Sibutramine

Sample preparation Mix 1 mL plasma, 50 ixL 80 iJig/mL IS in MeOH, 1 mL saturated sodium bicarbonate, and 5 mL cyclohexane, centrifage. Evaporate the organic layer to dryness under a stream of nitrogen, reconstitute the residue with 100 (aL mobile phase, inject a 50 p,L aliquot. 

Mobile phase MeOH 10 mM pH 3.5 ammonium acetate buffer 75 25 (divert first 3 min to waste) 

Detector MS, quadrupole, electrospray, drying gas nitrogen 10.5 L/min, nebulizer 45 psi, drying gas 350°, capillary 4 kV, positive ion mode, fi agmenter 70 V, m/z 280 

Internal standard phenoprolamine HCI (A -(2-(3,4-dimethox5q)henyl)ethyl)-lV-(2-(2,6-dimethylphenoxy)-l-methylethyl)amine) (m/z 344) (3.5) 

Simultaneous determination of sibutramine and its JV-desmethyl metabolites in human plasma by liquid diromatography-electrospray ionization-mass spectrometry method and clinical applications. Area/.C/iim.Acbi, 2003, 492, 241-248. 

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Sibutramine (Table 1) has been in the market for several years and inhibits the reuptake of serotonin, noradrenaline and, to a lesser extent, dopamine. It acts... 

C3HfiBr2 109-64-8) see Brinzolamide Carpipramine Dibrornpropamidine Ethoheptazine Pentoxifylline Sibutramine hydrochloride 23-dibromo-1 -propanol... 

C 4H 4N 201030-97-9) see Imiquimod (2-methylpropyl)magnesium bromide (C4H9BrMg 926-62-5) see Repaglinide Sibutramine hydrochloride... 

A link between 5-HT transmission and hypophagia is further reinforced by the pharmacology of drugs that reduce food intake ( anorectic agents), such as (7-fenfluramine or sibutramine. Both these compounds have actions that should lead to increased synaptic concentrations of 5-HT in the brain, albeit through different mechanisms (see below), but whether or not this actually explains the anorectic actions of (7-fenfluramine is controversial. 

An important distinction between the effects of sibutramine and i/-fenfluramine is highlighted by microdialysis studies (Heal et al. 1998). These show that the rate of increase in 5-HT efflux in the region of the PVN, after administration of sibutramine, is slow, progressive and long-lasting. This is because it relies on the accumulation of extracellular 5-HT following the inhibition of its reuptake after impulse-dependent release. This time-course contrasts with the rapid and transient increase in 5-HT efflux which results from the fenfluramine type of impulse-independent release from nerve terminals. In fact, this rapid increase in 5-HT release is thought to underlie the serious adverse side-effects of (i-fenfluramine that have led to its withdrawal from the clinic. 

A final, important distinction between sibutramine and (7-fenfluramine is that the actions of the former, but not the latter, rest on its modification of both 5-HT and noradrenergic transmission. Thus, the reduction in food intake by sibutramine is partially blocked by ai- or jSi-adrenoceptor antagonists as well as 5-HT2a/2C or 5-HT2b/2c antagonists. In fact, there appears to be a synergistic interaction between these two transmitter systems. This is illustrated by a study of the effects of the selective serotonin... 

Gillman, PK (1999) The serotonin syndrome and its treatment. J. Psychopharmacol. 13 100-109. Heal, DJ, Cheetham, SC, Prow, MR, Martin, KF and Buckett, WR (1998) A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying drugs. Brit. J. Pharmacol. 125 301-308. 

Jackson, HC, Needham, AM, Hutchins, LJ, Mazurkiewicz, SE and Heal, DJ (1997) Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Brit. J. Pharmacol. 121 1758-1762. 

Siuciak, JA, Clark, MS, Rind, HB, Whittemore, SR and Russo, AF (1998) BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J. Neurosci. Res. 52 149-158. Sprague, JE, Everman, SL and Nichols, DE (1998) An integrated hypothesis for the serotonergic axonal loss induced by 3,4-methylenedioxymethamphetamine. Neuro toxicology 19 427-A42. Stock, MJ (1997) Sibutramine a review of the pharmacology of a novel anti-obesity agent. Int. J. Obesity 21 (Suppl 1) S25-S29. 

Heal, DJ, Butyler, SA, Hurst, EM and Buckett, WR (1989) Antidepressant treatments, including sibutramine hydrochloride and electroconvulsive shock, decrease betal- but not beta2-adrenoceptors in rat cortex. J. Neurochem. 53 1019-1025. 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

Dextromethorphan, meperidine, and pentazocine ° Amphetamine, fenfluoramine, dexfenfluoramine, methylphenidate, and cocaine ° Sibutramine, St. John s wort, ondansetron, granisetron, dolasetron, and palonosetron... 

Sibutramine and its two active metabolites (Mj and M2) exert their effect by inhibiting the reuptake of serotonin, norepinephrine, and dopamine.29 Appetite becomes suppressed because patients feel a sense of satiety. 

Sibutramine Noradrenergic/serotonergic agent 5-1 5 mg Greater than 3 months3... 

Since no human data exist to determine its safe use in pregnant women, sibutramine is not recommended therefore, women of childbearing potential should use effective methods of contraception while taking sibutramine. Further, sibutramine is not recommended for lactating mothers because its excretion in breast milk is likewise unknown.29... 

Initiate sibutramine at a dose of 10 mg once daily, preferably in the morning without regard to meals. The dose may be increased after 4 weeks to 15 mg once daily if weight-loss goals are not attained. Doses exceeding 15 mg/day are not recommended. For patients intolerant of the 10 mg/day, a dose of 5 mg once a day may be used.29... 

Ionamin ). Sibutramine increases norepinephrine and serotonin. Phentermine increases norepinephrine only. 

Sibutramine is approved by the FDA for long-term management of weight loss it can be used for approximately one year. 

The starting dose of sibutramine is usually 10 to 15 mg once a day. The drawback of this drug is that, as with all medications used to treat obesity, the lost weight eventually reappears unless the patient continues to engage in healthy eating habits and an exercise program. 

One study of people who used sibutramine for two years (although the FDA only approved one year of use) showed one possibly positive effect of this drug continued weight maintenance. In this study, over 80% of people who took sibutramine for two years kept their weight constant. Along with the maintained weight loss, researchers also found that patients were able to decrease the lipid (fat) in their bloodstream, which has beneficial effects on the health of the heart. 

Sibutramine use also carries the risk of side effects, which include elevated blood pressure, increased heart rate, dry mouth, nausea, and dizziness. Abuse of sibutramine can cause dilated pupils, excessive bleeding or bruising, tremor, and anxiety. As with all prescription drugs, it is essential to use sibutramine according a doctor s instructions. The alternative is the possibility of unpleasant side effects and dangerous outcomes. 

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