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Biomedical subjects

D A Holt

Publications and source records attributed to D A Holt.

50 records · Page 3Linked to original sources
PubMed1990

Nocardia brasiliensis cellulitis in a heart transplant patient.

Three months after undergoing heart transplantation, a 55-year-old man presented with N. brasiliensis cellulitis resulting from a splinter wound acquired during yard work. Surgical débridement was necessary before the infection responded to medical treatment. Although pulmonary nocardiosis is a well-documented complication of immunosuppressive therapy, this is the 1st report of a nocardial infection associated with primary skin involvement in a heart transplant patient.

Journal Article↗
PubMed1989

Interaction between rat prostatic steroid 5 alpha-reductase and 3-carboxy-17 beta-substituted steroids: novel mechanism of enzyme inhibition.

Efforts to identify novel compounds capable of blocking the steroid 5 alpha-reductase (SR) catalyzed conversion of testosterone (T) to 5 alpha-dihydrotestosterone have resulted in the development of 17 beta-substituted-3-androstene-3-carboxylic acids as potent inhibitors of the rat prostatic enzyme. The dead-end inhibition patterns of one of these steroidal acrylates, 17 beta-N-(2-methyl-2-propyl)-carbamoyl-androst-3,5-diene-3-carboxylic acid were best evaluated with a linear uncompetitive kinetic model vs both T (Kii = 11 +/- 1 nM) and NADPH (Kii = 22 +/- 2 nM). To interpret these observations, the kinetic mechanism of the rat prostatic SR was shown to involve the binding of NADPH prior to that of T through a series of dead-end and product inhibition experiments. Within the context of this preferentially ordered kinetic mechanism, it is proposed that the uncompetitive inhibition patterns result from the association of the steroidal acrylate to an enzyme complex containing NADP+ in formation of a dead-end ternary complex of enzyme, NADP+, and inhibitor.

5-alpha Reductase Inhibitors↗
PubMed1989

Inhibitors of steroid 5 alpha-reductase in benign prostatic hyperplasia, male pattern baldness and acne.

Benign prostatic hyperplasia is an androgen-dependent disease which afflicts a large percentage of males over the age of fifty, and is usually treated by surgery. Dihydrotestosterone, a 5 alpha-reduced metabolite of testosterone, has been implicated as a causative factor in the progression of the disease, largely through the clinical study of males who are genetically deficient in the dihydrotestosterone-producing enzyme, steroid 5 alpha-reductase. As a result, inhibition of this enzyme has become a pharmacological strategy for the treatment of benign prostatic hyperplasia as well as other dihydrotestosterone-related disorders such as acne and male pattern baldness. In this review, Brian Metcalf and colleagues focus on the chemical and kinetic mechanisms of steroid 5 alpha-reductase, and known inhibitors of this enzyme, and discuss the rationale behind the design of a mechanistically distinct class of steroid 5 alpha-reductase inhibitors.

5-alpha Reductase Inhibitors↗
PubMed1989

Cryptococcal pyarthrosis complicating gouty arthritis.

Cryptococcal arthritis remains a rare entity. Crystalline arthropathy has been described in association with bacterial infection, but no similar association has been described for crystalline joint disease and fungal infection. We have described a renal transplant patient with concurrent gout and cryptococcal arthritis that responded favorably to treatment. Joints with crystalline arthropathy should be cultured for both bacteria and fungi.

Acute Disease↗
PubMed1987

Inhibition of 3(17)beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni by steroidal A ring fused pyrazoles.

Several 2,3- and 3,4-steroidal fused pyrazoles have been investigated as potential inhibitors of NAD(P)H-dependent steroid oxidoreductases. These compounds are proven to be potent, specific inhibitors for 3(17) beta-hydroxysteroid dehydrogenase from Pseudomonas testosteroni with Ki values of 6-100 nM. In contrast, the activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase from Streptomyces hydrogenans, steroid 5 alpha-reductase from rat prostate, and 3 alpha-hydroxysteroid dehydrogenase from rat liver were unaffected by micromolar concentrations of these compounds. Product and dead-end inhibition studies indicate an ordered association to the beta-dehydrogenase with the cofactor binding prior to substrate or inhibitor. From the results of double inhibition experiments, it is proposed that inhibition occurs through formation of an enzyme-NAD+-inhibitor ternate. On the basis of pH profiles of Vm/Km, Vm, and 1/Ki and of absorbance difference spectra, a hypothetical mechanism of inhibition by the steroidal pyrazoles, drawn by analogy from the inhibition of liver alcohol dehydrogenase by alkylpyrazoles [Theorell, H., & Yonetani, T. (1963) Biochem. Z. 338, 537-553; Andersson, P., Kvassman, J. K., Lindström, A., Oldén, B., & Pettersson, G. (1981) Eur. J. Biochem. 113, 549-554], is reconsidered. The pH studies and enzyme modification experiments by diethyl pyrocarbonate suggest the involvement of histidine in binding of the inhibitor. A modified proposal for the structure of the enzyme-NAD+-steroidal pyrazole complex is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxysteroid Dehydrogenases↗
PubMed1981

Rheumatoid factor and monosodium urate crystal-neutrophil interactions in gouty inflammation.

A monolayer system was designed to study the interactions between human neutrophils and monosodium urate crystals important in gouty inflammation. The effects of rheumatoid factor on gouty inflammation were then examined in this system and in patients with acute gouty arthritis. Monosodium urate crystal phagocytosis was apparent at 30 min, and this phagocytosis was accompanied by lysosomal enzyme release and decreased neutrophil adherence to plastic petri dishes. Rheumatoid factor did not affect phagocytosis, adherence, or lactic dehydrogenase release and appeared to variably enhance lysosomal enzyme release. Two of 19 acute gouty patients were found to have low titers of rheumatoid factor and, of these, one exhibited mild disease and the other tophaceous destructive disease.

Adult↗
PubMedDate not supplied

Inhibition of pyridine-nucleotide-dependent enzymes by pyrazoles. Synthesis and enzymology of a novel A-ring pyrazole steroid.

A novel A-ring pyrazole steroid, 2,3-bisaza-A-nor-1,5(10)-estradien-17 beta-ol (3), was synthesized as a potential inhibitor of steroidal NAD(P)H-dependent oxidoreductases. Compound 3 proved to be a potent inhibitor of 3(17)beta-hydroxysteroid dehydrogenase (from P. testosteroni) exhibiting a Ki of 90 +/- 20 nM. The activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase (from S. hydrogenans), steroid-5 alpha-reductase (from rat prostate), and 3 alpha-hydroxysteroid dehydrogenase (from rat liver) were unaffected by pyrazole 3. Dead end inhibition studies indicate an ordered binding of cofactor prior to substrate or pyrazole inhibitor.

3-Hydroxysteroid Dehydrogenases↗