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MSMR Jan 2024The U.S. military has witnessed rising obesity among active component service members. The Department of Defense authorized coverage of weight loss medications in 2018,...
The U.S. military has witnessed rising obesity among active component service members. The Department of Defense authorized coverage of weight loss medications in 2018, but no study has evaluated prescription prevalence within the active component. This descriptive retrospective cohort study analyzed data from active component U.S. military service members from January 2018 through June 2023. The study used data from the Defense Medical Surveillance System to determine prescription period prevalence of weight loss medication. Data on demographics, body mass index, and history of diabetes were considered. The study revealed a 100-fold increase in the prescription period prevalence of weight loss agents in the active component from their initial authorization date. Demographics associated with higher prescription period prevalence were non-Hispanic Black race and ethnicity, female sex, and older age. Service members in the health care occupations and the Navy had higher prevalence compared to other service branches and occupations. The findings indicate a significant rise in the period prevalence of weight loss prescriptions over time. Further research is recommended to assess the effectiveness, safety, and use in austere military environments.
Topics: Female; Humans; United States; Prevalence; Retrospective Studies; Military Personnel; Anti-Obesity Agents; Weight Loss
PubMed: 38359359
DOI: No ID Found -
The Journal of Biological Chemistry 2021Interactions of membrane-bound mammalian cytochromes P450 (CYPs) with NADPH-cytochrome P450 oxidoreductase (POR), which are required for metabolism of xenobiotics, are...
Interactions of membrane-bound mammalian cytochromes P450 (CYPs) with NADPH-cytochrome P450 oxidoreductase (POR), which are required for metabolism of xenobiotics, are facilitated by membrane lipids. A variety of membrane mimetics, such as phospholipid liposomes and nanodiscs, have been used to simulate the membrane to form catalytically active CYP:POR complexes. However, the exact mechanism(s) of these interactions are unclear because of the absence of structural information of full-length mammalian CYP:POR complexes in membranes. Herein, we report the use of amphipols (APols) to form a fully functional, soluble, homogeneous preparation of full-length CYP:POR complexes amenable to biochemical and structural study. Incorporation of CYP2B4 and POR into APols resulted in a CYP2B4:POR complex with a stoichiometry of 1:1, which was fully functional in demethylating benzphetamine at a turnover rate of 37.7 ± 2.2 min, with a coupling efficiency of 40%. Interestingly, the stable complex had a molecular weight (M) of 338 ± 22 kDa determined by multiangle light scattering, suggestive of a tetrameric complex of 2CYP2B4:2POR embedded in one APol nanoparticle. Moreover, negative stain electron microscopy (EM) validated the homogeneity of the complex and allowed us to generate a three-dimensional EM map and model consistent with the tetramer observed in solution. This first report of the full-length mammalian CYP:POR complex by transmission EM not only reveals the architecture that facilitates electron transfer but also highlights a potential use of APols in biochemical and structural studies of functional CYP complexes with redox partners.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Catalysis; Cytochrome P450 Family 2; NADPH-Ferrihemoprotein Reductase; Polymers; Propylamines; Protein Binding; Protein Conformation; Protein Multimerization; Rabbits
PubMed: 33839156
DOI: 10.1016/j.jbc.2021.100645 -
Biochemistry May 2019NADPH-cytochrome P450 oxidoreductase (CYPOR), the essential flavoprotein of the microsomal cytochrome P450 monooxygenase system, is anchored in the phospholipid bilayer...
NADPH-cytochrome P450 oxidoreductase (CYPOR), the essential flavoprotein of the microsomal cytochrome P450 monooxygenase system, is anchored in the phospholipid bilayer by its amino-terminal membrane-binding domain (MBD), which is necessary for efficient electron transfer to cytochrome P450. Although crystallographic and kinetic studies have established the structure of the soluble catalytic domain and the role of conformational motions in the control of electron transfer, the role of the MBD is largely unknown. We examined the role of the MBD in P450 catalysis through studies of amino-terminal deletion mutants and site-directed spin labeling. We show that the MBD spans the membrane and present a model for the orientation of CYPOR on the membrane capable of forming a complex with cytochrome P450. EPR power saturation measurements of CYPOR mutants in liposomes containing a lipid/Ni(II) chelate identified a region of the soluble domain interacting with the membrane. The deletion of more than 29 residues from the N-terminus of CYPOR decreases cytochrome P450 activity concomitant with alterations in electrophoretic mobility and an increased resistance to protease digestion. The altered kinetic properties of these mutants are consistent with electron transfer through random collisions rather than via formation of a stable CYPOR-P450 complex. Purified MBD binds weakly to cytochrome P450, suggesting that other interactions are also required for CYPOR-P450 complex formation. We propose that the MBD and flexible tether region of CYPOR, residues 51-63, play an important role in facilitating the movement of the soluble domain relative to the membrane and in promoting multiple orientations that permit specific interactions of CYPOR with its varied partners.
Topics: Catalytic Domain; Cell Membrane; Crystallography, X-Ray; Cysteine; Cytochrome P-450 Enzyme System; Electron Transport; Escherichia coli; Flavoproteins; Hydrophobic and Hydrophilic Interactions; Kinetics; Lipid Bilayers; Liposomes; NADP; NADPH-Ferrihemoprotein Reductase; Oxidoreductases, N-Demethylating; Plasmids; Protein Structure, Tertiary; Sequence Analysis, Protein
PubMed: 31009206
DOI: 10.1021/acs.biochem.9b00130 -
Chemical Communications (Cambridge,... May 2018Investigating the interplay between cytochrome-P450 and its redox partners (CPR and cytochrome-b5) is vital for understanding the metabolism of most hydrophobic drugs....
Investigating the interplay between cytochrome-P450 and its redox partners (CPR and cytochrome-b5) is vital for understanding the metabolism of most hydrophobic drugs. Dynamic structural interactions with the ternary complex, with and without substrates, captured by NMR reveal a gating mechanism for redox partners to promote P450 function.
Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzphetamine; Butylated Hydroxytoluene; Cyclohexanes; Cytochrome P450 Family 2; Cytochromes b5; Ligands; Methoxyflurane; Models, Chemical; Multiprotein Complexes; NADPH-Ferrihemoprotein Reductase; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Domains; Protein Multimerization; Rabbits; Rats; Substrate Specificity
PubMed: 29781479
DOI: 10.1039/c8cc02525h -
Pharmacology, Biochemistry, and Behavior May 2017Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use...
Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment.
Topics: Animals; Behavior, Animal; Benzphetamine; Dextroamphetamine; Macaca mulatta; Male; Methamphetamine
PubMed: 28373066
DOI: 10.1016/j.pbb.2017.03.008 -
Journal of Menopausal Medicine Dec 2014Obesity is an important risk factor for metabolic disease and various cancers. Treatments of obesity include lifestyle intervention, pharmacotherapy, and bariatric... (Review)
Review
Obesity is an important risk factor for metabolic disease and various cancers. Treatments of obesity include lifestyle intervention, pharmacotherapy, and bariatric surgery. If weight loss with lifestyle intervention is only modest, pharmacotherapy might be needed. Pharmacotherapy agents can be grouped by treatment period as short term or long term use agent. Several sympathomimetic drugs such as benzphetamine, diethylpropion, phendimetrazine and phentermine, are approved for short term treatment due to their safety issues. For long term treatment, orlistat, lorcaserin, and combination of phentermine/topiramate are approved by U.S. Food and Drug Administration (FDA). Orlistat partially blocks intestinal digestion of fat, therefore producing weight loss. Lorcaserin is a serotonin 2C receptor agonist. The combination of phentermine/topiramate produces a mean weight loss of 8-10 kg. Side effects of each drug are quite different. For obesity patient, side effects are important factor when choosing drugs. The goal of this article is to review currently available anti-obesity drugs.
PubMed: 25580419
DOI: 10.6118/jmm.2014.20.3.90 -
Pharmacotherapy Dec 2013To examine national trends in prescription antiobesity drug use in the United States.
STUDY OBJECTIVE
To examine national trends in prescription antiobesity drug use in the United States.
DESIGN
Data analysis.
DATA SOURCE
The IMS Health Vector One National and Total Patient Tracker and Encuity Research Treatment Answers databases, the Source Healthcare Analytics Source Lx database, and IMS LifeLink database.
MEASUREMENTS AND MAIN RESULTS
National drug use estimates from 1991-2011 were extracted from the IMS Health Vector One National database, and patient characteristics from 2008-2011 were extracted from the Vector One Total Patient Tracker and Encuity Research Treatment Answers databases. The Source Healthcare Analytics Source Lx database was used to examine duration of antiobesity drug use from 2002-2011, with a sensitivity analysis performed using the IMS LifeLink database. In 2011, approximately 2.74 million patients used antiobesity drugs, predominantly phentermine (2.43 million patients). The use of prescription orlistat and sibutramine was relatively uncommon. Eighty-five percent of antiobesity drug users were female, 62% were aged 17-44 years, and 4.5% had a body mass index of ≤ 24.9 kg/m(2) . Duration of use was generally short and most patients only had one episode of antiobesity drug use during the observation period. The longest episode of use was 30 days or less in 47-58% of patients. Approximately one quarter of the patients used antiobesity drugs for longer than 90 days, including phentermine and other amphetamine congeners whose labels recommend short-term use, not exceeding "a few weeks." Only 1.3-4.2% of antiobesity drug users used them for longer than 1 year. Concomitant use of two or more prescription weight-loss drugs was generally uncommon, although phentermine was dispensed during 13-16% of benzphetamine, diethylpropion, or phendimetrazine episodes of use.
CONCLUSION
Phentermine dominated the prescription weight-loss market. Despite the indication of short-term use for amphetamine congeners, duration of use was similar to other antiobesity drugs. Nevertheless, the reasons for and implications of the limited duration of use observed with all prescription antiobesity drugs deserve further investigation.
Topics: Adolescent; Adult; Anti-Obesity Agents; Child; Child, Preschool; Databases, Factual; Female; Humans; Infant; Male; Middle Aged; Obesity; Practice Patterns, Physicians'; Time Factors; United States; Weight Loss; Young Adult
PubMed: 24019195
DOI: 10.1002/phar.1342 -
The Journal of Neuroscience : the... Jul 2013Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene...
Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.
Topics: Aging; Animals; Anxiety; Benzamides; Benzphetamine; Central Nervous System Stimulants; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Enkephalins; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Long-Term Synaptic Depression; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Precursors; Pyrazoles; Pyridines; Receptors, Metabotropic Glutamate; Recognition, Psychology
PubMed: 23904614
DOI: 10.1523/JNEUROSCI.0290-13.2013 -
Drug Metabolism and Disposition: the... Jan 2013Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another...
Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another isoform. In this study, we assessed whether CYP2E1 could influence the catalytic activity of CYP2B4 under steady-state turnover conditions. The results show that CYP2E1 inhibits CYP2B4-mediated metabolism of benzphetamine (BNZ) with a K(i) of 0.04 µM. However, CYP2B4 is not an inhibitor of CYP2E1-mediated p-nitrophenol hydroxylation. When these inhibition studies were performed with the artificial oxidant tert-butyl hydroperoxide, CYP2E1 did not significantly inhibit CYP2B4 activity. Determinations of the apparent K(M) and k(cat) of CYP2B4 for CPR in the presence of increasing concentrations of CYP2E1 revealed a mixed inhibition of CYP2B4 by CYP2E1. At low concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR increased up to 23-fold with virtually no change in the k(cat) for the reaction, however, at higher concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR decreased to levels similar to those observed in the absence of CYP2E1 and the k(cat) also decreased by 11-fold. Additionally, CYP2E1 increased the apparent K(M) of CYP2B4 for BNZ by 8-fold and the apparent K(M) did not decrease to its original value when saturating concentrations of CPR were used. While the individual apparent K(M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K(M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR.
Topics: Aryl Hydrocarbon Hydroxylases; Base Sequence; Catalysis; Cytochrome P-450 CYP2E1; Cytochrome P450 Family 2; DNA Primers; Hydroxylation; NADPH-Ferrihemoprotein Reductase; Substrate Specificity
PubMed: 23043184
DOI: 10.1124/dmd.112.046094 -
Biochimica Et Biophysica Acta Jan 2011Mammalian cytochrome P450 2B4 (CYP2B4) is a phenobarbital-inducible rabbit hepatic monooxygenase that catalyzes the N-demethylation of benzphetamine and metabolism of...
Stabilization and spectroscopic characterization of the dioxygen complex of wild-type cytochrome P4502B4 (CYP2B4) and its distal side E301Q, T302A and proximal side F429H mutants at subzero temperatures.
Mammalian cytochrome P450 2B4 (CYP2B4) is a phenobarbital-inducible rabbit hepatic monooxygenase that catalyzes the N-demethylation of benzphetamine and metabolism of numerous other compounds. To probe the interactions of the heme environment and bound benzphetamine with the dioxygen (O₂) complex of CYP2B4, homogeneous O₂ complexes of the wild-type enzyme and three mutants at sites of conserved amino acids, two on the heme distal side (T302A and E301Q) and one on the proximal side (F429H), have been prepared and stabilized at ~-50°C in mixed solvents (60-70% v/v glycerol). We report that the magnetic circular dichroism and electronic absorption spectra of wild-type oxyferrous CYP2B4, in the presence and absence of substrate, are quite similar to those of the dioxygen complex of bacterial cytochrome P450-CAM (CYP101). However, the oxyferrous complexes of the T302A and E301Q CYP2B4 mutants have significantly perturbed electronic structure (~4 nm and ~3 nm red-shifted Soret features, respectively) compared to that of the wild-type oxyferrous complex. On the other hand, the heme proximal side mutant, CYP2B4 F429H, undergoes relatively facile conversion to a partially (~50%) denatured (P420) form upon reduction. The structural changes in the heme pocket environments of the CYP2B4 mutants that lead to the spectroscopic distinctions reported herein can be related to the differences in oxidation activities of wild-type CYP2B4 and its E301Q, T302A and F429H mutants.
Topics: Amino Acid Substitution; Animals; Aryl Hydrocarbon Hydroxylases; Benzphetamine; Catalytic Domain; Circular Dichroism; Cold Temperature; Cytochrome P450 Family 2; Heme; Iron; Models, Molecular; Mutation; Organometallic Compounds; Oxygen; Protein Binding; Protein Structure, Tertiary; Rabbits; Spectrophotometry; Substrate Specificity
PubMed: 20637316
DOI: 10.1016/j.bbapap.2010.07.012