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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 -
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 -
Current Medicinal Chemistry 2009Obesity is an increasingly serious socioeconomic and clinical problem. Between (1/4)-(1/3) of population in the developed countries can be classified as obese. Four... (Review)
Review
Obesity is an increasingly serious socioeconomic and clinical problem. Between (1/4)-(1/3) of population in the developed countries can be classified as obese. Four major etiological factors for development of obesity are genetic determinants, environmental factors, food intake and exercise. Obesity increases the risk of the development of various pathologic conditions including: insulin-resistant diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, endocrine problems, and certain forms of cancer. Thus, obesity is a negative determinant for longevity. In this review we provide broad overview of pathophysiology of obesity. We also discuss various available, and experimental therapeutic methods. We highlight functions of adipocytes including fat storing capacity and secretory activity resulting in numerous endocrine effects like leptin, IL-6, adiponectin, and resistin. The anti-obesity drugs are classified according to their primary action on energy balance. Major classes of these drugs are: appetite suppressants, inhibitors of fat absorption (i.e. orlistat), stimulators of thermogenesis and stimulators of fat mobilization. The appetite suppressants are further divided into noradrenergic agents, (i.e. phentermine, phendimetrazine, benzphetamine, diethylpropion), serotoninergic agents (i.e. dexfenfluramine), and mixed noradrenergic-serotoninergic agents (i.e. sibutramine). Thus, we highlight recent advances in the understanding of the central neural control of energy balance, current treatment strategies for obesity and the most promising targets for the development of novel anti-obesity drugs.
Topics: Animals; Anti-Obesity Agents; Appetite Depressants; Humans; Obesity
PubMed: 19199918
DOI: 10.2174/092986709787315568 -
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 Toxicological Sciences Aug 1982A typical lot of Kanemi rice oil ingested by patients with yusho (PCB poisoning) and the blood, liver and adipose tissue of the patients were analyzed for individual... (Review)
Review
A typical lot of Kanemi rice oil ingested by patients with yusho (PCB poisoning) and the blood, liver and adipose tissue of the patients were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) by gas chromatography and gas chromatography-mass spectrometry. The individual congeners identified were assayed for biological properties such as accumulation ability in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase and DT diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the seven PCB congeners detected in yusho patients, 2, 3, 4, 5, 3', 4'-hexa-CB seems to be the most related compound to yusho by its strong effects on induction of the liver enzymes, and on atrophy of the thymus and hypertrophy of the liver in rats. PCDF congeners identified in the patients showed severe toxicity in rats than this PCB, exhibiting stronger enzyme induction and gravimetric changes of the tissues even at very low doses of 1-10 micrograms/kg. These PCDFs, especially 2, 3, 4, 7, 8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for current symptoms of yusho.
Topics: Adipose Tissue; Animals; Benzofurans; Chromatography, Gas; Cytochrome P-450 Enzyme System; Dibenzofurans, Polychlorinated; Foodborne Diseases; Gas Chromatography-Mass Spectrometry; Haplorhini; Humans; Liver; Organ Size; Polychlorinated Biphenyls; Rats
PubMed: 6818356
DOI: 10.2131/jts.7.161 -
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 -
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 -
The Journal of Biological Chemistry Oct 1995The complete stoichiometry of the metabolism of the cytochrome b5 (cyt b5)-requiring substrate, methoxyflurane, by purified cytochrome P-450 2B4 was compared to that of...
The complete stoichiometry of the metabolism of the cytochrome b5 (cyt b5)-requiring substrate, methoxyflurane, by purified cytochrome P-450 2B4 was compared to that of another substrate, benzphetamine, which does not require cyt b5 for its metabolism. Cyt b5 invariably improved the efficiency of product formation. That is, in the presence of cyt b5 a greater percentage of the reducing equivalents from NADPH were utilized to generate substrate metabolites, primarily at the expense of the side product, superoxide. With methoxyflurane, cyt b5 addition always resulted in an increased rate of product formation, while with benzphetamine the rate of product formation remained unchanged, increased or decreased. The apparently contradictory observations of increased reaction efficiency but decrease in total product formation for benzphetamine can be explained by a second effect of cyt b5. Under some experimental conditions cyt b5 inhibits total NADPH consumption. Whether stimulation, inhibition, or no change in product formation is observed in the presence of cyt b5 depends on the net effect of the stimulatory and inhibitory effects of cyt b5. When total NADPH consumption is inhibited by cyt b5, the rapidly metabolized, highly coupled (approximately equal to 50%) substrate, benzphetamine, undergoes a net decrease in metabolism not counterbalanced by the increase in the efficiency (2-20%) of the reaction. In contrast, in the presence of the slowly metabolized, poorly coupled (approximately equal to 0.5-3%) substrate, methoxyflurane, inhibition of total NADPH consumption by cyt b5 was never sufficient to overcome the stimulation of product formation due to an increase in efficiency of the reaction.
Topics: Animals; Benzphetamine; Cytochrome P-450 Enzyme System; Cytochromes b5; Dealkylation; Male; Methoxyflurane; NADP; Rabbits; Superoxides
PubMed: 7559586
DOI: 10.1074/jbc.270.42.24707 -
Japanese Journal of Pharmacology Apr 1978Effects of benzphetamine, acetone, metyrapone and dimethylsulfoxide administration to rats on the metabolism of drugs by liver 9,000 x g supernatant fraction were...
Effects of benzphetamine, acetone, metyrapone and dimethylsulfoxide administration to rats on the metabolism of drugs by liver 9,000 x g supernatant fraction were studied herein. Activities for aniline hydroxylation and phenacetin O-deethylation were increased while ethylmorphine and benzphetamine N-demethylations were unchanged by the single administration of acetone, metyrapone or dimethylsulfoxide. Increase in aniline hydroxylase activity by about 53.4% and in phenacetin O-deethylase activity by about 44.4% were observed at 30 min after the single administration of benzphetamine whereas ethylmorphine N-demethylase activity was slightly decreased. NADPH-cytochrome P-450 reductase activity and cytochrome P-450 content were unaltered until 12 hr after the single administration of benzphetamine. Aniline hydroxylation was increased by the addition of benzphetamine to the incubation mixture and the increase in aniline hydroxylation caused by benzphetamine could be reversed by washing the microsomes.
Topics: Acetone; Aniline Compounds; Aniline Hydroxylase; Animals; Benzphetamine; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Ethylmorphine; Male; Metyrapone; Microsomes, Liver; Oxidation-Reduction; Phenacetin; Phenethylamines; Rats; Stimulation, Chemical; Sulfoxides
PubMed: 691869
DOI: 10.1254/jjp.28.213 -
The Journal of Biological Chemistry Jun 1983Benzphetamine demethylase and aniline hydroxylase activities were determined with various hemoproteins including indoleamine 2,3-dioxygenase in a cytochrome P-450-like...
Benzphetamine demethylase and aniline hydroxylase activities were determined with various hemoproteins including indoleamine 2,3-dioxygenase in a cytochrome P-450-like reconstituted system containing NADPH, NADPH-cytochrome P-450 reductase, and O2. The highest specific activities, almost comparable to those of liver microsomal cytochrome P-450, were detected with indoleamine 2,3-dioxygenase from the rabbit intestine. The indoleamine 2,3-dioxygenase-catalyzed benzphetamine demethylation reaction was inhibited by catalase but not by superoxide dismutase. Exogenous H2O2 or organic hydroperoxides was able to replace the reducing system and O2. The stoichiometry of H2O2 added to the product formed was essentially unity. These results indicate that the dioxygenase catalyzes the demethylation reaction by the so-called "peroxygenation" mechanism using H2O2 generated in the reconstituted system. On the other hand, the dioxygenase-catalyzed aniline hydroxylation reaction was not only completely inhibited by catalase but also suppressed by superoxide dismutase by about 60%. Although the O2- and H2O2-generating system (e.g. hypoxanthine-xanthine oxidase) was also active as the reducing system, neither exogenous H2O2 nor the generation of O2- in the presence of catalase supported the hydroxylation reaction, indicating that both H2O2 and O2- were essential for the hydroxylation reaction. However, typical scavengers for hydroxyl radical and singlet oxygen were not inhibitory. These results suggest that a unique, as yet unidentified active oxygen species generated by H2O2 and O2- participates in the dioxygenase-mediated aniline hydroxylation reaction.
Topics: Aniline Compounds; Aniline Hydroxylase; Animals; Aryl Hydrocarbon Hydroxylases; Benzphetamine; Catalase; Hydrogen Peroxide; Intestine, Small; Kinetics; Mixed Function Oxygenases; NADPH-Ferrihemoprotein Reductase; Oxygenases; Phenethylamines; Rabbits; Superoxide Dismutase; Tryptophan Oxygenase
PubMed: 6406489
DOI: No ID Found