Erich Gerhards

THE METABOLISM OF DIMETHYL SULFOXIDE AND ITS METABOLIC EFFECTS IN MAN AND ANIMALS

35 After intravenous and cutaneous application of S-labeled dimethyl sulfoxide (DMSO) to normal persons and rats the unchanged compound and dimethylsulfone (DMS02) were excreted in the urine. DMSO and DMSOz were isolated and identified.* In FIGURE 1 is shown how the 35S activity in human urine is distributed between DMSO and DMSOz. After intravenous (person A) as well as after cutaneous application of DMSO (persons B, C, D) the excretion of the unchanged compound is rapidly diminished. 24 hrs after the administration there is hardly any DMSO detectable. Up to 24 hrs after intravenous administration of 35S-labeled DMSO with 25 pc to rats less than 0.02% of the administered activity were detectable in the sulfate fraction in urine after precipitation with BaC12. This means that DMSO is hardly demethylated and oxydized to sulfate in vivo. We have studied the intracellular localization and cofactor requirement of DMSO metabolism with liver of male rats. In all the incubations* the enzyme preparation was equivalent to 125 mg of liver. DMSOisoxydized to DMSO:! by microsomes in the presence of NADPH2 and molecular oxygen. NADPH2 can be replaced by NADH2. In a nitrogen atmosphere DMSO is not oxydized to DMS02 (FIGURE 2). The formation of DMSOz is markedly enhanced by liver microsomes, prepared from animals treated with phenobarbital for three days. This result is in accordance with several reports in the literature regarding the stimulating effect of phenobarbital treatment on microsomal drug-metabolizing enzymes. The following in vitro studies were done to get some information about the ability of different tissues to bind DMSO and about the important question, whether or not DMSO might accumulate in any of the tissues studied. The binding of DMSO was determined by equilibrium dialysis.

New biologically active pregnan-21-oic acid esters

Abstract Among the metabolites of fluocortolone (IV), isolated from human urine, there was found fluocortolone-21-acid (XI). This metabolite and several ester derivatives were synthesized by different routes starting from fluocortolone. The synthetic methods used to prepare the fluocortolone acid esters were extended to other corticoid derivatives. Several pregnan-21-oic acid esters possess the unique activity that they are topical anti-inflammatory agents with no side effects. Even when administered at high dosages, the usual systemic activity associated with corticosteroid treatment could not be observed.

Influence of hormonal contraceptives on carbohydrate and lipid metabolism in the rat.

To further determine the metabolic effects of hormonal contraceptives on human metabolism 60 female Wistar rats were administered 3 different steroids subcutaneously in 5 different combinations once daily for 14 days. 10 rats each received ethinyl estradiol 5 mcg/kg d1-norgestrel 5 mcg/kg and norethindrone acetate 400 mcg/kg alone and ethinyl estradiol with noregestrel or norethindrone in combination at doses 6 times the normal human range per weight. 10 normal untreated rats served as controls. Metabolic tests from autopsies revealed that blood glucose levels were not changed by any of the steroids. A significant increase in liver glycogen was seen when estrogen was taken alone or along with either gestagen. This effect was dependent on the dosage size and the presence of the adrenal gland. Free fatty acids remained unaffected by any steroid and cholesterol and phospholipids were not affected by either of the combinations or by gestagen alone. Estrogen alone or with norgestrel caused a significant increase in total glycerol levels and estrogen alone caused a similar rise in total cholesterol levels. A very high dose of estrogen reached toxic proportions seriously depressing total glycerol cholesterol and phospholipid levels. None of the steroids affected insulin sensitivity. Norgestrel alone caused an increase in liver weight and total lipids and further research is suggested into the metabolic effects of this steroid. Estrogen alone caused a marked increase in serum triglycerides but this effect was counteracted when administered simultaneously with norethindrone. Estrogen did not enhance lipolytic activity in adipose tissue. It is concluded that estrogen clearly causes the most significant metabolic alterations both in carbohydrate and lipid metabolism in the rat. Simultaneous administration of norgestrel or norethindrone occasionally counteracted this effects depending on the dose but often did not and thus further research is needed to enumerate more clearly specific steroid metabolic actions.

NEW BIOLOGICALLY ACTIVE PREGNAN-21-OIC ACID ESTERS

Among the metabolites of fluocortolone (IV), isolated from human urine, there was found fluocortolone-21-acid (XI). This metabolite and several ester derivatives were synthesized by different routes starting from fluocortolone. The synthetic methods used to prepare the fluocortolone acid esters were extended to other corticoid derivatives. Several pregnan-21-oic acid esters possess the unique activity that they are topical anti-inflammatory agents with no side effects. Even when administered at high dosages, the usual systemic activity associated with corticosteroid treatment could not be observed.