The Effect of Sibutramine, a Serotonin-Norepinephrine Reuptake Inhibitor, on Platelets and Fibrin Networks of Male Sprague-Dawley Rats: A Descriptive Study

Abstract

Sibutramine is used in the treatment of obesity due to its ability to influence feelings of hunger and satiety by inhibiting the re-uptake of serotonin and noradrenalin in the central nervous system (CNS). Sibutramine use has been associated with numerous adverse events in particular cardiovascular complications possibly due to the formation of thrombi. This ultrastructural descriptive study investigated the effect of sibutramine on blood coagulation, specifically the effect on morphology of platelets and fibrin networks using scanning electron microscopy. Male Sprague-Dawley rats treated with either a recommended therapeutic dose [low dosage 1.32 mg/kg] or a toxicological higher dose [high dosage 13.2 mg/kg] of sibutramine for 28 days were used and compared to control animals. Blood samples were collected and plasma smears were prepared for platelet evaluation. Following the addition of thrombin to the plasma samples, the morphology of the fibrin clots was evaluated. Platelet evaluation by scanning electron microscopy revealed morphology typical of a prothrombotic state with a characteristic excessive platelet activation in both low-dose (LD) and high-dose (HD) rats. The fibrin clots of sibutramine-treated rats, LD and HD revealed fused thick fibers with thin fibers forming a netlike structure over the thick fibers which differ considerably from the organized structure of the control animals. It can be concluded that sibutramine alters the ultrastructure of platelets and fibrin networks creating a prothrombotic state.

Natural Products with Anti-obesity Effects and Different Mechanisms of Action

“…The 5-HT-NE re-uptake inhibitor, sibutramine, approved by the FDA in 1997, was used as an anti-obesity drug because of its ability to influence feelings of hunger and satiety at the CNS level . However, cardiovascular complications possibly arising from thrombus formation after sibutramine treatment led to its market withdrawal in 2010 . Synergism between neuropeptide Y2 and Y4 receptor signaling in controlling fat mass may be linked to differences in mitochondrial oxidative capacity, which increase peroxisome proliferator-activated receptor (PPAR)-γ gamma coactivator 1-α (PGC-1α) and mitochondrial respiratory chain complexes I and III .…”

“…34 However, cardiovascular complications possibly arising from thrombus formation after sibutramine treatment led to its market withdrawal in 2010. 35 Synergism between neuropeptide Y2 and Y4 receptor signaling in controlling fat mass may be linked to differences in mitochondrial oxidative capacity, which increase peroxisome proliferator-activated receptor (PPAR)-γ gamma coactivator 1-α (PGC-1α) and mitochondrial respiratory chain complexes I and III. 36 A dual neuropeptide Y2/Y4 receptor agonist, obinepitide, has a long-term influence on suppressing appetite and reducing body weight in rodents and is presently in phase II clinical trials.…”

Herbal Medicine for the Treatment of Obesity: An Overview of Scientific Evidence from 2007 to 2017

“…However, the weight loss drugs prescribed in conventional medicine induce many adverse reactions, primarily effecting monoamine neurotransmitters, and causing drug abuse or dependence [10]. For example, sibutramine has been reported to commonly cause adverse events, including dry mouth, insomnia, anorexia, constipation, formation of thrombi, and neurological symptoms [11, 12]. Surgery is commonly used in morbidly obese patients (BMI ≥ 40 kg/m 2 ) or in patients with comorbidities, such as hypertension, diabetes, and obstructive sleep apnea [13].…”

Comparative Analyses of Poly(ADP-Ribose) Polymerase Inhibitors

“…[4][5][6][7]19 For example, the increased thrombocytopenia observed with niraparib in mBRCA1/2 ovarian cancer cannot be sufficiently explained by primary pharmacology alone, but can potentially be attributed to the SERT and NET inhibition by niraparib alone since the SERT and NET reuptake inhibitor (sibutramine) has been shown to produce a prothrombotic state by altering the ultrastructure of platelets and fibrin networks. 7,36 Similarly, the higher incidence of grade ≥3 anemia with talazoparib versus olaparib in breast cancer patients can potentially be attributed not only to the primary pharmacology, 19 which includes superior PARP trapping affecting the BM cell viability, but also to the comparatively long systemic exposure of talazoparib versus olaparib (elimination half-life of 90 hour versus 15 hour) that likely prolongs the regeneration of the erythroid compartment (normal, 3 weeks). 4,6,15 In fact, the individual labels show that the higher incidence of talazoparib-induced anemia generally manifests around Days 21-24 following the initiation of treatment.…”