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Biomedical subjects

S R Donahue

Publications and source records attributed to S R Donahue.

7 recordsLinked to original sources
PubMed1998

Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone.

OBJECTIVE: To evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Ten women who had undergone surgical sterilization were enrolled in an open-label crossover study conducted in the Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with use of Medication Event Monitoring System (MEMS) caps. RESULTS: No changes were observed in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. The mean +/- SD area under the plasma concentration-time curve (AUC0-infinity) for ethinyl estradiol was 6580 +/- 1100 ng.h/L at baseline and 5970 +/- 1560 ng.h/L after the thalidomide regimen (paired t test, P > .05). The values for norethindrone were 103 +/- 54 micrograms.h/L and 107 +/- 58 micrograms.h/L (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for either ethinyl estradiol or norethindrone. No accumulation of thalidomide was seen after 21 days of therapy: day 1 AUC0-infinity 41.1 +/- 13.9 micrograms.h/mL; day 21 AUC0-infinity 59.6 +/- 27.3 micrograms.h/mL (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated but caused variable degrees of sedation. The average thalidomide compliance rate was 97%. CONCLUSIONS: The pharmacokinetics of thalidomide do not change with 3 weeks of daily dosing. Thalidomide does not alter the pharmacokinetics of ethinyl estradiol or norethindrone. Therefore there is no drug interaction between thalidomide and these 2 drugs. The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

Adult↗
PubMed1997

Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19.

A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.

Adult↗
PubMed1990

Fucosylation of glycolipids in PC12 cells is dependent on the sequence of nerve growth factor treatment and adenylate cyclase activation.

Synthesis of complex glycosphingolipids was analyzed in cultures of PC12 cells treated with nerve growth factor (NGF) and forskolin, either sequentially or simultaneously. For the sequential treatment, forskolin was added following 15 days of NGF treatment and cultures were continued for 3 additional days. For simultaneous treatment, cells maintained in medium with no additives received both agents and were then incubated for 3 additional days. Sequential NGF/forskolin treatment induced hypertrophy in PC12 cells and produced cells which had more neuron-like characteristics than cells treated with NGF alone. Simultaneous treatment initially accelerated the outgrowth of neurites and then reduced neurite elongation. Sequential treatment of PC12 cells resulted in a greater than 50% increase in the incorporation of fucose into neutral glycolipids and gangliosides compared to treatment with NGF alone. Galactose incorporation was unchanged, indicating that there was no net increase in glycolipid synthesis. The lack of an increase in total glycolipid accumulation was confirmed using monoclonal antibodies reacting with specific fucosylated and nonfucosylated PC12 cell glycolipids. However, TLC immunostaining analysis revealed that sequential NGF/forskolin treatment selectively altered the expression of some neutral glycolipid species. In contrast to the effects of the sequential treatment, simultaneous NGF and forskolin treatment was accompanied by a decrease in the incorporation of fucose and galactose into neutral glycolipids and gangliosides. These findings suggest that the timing of exposure to neuronotrophic factors and agents which activate adenylate cyclase might in part account for developmentally regulated patterns of glycoconjugate expression and provide further evidence that fucosylation of glycolipids may be associated with maturation of sympathetic neurons.

Adenylyl Cyclases↗
PubMed1989

Chromaffin cell proliferation in the adult rat adrenal medulla.

Epinephrine and norepinephrine-containing chromaffin cells proliferate in the adrenal glands of normal adult rats throughout life. Moreover, their rate of proliferation is markedly increased by short-term administration of reserpine, one of many agents which in long-term experiments are associated with the development of adrenal medullary tumors. Current data suggest that chromaffin cell proliferation in the adult rat adrenal is mediated by the interaction of neurogenic and hormonal signals. Reserpine is known to directly deplete catecholamine stores, and to reflexively increase the activity of the splanchnic nerve endings innervating the adrenal medulla to stimulate both secretion and synthesis of catecholamines and other secretory granule constituents. Its effect on chromaffin cell proliferation suggests that the same signals may regulate chromaffin cell number to meet physiological needs. The reserpine model might shed light on signal transduction mechanisms which normally promote or prevent proliferation of chromaffin cells and of other neuroendocrine cells during development or in adult life, and on ways in which such mechanisms are altered in the course of the development and progression of tumors. It also suggests the possibility that chromaffin cells might be propagated in vitro for use in basic biological studies or in transplants for the treatment of Parkinson's disease.

Adrenal Medulla↗
PubMed1989

Pharmacological stimulation of chromaffin cell proliferation in the adult adrenal medulla.

Many strains of rats develop adrenal medullary hyperplasia and/or neoplasia after chronic administration of a wide variety of pharmacologic agents. The same changes may occur spontaneously in the course of aging. Current evidence suggests that chromaffin cell proliferation in adult rats is regulated by a combination of hormonal and neurogenic signals. Drugs associated with adrenal medullary tumors might act directly or indirectly on the hypothalamic-endocrine axis or the autonomic nervous system to stimulate chromaffin cell proliferation through mechanisms which normally adjust cell number to meet physiological needs. The increased cell turnover rate might be a prelude to other events leading to neoplastic transformation.

Adrenal Medulla↗
PubMed1988

Lithium dramatically potentiates neurotensin/neuromedin N gene expression.

Lithium perturbs intracellular signal transduction pathways used by neurotransmitters, suggesting that changes in receptor signalling may underlie its actions in the treatment of manic depressive illness. Little attention, however, has been directed toward possible additional actions at the level of specific gene expression, particularly of genes encoding neurotransmitters or neuromodulators. In PC12 pheochromocytoma cells, lithium dramatically potentiates increases in intracellular levels of the neuropeptide neurotensin and the mRNA encoding it, caused by combinations of nerve growth factor, dexamethasone, and the adenylate cyclase activator, forskolin. This result demonstrates that lithium can profoundly influence the expression of a specific neuropeptide gene in a previously unanticipated manner and suggests that changes in gene expression might be involved in its therapeutic activity.

Adrenal Gland Neoplasms↗