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Biomedical subjects

A W Meikle

Publications and source records attributed to A W Meikle.

At least 19 recordsLinked to original sources
PubMed1992

The presence of a dehydroepiandrosterone-specific receptor binding complex in murine T cells.

We have investigated the ability of dehydroepiandrosterone (DHEA) to alter the production of interleukin-2 (IL-2) and to bind to a specific binding complex in antiCD3 epsilon activated T cells. Binding activity correlated with the presence of a specific DHEA binding complex in the cytosol and nuclei of DHEA-responsive T-cell hybridomas, as well as in CD4+ and CD8+ cells isolated from peripheral lymph nodes of normal mice. Scatchard analysis determined that intact lymphocytes and cytosolic fractions contained high affinity binding for [3H]DHEA (approx. 2.6 nM) with 1000-7000 binding sites existing per cell. Five of the T-cell hybridomas tested both responded to DHEA treatment with increased production of IL-2 and also contained specific high affinity [3H]DHEA binding. Four additional T-cell hybridomas were found to contain no specific [3H]DHEA binding and were also unresponsive to DHEA influences on IL-2 production. Sucrose density gradients demonstrated a 3-4s [3H]DHEA binding complex in high salt and a 7-8s binding complex in low salt. Specific binding was inhibited by preincubation of the cytosol fractions with either trypsin or chymotrypsin, or by heating to 60 degrees C for 1 h (less than 15% of control). [3H]DHEA binding was unaffected by preincubation of the cytosol fractions with ribonuclease, deoxyribonuclease, or phospholipase A. The DHEA-protein complexes bound to DNA-cellulose with the amount of binding being slightly increased by preincubation at 25 degrees C as compared to 4 degrees C. As expected, [3H]DHEA binding was inhibited by the addition of unlabeled DHEA, but was also modestly inhibited by dihydrotestosterone and cortisol. Binding of DHEA was unaffected by progesterone, dexamethasone, estradiol, androsterone, DHEAS, and beta-etiocholanolone at all concentrations tested. DHEA was incapable of inhibiting the binding of [3H]DHT to the androgen receptor or [3H]dexamethasone to the glucocorticoid receptor. Collectively, these findings suggest that murine T cells contain a specific DHEA receptor. We believe that DHEA is a steroid hormone that is directly involved in the regulation of IL-2 production by both normal and some T-cell hybridomas.

Animals↗
PubMed1992

A screening study of prostate cancer in high risk families.

In a study of the familial risk of prostate cancer 17 sets of 2 brothers with prostate cancer were identified. A total of 34 first-degree relatives of these probands (sons and brothers, 55 to 80 years old) underwent an intensive screening examination that included prostate specific antigen, digital rectal examination, transrectal ultrasound and systematic as well as clinically directed core needle biopsies. Previously unsuspected and clinically relevant cancers were found in 8 men (24%), compared to the approximately 1 expected (p less than 0.01). Of these cancers 2 were detected by the systematic biopsies. This study emphasizes the importance of thorough screening in first-degree relatives of prostate cancer patients.

Aged↗
PubMed1992

B-endorphin response to a low dosage of human corticotropin releasing hormone during metyrapone administration in depression.

This study defines the pituitary B-endorphin (BE) secretory response to a low dosage (0.3 ug/kg) of human corticotropin releasing hormone (CRH) in depressed patients and normal controls pretreated with metyrapone. We find no difference in the B-endorphin response to CRH in depressed subjects without evidence of HPA overactivity, compared with controls. This finding is contrasted with other data demonstrating a blunted B-endorphin response to CRH in depressives. The influence of metyrapone pretreatment on the pituitary B-endorphin response to CRH through a mechanism that minimizes the impact of cortisol negative feedback is discussed. Future studies which include low dose CRH infusion both in the presence and in the absence of metyrapone pretreatment will help investigate alterations in the regulation of pituitary B-endorphin secretion in depression including the possibility of increased pituitary sensitivity to the negative fast feedback of cortisol.

Adrenal Glands↗
PubMed1979

Alterations of glucocorticoid actions by other drugs and disease states.

Glucocorticoids are used in physiological and pharmacological amounts in the management of a variety of clinical conditions. Concomitant utilisation of other drugs or the presence of some diseases may affect the physiological action of the steroid in the tissues. Phenytoin, phenobarbitone, ephedrine and rifampicin accelerate the metabolism of glucocorticoids thereby decreasing their biological activity. A similar phenomenon occurs in patients with hyperthyroidism. In contrast, glucocorticoid action is enhanced in hypothyroid patients and in those with hepatic damage as the result of a defect in the clearance of the hormone from blood. In turn, glucocorticoids antagonise the effects of cholinesterase inhibitors and ganglion blocking agents. The above mentioned effects should be kept in mind whenever glucocorticoids are utilised in the diagnosis and management of endocrine or non-endocrine conditions.

Anticonvulsants↗
PubMed1978

"Normal suppression" to dexamethasone in Cushing's disease: an expression of decreased metabolic clearance for dexamethasone.

The adrenal cortical function of a patient with pituitary-dependent Cushing's syndrome exhibited normal responsiveness to conventional doses of dexamethasone (Dex) over several years of evaluation. "Periodic hormonogenesis" did not seem to explain the phenomenon. Plasma concentrations of Dex were measured to ascertain whether an abnormality in Dex metabolism might explain the apparent discrepancy in Dex responsiveness. Plasma levels of Dex after oral administration of the steroid were higher than normal, suggesting that decreased clearance of Dex accounts for the phenomenon of "normal suppression" in this patient with Cushing's syndrome.

Adrenocorticotropic Hormone↗
PubMed1978

Subnormal tissue 3 alpha-androstanediol and androsterone in prostatic hyperplasia.

We investigated the role of 3 alpha-androstanediol (3 alpha-diol) in the development of benign prostatic hyperplasia (BPH) and the apparent equilibrium of enzymes which metabolize it in normal and hyperplastic prostatic tissue of humans. We determined the endogenous concentrations of 3 alpha-diol, androsterone, its 3 alpha-17-keto metabolite or precursor, and 5 alpha-dihydrotestosterone (DHT), its 3-keto,17 beta-hydroxy product of precursor, by RIA after extraction and paper chromatography of the androgens from normal and hyperplastic prostate glands. The mean concentrations of 3 alpha-diol and androsterone were about one-third of normal in BPH. The mean ratio of the concentration of DHT to 3 alpha-diol was significantly higher (P less than 0.005) than normal in BPH, whereas no statistical difference was observed for the mean ratio of the tissue levels of 3 alpha-diol to androsterone in the two groups. Our data do not support the postulate that 3 alpha-diol is causally related to the development of BPH. However, they indicate that the apparent equilibrium of the 3 alpha-hydroxysteroid oxidoreductase favors the formation of the 3-keto-oxidized product, DHT, which may have relevance to the occurrence of the renewed growth of the prostate of aging men.

Androgens↗
PubMed1977

Effectiveness of prednisolone during phenytoin therapy.

The effects of diphenylhydantoin (DPH) on the clearance of prednisolone from plasma, its bioavailability, and its biologic effectiveness were studied in 5 persons before and after daily DPH therapy for more than 3 wek. DPH decreased the mean half-time of disappearance of prednisolone from plasma by 45% and increased its metabolic clearance rate by an average of 77%. The gastrointestinal absorption of prednisolone and its first-pass clearance through splanchnic tissues were not significantly altered by DPH. The mean oral midnight dose of prednisolone required to suppress the 8 A.M. plasma level of cortisol to 5 microgram/dl was doubled following treatment of DPH. The increment in dose of prednisolone varied from 58% to 260% in the five individuals.

Adult↗
PubMed1977

Assessment of 11beta-hydroxylase activity with plasma corticosterone, deoxycorticosterone, cortisol, and deoxycortisol: role of ACTH and angiotensin.

UNLABELLED: In this study we evaluated the role of ACTH and angiotensin on regulation of activities of 11beta-hydroxylases of the adrenal cortex. The ratio of the plasma concentrations of 11 deoxycorticosterone (DOC) to plasma corticosterone (B) reflected the activity of the enzyme of the B and/or aldosterone pathways, and the ratio of plasma 11-deoxycortisol (S) to plasma cortisol (F) as the activity of the enzyme in the F pathway. In normal subjects, both ratios were significantly lower at 0800-0900 h (Doc to B, .01+/-.004, mean+/-SE, n=10; and S to F, .01+/-.003) than at 2000 h (DOC to B, .028+/-.024 and S to F, .015+/-.005). The plasma levels of DOC, B, S and F were all significantly lower at 2000-2100 h than at 0800-0900 h. In contrast 9 patients with Cushing's syndrome exhibited no diurnal change in the ratios. The ratios increased substantially following dexamethasone or metyrapone administration. A high or low salt diet and an angiotensin infusion produced no significant effect on the ratios. The plasma concentration of all four steroids was increased by more than 50% by an infusion of angiotensin. Four hours after administration of 80 mg of Lasix at 0800 h to 10 normal subjects, the ratios of DOC to B and S to F increased significantly (P less than .02), an effect possibly related to a decreased secretion of ACTH. CONCLUSIONS: 1) 11beta-hydroxylase activity of the B and/or aldosterone and F pathways appears to change in parallel with ACTH secretion, and 2) although angiotensin stimulates steroidogenesis of the pathways, it has no apparent effect on 11beta-hydroxylase activity.

17-Hydroxycorticosteroids↗
PubMed1976

Gluconeogenic response to mannoheptulose in the rat.

Since administration of mannoheptulose induces temporary hyperglycemia, the present study was conducted to elucidate this phenomenon. The results indicate that mannoheptulose stimulates the activity of hepatic fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase, and enhances incorporation of alanine into blood glucose and hepatic glycogen. In addition, mannoheptulose increases plasma levels of glucagon and hepatic cyclic AMP concentration. Gluconeogenic effects of mannoheptulose appear to be mediated by glucagon.

Alanine↗
PubMed1976

Percutaneous absorption of dexamethasone estimated by a plasma radioimmunoassay.

Precutaneous absorption of dexamethasone and its effect on the pituitary adrenal axis were measured in vivo in normal human subjects after application to skin. Specific plasma dexamethasone and cortisol radioimmunoassays were used. Following application of 1% dexamethasone on 500 cm2 of normal skin, the plasma dexamethasone concentration was maximal at 2 hr, and the average absorption was 0.25% over 8 hr; significant cortisol suppression occurred at 2, 4, and 8 hr. This technique: (1) provides an accurate assessment of the in vivo absorption of dexamethasone applied to human skin, (2) avoids exposure of the subjects to radioactive steroids, (3)permits estimation of the quantity of unmetabolized steroids absorbed, and (4) serves as a possible model for the development of similar assays for other topical steroids.

Adult↗
PubMed1975

Single dose metyrapone test: 11 beta-hydroxylase inhibition by metyrapone and reduced metyrapone assayed by radioimmunoassay.

To assess the effects of metyrapone and reduced metyrapone on 11 beta-hydroxylase inhibition, the plasma levels of cortisol, 11-deoxycortisol, and the inhibitors were measured by radioimmunoassays in 34 normal subjects 8 h after they received a single oral dose of metyrapone at midnight. The ratio of 11-deoxycortisol to cortisol, as an index of 11 beta-hydroxylase inhibition, was compared to plasma levels of metyrapone and reduced metyrapone. One subject received an infusion of metyrapone ditartrate in order to study the sequential conversion of metyrapone to reduced metyrapone. A new radioimmunoassay was developed for measurement of plasma concentrations of metyrapone and reduced metyrapone. Following intravenous administration of metyrapone, it is rapidly converted to an active metabolite, reduced metyrapone. At 8 h after a dose was given, the average reduced metyrapone level was 1.5 times higher than the average metyrapone level. Following oral administration of the drug, we found a high correlation when plasma levels of metyrapone were compared to reduced metyrapone and when the ratio of 11-deoxycortisol to cortisol was related to metyrapone or to total metyrapone levels. In conclusion, the conversion of metyrapone to reduced metyrapone is such that by 8 hours after a single oral dose, more than one-half of the inhibitory effect on 11 beta-hydroxylase appears to be produced by reduced metyrapone. The inhibitory action of metyrapone and reduced metyrapone on the enzyme system is reflected by their concentration in plasma.

Humans↗