbau radioaktiv markierter Zwischenprodukte berichtet wird. Bei dem einen Weg wird 4-Dimethylallyl-tryptophan durchlaufen, eine Verbindung, deren Synthese im folgenden beschrieben wird.

An infusion of 7.5 mg/kg.h sodium nitroprusside (SNP) produced a fatal cyanide intoxication in conscious rabbits (n=6) after 60.8 +/- 6.7 min (chi +/- S.E.). When, however, the cyanide antidote sodium thiosulfate was infused simultaneously at a rate of 31.25 or 62.5 mg/kg.h, i.e. a molar SNP/thiosulfate ratio of 1:5 or 1:10 respectively, this high dose of SNP was well tolerated. In both concentrations, thiosulfate abolished the development of the severe metabolic acidosis that results from the infusion of toxic doses of SNP alone. In the presence of thiosulfate, the plasma level of thiocyanate rose linearly with the infusion time indicating a rapid detoxification of cyanide released in vivo from SNP, whereas at the end of the infusion of SNP alone no increase in plasma thiocyanate could be measured. No clear advantage of the higher thiosulfate dosage over the lower one could be established. The iron plasma level only rose during the first hour of SNP plus thiosulfate infusions reaching the iron binding capacity of plasma, and then remained stable throughout the experiment. This indicates that the iron plasma level is an unsuitable parameter for the control of SNP therapy. We suggest the simultaneous administration of SNP and thiosulfate at a molar ratio of 1:5 to make SNP a safer drug.

Sodium nitroprusside (SNP) and hydroxocobalamin (HC) - in molar ratios of 1:4, 1:5, and 1:8, respectively - were infused simultaneously during 4 h into two veins of separate ears of conscious rabbits. Controls received HC only. Sodium thiosulphate (ST) was infused with SNP at molar ratios of 1:4, 1:5, and 1:10. The observation period was 48 h. With the lowest dose of HC (1:4), SNP produced a severe metabolic acidosis; three of ten animals died during the infusion, an additional six within 24 h. When the 1:5 ratio was administered, the acidosis was less marked, but still three of seven animals succumbed within 24 h. The highest dose (1:8) prevented acidosis, however three of eight animals died. All doses of HC caused histological changes in the liver, the myocardium, and the kidney, independently if given alone or with SNP. In contrast to this, ST had a complete antidote effect, if administered in a 1:5 ratio; no acidosis was demonstrable and death did not occur. In neither dosage ST could prevent histological changes in the liver, but the kidney and the heart were not affected. In contrast to HC ST alone did not cause histological alterations. Consequently, ST is the preferable antidote and is superior to HC for preventing or treating intoxications with SNP.

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The simultaneous iv. infusion in conscious rabbits of 7.5 mg/kg.h sodium nitroprusside (SNP) plus sodium thiosulfate in the molar ratios 1:5 or 1:10, respectively, for 4 h produced perilobular necroses of liver cells. 21 days after the infusion, regeneration of the damaged cells was complete. No histological changes were found in various other organs after this high dose of SNP. No signs of liver toxicity were found in rabbits that had received 0.75 mg/kg.h SNP for 8 h daily during a period of 5 consecutive days. This dose was in the range of SNP doses recommended for clinical use in human patients. Nevertheless we suggest that apart from the thiocyanate plasma levels, also the GOT, GPT, and gamma-GT concentrations in blood be controlled, especially when high doses of SNP are to be given for prolonged periods in order to exclude possible hepatotoxic effects of SNP.