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May 8, 2018
Circadian
May 8, 2018

Ciccone Pharma Sibutra Lean

R450.00

  • Sibutramine HCL
  • 30mg per tab
  • 30 tabs
SKU: 889 Category: Tag: Brand:
Description

Sibutramine (BTS 54 524; N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug (Stock, 1997), that has recently been licensed for the treatment of obesity in several countries. The mechanisms of sibutramine-induced weight loss are thought to include enhancement of satiety (Halford et al., 1998) and an increase in thermogenesis (Connoley et al., 1999; Hansen et al., 1998; McNeely & Goa, 1998). Sibutramine markedly reduces feeding behaviour and is effective in inducing weight loss in lean and genetically obese rodents (Stricker-Kongrad et al., 1995). Moreover, it improves glucose tolerance and decreases plasma insulin levels in these animals, implying that sibutramine may improve insulin sensitivity (Day & Bailey, 1998).

Pre-treatment with 5-HT or noradrenaline antagonists can partially or completely reverse the hypophagic effect of sibutramine, indicating that both neurotransmitters are involved in its pharmacological actions. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to sibutramine’s action), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour (Jackson et al., 1997a). The use of selective monoamine antagonists has confirmed that the acute satiety-inducing effects of sibutramine involves α1 and β1 adrenoceptors, as well as 5HTc and possibly 5HT2A receptors (Jackson et al., 1997b). Since neither sibutramine nor its two metabolites exhibit affinity for α1, β1 or 5HT receptors, the drug appears to enhance monoaminergic function by inhibiting noradrenaline and 5HT uptake (Heal et al., 1998).

5-HT acts on the hypothalamus to cause anorexia, weight loss (Blundell et al., 1995) and increased thermogenesis (Le Feuvre et al., 1991). A large number of peptides and other neurotransmitters found in the hypothalamus have effects on energy balance, including neuropeptide Y (NPY), galanin, melanocyte stimulating hormone (via the melanocortin-4 receptor) and recently cocaine and amphetamine-related transcript (CART) (Williams et al., 2000). Evidence exists to suggest that the anti-obesity actions of serotonin may be mediated by inhibition of hypothalamic neurones that express the powerful appetite-stimulating peptide NPY (Dryden et al., 1996; Rogers et al., 1991), and this study therefore focused on the possible involvement of NPY in mediating the effects of sibutramine on energy balance.

NPY is synthesized in arcuate nucleus (ARC) neurones that project mainly to the hypothalamic paraventricular nucleus (PVN) and dorsomedial nucleus (DMN) (Chronwall et al., 1985; Morris, 1989). These two latter sites are important integrating centres in the control of energy homeostasis, and are closely related to the ventromedial nucleus (VMN) and other sites connected with the sympathetic and parasympathetic nuclei of the brain stem (Sawchenko et al., 1985). NPY injected into the PVN induces insatiable hyperphagia (Stanley et al., 1986) and decreases whole-body energy expenditure by reducing the sympathetic stimulation of thermogenesis in brown adipose tissue (BAT) (Billington et al., 1994; Walker & Romsos, 1993); its repeated administration leads to obesity with hyperinsulinemia and marked insulin resistance (Zarjevski et al., 1994). Postulated peripheral signals regulating the activity of NPY hypothalamic neurons include insulin (Schwartz et al., 1992) and leptin (Vuagnat et al., 1998; Wang et al., 1997). Centrally, serotonergic neurones in the raphe nucleus project to the hypothalamus and terminate around the NPY cell bodies in the arcuate nucleus (ARC) of the hypothalamus, and NPY-immunoreactive endings in the paraventricular nucleus (PVN) (Pelletier, 1990). Previous studies have suggested that some agents that mimic or enhance 5-HT action and which cause hypophagia and weight loss also inhibit NPY neuronal activity (Dryden et al., 1996), although this is not the case for all such agents (Wilding et al., 1992a). Conversely, drugs that block 5-HT release or antagonize its action at 5-HT1B and -C receptors stimulate feeding and NPY neuronal activity (Dryden et al., 1995). This implies that serotonin may tonically inhibit the NPY neurones, and that the latter may mediate the effects of serotonin on energy homeostasis.

Unlike in rat models the majority of human obesity is polygenic, and is due to difficulty in regulating intake in the face of an increased availability of highly palatable foods and a decline in physical activity (Andersson, 1996). Rats fed a highly palatable diet develop moderate obesity, which like most human obesity is associated (at least in younger animals), with increased food intake, increased thermogenesis and insulin resistance (Stock & Rothwell, 1986). We therefore chose this model for our studies which were designed to answer the following questions, as to whether sibutramine is effective at reducing body weight in DIO, and secondly whether sibutramine improved insulin resistance in this model and finally whether the effects of sibutramine were mediated in part by modulation of hypothalamic NPY neurons.