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Biomedical subjects

J M Feldman

Publications and source records attributed to J M Feldman.

At least 91 records · Page 5Linked to original sources
PubMed1981

The pharmacology of sulfonylureas.

In this report we review the pharmacology of the hypoglycemic sulfonylurea drugs. The early work with sulfonylureas is briefly described. The pharmacokinetics of first-generation sulfonylureas, such as tolbutamide, chlorpropamide, acetohexamide and tolazamide, are described. The first-generation sulfonylureas are compared with second-generation sulfonylureas such as glyburide, glipizide and glibornuride. These latter drugs have a more nonpolar or lipophilic side chain, which results in a marked increase in their hypoglycemic potency. Because of the low serum concentration required for effective therapy, it is necessary to measure the serum concentration of second-generation sulfonylureas by gas-liquid chromatography or radioimmunoassay. The second-generation sulfonylureas do not produce facial flushing after ethanol ingestion (Antabuse effect) and are not uricosuric. Glyburide (but not glipizide or glibornuride) has been evaluated for its effect on water excretion. Glyburide not only does not increase water retention but in fact also increases free water clearance. The second-generation sulfonylureas bind to human serum albumin by nonionic forces in contrast with tolbutamide and chlorpropamide which bind by ionic forces. Thus, anionic drugs such as phenylbutazone, warfarin and salicylate do not displace glyburide from albumin as they displace tolbutamide and chlorpropamide. Therefore, it may be safer to administer the second-generation sulfonylureas than the more polar sulfonylureas when concurrent administration of other pharmacologic agents is likely. The sulfonylurea drugs lower plasma glucose concentrations in diabetic patients by stimulating insulin secretion and by potentiating the biologic effect of the insulin on such tissues as skeletal muscle, fat and liver. The mechanism of the latter so-called extra-pancreatic effect may be activated by increasing the deficient numbers of insulin receptors on muscle, fat or liver cells.

Acetohexamide↗
PubMed1981

Effects of diabetes mellitus and chemical sympathectomy on tissue monoamine oxidase activity and norepinephrine concentration in the golden hamster.

The pancreatic islets of the golden hamster have an extremely high monoamine oxidase (MAO) activity and norepinephrine (NE) concentration. To determine the cellular component responsible for these high values, we assayed MAO activity and NE concentration in collagenase-isolated islets from normal, streptozotocin-induced diabetic, and 6-hydroxydopamine (6-OHDA) induced sympathectomized golden hamsters. There was a 53% reduction in islet MAO activity in the diabetic hamsters, with no alteration in islet MAO activity in the sympathectomized ones, suggesting that the pancreatic B cells contain a large proportion of the MAO activity. There was a 98% reduction in islet NE concentration in the sympathectomized hamsters, with no alteration in islet NE concentration in the diabetic hamsters, suggesting that the adrenergic nerve endings in the islets contain the majority of the NE. There was no alteration in the MAO activity or NE concentration in th cerebral cortex, pituitary gland, liver, kidney, acinar pancreas, or heart of diabetic hamsters. Although the MAO activity of the hypothalamus was not altered, the diabetic hamsters had a 166% increase in NE and a 199% increase in dopamine in their hypothalamus, with no change in these amines in their cerebral cortex.

Animals↗
PubMed1981

Phenylethanolamine-N-methyltransferase activity determines the epinephrine concentration of pheochromocytomas.

We evaluated the activity of phenylethanolamine-N-methyltransferase (PNMT) and dopamine-beta-hydroxylase (DBH) in 16 pheochromocytomas. Ten of the tumors were from patients with Multiple Endocrine Neoplasia and six of the tumors were from patients with sporadic pheochromocytomas. All of the pheochromocytomas contained PNMT and DBH activity. There was a significant correlation between PNMT activity and epinephrine concentration in the pheochromocytomas (r=0.61); there was no significant correlation between PNMT activity and norepinephrine concentration (r=0.38) or DBH activity and norepinephrine (r=0.06) or dopamine (r=0.31) concentration. In general, the patients with the highest PNMT activity in their pheochromocytomas tended to have paroxysmal (rather than sustained) hypertension and to excrete more E than NE in their urine.

Adolescent↗
PubMed1980

Effect of increased pancreatic islet norepinephrine, dopamine and serotonin concentration on insulin secretion in the golden hamster.

The purpose of this study was to determine if increased concentrations of pancreatic islet norepinephrine, dopamine, or serotonin after insulin secretion. Golden hamsters received intraperitoneal injections of the norepinephrine precursor DL-threo-dihydroxyphenylserine, the dopamine precursor L-3,4-dihydroxyphenylalanine, or the serotonin precursor 5-hydroxytryptophan with and without pretreatment of the hamsters with the monoamine oxidase inhibitor tranylcypromine. Administration of the monoamine precursors to animals pretreated with tranylcypromine resulted in a mean increase in plasma glucose of 192% and a mean decrease in plasma insulin of 58%. Using a collagenase isolation technique, islets from control and treated animals were evaluated for monoamine content and insulin secretory capacity. The monoamine concentrations in control islets, in mumol/kg wet weight, were: norepinephrine 42 +/- 8; dopamine 8 +/- 2; and serotonin 26 +/- 9. Administration of the appropriate precursor to control hamsters resulted in a 1.9-fold (norepinephrine), 6-fold (dopamine), and 22-fold (serotonin) increase in monoamines. There was no alteration in the glucose (16.3 mmol/l)-stimulated in vitro insulin secretion from islets obtained from these hamsters. Administration of the precursors to hamsters pretreated with tranylcypromine resulted in a 3.5-fold (norepinephrine), 22-fold (dopamine), and 59-fold (serotonin) increase in monoamines. Glucose-stimulated in vitro insulin secretion from islets obtained from these hamstes was completely blocked. This study suggest that high concentrations of norepinephrine, dopamine, and serotonin in the pancreatic islets can decrease glucose-stimulated insulin secretion.

5-Hydroxytryptophan↗
PubMed1980

Golden hamster pancreatic islets: a tissue rich in monoamine oxidase.

We compared the steady state monoamine oxidase (MAO) activity of collagenase-isolated pancreatic islets of the golden hamster with the steady state MAO activity of liver, kidney, median eminence, pituitary, acinar pancreas, and cerebral cortex. The MAO activity of the islets (5384 +/- 412 pmol/mg protein . min) was 3-fold greater than the activity of the next highest tissue (liver) and 12.5 times greater than the activity of the acinar pancreas. This high MAO activity was not due to collagenase exposure. The islet MAO was mainly of the so-called type B, although there was also some type A activity in this tissue. By assaying the formation of new islet MAO after the irreversible activation of MAO by the MAO inhibitor pargyline, we found that the t 1/2 of islet MAO (5.9 days with 95% confidence limits of 4.1-10.5 days) did not differ from the t 1/2 of MAO in tissues with lower steady state MAO activities. This suggested that the high steady state MAO activity in golden hamster islets is due to a high rate of synthesis rather than to a lower rate of degradation. Although rats, Chinese hamsters, guinea pigs, mice, and rabbits had substantial MAO activity in their pancreatic islets, their levels, at most, were only 16% that of the golden hamster. When the MAO activity of golden hamster islets was inhibited by the administration of pargyline plus clorgyline, there was a 3-fold increase in islet serotonin concentration, with no increase in islet norepinephrine concentration, suggesting that islet MAO activity plays a role in regulating islet serotonin concentration.

Animals↗
PubMed1979

Effect of metastatic cancer on platelet monoamine oxidase activity and serotonin metabolism.

Platelet monoamine oxidase (MAO) activity and urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, tyramine and tryptamine were measured in patients with a variety of metastatic cancers and in healthy control subjects. The patients with cancer had higher platelet MAO activity and lower urinary excretion of 5-HIAA, sertonin and tyramine than the healthy subjects. The urinary tryptamine excretion was not significantly different in the two groups. At the present time it is unclear if the alterations in platelet MAO activity and monoamine excretion are casually related.

Adult↗
PubMed1979

Monoamine oxidase and catechol-O-methyltransferase activity in hamster and rat insulinomas.

Hamster and rat insulinomas were assayed for norepinephrine, dopamine and serotonin concentration and for monoamine oxidase and catechol-o-ethyltransferase (COMT) activity. The concentration of norepinephrine (mean 0.55 mumol/kg, range less than 0.20 to 2.64 mumol/kg) and serotonin (mean 5.22 mucol/kg, rang less than 0.6 to 26.5 mumol/kg) in hamster insulinomas were comparable to previously reported concentrations. Dopamine conentration (mean 0.34 mumol/kg, range less than 0.20 to 0.95 mumol/kg) was only 2 to 2.5% of that reported previously. Monoamine oxidase activity of the hamster and rat insulinomas were comparable to those of normal hamster islets. In contrast, the COMT activity of both insulinomas was much greater than the COMT activity of normal pancreatic islets of both species and was greater than in several other tissues and tumours. The tumour COMT, which was predominantly in the cytosol, was Mg2+ dependent and had a comparable sensitivity to inhibition by tropolone as purified beef-liver COMT. Hamster insulinoma monoamine oxidase was more sensitive than rat insulinoma monoamine oxidase to inhibition by tranylcypromine and deprenyl, while rat insulinoma monoamine oxidase was more sensitive to inhibition by clorgyline and was more heat labile.

Adenoma, Islet Cell↗
PubMed1979

Adrenal-cortical function in patients with medullary carcinoma of the thyroid and pheochromocytoma.

Medullary carcinoma of the thyroid (MCT) is reported to synthesize ACTH. This ACTH is believed to be responsible for the development of Cushing's syndrome in some patients with MCT. To determine the frequency of occurrence of adrenal cortical overactivity in patients with MCT, we measured plasma cortisol concentration and the urinary excretion of 17-hydroxycorticosteroids, 17-ketosteroids and urinary free cortisol in 22 patients with MCT and 7 patients with MCT plus pheochromocytomas. The patients with MCT and MCT plus pheochromocytoma had similar adrenal cortical function to age and sex matched normal subjects. We conclude that adrenal cortical function is usually normal in patients with MCT.

17-Hydroxycorticosteroids↗
PubMed1979

Urinary free cortisol excretion in patients with hyperserotoninaemia from the carcinoid syndrome.

To determine if patients with chronic hyperserotoninaemia from the carcinoid syndrome have increased basal adrenocortical function, I have determined the urinary free cortisol excretion of seventeen patients with carcinoid tumours and the carcinoid syndrome, twelve patients with carcinoid tumours without the carcinoid syndrome and seventeen normal subjects. There was no significant difference in the urinary free cortisol excretion of the patients with carcinoid tumours and the carcinoid syndrome (133 +/- 20.0 nmoles/24 h), patients with carcinoid tumours without the carcinoid syndrome (115 +/- 29 nmoles/24 h) and the normal subjects (96 +/- 9 nmoles/24 h). There was no correlation between the urinary free cortisol secretion and urinary 5-hydroxyindoleacetic acid or serum serotonin concentration in the patients with the carcinoid syndrome. There was a suggestion that patients with 5-hydroxytryptophan (5-HTP) secreting carcinoid tumours had higher urinary free cortisol excretion than patients with predominantly serotonin (5-HT) secreting carcinoid tumours. This may be due to the fact that the non-polar 5-HTP molecule penetrates the blood-brain barrier more effectively than the polar 5-HT molecule. 5-HTP is then converted to 5-HT within the brain. None of the twenty-nine patients with carcinoid tumours had clinical or laboratory evidence of the ectopic ACTH syndrome.

5-Hydroxytryptophan↗
PubMed1979

Elevated hypothalamic norepinephrine content in mice with the hereditary obese-hyperglycemic syndrome.

There is evidence that hypothalamic norepinephrine (NE) plays a role in the control of appetite in the rat. Using specific and sensitive radioenzymatic assays, we determined if there was a difference in the tissue (hypothalamus, cerebral cortex and kidney) concentration of NE or of dopamine (DA) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob) and their normal weight littermates, both when they were in the rapid growth phase (2--3 months of age) and when they were mature (6--7 months of age). The concentration of NE was similar in the cerebral cortex of obese and normal mice and in the kidneys of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice. The concentration of DA was similar in the hypothalamus of obese and normal mice and in the cerebral cortex of obese and normal mice. These observations support the concept that alterations in hypothalamic NE may play a role in the obesity of ob/ob mice.

Animals↗