PF-05231023, a long-acting FGF21 analogue,decreases body weight by reduction of food intake in non-human primates

PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure. Here, we present a semi-mechanistic mathematical model of energy balance and body composition developed from similar work in mice. This model links PF-05231023 administration and washout to changes in food intake, which in turn drives changes in body weight. The model is calibrated to and compared with recently published data from cynomolgus macaques treated with PF-05231023, demonstrating its accuracy in describing pharmacotherapy-induced weight loss in these animals. The results are consistent with the hypothesis that PF-05231023 decreases body weight in cynomolgus macaques solely by a reduction in food intake, with no direct effect on energy expenditure.     

The effect of topiramate on energy balance in obese men: a 6-month double-blind randomized placebo-controlled study with a 6-month open-label extension

Objective Topiramate (TPM) has been reported to reduce body weight beyond a placebo in the treatment of obese participants, but the effect of this agent on components of energy balance has not yet been established in humans. Thus, the aim of this study was to study the impact of TPM on food preferences, measures of satiety, food intake, resting metabolic rate (RMR), and 24-h energy expenditure. Methods The study design consisted of a 6-month, single-center, randomized, double-blind, parallel group, placebo-controlled trial with a 6-month open-label extension. The study included 68 sedentary men with abdominal obesity (waist circumference ≥100 cm), of between 25 and 55 years of age, with a dyslipidemic profile and a body mass index (BMI) ≥27 and ≤40 kg/m². Results Treatment with TPM produced significant changes in anthropometric variables and body composition compared with placebo. However, at the end of the 1-year study, the placebo/TPM group showed similar weight loss and reduction in body fatness compared with the TPM/TPM group. For instance, at the end of the 12-month intervention, mean percentage of body weight loss from baseline was about −5% in both groups (−4 kg fat loss). Topiramate treatment reduced energy intake, be it in the context of an ad libitum buffet-type meal or under free living conditions. The 24-h daily energy expenditure (DEE) assessed by whole-body indirect calorimetry adjusted for body weight and age was not altered by TPM treatment. Conclusion Topiramate treatment produced significantly greater weight loss than placebo and the majority of this loss was explained by a decrease in body fat stores. Most of the weight loss effect produced by TPM therapy was observed within a period of 6 months. Finally, TPM treatment had an impact on energy balance through a reduction in food intake that appears to have created an energy deficit of about 30,000–40,000 kcal compared with treatment with the placebo over 6 months.     

Leptin signaling as a therapeutic target of obesity

Introduction: Leptin is a hormone with a key role in food intake and body weight homeostasis. Congenital leptin deficiency (CLD) is a rare disease that causes hyperphagia and early severe obesity. However, common obesity conditions are associated with hyperleptinemia and leptin resistance.

Areas covered: The main signaling pathways activated by leptin as well as the mechanisms underlying the regulatory actions of leptin on food intake and on lipid and glucose metabolism are reviewed. The potential mechanisms involving leptin resistance and the main regulatory hormonal and nutritional factors controlling leptin production/functions are also analyzed. The pathophysiology of leptin in human obesity, and especially the trials analyzing effects of leptin replacement therapy in patients with CLD or in subjects with common obesity and in post-obese weight-reduced subjects are also summarized.

Expert opinion: The use of drugs or specific bioactive food components with anti-inflammatory properties to reduce the inflammatory state associated with obesity, especially at the hypothalamus, may help to overcome leptin resistance. Research should also be focused on investigating dietary strategies, food supplements or drugs capable of avoiding or reversing the leptin fall during weight management, in order to promote sustained body weight lowering and weight loss maintenance.     

Predictors of Dually Diagnosed Patients' Psychiatric Symptom Exacerbation During Acute Substance Use Disorder Treatment

ABSTRACT

Objectives: This study identified intake risk factors that predicted dual diagnosis patients' exacerbation of psychiatric symptoms during acute substance use disorder care; and examined whether receipt of recommended services for dual diagnosis patients reduced the likelihood of exacerbation, and whether additional help post-discharge was associated with improved symptoms at a 1-year follow-up.

Methods: Dual diagnosis patients (N = 230) who received treatment in one of 14 residential substance abuse programs were evaluated at in-take, discharge (98%), and 1-year follow-up (80%).

Findings: Patients who, at intake, were anxious, untroubled by their psychiatric problems, using more than one substance, had less severe alcohol problems, lived with a problem drinker, and had no close friends were at greater risk of exacerbation of psychiatric symptoms at discharge. Patients who received, during acute treatment, recommended services (e.g., individual counseling, vocational counseling, discharge planning) were more likely to improve, even when intake risk was controlled. Additional outpatient treatment post-discharge was associated with fewer psychiatric symptoms at 1 year.

Conclusions: Substance abuse treatment staff should be vigilant about identifying and preventing dual diagnosis patients' psychiatric symptom exacerbation. Attending to changes in psychiatric symptoms and tailoring interventions to patients at greatest risk could help reduce the likelihood of in-treatment increases in psychiatric symptoms.     

Anamorelin hydrochloride for the treatment of cancer-anorexia-cachexia in NSCLC

Introduction: Cancer anorexia-cachexia syndrome (CACS) is associated with increased morbidity and mortality. Anamorelin is a novel, orally active ghrelin receptor agonist in clinical development for the treatment of CACS in NSCLC. The aim of this review is to summarize preclinical and clinical studies evaluating anamorelin as a potential promising treatment for CACS in NSCLC.

Areas covered: Pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability of anamorelin for the treatment of CACS in NSCLC were reviewed. Anamorelin administration may lead to increases in food intake, body weight and lean body mass, and a stimulatory effect on growth hormone secretion in NSCLC patients. Anamorelin is well tolerated with no dose-limiting toxicities identified to date.

Expert opinion: Targeting ghrelin receptors presents the advantage of potentially addressing multiple mechanisms of CACS simultaneously including appetite, muscle protein balance, adipose tissue metabolism, energy expenditure and inflammation. Clinical data suggest that anamorelin is well tolerated and it effectively increases appetite, body weight and lean mass in patients with advanced NSCLC. Long-term safety remains unknown at this time. The potential synergistic effects of anamorelin with nutritional support or exercise as well as its efficacy/safety in other tumor types are also unknown.     

Ghrelin and ghrelin receptor inhibitors: agents in the treatment of obesity

Background: Current medical treatment of obesity is highly ineffective. Soon after its discovery as the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R), ghrelin was shown to stimulate food intake (including in humans) and promote body weight gain and adipogenesis. Objectives: This review discusses the role of the ghrelin/GHS-R pathway in energy homeostasis regulation and its role as a novel molecular target for the treatment of obesity. Methods: Medline was searched for relevant articles published in English. Results/conclusion: A large series of animal studies shows that inhibition of the ghrelin/GHS-R pathway reduces food intake, body weight and adiposity, through reduction of appetite and augmentation of energy expenditure and fat catabolism. This suggests that inhibition of this novel pathway may be used to treat/prevent obesity and its complications.     

Melanocortin receptors as targets in the treatment of obesity

The central melanocortin system plays a critical role in energy homeostasis. It is well established that melanocortin-containing neurons are nutritionally regulated and that genetic alterations in the melanocortin system produce profound effects on food intake, energy expenditure, and body weight. Within the brain, melanocortin-producing neurons originate in the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the brainstem and project to various nuclei modulating energy balance. A large body of pharmacological and genetic evidence implicates the central melanocortin 4 receptors (MC4Rs) in the effects of melanocortin peptides on ingestive behaviour, energy expenditure, and body weight. Preclinical studies with endogenous and synthetic melanocortin ligands demonstrate that they produce potent effects on food intake and energy expenditure. Clinical studies thus far have been somewhat less successful and have been hampered by the induction of side effects, which present obstacles to the development of successful therapeutic agents. However, various promising strategies are being pursued to overcome these limitations, including the synthesis of more selective and potent melanocortin analogs.     

An Exploration of Readiness to Change Processes in a Clinical Sample of Military Service Members

Abstract

The purpose of this project was to examine readiness to change (RTC) processes in a sample of substance dependent military service members who completed an intensive substance abuse treatment program. The patients completed the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), which is an RTC assessment instrument, at intake and completion of the treatment program. It was predicted that patients would show positive changes in their RTC from intake to treatment completion. Scores on two of the three SOCRATES subscales were significantly improved. The findings suggest that RTC processes measurably change during treatment and further suggest that the SOCRATES is an appropriate tool for assessing short term changes in RTC.     

Pubertal Timing and Substance Abuse Treatment Outcomes: An Analysis of Early Menarche on Substance Use Patterns

ABSTRACT

This article examines the influence of pubertal timing on substance use patterns, specifically the relationship between onset of menarche and onset of substance use and substance abuse treatment outcomes. Findings show a significant relationship between pubertal timing and age of onset of substance use and age of onset of substance use and substance use severity at intake into treatment. The article concludes with a call for further research into the possible relationship between pubertal timing and treatment outcomes as well as effective gender-specific interventions for prevention and treatment of substance abuse among adolescent girls.     

Protective effects of Cassia tora leaves in experimental cataract by modulating intracellular communication,membrane co-transporters,energy metabolism and the ubiquitin-proteasome pathway

Context: Cataract is the clouding of eye lens which causes impairment in vision and accounts for the leading factor of global blindness. Functional food-based prevention of cataract finds application in vision research because of its availability and easy access to all classes of the society. Cassia tora Linn. (Caesalpinaceae) is an edible plant mentioned in the traditional systems of medicine for whole body health, especially to the eyes.

Objective: The present study evaluates the potential of ethyl acetate fraction of Cassia tora leaves (ECT) on experimental cataract.

Materials and methods: Cataract was induced by a single subcutaneous injection of sodium selenite (4?μg/g body weight) on 10th day. ECT was supplemented orally from 8th day up to 12th day at a concentration of 5?μg/g body weight and marker parameters were evaluated after 30 days.

Results: The production of MPO and the activation of calpain were reduced 52.17% and 36.67% by ECT in lens tissue, respectively. It modulated the energy status by significantly increasing the activity of CCO 1 (55.56%) and ATP production (41.88%). ECT maintained the ionic balance in the lens by reducing the level of sodium (50%) and increasing the level of potassium (42.5%). It also reduced cell junction modifications and preserved a functional ubiquitin-proteasome pathway.

Discussion and conclusion: The results reinforce the growing attention on wild plant food resources for preventive protection against cataract. The data suggest the value of Cassia tora leaves as a functional food for ameliorating cataract pathology.     

The Cannabinoid Receptor Agonist THC Attenuates Weight Loss in a Rodent Model of Activity-Based Anorexia

Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA). The effect of subchronic (6 days) Δ⁹-tetrahydrocannabinol (THC) treatment (0.1, 0.5, or 2.0 mg/kg/day) was assessed on chow and high-fat diet (HFD) intake, body weight, running wheel activity (RWA) as well as thermogenesis in brown adipose tissue (BAT) and lipid metabolism in white adipose tissue (WAT). Limited time availability of food and continuous access to running wheels led to anorexia and significantly reduced body weight. THC treatment (0.5 and 2.0 mg/kg/day) transiently stimulated chow intake with a moderate effect on RWA. THC (2.0 mg/kg/day) significantly reduced body weight loss and shifted markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and lipolysis. THC (2.0 mg/kg/day) combined with HFD, produced a transient increase in food intake, reduction in RWA, attenuation of body weight loss, and changes in markers of thermogensis in BAT and lipolysis in the WAT. These changes were significantly greater than those seen in vehicle (HFD), vehicle (chow), and THC (chow)-treated animals. These data show for the first time the effectiveness of the endocannabinoid system in attenuating the weight loss associated with the development of ABA via a mechanism involving reduced energy expenditure.     

Neural regulation of glucose homeostasis

The regulation of blood glucose is generally stated to be under the control of the endocrine system. But the endocrine secretion is itself regulated by the central nervous system, especially the hypothalamus. The brain can sense the energy status of the body by using neural afferent signals and metabolic cues such as glucose. A variety of experimental evidences have been put forth to support the postulate that there are "glucoreceptors", sensitive to blood glucose and glucose utilization, in the hypothalamus. Gastrointestinal afferents, which carry information about the energy intake, reach the hypothalamic regions and interact with the glucose sensitive mechanisms. Available evidence suggests that obesity and decreased body weight, resulting from lesions of the hypothalamic 'satiety' and 'feeding' centres respectively, are not only due to altered food intake, but also to derangement in glucose homeostasis. The medial preoptic area does the fine tuning of energy balance (regulation of food intake) in response to alterations in the temperature, locomotor activity and sleep wakefulness. Thus the hypothalamus regulates energy balance through its control of energy intake on the one hand, and its expenditure and storage on the other. Neuroendocrine system and autonomic nervous system deal with storage and expenditure of energy.     

Medical student views of substance abuse treatment,policy and training

Purpose: This study examined the impact of medical education on students’ views of substance abuse treatment, public policy options and training.

Method: A longitudinal survey was conducted on a single-class cohort of 101 students in a major American, urban medical school. The survey was administered in the Spring semesters of the first to third years of the curriculum. The survey evaluated attitudes in three areas: (1) Treatment: efficacy of treatment and ideal level of physician involvement in substance abuse issues, (2) Public policy: degrees of support for competing public policy strategies and (3) Training: the amount of substance abuse education offered in medical school.

Results: Response rates were 92% in the first year, 90% in the second and 75% in the third. About 54% of respondents were female, 55% were white (non-Hispanic) and 71% were 20–24 years old. Treatment: students held consistent views towards treating substance abuse patients, but there was a significant decline in the percentage who felt that drug addiction can be successfully treated (from 47 to 22%, p < 0.001). Public policy: support for public health approaches ranged from 86 to 92%, but most criminal justice approaches were favoured by fewer than 40% of respondents. Training: respondents reported a significant increase in any degree of substance abuse training (p = 0.0001); classroom and clinical experiences were the predominant sources of training.

Conclusions: Surveyed medical students retained many of their a priori beliefs about substance abuse, though there were some significant changes during the survey period. Further studies are required to evaluate how these views were established and how medical education impacts potentially malleable attitudes.     

Birth outcomes for infants born to women participating in integrated substance abuse treatment programs: A meta-analytic review

Background: Infants born to women with substance abuse issues are at increased risk for prematurity, low birth weight, and impaired physical development. Integrated programs (programs that integrate on-site pregnancy-, parenting-, or child-related services with substance use treatment) have been developed to address these risks, barriers to accessing care, and the unique needs of pregnant women who abuse substances.

Method: To examine the effects of integrated programs on birth outcomes, we compiled a database of 10 studies (N?=?2471) of integrated programs published between 1990 and 2009 with birth outcome data. Data were summarized and meta-analyses were performed.

Results: Compared to women with substance abuse issues not in treatment, women in integrated programs had infants with significantly higher birth weights, larger head circumferences, fewer birth complications, positive toxicology screens, and low birth weight classifications (d's?=?0.42–0.87). Women in integrated programs attended significantly more prenatal visits (d?=?2.20) and had significantly fewer pre-term births (d?=?0.35) than women in non-integrated programs.

Conclusions: This is the first systematic quantitative review of studies evaluating the impact of integrated programs on birth outcomes. Findings suggest that integrated programs may be associated with advantages over non-integrated programs in increasing women's participation in prenatal care and decreasing premature delivery. This review highlights the need for further research with improved methodology, study quality, and reporting to improve our understanding of how best to meet the needs of pregnant women with substance abuse issues.     

Catecholamine reuptake inhibition causes weight loss by increasing locomotor activity and thermogenesis.

Bupropion (BUP) is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor that causes mild weight loss in obese adults. Subchronic (7 day) coadministration of selective DA and NE reuptake inhibitors also causes weight loss in mice. Because weight loss was not associated with decreased caloric intake, subchronic BUP might cause weight loss through increased energy expenditure. Acute studies demonstrate that BUP or DA+NE reuptake inhibitors cause transient hypophagia and increased locomotion; though the effects on temperature are inconsistent. Because subchronic DA+NE reuptake inhibition does not affect appetite, there is clearly a difference between the acute and subchronic effects of DA+NE reuptake inhibitors; however the effects of chronic (or subchronic) BUP on energy balance have never been directly studied in an animal model. Therefore, the acute and subchronic effects of BUP or selective DA and NE reuptake inhibitors on food intake, body weight, locomotor activity, and interscapular temperature were determined in mice. Generally, selective inhibition of DA reuptake (by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA+NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss because daily food intake was not increased. The results of this study suggest that the mild weight loss effect of BUP in humans may be due to increased locomotion or heat production. More importantly, inhibition of DA+NE reuptake (with GBR+NIS) increased energy expenditure without a compensatory increase in food intake, supporting a role for novel combination catecholamine reuptake inhibitors in pharmacotherapy for obesity.     

Clinical applicability of a substance abuse screening instrument

Abstract

The clinical applicability of the Perceived‐Benefit of Drinking and Drug Use Scales was evaluated as an approach to screening for adolescent substance abuse on 260 consecutive admissions to an adolescent inpatient psychiatric unit. Evidence of convergent and divergent validity is presented. The scales' strong relationships with self‐reported substance abuse indicators and clinical judgments support their use as proxy measures for assessing the substance involvement of adolescent psychiatric patients. Results indicate that the instrument is practical and easy‐to‐administer as part of clinical intake procedures.     

Limited access to HIV risk-reduction services in South African substance abuse treatment facilities

Background: Although HIV risk-reduction service provision is an important indicator of substance abuse service quality, the extent to which these services are provided in South African substance abuse treatment facilities is unknown.

Aims: To examine (i) the extent to which South African substance abuse treatment services provide HIV risk-reduction services to clients and (ii) whether the provision of these services varies by type of facility and by geographic region.

Method: Cross-sectional surveys of substance abuse treatment services were conducted in Gauteng and KwaZulu-Natal provinces (2006–2007) and the Central and Northern region of the country (2007–2008). Questions on the availability of testing for HIV and co-occurring infectious diseases, opioid substitution treatment (OST), and harm-reduction interventions for injection drug users were included within the larger survey questionnaire. Response rates of 84% and 83% were obtained for each survey, respectively.

Results: Less than half of the facilities surveyed provide HIV counselling and testing services to clients or test clients for co-occurring infectious diseases. Less than one-third conduct harm-reduction interventions among injection drug users and OST is largely unavailable. Facilities that offer residential/inpatient services and employ medically trained staff are more likely to offer clients HIV risk-reduction services than outpatient services or services without medically trained staff.

Conclusions: Findings point to the limited availability of HIV risk-reduction services within South African substance abuse treatment facilities. Recommendations are made to enhance access to these services.     

Neuropeptides controlling energy balance: orexins and neuromedins

In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.     

From substances to food: an examination of addiction shift in individuals undergoing residential treatment for substance use

Background: Addiction shift (also known as “Cross,” “Transfer,” or “Substitute” addiction) is a common theme that emerges in the literature on recovery from substance use disorders. Some research has suggested that those who recover from one substance use disorder are at increased risk of developing another. Despite existing research in this area, little is known about how individuals may be at risk of developing an addiction to food as they recover from a substance use disorder.

Methods: The current study sought to examine addiction shift, specifically from substances to food in 44 participants undergoing residential treatment for substance use disorders. It was hypothesized that drug and/or alcohol use cravings would go down from pre (at intake to residential treatment) to post (at discharge from residential treatment), while food addiction and/or food craving would increase.

Results: Significant changes were observed from pre to post for mean body mass index, and scores from measures assessing alcohol cravings, impulsive behaviors, distress tolerance, depression, and anxiety. No significant differences from pre to post were observed for scores measuring food addiction or food cravings.

Conclusions: Changes in pre to post measures indicated that drug and/or alcohol use cravings decreased. Contrary to original hypotheses, food addiction and food craving was relatively low at baseline and did not change from pre to post. Exploratory post-hoc analyses of psychological factors suggested that impulsivity, distress tolerance, depression, and anxiety went down from pre to post. Short follow-up timeframe and competition theory are likely important factors in these findings.     

1H NMR-based metabolic study reveals the improvements of bitter melon (Momordica charantia) on energy metabolism in diet-induced obese mouse

Context: Obesity can be ameliorated by some natural products such as polyphenol, flavones and saponin. As a typical medicinal plant, Momordica charantia L. (Cucurbitaceae) (bitter melon, BM) contains these natural chemicals and reduces diet-induced obesity in mice.

Objective: This study evaluates the metabolic effects of dietary BM supplement, investigates a global metabolic profile and determines associated perturbations in metabolic pathways.

Materials and methods: Male C57BL/6 mice were fed with low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 5% BM based on 37.6?g/kg body weight in average for 12 weeks, respectively. Then energy metabolism was quantified using PhenoMaster/LabMaster. The spectroscopy of urine was acquired by nuclear magnetic resonance and latent biomarkers were identified. Pattern recognition analysis was used to discriminate associated metabolic profiles.

Results: Dietary BM supplement reduced body weight gain (?0.15-fold, p?<?0.01) and blood glucose levels (?0.19-fold, p?<?0.01) in HFD-fed mice. Meanwhile, the levels of energy metabolism were enhanced (0.08–0.11-fold, p?<?0.01). According to pattern recognition analysis, dietary BM supplement changed metabolic profiles in HFD-fed mice and the modified profiles were similar to those in LFD-fed mice. Finally, the mapping of metabolic pathways showed that dietary BM supplement primarily affected glucose metabolism-associated pathways.

Discussion and conclusion: The results indicated that BM improves weight loss in diet-induced obesity and elevate energy expenditure in HFD-fed mice. The pattern recognition with metabolic study may be used as a noninvasive detection method to assess the effects of dietary BM supplement on mouse energy metabolism.