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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 -
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 -
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 -
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 Jul 2002The compound herbal medicine Wu-chu-yu-tang is used for the treatment of migraine and vomiting accompanying a cold. To assess the interactions of herb and drug...
The compound herbal medicine Wu-chu-yu-tang is used for the treatment of migraine and vomiting accompanying a cold. To assess the interactions of herb and drug metabolism, effects of Wu-chu-yu-tang on hepatic and renal cytochrome P450 (CYP), UDP-glucuronosyl transferase (UGT) and glutathione S-transferase (GST) were studied in C57BL/6J mice. Treatment of mice with 5 g/kg per day Wu-chu-yu-tang for 3 days caused 2.5-fold and 2.9-fold increases of liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activities, respectively. However, CYP activities toward 7-ethoxycoumarin, benzphetamine, N-nitrosodimethylamine, erythromycin and nifedipine, and conjugation activities of UGT and GST were not affected. In kidney, Wu-chu-yu-tang-treatment had no effects on Cyp, UGT and GST activities. Among the four component herbs of Wu-chu-yu-tang, only Evodiae Fructus (Wu-chu-yu) extract increased EROD activity and CYP1a2 protein level. In E. Fructus, rutaecarpine, evodiamine and dehydroevodiamine are the main active alkaloids. At the doses corresponding to their contents in Wu-chu-yu-tang, rutaecarpine-treatment increased hepatic EROD activity, whereas evodiamine and dehydroevodiamine had no effects. These results demonstrated that ingestion of Wu-chu-yu-tang elevated mouse hepatic Cyp1a2 activity and protein level. E. Fructus and rutaecarpine contributed at least in part to the CYP1a2 induction by Wu-chu-yu-tang. Patients should be cautioned about the drug interaction of Wu-chu-yu-tang and CYP1A2 substrates.
Topics: Alkaloids; Animals; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Evodia; Kidney; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Plant Extracts; Quinolines
PubMed: 12184732
DOI: 10.1254/jjp.89.267