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Biomedical subjects

M A Shaw

Publications and source records attributed to M A Shaw.

At least 73 records · Page 4Linked to original sources
PubMed1988

Aminoglutethimide and ketoconazole: historical perspectives and future prospects.

Aminoglutethimide and ketoconazole, although originally developed as an anticonvulsant and antifungal agent respectively, have both been used to suppress steroid biosynthesis in patients with hormone-sensitive cancer. Aminoglutethimide inhibits several enzymes involved in the synthesis of corticosteroids as well as the aromatase enzyme which converts androgens to oestrogens. About one third of patients with breast cancer show objective improvement with aminoglutethimide, and it may also be of use in the treatment of adrenal carcinoma. However, its toxicity, and the need for concomitant cortisol replacement, severely limit its usefulness. Ketoconazole also inhibits several steroidogenic enzymes, notably C17,20-lyase, and has been used to treat carcinoma of the prostate. Again however, its toxicity and limited efficacy limit its value, although it may be useful in the treatment of certain endocrine conditions such as precocious puberty. Several aromatase inhibitors similar in structure to aminoglutethimide have been developed in an attempt to create more selective and efficient inhibitors. Some of these compounds have been tested in animals but none have as yet been subjected to clinical trials. Attempts to produce imidazole inhibitors of steroidogenesis are less advanced, although one compound (CGS 16949A) has been reported to be a more selective and potent aromatase inhibitor than aminoglutethimide. Selective and effective compounds could be of great value in the treatment of hormone-sensitive carcinoma.

Adrenal Gland Neoplasms↗
PubMed1988

In-vivo effects of itraconazole on hepatic mixed-function oxidase.

The effects of itraconazole, a triazole antifungal agent, on cytochrome P450 were investigated by measuring the anti-convulsant activity of phenytoin in mice, and zoxazolamine paralysis time, tolbutamide clearance, and plasma dicoumarol concentrations after a single injection of dicoumarol, in rats. Itraconazole, given either as a single dose of 5 or 10 mg/kg, or daily at these levels for five days, had no significant effect on any of the measures. The drug therefore appears to be free of enzyme inhibiting or inducing activity, although an effect on other cytochrome P450 isozymes can not be discounted. Thus itraconazole may possibly show fewer clinically significant drug interactions at the level of hepatic mixed function oxidase than other azole antifungal agents.

Animals↗
PubMed1988

The circulating growth hormone (GH)-binding protein complex: a major constituent of plasma GH in man.

The recent discovery of a specific binding protein for human GH (hGH) in human plasma suggests that hGH circulates in part as a complex in association with the binding protein(s). However, the magnitude of the complexed fraction prevailing under physiological conditions is unknown because of 1) dissociation of the complex during analysis and 2) potential differences in the binding characteristics of radiolabeled and native hGH. We conducted experiments designed to minimize dissociation during analysis (gel filtration in prelabeled columns, frontal analysis, and batch molecular sieving) with both native and radioiodinated hGH. All three methods yielded similar estimates for the complexed fraction. In normal plasma the bound fraction for 22 K hGH averaged 50.1% (range, 39-59%), that for 20 K hGH averaged 28.5% (range, 26-31%). Above a hGH level of about 20 ng/ml the bound fraction declines in concentration-dependent manner due to saturation of the binding protein. We conclude that a substantial part of circulating hGH is complexed with carrier proteins. This concept has important implications for the metabolism, distribution, and biological activity of hGH.

Carrier Proteins↗
PubMed1988

A rapid and simple assay for growth hormone-binding protein activity in human plasma.

The newly discovered circulating growth hormone binding proteins dictate a re-evaluation of the state of GH in plasma in health and disease as the binding proteins are known to affect GH metabolism and action. We describe a rapid and simple GH-binding assay that allows determination of free and complexed plasma GH, as well as GH-binding protein activity as an index of GH-binding protein levels, with relative ease. The method is based on incubation of plasma with 125I-GH and separation of bound from free GH on small DEAE-cellulose columns; it can be used on a large scale for routine determinations. The results obtained by this method are comparable to those obtained with the previously used slow and more cumbersome gel filtration technique. Initial data obtained in normal subjects and certain disease states show that the bound fraction of plasma GH is similar in men, women and children, is unaffected by pregnancy or acute infection, but is marginally decreased in liver cirrhosis. In acromegaly, binding protein activity also appears normal when allowance is made for partial saturation of the binding proteins by the high prevailing GH levels. The technique we describe should facilitate investigations of normal and abnormal regulation of the GH binding proteins.

Adolescent↗
PubMed1987

Phototoxic effects of fluoranthene, a polycyclic aromatic hydrocarbon, on bacterial species.

Fluoranthene, a non-carcinogenic polycyclic aromatic hydrocarbon, inactivates Escherichia coli cells in the presence of near-ultraviolet light (NUV; 300-400 nm). E coli cells carrying defects in the uvrA6 or katF genes are sensitized to inactivation by the simultaneous treatment with fluoranthene and NUV, suggesting that DNA is a target and that hydrogen peroxide is generated. Haemophilus influenzae transforming DNA can be inactivated by the simultaneous treatment with fluoranthene and NUV confirming DNA as a target. Using the photooxidation of imidazole and histidine as probes, fluoranthene was found to generate singlet oxygen in organic and aqueous media. In water, it participated in electron transfer reactions, reducing nitro blue tetrazolium as well as ferricytochrome C. This reduction took place both in the presence of air, where superoxide anion was formed, and under argon. Simultaneous treatment with fluoranthene and NUV was incapable of inducing histidine-independent mutations. Simultaneous treatment with fluoranthene and NUV was incapable of inducing the uvrA gene product as evidenced by the absence of the induction of beta-galactosidase in an E coli operon fusion strain [uvrA215::Mud(Ap,lac)].

DNA Damage↗
PubMed1987

Plasma binding of oestradiol in progesterone-treated rats.

Progesterone treatment of female rats causes an increase in body weight possibly via suppression of oestradiol secretion. This study was carried out to investigate the effect of progesterone on the non-protein bound and hence presumably biologically active fraction of oestradiol. Oestradiol binding to plasma proteins was studied in female Wistar rats during the oestrous cycle and after 12 days of treatment with progesterone (5 mg/day). There was no change in either the unbound fraction of oestradiol or plasma albumin concentrations during the oestrous cycle. Plasma oestradiol concentrations in progesterone-treated rats were similar to those seen during dioestrus, as were the degree of oestrogen binding and the plasma albumin concentrations. Although it was not feasible to calculate unbound concentrations, these results suggest that the increased body weight seen in progesterone-treated rats, and also during pregnancy, may be a result of suppression of unbound oestradiol concentrations to levels similar to those occurring during dioestrus.

Animals↗
PubMed1987

Absence of the plasma growth hormone-binding protein in Laron-type dwarfism.

We recently described a specific, high affinity binding protein (BP) for growth hormone (GH) in normal human plasma. Little is known about the source, regulation and biological role of this BP. Because its specificity is similar to that of the GH receptor, we considered the possibility that it represented a circulating receptor subunit or fragment. Laron-type dwarfism is a rare disorder characterized by severe growth failure, resistance to GH, and GH receptor deficiency. To probe the relationship between the receptor and the circulating binding protein, we measured the binding of GH to plasma from a child with Laron-type dwarfism and compared it with that in plasma of normal children and adults. Normal plasma samples were supplemented with unlabeled GH to the endogenous GH level in the plasma of the Laron patient to yield comparable saturation of the BP. After incubation of plasma with radiolabeled GH, bound GH was separated from free GH by gel filtration on Sephadex G-100. There was no detectable binding (less than 1.5%) of GH in the plasma of the Laron-type dwarf, whereas in normal children the bound GH fraction averaged 24.0 +/- 6.1% (mean +/- SD). Thus, the GH-BP is either absent or functionally abnormal in Laron-type dwarfism. This finding suggests that the circulating GH-BP is related to and/or may be derived from the GH receptor. Alternatively, it is possible that the BP plays an as yet poorly understood pivotal role in the promotion of somatic growth.

Carrier Proteins↗
PubMed1986

A family demonstrating inheritance of the Leach phenotype: a Gerbich-negative phenotype associated with elliptocytosis.

The proposita of a Canadian family and 2 of her sibs have the rare Leach phenotype and provide the first evidence that the Leach phenotype is an inherited condition. Their red cells are Ge: -2, -3 and fail to react, by the antiglobulin test, with the monoclonal antibodies GERO, BRIC 4 and BRIC 10. The minor sialoglycoproteins beta, beta 1 and gamma are apparently absent from their red cell membranes. A proportion of their red cells are elliptocytes indicating that beta and/or beta 1 and/or gamma have a function in maintaining normal red cell shape.

Antibodies, Monoclonal↗
PubMed1985

Abnormal minor human erythrocyte membrane sialoglycoprotein (beta) in association with the rare blood-group antigen Webb (Wb).

Individuals whose erythrocytes are positive for the rare blood-group antigen Webb (Wb) have an altered form of the minor sialoglycoprotein beta (synonyms glycophorin C and glycoconnectin). This altered sialoglycoprotein beta (beta Wb) has an Mr about 2700 lower than that of normal sialoglycoprotein beta. Treatment of normal sialoglycoprotein beta with endo-beta-N-acetylglucosaminidase F decreased its Mr by about 3600, but similar treatment of sialoglycoprotein beta Wb had no effect. These results suggest the possibility that sialoglycoprotein beta Wb lacks the N-glycosidically linked oligosaccharide found on normal sialoglycoprotein beta.

Blood Group Antigens↗
PubMed1985

The expression of human glycerol-3-phosphate dehydrogenase in human/rodent somatic-cell hybrids.

Our previous studies using rodent/human somatic-cell hybrids suggested that the expression of human mitochondrial glycerol-3-phosphate dehydrogenase (GPDM) is dependent on the presence of human mitochondria. This has now been tested directly by analysis of GPDM activity in a series of nine hybrid-cell lines, four segregating human chromosomes and five losing rodent chromosomes (reverse segregants). The chromosome composition of the hybrids was deduced from analysis of biochemical markers and examination of G- and G11-banded metaphase spreads and the mitochondrial content was determined by Southern blot analysis, using cloned mouse and human mtDNA sequences as probes. We found that the mtDNA species present in these hybrids correlated exactly with the pattern of chromosome segregation such that the conventional hybrids contained rodent mtDNA and the reverse segregants human mtDNA. However, the pattern of GPDM expression was not directly correlated with the species of chromosomes or mitochondria present: all the hybrids showed strong rodent GPDM activity and two from each class of hybrid also showed human GPDM activity but the other hybrids were negative for human GPDM. We conclude that rodent GPDM readily integrates into human mitochondria, that the expression of rodent GPDM is not dependent on the presence of rodent mitochondria, and that GPDM is not coded by mtDNA. Human GPDM either is not capable of being inserted into the rodent mitochondrial membrane or is regulated in some way in the hybrid cells by an unidentified rodent factor.

Animals↗
PubMed1985

A non-chromatographic radioimmunoassay for 3-oxo desogestrel.

A non-chromatographic radioimmunoassay for 3-oxo desogestrel (13 beta-ethyl-17-hydroxy-11-methylene-18,19-dinor-pregn-4-en-20-yn-3- one), the biologically-active metabolite of desogestrel (13 beta-ethyl-11-methylene-18,19-dinor-pregn-4-en-20-yn-17-ol), has been developed to facilitate studies of the pharmacokinetics of this steroid. The method uses an antiserum raised against levonorgestrel (13 beta-ethyl-17-hydroxy-18,19-dinor-pregn-4-en-20-yn-3-one). None of the steroids tested which showed significant cross-reactions are believed to be present in plasma after ingestion of desogestrel; furthermore, dilutions of standards and unknowns gave parallel responses in the assay. Intra- and inter-assay coefficients of variation were 12.9 and 11.8% respectively. The sensitivity of the assay was approx 0.02 ng/ml. The peak concentrations of 3-oxo desogestrel after a 150 micrograms dose of desogestrel in three subjects were between 0.48-0.71 ng/ml, and in two subjects 3-oxo desogestrel was still detectable 24 h after dosing.

Adult↗
PubMed1985

Expression of Xg and the 12E7 antigen in primates.

Tests on cells from various non-human primates showed that expression of the 12E7 antigen is the same on cultured fibroblasts, peripheral blood lymphocytes and red blood cells. No quantitative polymorphism of 12E7 expression was observed in any of the animals tested. Tests on red blood cells of these primates confirm that anti-Xga and the monoclonal antibody 12E7 define different determinants.

Animals↗