New Drugs for Obesity Treatment / 대한내과학회지

There have recently been many advances in obesity treatment, including lifestyle modifications and pharmacological and surgical treatments. Specifically, pharmacological strategies have improved significantly. However, the history of the development of medications aimed at weight loss is complicated. The Federal Drug Administration (FDA) withdrew anti-obesity drugs such as fenfluramine, dexfenfluramine, and phenylpropylamine due to their unwanted side effects. Moreover, sibutramine was voluntarily withdrawn from the market and a new drug, rimonabant, has been suspended in the middle of a clinical trial due to unacceptable side effects. The FDA has approved four new anti-obesity drugs in recent years. Lorcaserin is a selective 5-hydroxytryptamine receptor 2c (5-HT2c) agonist. The pharmacological mechanism of action of this drug is similar to fenfluramine and dexfenfluramine, but lorcaserin is specific for 5-HT2c, which are located almost exclusively in the central nervous system and are not found in heart valves. Three phase 3 clinical trials for lorcaserin have been published recently; weight reduction was successful and no side effects involving the heart were found. Furthermore, the FDA has also approved phentermine/topiramate controlled-release (PHEN/TPM CR), which is composed of a combination of immediate-release phentermine and controlled-release topiramate. Weight reduction achieved with PHEN/TPM CR was demonstrated to be better than all other anti-obesity drugs. Lastly, the combination therapy bupropion/naltrexone activates proopiomelanocortin neurons and inhibits opioid-mediated negative feedback by synergism. Similar to liraglutide, a long-acting analogue of the hormone glucagon-like peptide-1, this treatment showed significant weight loss and metabolic improvements. However, in addition to its efficacy, clinicians should consider its side effects before use.

Weight Loss Drugs Recently Approved by the FDA / 임상당뇨병

There have been many advances in obesity treatment, including life-style modification and pharmacological and surgical treatments. It seems that the most remarkable advances in obesity treatment are those of pharmacological strategies. However, weight loss medications have a long history of development. The FDA has withdrawn anti-obesity drugs such as fenfluramine, dexfenfluramine, and phenylpropylamine due to unwanted side effects. Sibutramine was voluntarily withdrawn from the market, and new drugs such as rimonabant have been suspended in the middle of clinical study due to unacceptable side effects. Last year, the FDA approved two new anti-obesity drugs for the treatment of obesity. Lorcaserin is a selective 5-hydroxytryptamine receptor 2c (5-HT2c) agonist whose pharmacological mechanism of action is similar to those of fenfluramine and dexfenfluramine. However, lorcaserin is specific for 5-HT2c, which is located almost exclusively in the CNS and is not found on heart valves. Three exciting phase 3 clinical trials for lorcaserin have been published recently. Lorcaserin has been shown to successfully result in weight reduction, and the drug was not found to lead to heart disease, as is the case with some other such drugs. Furthermore, the FDA also approved controlled release phentermine/topiramate (PHEN/TPM CR), a drug composed of immediate-release phentermine and controlled-release topiramate. Weight reduction by PHEN/TPM CR is better than any other anti-obesity drugs in the world. Along with this excellent efficacy, however, come painful side effects that clinicians should consider.

Retrait du benfluorex dans plusieurs pays

N. A.

Perspectivas no tratamento medicamentoso da obesidade / Perspectives of drug treatment of obesity

As perspectivas no tratamento medicamentoso da obesidade discutidaspodem ser divididas em duas categorias, a saber: medicamentos comercializados, em estudo clínico avançado ou em via deaprovação, ou drogas em início de investigação. Entre os primeiros destacam-se anticonvulsivantes como o topiramato (que embora tenha sido estudado na indicação de tratamento de obesidade foi descontinuado para esta indicação devido ao elevado número deabandono por efeitos adversos) e a zonisamida (com alguns estudosde curta duração em adultos obesos); antidepressivos como a bupropiona (que não somente leva a reduções de peso como minimiza o ganho de peso associado a cessação de tabagismo) e aradafaxina (metabólito da bupropiona, sem estudos documentados em obesos); análogos do glucagon-like peptide-1 como a exenatida (exendina-4), a pramlintida e a liraglutida (com estudos em diabéticos tipo 2 obesos) e um bloqueador seletivo do receptor canabinóide tipo 1, o rimonabant, cujos estudos (Rimonabant in Obesity), RIOEurope, RIO-North America, RIO-Lipids e RIO-Diabetes, envolvemmais de 6.600 pacientes com obesidade, com e sem diabetes e que se apresenta como perspectiva importante de tratamento da obesidade. Em início de investigação, estão moduladores da homeostase energética como antagonistas do neuropeptídeo Y, agonistas da melanocortina, leptina e análogos da leptina e fator neurotróficociliar (axokine); agentes termogênicos como os agonistas do receptor adrenérgico beta-3, agentes desacopladores da membranamitocondrial e moduladores periféricos da homeostase energética como a colecistoquinina.

Tratamento medicamentoso atual / Current obesity drug tratment

O tratamento farmacológico da obesidade é uma área de bruscasmudanças, desenvolvimento de novos produtos e propostas de tratamento. A informação apresentada nesta revisão oferece uma visão dos agentes fisiológicos, da terapêutica corrente, bemcomo de medicamentos amplamente usados e que não mais estão disponíveis.

Influence of serotonergic transmission and postsynaptic 5-HT2C action on the feeding behavior of Coturnix japonica (Galliformes: Aves)

Investigamos nesse estudo o papel dos receptores 5-HT2C e da transmissão serotonérgica no controle do comportamento alimentar em codornas. Em grupo de aves em jejum, a administração do liberador de serotonina, fenfluramina (FEN) e dos agonistas 5-HT2C, mCPP e MK212, nas doses de 1,0 e 3,3 mg/Kg induziu a uma redução significativa da ingestão alimentar (0,71 ± 0,18 g e 0,47 ± 0,2 g; 0,49 ± 0,22 g e 0,48 ± 0,29 g; 0,82 ± 0,13 g e 0,71 ± 0,16 g; respectivamente). A ingestão de alimento nos grupos controles variou de 2,89 ± 0,21 g a 2,97 ± 0,22 g, 60 min após a reapresentação de alimento, P < 0,0001). Resultados similares foram obtidos com as codornas normoalimentadas. Tanto o liberador de serotonina, FEN, quanto os agonistas 5-HT2C, mCPP e MK212 em doses de 3,3 mg/Kg induziram resposta hipofágica (FEN, 0,78 ± 0,08 g; mCPP, 0,89 ± 0,07 g; MK212, 1,25 ± 0,17 g vs. controles, 2,05 ± 0,12 g, 120 min após a oferta de alimento, P < 0.0001 a P < 0.01). A administração prévia do antagonista 5-HT2C, LY53857 (5,0 mg/Kg) bloqueou a resposta hipofágica induzida pelos agonistas 5-HT2C, 60 min após a apresentação de alimento. Os resultados obtidos demonstram o papel modulatório da liberação de serotonina e dos receptores pós-sinápticos 5-HT2C, no controle do comportamento alimentar de codornas.

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean ± SEM, pg/20 æl, was 3.0 ± 0.4 for LDS, 3.8 ± 0.3 for HDS and 6.4 ± 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (±)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500 percent) as compared with LDS (248 percent) or RDS (243 percent) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900 percent in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line

Effects of changes in conformation and configuration of N-containing compounds on NMR spactra / 药学学报

<p><b>AIM</b>To find the cause of abnormal NMR spectra of lomerizine dihydrochloride, cetirizine dihydrochloride and flenfluramine camphoramide.</p><p><b>METHODS</b>Hypothesizing, in given conditions, there are changes of stereoisomeric conformation and configuration in structure of N-containing compounds, it results in abnormality of NMR spectra. By using the method of NMR, it is confirmed credibily.</p><p><b>RESULTS AND CONCLUSION</b>The moving balance exists between two chair conformations in lomerizine dihydrochloride and cetirizine dihydrochloride. It causes that spin-nuclei of whole molecule are placed in two chemical circumstance. In solution of DMSO-d6, the speed of conformation reversal equals to the NMR time scale, so that chemical shift of spin-nuclei can not be definitely determined, peaks are broadened and even collapsed. After dropping D2O or increasing the temperature, the viscosity of the solution is decreased, the speed of reversal is quicker than NMR time scale, then normal spectra are obtained. Owing to the reversal of the three bonds of nitrogen in flenfluramine camphoramide is limited, other pair of diastereoisomer resulted from the asymmetric nitrogen can be detected by NMR. Multiplication of the peaks of 13CNMR is reasonably explained.</p>

Two Cases of Acute Fenfluramine Intoxication

Fenfluramine is an amphetamine-derived substance first developed in the late 1960s for appetite control. Because of its known side effects at therapeutic doses, it is now controlled by the government and has been withdrawn from the market, but the underground market is still big. When over-dosed, it can produce a wide range of neurologic and cardiovascular symptoms, and even death, when a large amount is ingested. We report two cases of acute fenfluramine overdose: a fatal case with generalized seizure and pulseless electrical activity, and a case of relatively mild intoxication.

A case of toxic hepatitis caused by the chinese diet food / 대한내과학회지

Recently over 500 victims with toxic hepatitis associated with some sort of Chinese diet food for weight reduction were developed in Japan, China, Singapore and Malaysia. These Chinese goods contain several kinds of Chinese herbs and fenfluramine, the well known anti-appetite drug. However, until today, it is not determined which component of the diet food is responsible for the hepatic injury. Nowadays, toxic hepatitis is frequently seen in daily practice, second only to viral origin in Korea. We present a 38-year-old woman who developed mixed cholestatic and hepatocellular injury after 5 week's ingestion of the Chinese diet food. The causality of this agent to the hepatotoxicity was assessed by RUCAM and M and V scale. Herein we described the clinical course and liver pathology of this patient.

Daño valvular aórtico, mitral y tricuspídeo asociado con el uso crónico de fenfluramina y dexfenfluramina

Se presentan 3 pacientes que consultaron a la sección de endocrinología de la Fundación Santa Fe de Bogota para evaluación de la funcion tiroidea. Todos tenian diagnostico de hipotiroidismo de varios años de evolución, tratado con medicamentos anorexiantes serotoninergicos tipo fenfluramina o dexfenfluoramina. Los tres pacientes fueron de sexo femenino, de 58, 34 y 44 años de edad, ninguna tenia historia de enfermedad valvular. El paso fue de 59,61 y 69 Kg. con indices de masa corporal de 23, 24 y 26 Kg/m respectivamente. Las pacientes 1 y 2 recibieron fenfluoramina (60 mg/dia) por nueve y siete años respectivamente y la 3 recibio dexfenfluoramina por diez meses a dosis de 30 mg diarios por tener antecedentes de sobrepeso u obesidad. Se confirmaron en las pacientes 1 y 3 insuficiencia aortica y mitral y en la 2 insuficiencia aortica, mitral y tricuspidea. La apciente 1 requirio remplazo valvular aortico y mitral y la patologia evidencio cambios compatibles con sindrome carcinoide. Comclusiones: los tres caso sugieren asociacion del uso de fenfluoramina y dexfenfluoramina a largo y mediano plazo, con daños valvulares e insuficiencias mitral, aortica y tricuspidea. El estudio histopatologico similar al sindrome carcinoide en uno de los casos, reafirma la sospecha

Effects of sumpathomimetic anorexigenic agent [fenfluramine] on some hepatic, haematological and thyroid functions in rabbits

Fenfluramine is a sympathomimetic-anorexigenic amphetamine derivative. Fentluramine may affect variable body systems during continuous use. No data as regard the influence of fenfluramine on ferrokinetics and hence this necessitates a proper line of investigation. This study was performed on 40 male Rabbits, divided into two groups; group I for studying liver functions,% saturation of transferrin, and some haematological parameters, group II for studying thyroid functions and radio-active 58Fe ferrokinetics. The results had shown that: 1. The chemical had led to significant decrease in liver functions and in serum iron. 2. No significant change was shown in the haematological parameters. 3. There was significant decrease in radio-iron in the plasma. 4. There was significant increase in T3 and T4. Thus the drug might have a deleterious effect on ferrokinetics, liver cells and thyroid gland therefore, it should be used cautiously

Alteration in the activities of the membrane-integrated enzymes of polymorphonuclear leukocytes in obesity.

Oubain sensitive and insensitive adenosine triphosphatase showed decrease in their activities in the polymorphonuclear leukocytes of obese patients while the activity of acetylcholinesterase was found to be increased significantly. The contents of sodium, potassium and magnesium were found to be significantly decreased in polymorphonuclear leukocytes of obese patients. Polymorphonuclear leukocytes obtained from treated obese patients showed considerable restoration.

Hormonal response during a fenfluramine-associated panic attack

Secretion curves for prolactin, cortisol, TSH, and GH from a 37-year old woman with dysthymia and panic disorder with agoraphobia were determined one day prior to (day I), and during a panic attack (day II) associated with an oral dose of 60 mg dl-fenfluramine, a drug known to increase anticipatory anxiety. The increased cortisol secretion observed is discussed in relation to the hormonal correlates of anxiety and the possible role of depresion, dl-fenfluramine, and serotonergic receptor sensitivity.