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Biomedical subjects

A Doble

Publications and source records attributed to A Doble.

At least 91 records · Page 5Linked to original sources
PubMed1988

Degradation of atrial natriuretic peptides by an enzyme in rat kidney resembling neutral endopeptidase 24.11.

The inactivation of rat atrial natriuretic factor (ANF) was studied using a bioassay, ANF-stimulated guanylate cyclase activity. Rat kidney membranes degraded ANF into biologically inactive forms. The primary cleavage site appears to be the Cys105-Phe106 bond. The degradation, measured by HPLC, followed classical Michaelis-Menten kinetics. The sensitivity of the enzyme to inhibitors suggested it to be a metalloendopeptidase, resembling neutral endopeptidase 24.11. When this enzyme, characterised by its enkephalin-degrading activity, was compared to the enzyme responsible for ANF inactivation, striking differences were found in tissue distribution, pH-dependence and sensitivity to protein-modifying reagents. It is concluded that an enzyme similar to endopeptidase 24.11 may be responsible for inactivation of atrial peptides in the rat.

Animals↗
PubMed1988

Gummatous penile ulceration and generalised lymphadenopathy in homosexual man: case report.

A case of granulomatous penile ulceration associated with generalised lymphadenopathy in a homosexual man aged 43 is presented. His serum gave positive results to tests for syphilis, but was negative for antibody to human immunodeficiency virus (HIV). His condition responded briskly to treatment with procaine penicillin, and we conclude that the clinical features were attributable to infection with Treponema pallidum.

Adult↗
PubMed1988

Infection of the epididymis by Ureaplasma urealyticum.

Ureaplasma urealyticum organisms (ureaplasmas) were isolated from the urethra and epididymal aspirate of a man aged 24 who had acute right sided epididymitis. No other microorganisms were detected, and he had no chlamydial antibody response. A fourfold antibody response to the epididymal ureaplasma isolate was detected by two methods, however, and the patient responded clinically to doxycycline, to which the ureaplasmal isolates were susceptible in vitro. These findings suggest that U urealyticum had a causative role.

Adult↗
PubMed1987

Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H]PK 11195: anatomical and subcellular distribution.

The peripheral-type benzodiazepine binding site, erstwhile characterized in the rodent and feline brain, has now been characterized in post-mortem human brain using [3H]PK 11195. The kinetics and pharmacological properties of the binding of this ligand are similar to peripheral-type benzodiazepine binding sites elsewhere. The potency of RO5-4864 for this site in human brain is close to that seen in ruminant and carnivore tissues but considerably lower than in rodent tissues. The regional distribution of these binding sites would suggest a neuronal rather than a glial localization. [3H]PK 11195 bound in a similar fashion to slide-mounted sections of human brain, thus allowing quantitative studies of the regional distribution of peripheral-type benzodiazepine binding sites to be made. The binding sites were distributed heterogeneously, but were restricted to the grey matter. Highest densities of binding sites were found in forebrain structures. The localization was not limited to any functional system, nor did it resemble any previously described transmitter system. The similarities between peripheral-type benzodiazepine binding sites in human and in feline brain in terms of their pharmacological characteristics and their regional and subcellular distribution suggest that the cat, rather than the rat, may be the better model for studying a possible role for this site in human cerebral function.

Animals↗
PubMed1987

Partial purification and pharmacology of peripheral-type benzodiazepine receptors.

This report describes the results obtained with a new photoaffinity ligand for the "peripheral-type" benzodiazepine binding site (PBS), using a digitonin solubilized preparation from rat heart or adrenals. The specific binding activity of the solubilized adrenal preparation is higher than 50 pmol/mg protein, with binding properties and pharmacological specificity identical to the membrane bound PBS. The apparent molecular weight of the solubilized PBS, determined by gel filtration is 215 KDa. The photoaffinity ligand (PK 14105) is a nitrophenyl derivative of PK 11195, which attaches covalently and specifically to all the PBS when cardiac membranes are irradiated with this compound under ultraviolet light. After photolabelling with [3H]PK 14105 and solubilization in SDS of heart or adrenal membranes, gel electrophoresis indicates the existence of a single protein band whose molecular weight (18 KDa) is unaltered by incubation with sulphydryl-reducing or protein cross-linking agents. This molecule seems to be a low molecular weight, acidic protein. Diethylpyrocarbonate decreases partially (60%) the binding of [3H]PK 11195 without affecting [3H] RO5-4864 binding, which implies a vital histidine residue in the binding domain of [3H]-PK 11195. Treatment with phospholipase A2 or mellitin, a stimulant of endogenous PLA2, led to a selective loss of [3H] RO5-4864 binding with no change in the binding of [3H]PK 11195. Such differences between a benzodiazepine ligand and an isoquinoline ligand suggest that these compounds may induce, on binding, different conformational changes in the PBS, which is compatible with the hypothesis that RO5-4864 and PK 11195 may be an agonist and an antagonist respectively at the PBS.

Adrenal Glands↗
PubMed1987

Photoaffinity labeling of peripheral-type benzodiazepine-binding sites.

The use of a novel photoaffinity label for the peripheral-type benzodiazepine-binding site is described. This compound, PK 14105, has high affinity (4 nM) and selectivity for cardiac benzodiazepine-binding sites. Under ultraviolet light, PK 14105 couples covalently to an 18,000-Da membrane protein which apparently corresponds to the (or a part of the) cardiac benzodiazepine-binding site. Since covalent attachment of PK 14105 totally precludes the binding of other ligands to this binding site, it is suggested that, during ultraviolet irradiation, this compound inserts covalently into the binding domain of the peripheral-type benzodiazepine-binding site.

Affinity Labels↗
PubMed1986

Stereoselective inhibition of the binding of [3H]PK 11195 to peripheral-type benzodiazepine binding sites by a quinolinepropanamide derivative.

The specific binding of [3H]PK 11195 to the peripheral-type benzodiazepine binding site is inhibited by the l-enantiomer of N,N-diethyl-alpha-methyl-2-phenyl-4-quinolinepropanamide ((-)Q1) but not by its d-enantiomer ((+)Q1). (-)Q1 inhibited [3H]PK 11195 binding to several rat tissues with an IC50 of less than 10 nM whereas (+)Q1 was at least 500 times less potent. This stereoselectivity was observed in all the tissues tested (brain, heart, kidney and adrenals). The same stereoselectivity was found for the displacement of the binding of [3H]PK 11195 in vivo, where (-)Q1 had an ID50 between 4-15 mg/kg and (+)Q1 was completely inactive at all doses tested (i.e. up to 40 mg/kg). Neither isomer had appreciable affinity for central-type benzodiazepine binding sites ([3H]diazepam) nor for voltage-sensitive calcium channels ([3H]PN 200210 and [3H]verapamil).

Adrenal Glands↗
PubMed1986

PK 11195, an antagonist of peripheral type benzodiazepine receptors, modulates Bay K8644 sensitive but not beta- or H2-receptor sensitive voltage operated calcium channels in the guinea pig heart.

In a partially depolarized guinea pig papillary muscle preparation, BAY K8644 stimulated voltage-operated calcium channels, promoting slow action potentials; this effect was dose-dependent over a concentration range of 3 X 10(-7) M to 3 X 10(-6) M. Isoproterenol and histamine also induced slow action potentials by stimulating beta or H2 receptors, respectively. PK 11195, the antagonist of peripheral type benzodiazepine receptors, inhibited the effect of BAY K8644, but not those of histamine or isoproterenol. Moreover, PK 11195 "dose-dependently" antagonized the ability of RO5-4864 to inhibit the slow action potentials elicited by barium chloride. Thus, in the heart, PK 11195, an antagonist of peripheral type benzodiazepine receptors, can modulate voltage-operated calcium channels when they are activated directly, but not when they are activated by stimulation of neurotransmitter receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Objective responses to ketoconazole therapy in patients with relapsed progressive prostatic cancer.

The contribution of adrenal androgens to the maintenance and progression of so-called hormone-unresponsive prostatic carcinoma was studied in 20 patients with advanced relapsed disease. The role played by testicular androgens had been negated by prior orchiectomy or concurrent LHRH analogue therapy. Ketoconazole, an antifungal agent which inhibits adrenal and testicular androgenesis, administered in a dose of 400 mg 8-hourly, resulted in optimal suppression of adrenal androgens. The mean serum androstenedione concentration fell from 8.01 +/- 0.84 nMol/l to 1.55 +/- 0.25 nMol/l, P less than 0.001, and serum testosterone from 1.25 +/- 0.14 nMol/l to 0.36 +/- 0.06 nMol/l, P less than 0.01, after 6 months treatment. There was, however, no significant difference between patients receiving 400 and those receiving 200 mg. Androgen suppression resulted in six objective and ten subjective clinical responses. Ablation of both testicular and adrenal androgens can now be achieved using ketoconazole in combination with orchiectomy or LHRH analogues, but the high incidence of side effects may preclude its use in all patients with prostatic cancer. The results of this study support the concept of "total androgen ablation" as primary therapy in advanced prostatic cancer as a possible means of improving survival in this common malignancy.

Acid Phosphatase↗
PubMed1985

Dihydropyridine and peripheral type benzodiazepine binding sites: subcellular distribution and molecular size determination.

Electrophysiological and pharmacological studies have shown that peripheral-type benzodiazepine receptors modulate voltage-sensitive calcium channels in the heart. We have compared these binding sites with binding sites for [3H]dihydropyridines, which are believed to label such channels. Although no direct or allosteric interaction could be demonstrated between the two sites, their subcellular distribution--sarcolemma and ryanodine-sensitive sarcoplasmic reticulum--was parallel. Size determination of the two sites suggests that the receptors for these two classes of compounds are separate molecules packaged in the same membrane compartment.

Animals↗
PubMed1985

Electrophysiological and pharmacological evidence that peripheral type benzodiazepine receptors are coupled to calcium channels in the heart.

PK 11195, an antagonist of the peripheral type benzodiazepine receptor, does not affect either the duration of the action potential or the tension of the guinea pig papillary muscle. However, it antagonized the effects of the calcium channel blockers, nitrendipine, verapamil, diltiazem, and of BAY K8644, a calcium channel agonist in this heart preparation. On the other hand, PK 11195 does not change the increase in the action potential duration provoked by the potassium channel blocker tetraethylammonium. RO5-4864, an agonist of the peripheral type benzodiazepine receptor, decreased the tension of the guinea pig papillary muscle. The effect was reversed by increasing extracellular Ca2+ concentrations up to 4 mM. These results suggest that in the heart the peripheral type benzodiazepine receptors are coupled to calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Experience with an LHRH analogue in the management of relapsed progressive prostatic cancer.

Seventeen patients with advanced progressive prostatic cancer who had relapsed or failed to respond to conventional endocrine therapy with oestrogens, orchiectomy or antiandrogens were treated with the LHRH analogue, ICI 118630. No significant objective tumour responses were seen, though 11 of 15 patients who presented with symptomatic metastatic bone pain had rapid short-term pain relief. The lack of objective clinical response seen in this study indicates no justification for the use of LHRH analogues in this group of patients. Though a significant subjective response was seen there was no added advantage over regular analgesics.

Acid Phosphatase↗
PubMed1983

Putative mediators of insulin action regulate hepatic acetyl CoA carboxylase activity.

Incubation of rat liver plasma membranes with insulin enhances the production of small molecular weight substances which regulate the activity of liver acetyl CoA carboxylase. While low concentrations of insulin cause the release of a carboxylase stimulator from membranes, concentrations greater than 10(-9) M generate less stimulating activity. This biphasic concentration curve for insulin can be resolved by differential alcohol extraction into two fractions which have antagonistic activity. The production of both substances is enhanced by insulin. Chemical and chromatographic evidence suggest that these substances are identical to the previously described "mediators" which regulate both pyruvate dehydrogenase and adenylate cyclase activities.

Acetyl-CoA Carboxylase↗
PubMed1983

Prostatic cancer: treatment with long-acting LHRH analogue.

Fifteen patients with advanced carcinoma of the prostate were treated with a luteinising hormone releasing hormone agonist ICI 118 630. Three of 5 patients who had failed conventional hormone therapy have had a marked alleviation of bone pain, though no objective evidence of disease regression. Nine of 10 patients previously untreated have shown objective evidence of disease response. This drug appears to have advantages over conventional hormone therapy.

Aged↗
PubMed1983

Comparative thermodynamics of benzodiazepine receptor ligand interactions in rat neuronal membranes.

The effects of temperature on the interaction of various ligands with the benzodiazepine receptor were studied in rat brain membrane preparations. The affinities of all ligands studied were reduced on raising the temperature from 4 to 37 degrees C. The variation of affinity constant with temperature deviated from the classical relationship for both the anticonvulsant ligand [3H]flunitrazepam and the proconvulsant ligand [3H]ethyl beta-carboline-3-carboxylate. This implies a variation of observed enthalpy change of binding with temperature. Possible reasons for this are discussed. Gamma-Aminobutyric acid and sodium chloride both enhance the binding of [3H]flunitrazepam--the former by an increase in the entropic component of the binding energy, and the latter by an increase in the enthalpic component. In a series of ligands of different biological activities, no simple correlation was observed between biological activity and temperature dependence of binding.

Animals↗