Anti-obesity Drug Discovery and Development: Volume 3 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Anti-obesity Drug Discovery and Development
- Sprache: Englisch
Obesity is a complex health problem, caused by a number of factors such as excessive food intake, lack of physical activity, genetic predisposition, endocrine disorders, medications and psychiatric illnesses. Onset of obesity in both the developing and the developed world has reached epidemic proportions. In response to this, efforts to control and treat obesity have also been vigorously pursued, ranging from raising awareness about lifestyle changes to the discovery and development of safe and effective anti-obesity drugs.
Anti-obesity Drug Discovery and Development is focused on this very important area of healthcare research. The third volume of this series is dedicated to anti-obesity treatments including updates on new therapeutics for obesity, Nesfatin-1 and its therapeutic uses, the role of proteomics in pediatric anti-obesity treatment, the role of oxidative stress in childhood obesity and a review of data on gut microbiota as a treatment option for obesity.
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Anti-Obesity Drug Discovery
and Development
(Volume 3)
Edited By
Atta-ur-Rahman, FRS
M. Iqbal Choudhary
BENTHAM SCIENCE PUBLISHERS LTD.
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PREFACE
An epidemic of obesity is among the most important global healthcare challenges of the 21st century, causing considerable morbidity and mortality in a large segment of human population. Obesity has been identified as the largest preventable cause of numerous diseases. Obese and overweight population are at risk for a number of conditions, including high cholesterol levels, high blood pressure, heart diseases, diabetes, bone problems, skin diseases, neurological and psychological disorders, and increased chances of various malignancies. At individual level, obesity adversely effects the state of health and the quality of life, whereas at national level, it is a significant burden on the current healthcare systems. Unfortunately existing anti-obesity drugs are associated with numerous side effects, and are only prescribed when the benefits of treatment outweigh their risks.
The regulation of body weight is a complex process which involves cascades of mechanisms, including a variety of neuropeptides and transmitters in the brain, and endocrine and metabolic signalling molecules. Many of these processes are only superficially understood and extensive research is being conducted to decipher the complex biomolecular pathways behind the obesity syndrome. Understanding these inherent pathways, as well as the role of other factors, such as dietary habits, physical activities, gut microflora, etc. is critically important in devising successful strategies to combat obesity epidemics, including the discovery and development of improved treatments.
The 3rd volume of the book series entitled “Anti-Obesity Drug Discovery and Development” presents the most exciting recent developments in the field of obesity and its treatment. This book comprises five authoritative reviews ranging from identification of new drug targets to novel pharmacological and non-pharmacological interventions.
The first chapter by Ohta et al. presents a comprehensive account of recent literature on various treatment options available for obesity. Primary treatment of obesity disorder involves dietary restrictions, and exercise. However, in many cases, pharmacotherapy is imperative. The authors have categorised anti-obesity drugs into three classes, i.e. appetite suppressors, agents which inhibit nutritional absorptions, and drugs which accelerate energy expenditures. Various molecular targets in all three categories have been described, with merits and demerits of drugs developed against them.
Nesfatin-1 is a peptide which has attracted considerable attention as a possible antibody treatment of obesity. Nesfatin-1 is secreted by peripheral tissues, central and peripheral nervous system and it can pass the blood-brain barrier. It is involved in the regulation of energy homeostasis related with food regulation and water intake. It suppresses the urge for food independently from the leptin pathway and increases insulin secretion of the pancreatic beta islet cells. The use of Nesfatin-1 for the treatment of obesity has been widely investigated. Finelli has contributed a comprehensive review in chapter 2 on the potential of Nesfatin-1 as a new treatment for obesity and related disorders, its effects on other physiological parameters and the proposed mechanisms of action.
In chapter 3, Walker et al. focus on obesity in children, and identification of appropriate drug targets. Paediatric obesity is a growing menace with increasing prevalence globally. Overweight and obese children are at high risk of becoming overweight adolescents and adults, developing chronic diseases, such as heart disease and diabetes later in life. They are also more prone to develop stress, sadness, and low self-esteem. Adipose tissues (AT) play an important role in obesity. AT dysfunction leads to chronic inflammation, weight homeostasis, and insulin resistance. Understanding AT dysfunction at receptors and secondary messenger pathways is critically important in understanding the unique features of paediatric obesity at molecular levels. The authors have reviewed recent advances in the field of proteomics technologies with reference to their use in identifying key components of adipose proteome. This helps in understanding the pathogenesis of adipose tissue dysfunction in obesity
Mancini et al. have contributed a chapter on vascular, histopathological and metabolic changes that occur in obese children, which in many cases lead to metabolic syndrome, such as insulin resistance, type 2 diabetes, dyslipidemia, endothelial dysfunctions and cardiovascular disorders. The authors have focussed on the role of neuroendocrine peptides and cytokines in chronic inflammation and oxidative stress (OS). These mediators of chronic inflammation and OS are produced in adipose tissues, and are thus, directly responsible for endothelial dysfunction and insulin resistance. An extensive commentary on the role of oxidative stress in the onset of various obesity related diseases, such as atherogenesis and diabetes, is presented. Based on this, the authors have moved on to discuss the strategies to lower the chronic inflammation and oxidative stress in childhood obesity in order to prevent metabolic syndrome.
Gut microflora are perceived to play an important role in the prevention of various diseases, including obesity. Comparative studies have been conducted on bacterial flora of obese and lean individuals, and substantial differences were recorded. The disequilibrium in the composition of microorganisms that inhabit the human body can cause various diseases. High-throughput sequencing techniques and new tools used in bioinformatics have indicated strong relationships between the gut microbiota, and host's physiology. Disruption of the ecological equilibrium in the gut is called dysbiosis. Diet is a strong determinant of gut microbial balance. In chapter 5, Johnson et al. present a comprehensive discussion on state-of the-art understanding of the role of intestinal dysbiosis in the on-set of obesity disorder. They reviewed the most recent literature on the restoration of microflora in gut as a novel therapeutic option against the obesity epidemics. Strategies for the manipulation of intestinal microflora, such as antibiotic therapy against xenobiotic flora, supplementation of normal flora through probiotics and prebiotics and symbiotics (combination of probiotics and prebiotics), fecal microbiota transplant, etc. have been discussed. The role of intestinal microflora in metabolic programming is also extensively discussed.
In brief, the above cited reviews contributed by leading researchers in the field make this volume an interesting and useful reading for scientists and graduate students. We wish to express our felicitation and gratitude to all the authors for their excellent and scholarly contributions for the 3rd volume of this reputed series. We also greatly appreciate the efforts of the entire team of Bentham Science Publishers for efficient processing and timely management of the publication. The efforts of Ms. Faryal Sami (Assistant Manager Publications), Mr. Shehzad Naqvi (Senior Manager Publications) and the leadership of Mr. Mahmood Alam (Director Publications) are specially praiseworthy. We hope that like the previous volumes of this internationally recognized book series, the current compilation will also receive a wide readership and appreciation.
Prof. Dr. Atta-ur-Rahman FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UK &Prof. Dr. M. Iqbal Choudhary H.E.J. Research Institute of Chemistry International Center for Chemical and Biological Sciences University of Karachi Karachi PakistanList of Contributors
Current Status of Medical Therapy and New Targets for Anti-Obesity Drug Development
Chihiro Okuma,Yukihito Ishii,Takeshi Ohta*Abstract
Obesity is considered to be caused by an imbalance in individual energy. The basic therapies for obesity are appropriate dietary restriction for the purpose of decreasing energy intake and effective exercise for the purpose of promoting energy expenditure. At present, drug therapies for obesity are secondary treatments. Therapeutic strategies using pharmacotherapy are divided into the following three types: 1) suppressing appetite, 2) inhibiting nutritional absorption, and 3) accelerating energy expenditure. Mazindol and Phentermine have long been recognized as drugs for increasing satiety, and Orlistat and Cetilistat have been developed as drugs that inhibit lipid absorption from the intestine. Moreover, ß3 agonists have been developed to accelerate energy combustion. In this chapter, we first introduce drugs that are on the market, after which drugs that are in clinical or preclinical stages of development will be introduced. Furthermore, obese animal models that are now available will be introduced in the last section.
INTRODUCTION
The number of obese patients is rapidly increasing all over the world due to changes in lifestyle, such as habits of consuming high calorie diets and sedentary lifestyles. Obesity and obesity-related diseases, such as diabetes mellitus, dyslipi-demia, and hypertension, deteriorate the quality of life (QOL) of patients and result in high medical expenses [1-3].
Energy homeostasis in the body is maintained by a balance between energy intake and energy expenditure. When the former exceeds the latter, overt energy is accumulated in adipose tissues, resulting in obesity. Regulating food intake and
energy expenditure and integrating this balance is important in preventing obesity [4, 5]. Lifestyle modifications, such as diet therapy and exercise, as well as medications, chiefly occupy the treatments for obesity and related diseases; however, bariatric surgery is sometimes performed on patients with overt obesity (ex. Body mass index (BMI) over 35) [6-8].
Basically, medical therapy is a pivotal step in reducing excess fat accumulation. To reduce excess fat accumulation and excess body weight, several anti-obesity drugs that reduce appetite or lipid absorption in the intestine have been developed. Mazindol is now available only in Japan [9]. In the 1990s, another type of anti-obesity drug, Orlistat, was approved in the U.S. and Europe. Orlistat inhibits lipid absorption in the intestine and is now also available [10, 11]. Thereafter, Sibutramine and Rimonabant were developed; however, both drugs were withdrawn because of adverse effects [12]. Drug combinations, including Qsymia and Contrave, have been developed [13] and serotonin (5HT2c)-R agonist Lorcaserin was approved by the FDA in 2012 [14].
In addition, a variety of drugs with various mechanisms, such as microsomal triglyceride transfer protein (MTP) inhibitors, diacylglycerol acyltransferase 1 (DGAT1) inhibitors, monoacylglycerol acyltransferase (MGAT) inhibitors, and protein tyrosine phosphatase 1B (PTP1B) inhibitors, have been investigated in clinical and basic research stages of development [15-20]. Several anti-obesity drugs were withdrawn because of adverse effects; however, a tremendous amount of research to develop novel anti-obesity drugs is still ongoing all over the world. In this chapter, we focus on the effects of these drugs and will introduce preclinical and clinical data.
Approved Drugs
Anti-obesity drugs launched in the past years are shown in Table 1. Ten drugs have been launched to date, but the six drugs were withdrawn because of the severe side effects. The drug properties, including efficacy and adverse events, are shown in Table 2. Efficacy indexed by body weight change was approximately 5-10 kg decrease in body weight. Mazindol showed pronounced clinical efficacy, - 14.2 kg, whereas the decrease in BELVIQ, - 5.8 kg, was mild as compared with the other drugs. Adverse events related to the central nervous system, such as nervousness, anxiety, and dizziness, were observed as responses to TAAR1 agonists, monoamine-reuptake inhibitors, and serotonin receptor agonists. Moreover, digestive symptom, such as, oily stool, faecal urgency, and oily spotting was observed in orlistat. Detailed features of each anti-obesity drug are included in Table 2.
Phentermine
Phentermine is a sympathomimetic amine (Fig. 1A) and anorectic agent that is used for short-term therapy of obesity (less than 12 weeks) in combination with behavioral modification, caloric restriction and exercise. In 1959, phentermine received approval from the FDA as an appetite-suppressing drug, after which a hydrochloride form of the drug became available in the early 1970s. In 1999, phentermine was removed from the market in the EU; however, the drug is also currently sold as a generic in the U.S., and is still available in most countries, including the U.S [21, 22].
Phentermine, which is a trace amine-associated receptor 1 (TAAR1) agonist, is a structural analogue of amphetamine (Fig. 1B), and demonstrates some similarities in terms of mechanisms of action, such as suppressing appetite, but also demonstrates several of the central nervous system effects of amphetamine [23]. Amphetamine stimulates neurons to release and sustain the levels of neurotransmitters known as catecholamines, such as norepinephrine, serotonin, and dopamine. The elevation of catecholamines inhibits hunger signals and appetite. The pharmacological effects of phentermine in increasing weight loss are mediated by anorectic activity that is the result of catecholamine release from the appetite center of the brain. Phentermine is also considered to inhibit the reuptake of catecholamines through the inhibition or reversal of reuptake transporters [24, 25]. Phentermine may inhibit monoamine oxidase (MAO) enzymes, leaving more neurotransmitters available at the synapse. Phentermine works on the hypothalamus portion of the brain to stimulate adrenal glands to release norepinephrine. Moreover, phentermine works outside the brain to release epinephrine (adrenaline), causing fat cells to promote lipolysis. However, the principal basis of efficacy is hunger reduction. Phentermine is considered to indirectly increase the levels of leptin that signal satiety in the brain through catecholamine elevation. The elevation of catecholamine levels is also considered partially responsible for halting another chemical messenger, neuropeptide Y, which initiates eating, decreases energy expenditure and increases fat storage.
A double-blind clinical study, wherein 36 weeks of continuous and intermittent treatment with phentermine and placebo were evaluated, was reportedly conducted in 108 obese patients [26]. In this study, the weight loss effect reached a plateau after about 24 weeks of treatment. In patients who completed the study, weight loss in the intermittent phentermine group was as effective as that in the continuous group and was more effective than that in the placebo group. Phentermine treatment resulted in the reduction of appetite; however, the effectiveness in individual patients varied and was not clearly related to the degree of obesity, age, or dietary habits, thereby making a determination on the duration of appetite-reducing effects of phentermine difficult. In patients treated intermittently or continuously with the drug, a 56% decrease in weight during the last 16 weeks of treatment compared with 28% in the placebo group was observed. In all groups, weight loss diminished with duration of treatment. Adverse events related to central nervous system-stimulating effects, such as insomnia, irritability, agitation, nervousness, and anxiety, were observed.
Mazindol
Mazindol is also a sympathomimetic amine (Fig. 2), which is similar to an amphetamine, and is used in short-term treatment (a few weeks) of overt obesity in combination with behavioral modification, caloric restriction and exercise in patients with a body mass index (BMI) that is 30 kg/m2 or higher, or BMI that is 27 kg/m2 or higher in the presence of risk factors, such as diabetes, hyperlipidemia and hypertension [27]. Mazindol reportedly suppresses food intake by stimulating beta-adrenergic receptors, inhibiting the feeding center and stimulating the satiety center in the hypothalamus. The drug is not currently available for the treatment of obesity in the EU and U.S., and only the use in treatment of Duchenne muscular dystrophy is approved in the U.S. This drug is also now available in Japan [25, 28].
In basic research studies, mazindol suppressed the firing rate of glucose-sensitive neurons in the lateral hypothalamus, suggesting that the drug directly suppresses a feeding center in the hypothalamus [29]. The direct inhibitory activity of hypothalamic leads to the inhibition of gastric acid release, which may contribute to the suppression of appetite [30]. Moreover, the drug treatment reportedly increased locomotor activity, which may contribute to an increase in energy expenditure [31]. Furthermore, the treatment attenuated hypersecretion of insulin in ventromedial-hypothalamic-lesioned (VMH) obese rats, suggesting that this phenomenon was induced by decreases in body weight due to anorectic effects and/or inhibition of vagal hyperactivity [32, 33]. Mazindol treatment also reduced glucose absorption in the small intestine of rats, and anti-obesity effects were expected based on the regulation of calorie intake (food intake) [34, 35]. The weight loss effects of mazindol were investigated in two types of obesity: VMH and diet-induced obesity (DIO) in rats [36]. Results demonstrated that weight loss was significantly higher in VMH obesity than in DIO obesity. This result suggests that mazindol is more effective in central nervous system-induced obesity than other types of obesity.
As mentioned above, mazindol is now only available in Japan, and data from clinical studies conducted in Japan was described as follows. In an open-label clinical study, mazindol was administered according to the flexible schedule (0.5–3 mg/day, every 2 or 4 weeks) for 14 weeks in simple or symptomatic obese patients [36]. Results demonstrated that patients treated with mazindol lost 4.6 kg of body weight and 9.2% of relative excess weight in 14 weeks. In female patients, mazindol treatment resulted in decreases of skinfold thickness. Appetite was suppressed by mazindol in 71.3% of the patients and this rate was similar to the percent that showed body weight loss (79.8%). Appetite suppression continued until the end of the study; however, the suppression rate decreased in the follow-up period for 4 weeks. In the double-blind study, in which mazindol was given for 12 weeks, treatment with the drug resulted in significant reductions in body weight and relative body weight, and skinfold thickness reductions. Side effects, such as dry mouth, constipation, stomach discomfort, nausea, sleep disturbance and dizziness, were observed; however, most were transient or mild.
Fenfluramine/Dexfenfluramine
Fenfluramine, similar to phentermine or mazindol, is a structural analogue of amphetamine (Fig. 3) and was approved in the U.S. in 1973. Fenfluramine is a serotonergic anorectic drug, and reduces appetite by increasing serotonin levels in the brain. This compound is the racemic mixture of two enantiomers, dextro-fenfluramine (D-fenfluramine) and levofenfluramine (L-fenfluramine). Since D-fenfluramine showed more potential for efficacy than that of L-fenfluramine, D-fenfluramine was approved as dexfenfluramine in 1996 [37, 38]. However, the drugs were withdrawn from the market in the U.S. in 1997 after reports of heart valve disease, and pulmonary hypertension, including a condition known as cardiac fibrosis [39, 40]. After the withdrawal of the drugs in the U.S., the drugs were also withdrawn from other countries around the world.
Fenfluramine binds to the serotonin reuptake pump, and inhibits serotonin uptake and increases in serotonin levels. The elevation of serotonin leads to greater serotonin receptor activation, which in turn leads to the enhancement of serotonergic transmission in the center of feeding behavior located in the hypothalamus [41, 42]. The reason for the adverse effect of heart disease was also considered. The valvular abnormality seen with fenfluramine was the thickening of leaflet and chordae tendineae. The pathological findings in the heart are considered to involve heart valve serotonin receptors that regulate growth. Since fenfluramine stimulates serotonin receptors, this may lead to valvular abnormalities in patients using fenfluramine [43, 44].
In preclinical studies, the chronic administration of fenfluramine induced sustained body weight loss with normal food intake [45]. Unlike other appetite inhibitory drugs, fenfluramine suppresses rather than increases locomotor activity in animals. Another possible explanation for the sustained weight loss could be the disruption in intestinal absorption of nutrients. The chronic administration of dexfenfluramine, however, has no effect on the digestibility of a high-carbohydrate diet or a high-fat diet [45]. Therefore, the sustained weight loss observed in animals with chronic treatment of fenfluramine is neither caused by alterations in behavioral activity nor by nutrient absorption. These phenomena indicate that fenfluramine increases metabolic rate. The effects of fenfluramine in animals along with meal administration were investigated [46]. Fenfluramine at a dose of 20 mg/kg administered with a meal induced 10-20% increases in postprandial metabolic rate as indicated by an increase in oxygen uptake. Furthermore, the ability of fenfluramine to potentiate the thermic effects of food (TEF) for nutrients was evaluated. Results demonstrate that the drug potentiated TEF for carbohydrates, but had little effect on fat diets. Fenfluramine clearly increased energy expenditure. This result is considered to be one energic explanation for the sustained weight loss in the presence of normal food intake. Fenfluramine can potentiate TEF without having a calorigenic effect when administered alone; however, the details of the mechanism have not been fully elucidated. In a chronic treatment study for 6 weeks, fenfluramine treatment resulted in decreases in weights that were ~15% lower than results observed in control animals.
Numerous clinical studies, including open or double-blind studies, were conducted for fenfluramine and dexfenfluramine. Hudson reported results from an open-label study for 52 weeks comparing the effects of fenfluramine plus diet with diet alone [47]. The patients were given a low-carbohydrate diet. Mean weight loss was highest in patients treated with fenfluramine plus diet (80-120 mg Fenfluramine, -7.6%; Fenfluramine + diet, -8.7%; Control, -4.5%). The rate of weight loss was higher during the first 3 months of treatment than at subsequent intervals, and the weight loss effect reached a plateau after 6 months of therapy. In other open-label clinical studies, fenfluramine treatment resulted in 10-15% decreases in baseline weights [48-50]. Douglas et al. reported that there were no statistically significant weight differences in endpoints in a double-blind clinical study conducted for 52 weeks [51]. In clinical studies assessing dexfenfluramine treatment, the drug administered at a dose of 15 mg, twice a day, resulted in approximately 3-10% decreases in baseline weights [52-54]. In double-blind dexfenfluramine studies, the difference between active therapy and placebo for patients who completed the study assessments was approximately 3 kg. Several reports indicated that some patients might regain weight despite continued treatment [26, 49, 51].
Orlistat
Orlistat is a gastric and pancreatic lipase inhibitor, and is the first non-centrally acting anti-obesity agent that acts on the gastrointestinal tract. The main effect of the drug is suppression of fat absorption, thereby reducing caloric intake. Orlistat was approved for use in Europe in 1998, in the U.S. in 1999, and has been sold all over the world, including Asian countries. The drug is currently available as an over-the-counter drug in the UK and .U.S. Because of reports of an increased risk of serious liver injury with the use of orlistat, The FDA approved a revised label that includes added safety information regarding cases of liver injuries in 2010.
Orlistat is a hydrogenated derivative of lipstatin (Fig. 4), which is produced by Streptomyces toxytricini [55]. Orlistat potently inhibits various lipases, such as pancreatic lipases, and carboxylester lipase, but minimally inhibits digestive enzymes such as amylase, trypsin and phospholipase. Because of its minimal absorption, the bioavailability of orlistat is less than 1%. In fact, the plasma concentration of orlistat was <5 ng/mL after a single dose of 800 mg [56]. Therefore, orlistat is considered to show effects in the digestive tract only. Inactivation of pancreatic lipase by orlistat suppresses the hydrolysis of dietary fat, i.e., decomposition from triglycerides to absorbable fatty acids and monoacylglycerol. As undigested triglycerides are excreted in feces, the reduction of energy intake into the body has a favorable effect on body weight.
In preclinical studies, the effects of orlistat on fat absorption were investigated through the measurement of plasma TG after olive oil loading in mice fed Western diets. Increases in triglyceride levels after oral fat loading were significantly reduced in orlistat-treated mice [57, 58]. Anti-obesity effects were investigated in a high-fat diet-induced obese model. Body weight and adipose tissue decreased in the orlistat administration group [57, 59]. Moreover, orlistat reduced the progression of atherosclerosis through a triglyceride-lowering effect based on the inhibition of fat absorption in ApoE knockout mice fed Western diets [58].
Sjöström et al. reported results from a double-blind study in which the effect of orlistat on weight loss and preventing weight regain in obese patients were evaluated [56]. Obese patients received orlistat 120 mg three times daily before meals over 2 years with a hypocaloric diet. In the first year of the clinical study, mean weight loss was highest in patients treated with orlistat compared with placebo (120 mg orlistat, -10.3kg; placebo, -6.3 kg from baseline). The percentage of patients with decreases in body weight that were >20% of initial body weight was 2.1% in the placebo group and 9.3% in the orlistat group. At the end of the second year, a recurrence of weight gain was prevented compared with placebo (differences in weight loss between orlistat and placebo were 3.6 kg) in patients who continued treatment with orlistat. Significant reductions in LDL cholesterol, and total cholesterol, and glucose and insulin level were also observed with orlistat treatment. In meta-analyses of 22 studies, the average weight reduction at 12 months was higher in patients in the orlistat group than those in the placebo group (-8.1kg vs. -5.2kg, respectively) [60]. A large 4-year prospective study (XENDOS study) was performed to evaluate the effect of orlistat on preventing the onset of type 2 diabetes in obese patients [61]. The cumulative incidence of diabetes was 9% in the placebo group, and 6.2% in the orlistat group. Orlistat reduced the progression to type 2 diabetes by 37%. In addition, orlistat improved other cardiovascular risks, such as blood pressure, waist circumference and dyslipidemia. The most common adverse effects with orlistat were gastrointestinal disorders, such as diarrhea, fecal incontinence, oily spotting, flatulence and dyspepsia [42, 62]. These adverse effects were observed in 15-30% of patients receiving orlistat treatment. Since orlistat partially suppresses the absorption of fat-soluble vitamins, co-prescriptions of daily vitamin supplements are recommended. Systemic side effects are rarely observed because of minimal systemic absorption.
Shibutramine
Sibutramine selectively inhibits noradrenaline/serotonin reuptake (Fig. 5). The main effect of sibutramine is the suppression of energy intake by appetite suppression, and the drug also has an effect on increasing energy consumption [63, 64]. Initially, sibutramine was developed as an antidepressant agent; however, antidepressant effects were not confirmed in clinical studies. Nevertheless, sibutramine treatment resulted in significant weight reductions in phase 2 studies in patients with depression, and the drug was therefore developed as a treatment for obesity. Sibutramine was approved in the U.S. in 1997 and Europe in 1999 [65]. The drug was withdrawn from markets in 2010 due to increased risks of heart attack and stroke in patients with a history of cardiovascular disease [66, 67].
Sibutramine is a selective inhibitor of presynaptic reuptake of monoaminergic neurotransmitters serotonin (5-HT), noradrenaline (NA), and dopamine in the central nervous system. The increase in levels of these neurotransmitters enhances the suppressive effect on appetite [67]. Unlike the early structural analogues of amphetamine, such as phentermine and fenfluramine, sibutramine does not stimulate the secretion of catecholamines. Therefore, sibutramine does not cause neurotoxicity [68]. In addition to appetite suppression, sibutramine increases energy expenditure based on two different effects. One effect is that sibutramine prevents decreases in basal energy consumption following weight loss via melanocortin receptor 4 (MCR-4) activation [69, 70]. The other effect is the increase in thermogenesis through the activation of ß 3 adrenergic receptors [71].
In basic research studies, a single administration of sibutramine reduced cumulative food intake at 2, 4, and 8 hr after administration [72]. Chronic sibutramine treatment resulted in suppression of food intake and reduction of body weight gain in dietary-induced obese Wistar rats. Sibutramine also remarkably reduced fat weight compared to muscle in diet-induced obesity rats. Furthermore, sibutramine treatment also ameliorates insulin resistance, which is a characteristic parameter in this model of obesity. Unlike serotonin-releasing agents, sibutramine acts independently of the hypothalamic NPY signaling system, which controls appetite [73]. In a genetic obesity model, sibutramine treatment ameliorated impaired obesity, reduced food consumption and increased energy expenditure in ZF rats without changes in hypothalamic NPY and orexins [74].
Smith et al. reported results from a double-blind study for 12 months in which the effects of sibutramine on weight loss in obese patients given dietary advice were evaluated. Mean weight loss was highest in patients treated with 10 mg and 15 mg of sibutramine (10 mg sibutramine, -4.4 kg; 15 mg sibutramine, -6.4 kg; placebo, -1.6 kg from baseline). The percentage of patients with decreases in body weight >5 kg was 20% in the placebo, 39% in the sibutramine 10 mg, and 57% in the sibutramine 15 mg groups. A significantly higher proportion of patients taking sibutramine lost >10 kg from baseline (10 mg sibutramine, 19% 15 mg sibutramine, 34%) compared with patients taking placebo (7%) [75]. Furthermore, sibutramine showed potential benefits by improving cardiometabolic risk factors, such as high glucose, insulin or lipid levels [76]. The Sibutramine Cardiovascular Outcomes (SCOUT) study was conducted to evaluate the long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular deaths among patients with high cardiovascular risk. The results from SCOUT showed that long-term sibutramine treatment increased the risk of nonfatal myocardial infarction and stroke, but not cardiovascular deaths [77]. From this study, the EMA and FDA recommended the suspension of use of sibutramine. The drug was withdrawn from the market in 2010.
Rimonabant
Rimonabant is a cannabinoid-1 (CB1) receptor antagonist (Fig. 6), which controls the uptake of cannabinoid and is the first agent that targets the endocannabinoid system. The main effect is suppression of appetite. Rimonabant was approved for use in Europe in 2006, but was not approved in the United States. Due to the risk of serious psychiatric problems, including suicide, the drug was withdrawn from the market in 2009 [78].
The CB1 receptor is a member of the 7-transmembrane G protein-coupled receptor family [79]. This receptor is expressed mainly in the brain, in particular in the basal ganglia, hippocampus, cerebral cortex and hypothalamus. These receptors are also present in the testes, adrenal gland, ovaries and adipose tissues [79-81]. The CB1 receptor is coupled to Gi/o proteins, but the details of the second messenger transduction of CB1 receptor signaling are complex [80]. The two main endogenous cannabinoid agonists are anandamide and 2-arachidonoyl glycerol, which act as neurotransmitters or neuromodulators [82-84]. These endocannabinoids play important roles in energy homeostasis and regulation of appetite [85]. Peripheral sites of activity may also be regulated by endocannabinoids via CB1 receptors that are present in peripheral tissues, such as the liver, skeletal muscles and pancreas [86]. Delta(9)-tetrahydrocannabinol (THC), which binds equally to CB1 and CB2 receptors, was identified from the cannabis plant in 1974. Synthetic THC, like dronabinol, is used for the treatment of emesis or nausea after chemotherapy [87]. The structure of THC has been modified to develop selective CB1 receptor antagonists since the late 1980s. After lengthy research, Rinaldi-Carmona et al. ultimately designed the compound, rimonabant, which is a selective CB1 receptor antagonist that has 1000-fold CB1 selectivity over CB2 [88].
In preclinical studies, rimonabant transiently reduced food intake in ob/ob mice, db/db mice and Zucker fatty rats, which are genetically obese animal models. However, the effects of rimonabant on body weight were sustained when compared with inhibitory effects on food intake in those rodents [89]. Rimonabant also remarkably reduced fat weight compared to muscle in diet-induced obesity mice. Furthermore, continuous inhibition of the CB1 receptor resulted in improvements in hyperlipidemia and dyslipidemia, which are characteristic metabolic parameters in obese models [90]. Similar to rimonabant, CB1 receptor knockout mice were hypophagic, and resistant to the development of obesity induced by high-fat diets, and had improved insulin and leptin resistance in comparison with wild-type mice [91]. From these results, the anti-obesity effects of CB1 receptor antagonists were considered to be attributed not only to suppression of food consumption, but also to decreases in fat weight, TG accumulation and accelerated energy consumption. In fact, rimonabant treatment increased O2 consumption and soleus muscle glucose uptake in ob/ob mice [92].
Després et al. reported results from a phase 3 study; Rimonabant in Obesity (RIO)-Lipids, in which the effect of rimonabant on weight loss in overweight patients with dyslipidemia was evaluated [93]. The study compared treatment with 5 mg and 20 mg of rimonabant to placebo in a group of obese patients with untreated dyslipidemia for twelve months under dietary restrictions. The percentage of patients with decreases in body weight >5 kg was 28% in the placebo, 42% in the rimonabant 5 mg, and 75% in the rimonabant 20 mg groups. Improvement in cardiovascular risk factors was observed with 20 mg of rimonabant treatment. The changes observed included 16% reductions in triglycerides, 23% increases in HDL cholesterol and glucose tolerance improvement, as well as blood pressure reduction. Other key RIO studies, RIO-North America, RIO-Europe, and RIO-diabetes reported similar results, and the differences were only in the number and type of patients, and location [94-96]. In patients in RIO-North America from the U.S. and Canada with dyslipidemia and obesity, similar to RIO-Lipids, rimonabant decreased body weight and abdominal circumference, and improved hypertriglyceridemia, hypoHDLemia and insulin resistance [95]. RIO-Europe was conducted to study overweight patients with dyslipidemia and hypertension, not diabetes. In addition to weight loss, significant improvements in lipid and glycemic variables were observed with rimonabant treatment [94]. RIO-diabetes evaluated the effects on patients with type II diabetes for one year. Increases in the percentage of patients with hemoglobin A1C <7% and decreases in body weight were observed with rimonabant therapy [96]. In safety data obtained from these studies, the major side effects were nausea, diarrhea, depressive moods, depression and anxiety [83].
Qsymia
Qsymia is a combination oral product composed of phentermine hydrochloride and topiramate (Fig. 7), and the drug was approved by the FDA in 2012. Both Qsymia and BELVIQ (Term 2.8.) were approved in 2012, and these new drug approvals for anti-obesity therapy were the first in 13 years [3, 13, 97]. Phentermine is a sympathomimetic amine anorectic agent for short-term therapy mentioned previously in Section 2.1., and topiramate is an oral drug that is used to prevent seizures or epilepsy, and is an anti-seizure or anti-epileptic drug [98-100], that was approved by the FDA in 1997.
Epilepsy and seizures occur due to abnormal activity of nerves in the brain, and the abnormalities spread to smaller or larger portions of the brain. Although the exact mechanism of action for topiramate is unknown, the drug reportedly alters neurotransmitters, including Gamma-amino butyric acids (GABAs) in the brain [101, 102]. By altering the production or activity of neurotransmitters, topiramate is considered to inhibit the abnormal activity of nerves in the brain. Other studies also indicate that topiramate may directly suppress the nerves and lessen the likelihood of these nerves firing. Topiramate is considered to bind to certain membrane ion channel proteins at phosphorylation sites, thereby allosterically modulating channel conductance and inhibiting secondary protein phosphorylation [103]. Moreover, York et al. reported that topiramate reduced food intake acutely and increased the metabolic rate in rats fed a high-fat diet [104]. In the hypothalamus, the drug increased mRNA levels for neuropeptide-Y and reduced mRNA levels for neuropeptide-Y1 and Y5 receptors, corticotropin-releasing hormone and type II glucocorticoid receptors, but had no effect on mRNA levels of the leptin receptor. In peripheral tissues, topiramate reduced leptin mRNA levels in adipose tissue, and had no effect on uncoupling protein 1 mRNA levels in brown tissue, but had tissue-selective effects on uncoupling proteins 2 and 3 mRNA levels in fat and muscle.
In clinical studies, in particular in a phase 3 study, treatment with Qsymia resulted in significant weight loss compared with the placebo group [105, 106]. After 56 weeks of treatment, the percent of weight loss achieved with Qsymia was 10.6%, 8.4% and 5.1% with 15/92 mg of phentermine/topiramate, 7.5/46 mg, and 3.75/23 mg, respectively. The 52-week extension study (SEQUE study) showed sustained weight loss over 2 years, with 9.3% and 10.5% weight loss from baseline weights with 7.5/46 mg and 15/92 mg of phentermine/topiramate. Significant reductions in waist circumference, fasting triglyceride levels, and fasting glucose levels, were also observed with Qsymia treatment. Adverse effects, such as paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth, were observed in 5% or higher of patients in the study. In previous studies, phentermine monotherapy at a dose of 30 mg resulted in significant body weight loss [26]. In this clinical study, phentermine at a dose of 15 mg or lower resulted in significant sustained body weight loss, and a decrease in the dose of the drug with combination therapy is expected to lead to attenuation of adverse effects. Qsymia is a new, once-daily, controlled-release, combination weight-loss product approved as an adjunct to diet and exercise for chronic weight management of obese patients. Qsymia is modestly effective and a viable option for patients intending to losing weight.
BELVIQ (Lorcaserin)
BELVIQ has serotonergic properties and acts as an anorectic (Fig. 8). In 2012, FDA approved the drug for use in the treatment of obese patients with a BMI of 30 or higher, or patients with a BMI of 27 or higher who have at least one weight-related health condition, such as hypertension, type 2 diabetes, or dyslipidemia [3, 97, 107]. Qsymia and BELVIQ were approved by the FDA; however, both drugs have been withdrawn in the EU.
Lorcaserin is a selective 5-HT2C receptor agonist, and showed reasonable selectivity for 5-HT2C receptor over other related targets [107-109]. Lorcaserin showed a 100-fold selectivity for 5-HT2Cversus the closely related 5-HT2B receptor, and a 17-fold selectivity over the 5-HT2A receptor [108, 110, 111]. 5-HT2C receptors are located almost exclusively in the brain, such as the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. Activation of 5-HT2C receptors in the hypothalamus is considered to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety [112].
In pharmacological studies using rats, lorcaserin treatment resulted in an acute reduction in food intake, and chronic treatment with lorcaserin for 4 weeks maintained on a high-fat diet resulted in dose-dependent reductions in food intake and body weight gain [108, 111]. A single oral administration of lorcaserin (at a dose of 3, 6. 12, or 24 mg/kg) resulted in reductions in cumulative food intake at 2, 4, 6, and 22 h, with significant decreases continuing throughout the 22 h duration of the study only at the highest dose (24 mg/kg). With chronic lorcaserin administration to male DIO rats, drug treatment (4.5, 9, and 18 mg/kg p.o., b.i.d.) significantly reduced food intake over the first 13 days of dosing, after which tolerance to the food intake suppressing effects of lorcaserin developed dose-dependently.
In Phase 2 studies, lorcaserin treatment resulted in significantly higher weight loss when compared with placebo groups [113-115]. At the end of 12 weeks, body weights in lorcaserin treatment groups decreased by 4.0 pounds (10 mg/day), 5.7 pounds (15 mg/day), and 7.9 pounds (20 mg/day). The weight loss in placebo groups was 0.7 pounds. Patients in the Phase 2 study were tracked for 2 weeks post-study completion and all groups regained weight more rapidly than the pace at which the weight had originally decreased. In Phase 3 studies of lorcaserin, the cumulative proportion of patients who achieved a weight loss of 5% or higher over 12 months was about 47% with lorcaserin treatment versus 20-25% in the placebo group [116, 117]. Adverse effects, such as nausea, vomiting, headache, and dizziness were reported. In two of the three Phase 3 studies, lorcaserin treatment did not result in an observed increase in the risk of cardiac valvulopathy; however, in the other Phase 3 study that focused on patients with diabetes, drug treatment was associated with an increased rate of new valvulopathy.
Contrave
Contrave is a combination drug of two approved drugs, bupropion and naltrexone (Fig. 9) for the treatment of obesity [118-122]. The drug was marketed in the U.S. in 2014 and in the EU in 2015. Both bupropion and naltrexone have individually shown some evidence of efficacy in weight loss, and the combination therapy is expected to have a synergistic effect. A New Drug Application (NDA) for contrave was submitted to the FDA in 2010; however, the FDA decided that an extremely large-scale study of long-term cardiovascular effects of the drug would be needed, and the application was rejected.
Bupropion reportedly has several different biological targets and is widely known as a norepinephrine-dopamine reuptake inhibitor and neuronal nicotinic acetylcholine receptor-antagonist [123, 124]. Bupropion was approved by the FDA as an antidepressant in 1985, but a significant incidence of epileptic seizures at the recommended dose (400-600 mg) caused the withdrawal of the drug in 1986. Afterwards, bupropion was reapproved in 1989 at a lower maximum recommended dose [125, 126]. Bupropion was also approved by the FDA in 1997 for use as a smoking cessation aid. In basic research studies, bupropion was demonstrated as inhibiting norepinephrine-dopamine uptake and also inducing the release of dopamine and norepinephrine [127]. Moreover, pharmacological studies in rats undergoing nicotine withdrawal demonstrate that bupropion can dose-dependently lower changes in the brain-reward threshold and somatic signs of nicotine withdrawal [128]. Bupropion is one of the most widely prescribed antidepressants, and available evidence indicates that it is effective in clinical depression [129]. Bupropion has some features that distinguish it from other antidepressants, for instance, the drug does not cause sexual dysfunction [130, 131]. Furthermore, bupropion is reported to show anti-obesity effects. The drug, when used over a period of 6 to 12 months, causes weight loss of 2.7 kg over placebo, and the efficacy is not much different from that of several other medications, such as sibutramine, orlistat, and anferamone [60, 132].
Naltrexone is an opioid receptor antagonist used primarily for the management of alcohol dependence and opioid dependence. The main use of the drug is for the treatment of alcohol dependence, and was approved by the FDA in 1994 [133]. Naltrexone has generally been better studied for alcohol dependence than for treating opioid dependence; however, the use of the drug as a treatment for opioid addiction has already been approved in 1984 [134, 135]. Naltrexone is sometimes used as a treatment for other diseases, such as depersonalization disorder, tobacco dependence, self-injurious behaviors, and some behavioral addictions [136-138]. The most common adverse effects reported with naltrexone are non-specific gastrointestinal complaints, such as diarrhea and abdominal cramping.
Contrave, a bupropion and naltrexone combination therapy is reportedly useful for the potential treatment of obesity [119, 122, 139]. Greenway et al. reported results from a phase 3 study, in which the effect of naltrexone plus bupropion on weight loss in overweight and obese adults was evaluated [140]. In the phase 3 study conducted for 56 weeks, participants were randomly assigned to 3 groups, naltrexone 32 mg/day plus bupropion 360 mg/day, 16 mg/day plus bupropion 360 mg/day, or placebo. Results demonstrated that the mean change in body weight was -1.3% in the placebo group, -6.1% in the naltrexone 32 mg/day plus bupropion 360 mg/day group, and -5.0% in the naltrexone 16 mg/day plus bupropion 360 mg/day group. Adverse effects, such as headache, constipation, dizziness, vomiting, and dry mouth, were also more frequent in the naltrexone plus bupropion groups than in the placebo group. The combination of naltrexone plus bupropion is expected to be a useful therapeutic option for the treatment of obesity.
New Drug Targets (Table 3)
Late Phase Clinical Development
Cetilistat
Cetilistat is an inhibitor of gastric and pancreatic lipases that breaks down triglycerides in the intestine (Fig. 10). This drug has the same mechanism of action as orlistat previously described above. The main effect is suppression of fat absorption from the intestine. Cetilistat was approved for use in Japan; however, Cetilistat has not been sold in the market [141]. The structure of cetilistat has highly lipophilic benzoxazinon, which raises the possibility of fewer side effects compared with orlistat. Cetilistat forms a covalent bond with the 152 serine residue in the active center of pancreatic lipase, and reversibly inhibits the activity of lipase. Inhibition of pancreatic lipase decreases TG absorption from the small intestine, and unabsorbed fat is excreted in the feces. The suppression of approximately 30% of triglyceride absorption reduces the energy intake into the body, and is expected to reduce body weight.
In preclinical in vitro studies, cetilistat inhibited pancreatic lipase activity in humans and rats with an IC50 of 5.95 nmol/L, and 54.8 nmol/L, respectively [142]. The inhibitory effects of cetilistat were more potent in human pancreatic lipase than in rats. The effects on fat absorption were investigated in in vivo measurements of plasma TG after fat loading in Sprague-Dawley rats. Plasma TG in the cetilistat administration group decreased in a dose-dependent manner. Anti-obesity effects were investigated in F344 rats fed a high-fat diet. Body weight and adipose tissues in the cetilistat administration group decreased dose-dependently; however, liver weight was not affected. Fecal TG and free fatty acid content increased dose-dependently with cetilistat treatment. The suppression of food intake was not observed in rats fed a high-fat diet after cetilistat treatment. The anti-obesity effect of cetilistat was suggested as being attributed to the suppression of fat absorption. Analysis of blood biochemistry values showed that cetilistat had lowering effects on plasma TG and leptin levels, but not glucose [142].
In clinical studies, Kopelman et al. reported results from a phase 2 study in which the effects of cetilistat on weight loss in overweight patients were evaluated [143]. Obese patients received cetilistat at a dose of 60 mg, 120 mg, or 240 mg for 12weeks with a hypocaloric diet. Body weights in cetilistat treatment groups significantly decreased by 3.3 kg (60 mg/day), 3.5 kg (120 mg/day), and 4.2 kg (240 mg/day), respectively. The proportion of patients who achieved a weight loss of 5% or higher were higher in all three doses compared with placebo. Significant reductions in waist circumference, LDL cholesterol, and total cholesterol level were also observed in all three doses of cetilistat treatment. Gastrointestinal adverse effects, such as flatulence, oily spotting and soft stools, were observed in cetilistat treatment groups. However these adverse effects were observed in only 1.8-2.8% of patients in cetilistat treatment groups. Kopelman et al. also reported the effects of cetilistat on obese patients with type II diabetes [144]. Diabetic obese patients on metformin received cetilistat at a dose of 40 mg, 80 mg, or 120 mg for 12 weeks with a reduced calorie diet. Mean weight loss was significant in patients treated with 80 mg and 120 mg of cetilistat (80 mg cetilistat, -3.9 kg; 120 mg cetilistat, -4.3 kg; placebo, -2.9 kg from baseline). Significant reductions relative to placebo were shown for HbA1c in 80 mg and 120 mg cetilistat treatment groups (80 mg cetilistat, -0.54%; 120 mg cetilistat, -0.51%; placebo, -0.37% from baseline). In cetilistat treatment groups, the incidence of gastrointestinal adverse effects was higher than placebo. However, the incidence of non-gastrointestinal adverse effects was similar in all patients including placebo.
Empatic
Empatic is a combination drug of two approved drugs, bupropion and zonisamide, for the treatment of obesity, and the drug is currently being tested in a phase 3 study. The drug is being developed by Orexigen Therapeutics, and the company published positive results from a phase 2b study in 2009 [145, 146
