Safety pharmacology of sibutramine mesylate, an anti-obesity drug

Abstract

<jats:p> Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague <jats:sup>/</jats:sup> respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbitalinduced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric <jats:sup>/</jats:sup> Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions. </jats:p>

Serotonin and Norepinephrine Reuptake Inhibition and Eating Behavior

“…We confirmed the role of sibutramine treatment in increasing the habitual physical activity: the increase in reported daily walking time during the 4‐month placebo‐controlled period was significantly higher in the sibutramine‐treated than in the placebo group 60 . Spontaneous locomotor activity was also significantly increased in experimental animals following the administration of sibutramine 61 …”

“…60 Spontaneous locomotor activity was also significantly increased in experimental animals following the administration of sibutramine. 61 As mentioned before, SSRI have exhibited efficacy in reducing the frequency of binge-eating episodes and ameliorating depressive symptomatology in BED, but they have not demonstrated the ability to achieve long-term weight reduction. 42 On the contrary, the sibutramine treatment of BED resulted not only in a decreased frequency of binge eating and an improvement of comorbid conditions as depressive symptoms, but also in the reduction of body weight.…”

Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: Physicochemical characterization and pharmacokinetics in beagle dogs

“…Recently, considerable attention has been focused on the improvement of drug solubility by synthesizing different salt forms. Sibutramine mesylate (Kim et al, 2005) and sibutramine tartrate (HPC, 2006) have been synthesized, and showed an increase in solubility to 2500 and 500 mg/ml at pH 5.2, respectively. However, in order to use these new synthesized materials as commercial products, clinical tests must be carried out.…”

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

“…Compared to other behavioral assays such as the Irwin test, the locomotor activity and wheel-running assays have a number of advantages: they are relatively easy to implement, experimenters need little or no training, and data are objective and quantitative allowing for direct statistics-based comparisons across compounds. Drugs known to prevent or reduce sleep in humans such as sibutramine, modafinil, and ephedrine trigger a strong signal in the locomotor activity or wheel-running assays (Meng et al 1999;Kim et al 2005). Likewise, drugs that promote sleep or cause sedation in humans such as diazepam, zolpidem, and diphenhydramine will readily cause a decrease in locomotor activity in rats and mice (Kalivas 1982;Vlainic and Pericic 2009).…”