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Biomedical subjects

M Ayub

Publications and source records attributed to M Ayub.

15 recordsLinked to original sources
PubMed1992

TGF-beta stimulation of endometrial and breast-cancer cell growth.

Growth of the human endometrial carcinoma Ishikawa cell line was stimulated by transforming growth factor-beta1 when cultured in serum-containing and chemically defined culture medium. This response was not unique to endometrial carcinoma cells, as the breast-cancer cell line, T47-D, was similarly stimulated by TGF-beta 1. TGF-beta 1 stimulated growth of MCF-7 breast-cancer cells in chemically defined medium but inhibited growth of this cell line in serum-containing medium. The data provide a demonstration of a positive growth response to TGF-beta 1 in oestrogen-receptor-positive cells and do not support the hypothesis that this growth factor is simply a negative growth regulator in epithelial-cancer cell lines.

Adenocarcinoma↗
PubMed1991

An investigation of 'functional' somatic symptoms among patients attending hospital medical clinics in Pakistan--I. Characteristics of 'non-organic' patients.

Six hundred medical clinic attenders at the Mayo Hospital, Lahore, Pakistan, were screened using the Bradford Somatic Inventory (BSI) in Urdu. The physicians' clinical diagnosis was recorded. The characteristics of mood-disordered, functional and no-diagnosis groups were compared with patients receiving organic diagnoses. Of the non-organic patients, only the mood-disordered group reported significantly more BSI symptoms than the organic group. The functional group did not have especially high scores. All groups reported a greater mean number of BSI symptoms than a student comparison group. Among the non-organic patients, there was no relationship between the number of BSI symptoms reported and sex, age, education or occupational group.

Adult↗
PubMed1991

An investigation of 'functional' somatic symptoms among patients attending hospital medical clinics in Pakistan--II. Using somatic symptoms to identify patients with psychiatric disorders.

Among 600 medical clinic attenders in Lahore, Pakistan, screened using the Bradford Somatic Inventory in Urdu, significant differences in symptom endorsement between 'organic' and 'mood-disordered' patients were found in 14 BSI items. Counting only those symptoms reported as present on more than 15 days during the previous month, significant differences in symptom endorsement were found in 21 BSI items. Another 60 patients attending the same clinics were recruited to evaluate the BSI as a screening questionnaire for mood disorders. Each patient was interviewed by a psychiatrist and a diagnosis made according to DSM III-R and ICD-9. Optimal cutting points for the 14-item, 21-item and 44-item BSI were determined by Relative Operating Characteristic (ROC) analysis. The areas under the fitted ROC curves (an index of discriminating efficiency) were similar for the three versions. Using a cut-off score of 13/14, the BSI-21 identified DSM III-R psychiatric disorders with an estimated sensitivity of 75% and specificity of 75%. Assuming a 30% prevalence in medical clinics, a positive value of around 60% can be expected when screening for psychiatric disorders.

Adult↗
PubMed1990

The inhibition of human prostatic aromatase activity by imidazole drugs including ketoconazole and 4-hydroxyandrostenedione.

Ketoconazole, an orally active imidazole drug and bifonazole, clotrimazole, econazole, isoconazole, miconazole and tioconazole are known as inhibitors of cytochrome P450 dependent steroidogenic enzymes including human placental aromatase. The aim of the present study was to investigate the effectiveness of these imidazole drugs to inhibit human prostatic aromatase activity compared with the known inhibitor of aromatase 4-hydroxyandrostenedione (4-OHA). The imidazole drugs and 4-OHA inhibited prostatic aromatase activity in a dose-dependent manner. The order of decreasing inhibitory potency determined from IC50 values (mumol/L) was: 4-OHA (1.57) greater than bifonazole (1.6) greater than tioconazole (1.69) greater than clotrimazole (1.73) greater than econazole (1.87) greater than miconazole (2.0) greater than isoconazole (2.2) greater than ketoconazole (4.7). The IC50 values for the inhibition of prostatic homogenate aromatase activity are 3-9-fold higher than that for the inhibition of human placental aromatase activity, previously reported, except that of ketoconazole which was 1.5-fold lower than that for the inhibition of placental microsomal aromatase.

Androstenedione↗
PubMed1990

Fatty acid control of growth of human cervical and endometrial cancer cells.

Stearic acid and iodo-stearic and inhibited cell growth in a cervical cancer cell line (HOG-1) in a dose-related manner, with a half maximal effect at 50 microM stearic acid. Addition of oleic acid abrogated the effect of stearic acid. EGF-stimulated DNA synthesis and growth of HOG-1 cells was inhibited in the presence of stearic acid without any apparent effect on EGF receptor number or affinity.

Cell Division↗
PubMed1990

Suppression of plasma androgens by the antiandrogen flutamide in prostatic cancer patients treated with Zoladex, a GnRH analogue.

Chronic treatment with the GnRH (gonadotrophin hormone releasing hormone) agonist Zoladex causes suppression of testicular androgens. Use of antiandrogens has been advocated to block the effects of the initial surge of androgens, and to block any presumed effects of adrenal androgens. We have measured plasma concentrations of androgens and possible precursors before and during treatment in the following prostate cancer patients: 10 who received Zoladex alone (Z), nine who received Zoladex + the anti-androgen flutamide (Z + F) and five who were orchidectomized (O). Testosterone fell in the Z + F group to 0.84 +/- 0.21 nmol/l (mean +/- SD) significantly lower (Wilcoxon P less than 0.05) than after Z (1.58 +/- 1.84 nmol/l) alone. Progesterone and 17 alpha-hydryxyprogesterone did not change significantly in any group. Androstenedione and dehydroepiandrosterone sulphate (DHAS) showed significant falls in Z + F (from 3.44 +/- 0.34 to 1.92 +/- 0.18 mumol/l and from 3.88 +/- 0.64 to 1.92 +/- 0.36 mumol/l respectively) but not in other groups. These results are consistent with our demonstration of an inhibitory effect of flutamide, hydroxyflutamide and other antiandrogens on human adrenal microsomal 17 alpha-hydroxylase and 17,20-lyase activities in vitro.

17-alpha-Hydroxyprogesterone↗
PubMed1990

Absence of specific cell-surface binding of tissue plasminogen activator in uterine cells.

Tissue plasminogen activator (tPA), an arginine-specific serine protease, is an oestrogen-regulated protein in uterine and breast cancer tissue. It contains a domain which shares homology with epidermal growth factor (EGF). The aim of the present study was to determine whether specific tPA receptors or EGF receptors mediate the binding of tPA to cells and whether tPA possesses intrinsic mitogenic activity. The binding of 125I-labelled tPA to rat uterine and liver membranes was shown to be non-specific and could not be displaced by unlabelled tPA or EGF. Furthermore, acid washing of cell membranes did not unmask specific tPA-binding sites. In contrast, 125I-labelled EGF binding to both rat uterine and liver membranes was displaced in a dose-dependent manner by unlabelled EGF, and Scatchard analysis of the binding data revealed dissociation constant (Kd) values of 2.4 and 0.71 nM respectively. Unlabelled tPA (up to 20,000-fold excess) did not displace 125I-labelled EGF binding to these membranes. A study of the binding of 125I-labelled tPA and 125I-labelled EGF to endometrial carcinoma cells (Ishikawa), cervical carcinoma cells (HOG-1) and vulval carcinoma cells (A431) showed that up to a 100-fold excess of EGF or a 1000-fold excess of tPA did not displace 125I-labelled tPA binding to these cells. In contrast, 125I-labelled EGF binding was displaced by unlabelled EGF (Kd values for Ishikawa and HOG-1 cells were 2.72 and 1.92 nM respectively) but not by unlabelled tPA (1000-fold excess).(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed1989

The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins.

Ketoconazole an orally active imidazole drug and bifonazole, clotrimazole, econazole, isoconazole, miconazole and tioconazole are known inhibitors of cytochrome P-450 dependent steroidogenic enzymes. The aim of the present study was to determine whether these imidazole drugs also have an effect on [3H]R1881 binding to the human prostatic androgen receptor, [3H]5 alpha-dihydrotestosterone (5 alpha-DHT) binding to plasma sex hormone binding globulin (SHBG) and [3H]cortisol binding to plasma corticosteroid binding globulin (CBG). In comparison the effect of both steroidal (cyproterone acetate; CPA) and non-steroidal (anandron, flutamide, hydroxyflutamide, ICI 176344) antiandrogens on these steroid binding proteins was also determined. The results of the present study show that the imidazole drugs were without effect on [3H]R1881 binding to the androgen receptor and on [3H]cortisol binding to CBG up to 100 mumol/l. However, they were weak competitors of [3H]5 alpha-DHT binding to SHBG inhibiting 20-53% of binding at 100 mumol/l. In comparison the antiandrogens were strong competitors of [3H]R1881 binding to the androgen receptor, the order of decreasing potency, determined from ID50 (mumol/l) values were CPA (0.073) greater than ICI 176344 (0.4) greater than anandron (0.63) greater than hydroxyflutamide (1) greater than flutamide (greater than 100). The non-steroidal antiandrogens were without effect on [3H]cortisol binding to CBG whereas CPA caused 36% inhibition of binding at 100 mumol/l. Of the antiandrogens studied CPA was the strongest competitor of [3H]5 alpha-DHT binding to SHBG with an ID50 of 23 mumol/l, in contrast the non-steroidal antiandrogens were weak competitors causing less than 40% inhibition at 100 mumol/l. It is concluded that the primary mode of action of the imidazole drugs is through the inhibition of cytochrome P-450 dependent steroidogenic enzymes with little or no effect on steroid binding proteins. In comparison, the antiandrogens were strong competitors of [3H] binding to the androgen receptor but relatively weaker competitors of [3H] steroids binding to plasma binding proteins.

Androgen Antagonists↗
PubMed1989

Inhibition of human adrenal steroidogenic enzymes in vitro by imidazole drugs including ketoconazole.

The effect of several imidazole containing drugs including keto on human adrenal 17 alpha-hydroxylase, 17,20-lyase, 21-hydroxylase, 11 beta-hydroxylase and 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) activities was studied in vitro. The order of decreasing inhibitory potency as determined from ID50 values for both 17 alpha-hydroxylase (ID50 values ranged from 1.13-4.17 mumol/l) and 17,20-lyase (0.57-1.95 mumol/l) activities was: bifon greater than clot greater than keto greater than micon greater than econ greater than isocon greater than tiocon. Using [3H]progesterone (5.50-12.25 mumol/l) as the substrate for the 21-hydroxylase activity the order of decreasing inhibitory potency was: clot greater than bifon greater than isocon greater than micon greater than tiocon greater than econ greater than tiocon greater than keto. For the 11 beta-hydroxylation of [3H]deoxycortisol (1.48-2.34 mumol/l) the order of decreasing inhibitory potency was keto greater than bifon greater than clot greater than micon greater than econ greater than isocon greater than tiocon. The cytochrome P-450 dependent enzyme most sensitive to inhibition was 17,20-lyase and the least sensitive was 21-hydroxylase whereas the imidazole drugs were without effect on the cytochrome P-450 independent 3 beta-HSD-I activity. In agreement with previous results a common structural feature of the imidazole drugs having an inhibitory effect was the presence of aromatic rings on the N-1 substituent of the imidazole ring.

3-Hydroxysteroid Dehydrogenases↗
PubMed1987

Inhibition of testicular 17 alpha-hydroxylase and 17,20-lyase but not 3 beta-hydroxysteroid dehydrogenase-isomerase or 17 beta-hydroxysteroid oxidoreductase by ketoconazole and other imidazole drugs.

Ketoconazole, an orally active antifungal drug, is known to inhibit testicular androgen production both in vitro and in vivo. The aim of the present study was to examine the effect of ketoconazole and 13 other imidazole drugs on rat testicular microsomal 17 alpha-hydroxylase, 17,20-lyase, 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR). The order of decreasing inhibitory effect (determined from Ki values) on 17 alpha-hydroxylase (substrate [3H]progesterone; Km = 89 +/- 0.65 nmol/l; SEM, n = 8) was bifonazole (Ki = 86 +/- 3.3 nmol/l; SEM, n = 4) greater than ketoconazole (160 +/- 4.92) greater than clotrimazole (170 +/- 5.81) greater than miconazole (599 +/- 7.22) greater than econazole (688 +/- 6.98) greater than tioconazole (901 +/- 1.71) greater than isoconazole (1090 +/- 6.96) and on 17,20-lyase (substrate, [3H]17 alpha-hydroxyprogesterone; Km = 250 +/- 0.75 nmol/l; SEM, n = 8) was bifonazole (56.5 +/- 3.4) greater than clotrimazole (81.5 +/- 3.1) greater than ketoconazole (84 +/- 3.5) greater than miconazole (243 +/- 6.3) greater than econazole (325 +/- 5.1) greater than tioconazole (505 +/- 5.2) greater than isoconazole (610 +/- 6.34). However, these imidazole drugs did not inhibit the 3 beta-HSD-I or 17 beta-HSOR activities. A common structural feature of the imidazole drugs having an inhibitory effect was the presence of one or more aromatic rings on the imidazole side chain. In contrast, the imidazole drugs having the imidazole ring fused to a benezene ring, i.e. benzimidazoles (astemizole, mebendazole, thiabendazole) and those having an aliphatic side chain on the N-1 of the imidazole ring (carbimazole, metronidazole, nimorazole, tinidazole) did not inhibit 17 alpha-hydroxylase, 3 beta-HSD-I or 17 beta-HSOR enzyme activities. However some did inhibit 17,20-lyase activity but only at high concentrations. The results of the present study suggest that some imidazole drugs may be useful in clinical situations requiring the suppression of androgen production, for example in the treatment of hormone-dependent prostatic cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1979

Evidence for a thyrotropin inhibitory effect of histamine in man.

Because of certain side effects of cimetidine therapy which may be hormonally mediated (e.g. gynecomastia), there has been recent interest in the possible endocrine effects of this H2 histamine receptor-blocking agent used in the treatment of peptic ulcer disease. Accordingly, the effect of chronic cimetidine therapy on anterior pituitary function was examined in 12 adult men with mild peptic ulcer disease. TRH and insulin-hypolycemic stimulation tests were performed by standard methods. Serum for TSH and PRL RIA was obtained after TRH; serum for GH, cortisol, and PRL RIA was obtained after insulin-induced hypoglycemia. In addition, serum for LH, FSH, testosterone, and PRL was obtained every 4 h for 24 h. After these baseline studies, 300 mg cimetidine were administered orally 4 times a day for 4--8 weeks and the studies were repeated as before. Chronic treatment with cimetidine caused a significant increase in the peak TSH response to TRH at 30 min (mean peak TSH value before cimetidine, 7.0 microU/ml; after cimetidine, 10.2 microU/ml; P less than 0.05) as well as a significant increase in the TSH area under the curve. There was no statistically significant effect of cimetidine on basal TSH or basal or stimulated PRL secretion. Cimetidine had no effect on the GH, PRL, or cortisol response to insulin-induced hypolycemia or the 24-h secretion of LH, FSH, testosterone, or PRL.

Adult↗
PubMedDate not supplied

Diet therapy in severe clinical expression of debrancher deficiency.

An eleven year old boy was referred because of sudden loss of consciousness, muscular weakness, poor general health, severe hypoglycemia with seizures and hepatomegaly. Response to oral glucose and galactose increased blood lactic acid and glucose at different times. Fasting values of blood lactic was normal, but glucose was found at 33 mg/dl. Similar test made up two hours after feeding revealed hyperlactatemia (35-50 mg/dL) and hyperglycemia (129 mg/dL). Glucagon did not result in a rise of glucose at fasting or feeding. Hepatic glycogen content was found 15 gm/100 mg of tissue. The enzyme activities revealed a deficiency of the liver debranching enzyme while leukocytes had normal enzyme activity. Hepatic biopsy showed liver fibrosis. The present case had the clinical characteristics of severe form of glycogen storage disease. A low carbohydrate and high protein diet was indicated in order to increase the gluconeogenic precursors. Although debranching enzyme deficiency is almost always benign a high carbohydrate diet induced a more severe expression of the disease.

Child↗