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43 results on '"Seminerio, Michael J."'

29. Metabolism of megestrol acetate in vitro and the role of oxidative metabolites

Author

House, Larry, primary, Seminerio, Michael J., additional, Mirkov, Snezana, additional, Ramirez, Jacqueline, additional, Skor, Maxwell, additional, Sachleben, Joseph R., additional, Isikbay, Masis, additional, Singhal, Hari, additional, Greene, Geoffrey L., additional, Vander Griend, Donald, additional, Conzen, Suzanne D., additional, and Ratain, Mark J., additional

Published
2017
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30. Metabolism of megestrol acetate in vitro and the role of oxidative metabolites.

Author

House, Larry, Seminerio, Michael J., Mirkov, Snezana, Ramirez, Jacqueline, Skor, Maxwell, Sachleben, Joseph R., Isikbay, Masis, Singhal, Hari, Greene, Geoffrey L., Vander Griend, Donald, Conzen, Suzanne D., and Ratain, Mark J.

Subjects
*DRUG metabolism, *CYTOCHROME P-450, *DRUG approval, *GLUCURONOSYLTRANSFERASE, *NICOTINAMIDE adenine dinucleotide phosphate
Abstract

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 μM (HLM Km for metabolite 1; M1) and 28 μM (HLM Km for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 μM MA. 3. At 28 μM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR. [ABSTRACT FROM AUTHOR]

Published
2018
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40. s Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation

Author

Robson, Matthew J., Seminerio, Michael J., McCurdy, Christopher R., Coop, Andrew, and Matsumoto, Rae R.

Abstract

Background: Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with s receptors and s receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with s receptor antagonists failed to attenuate METHinduced hyperthermia in mice. This allowed us to determine whether the ability of s receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia. Methods: Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment. Results: The data indicate that the ability of s receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia. Conclusion: The ability of s receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.

Published
2013
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41. In vitro evaluation of guanidine analogs as sigma receptor ligands for potential anti-stroke therapeutics.

Author

Behensky, Adam A, Cortes-Salva, Michelle, Seminerio, Michael J, Matsumoto, Rae R, Antilla, Jon C, and Cuevas, Javier

Abstract

Currently, the only Food and Drug Administration-approved treatment of acute stroke is recombinant tissue plasminogen activator, which must be administered within 6 hours after stroke onset. The pan-selective σ-receptor agonist N,N'-di-o-tolyl-guanidine (o-DTG) has been shown to reduce infarct volume in rats after middle cerebral artery occlusion, even when administered 24 hours after stroke. DTG derivatives were synthesized to develop novel compounds with greater potency than o-DTG. Fluorometric Ca(2+) imaging was used in cultured cortical neurons to screen compounds for their capacity to reduce ischemia- and acidosis-evoked cytosolic Ca(2+) overload, which has been linked to stroke-induced neurodegeneration. In both assays, migration of the methyl moiety produced no significant differences, but removal of the group increased potency of the compound for inhibiting acidosis-induced [Ca(2+)](i) elevations. Chloro and bromo substitution of the methyl moiety in the meta and para positions increased potency by ≤160%, but fluoro substitutions had no effect. The most potent DTG derivative tested was N,N'-di-p-bromo-phenyl-guanidine (p-BrDPhG), which had an IC(50) of 2.2 µM in the ischemia assay, compared with 74.7 μM for o-DTG. Microglial migration assays also showed that p-BrDPhG is more potent than o-DTG in this marker for microglial activation, which is also linked to neuronal injury after stroke. Radioligand binding studies showed that p-BrDPhG is a pan-selective σ ligand. Experiments using the σ-1 receptor-selective antagonist 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) demonstrated that p-BrDPhG blocks Ca(2+) overload via σ-1 receptor activation. The study identified four compounds that may be more effective than o-DTG for the treatment of ischemic stroke at delayed time points.

Published
2013
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43. Sigma-1 receptors: potential targets for the treatment of substance abuse.

Author

Robson MJ, Noorbakhsh B, Seminerio MJ, and Matsumoto RR

Subjects
Animals, Central Nervous System Agents pharmacology, Humans, Sigma-1 Receptor, Central Nervous System Agents therapeutic use, Receptors, sigma agonists, Receptors, sigma antagonists & inhibitors, Substance-Related Disorders drug therapy
Abstract

Drug abuse is currently a large economic and societal burden in countries around the globe. Many drugs of abuse currently lack adequate therapies aimed at treating both the addiction and negative complications often associated with their use. Sigma-1 receptors were discovered over 30 years ago and have recently become targets for the development of pharmacotherapies aimed at treating substance abuse and addiction. In vivo preclinical studies have revealed that sigma receptor ligands are able to ameliorate select behavioral effects of many drugs of abuse including cocaine, methamphetamine, ethanol and nicotine. In addition, recent studies have begun to elucidate the mechanisms by which sigma-1 receptors modulate the effects of these drugs on neurotransmission, gene regulation and neuroplasticity. Overall, these recent findings suggest that compounds targeting sigma-1 receptors may represent a potential new class of therapeutics aimed at treating drug abuse. Future studies involving clinical populations will be critical for validating the therapeutic potential of sigma-1 receptor ligands for the treatment of substance abuse.

Published
2012
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