Alan K. Done

Studies of 17-hydroxycorticosteroids

Summary Plasma 17-hydroxycorticosteroidconcentrations were found to be elevated markedly in seven patients with salicylate intoxication and in guinea pigs given large doses of sodium salicylate intraperitoneally. Guinea pigs given sodium lactate or smaller amounts of sodium salicylate, intraperitoneally, were found to have levels of these steroids which were not significantly different from those of untreated animals.

Treatment of fever in 1982: a review.

While there is room for questioning the need, or even advisability, of routine antipyretic therapy, the available data do not yet constitute any sort of a contraindication. There are reasons for individualizing the decision. However, having once decided, there is no compelling reason for selecting one antipyretic over any other, and aspirin remains the most satisfactory in light of the available evidence. Some serious theoretic questions persist about the safety of acetaminophen use in sick persons, and clearly there are some precautions that should be taken with regard to the doses of flavored preparations of this and any future products whose attractiveness to children is thus enhanced.

Clinical pharmacology of systemic antidotes.

This review is restricted to those agents which are effective by systemic rather than local action. Thus, there are to be found discussions of chelating agents, narcotic antagonists, anticholinesterase antidotes, cyanide antidotes, fluoroacetate antidotes, bemegride, and agents useful in digitalis, methemoglobin, chlorpromazine, amphetamine, anticoagulant, and bromide poisonings.

Species Differences in Circulating 17-Hydroxycorticosteroid Concentrations.∗

Summary 1. Quantitative determinations of 17-hydroxycorticosteroid concentrations in the peripheral blood of rabbits, rats, guinea pigs and human subjects were made. 2. Considerable species differences in these concentrations were noted. These differences appear to be quantitative as well as qualitative. 3. Of the species observed, the guinea pig appears to be the best experimental animal for studies of 17-hydroxycorticosteroids.

Circulating 17-Hydroxyeorticosteroids in Ascorbic Acid-Deficient Guinea Pigs.

Summary 1. Quantitative determinations of plasma 17-hydroxycorticosteroids in guinea pigs with severe ascorbic acid deficiency were made. 2. Plasma concentrations of these steroids were found to be approximately 10 times those found in normal guinea pigs despite the virtual absence of adrenal ascorbic acid. 3. Scorbutic animals treated with ascorbic acid for 5 days prior to sacrifice had circulating 17-hydroxycorticosteroids in amounts not significantly higher than those of control animals.

Studies of glucuronidation. IV. Evidences of different processes for o-aminophenol and p-nitrophenol.

Summary Evidences are presented that p-nitrophenol (PNP) and o-aminophenol (OAP) utilize different enzyme systems for their glucuronide conjugation. Included are differences between the two substrates in the kinetics of the reaction, the response to mutual inhibition and to inhibition by a breast-milk inhibitor of bilirubin metabolism, intracellular localization, ability of the responsible enzyme to be solubilized, activity of the conjugating processes in the Gunn rat and in postmortem human liver specimens, and the effects of temperature upon the rate of conjugation. These findings support a concept of multiplicity of UDP-glucuronyl transferase enzymes.

Influence on circulating 17-hydroxycorticosteroid concentrations of compounds structurally related to salicylate.

Summary 1. Twenty-five compounds representing structural derivatives of benzoic acid were studied with regard to their effects on circulating 17-hydroxycorticosteroid (17-OHCS) concentrations in guinea pigs. 2. Benzoic acid had no effect on these concentrations. 3. Among the monohydroxybenzoic acids, the o- and m-substituted derivatives produced elevated plasma 17-OHCS concentrations. The latter compound exerted its effect earlier following administration than did salicylate. p-Hydroxybenzoate had no significant effect. 4. Among the mono-ether derivatives of benzoic acid only the o-substituted compounds produced significant elevations of plasma 17-OHCS concentrations. Significant elevations were produced by 3, 4, 5-trimethoxybenzoic acid. 5. Both o- and paminobenzoic acid produced steroid elevations of borderline significance. 6. The addition to the salicylate structure of a second hydroxyl group in the 3 or 6 position or of an ether group in the 3 position appeared to augment the effect on 17-OHCS concentrations. 7. Aspirin exerted the greatest effect on plasma 17-OHCS concentrations of any compound tested. 8. The salicylate metabolite, salicyluric acid, had no effect. 9. A comparison of the influence of these compounds on 17-OHCS concentrations with antirheumatic and anti-inflammatory properties and with effects on adrenal ascorbic acid concentrations, as reported by others, was attempted.

Studies of 17-hydroxycorticosteroids: IX. The influence of therapy on adrenal cortical function in patients with rheumatic fever

Summary 1. Data are presented concerning plasma 17-OHCS concentrations and the responses of these concentrations to ACTH in patients with rheumatic fever during the periods before and after hormone or salicylate therapy. 2. In all therapy groups, except the one treated with ACTH gel, the mean plasma 17-OHCS level was significantly lower during the post-therapy period than during the pre-therapy period, but not significantly lower than in untreated patients with active rheumatic fever of the same duration. 3. In all therapy groups, the 17-OHCS responses to intramuscular ACTH were normal during the pre-therapy period. During the post-therapy period the magnitude of this response was reduced significantly in the cortisone- and the salicylate-treated groups but not in the ACTH-treated groups. 4. The data presented are interpreted as indicating that a relative and temporary suppression of adrenal cortical responsiveness occurs following therapy with cortisone; this suppressive effect apparently persists for not more than one week. Within the range of size of dose and duration of therapy employed neither of these variables appeared to influence directly the adrenal hypofunction in the post-therapy period. 5. In the patients treated with salicylates, there appeared to be a decreased adrenal cortical responsiveness in the post-therapy period.

Studies of 17-hydroxycorticosteroids. XI. Relation of plasma concentrations to urinary excretion in patients treated for rheumatic fever.

Summary 1. The relationships of plasma 17-OHCS concentrations to urinary 17-OHCS excretions were observed in children with active rheumatic fever treated with oral cortisone, ACTH gel, or salicylates. 2. Elevations of plasma 17-OHCSconcentrations and urinary 17-OHCS excretions, proportional to the dose of hormone, were observed during cortisone and ACTH gel therapy; no such elevations occurred during salicylate therapy. ACTH gel was more potent than cortisone, in terms of I.U. ACTH vs. mg. cortisone, in producing the increases in plasma and urinary 17-OHCS values. 3. A temporary relative adrenal cortical refractoriness was observed in patients treated for considerable periods of time with hormones. Because of this it is suggested that a cautious program of tapering the dose be employed.

Evaluation of a new liquid dosage form ofhydrocortisone

Summary 1. Plasma 17-OHCS concentrations attained after administration of hydrocortisone cyclopentylpropionate (FCP) in dogs and in human subjects were compared with those attained after administration of free hydrocortisone. Although in dogs the elevations attained after the former were not as great, in human subjects they were of equal magnitude and greater duration than those attained after administration of free hydrocortisone. 2. After administration of FCP, theelevated plasma 17-OHCS concentrations do not reflect measurement of unhydrolyzed ester. Although the cyclopentylpropionate ester does react quantitatively with the phenylhydrazine-sulfuric acid reagent, it is not measurable by the technique employed since it is not present in the 25 per cent methanol-in-chloroform eluate from the chromatographic column. In addition, paper chromatographic analysis of plasma of human subjects two hours after administration of FCP failed to reveal any trace of this ester in the plasma. 3. Preliminary clinical observations indicate that FCP is a satisfactory administration from for hormone therapy in the young patient.