Coelogin ameliorates metabolic dyshomeostasis by regulating adipogenesis and enhancing energy expenditure in adipose tissue.

Obesity and associated metabolic disorders are heading up with an alarming rate in developing nations. One of highly sought solution for metabolic disorders is to identify natural molecule with an ability to reduce obesity and increase insulin sensitivity. Coelogin (CLN) is a phenanthrene derivative isolated from the ethanolic extract of Coelogyne cristata. In our constant efforts to identify novel anti-dyslipidemic and anti-adipogenic compounds using CFPMA (common feature pharmacophore model using known anti-adipogenic compounds) model, predicted possible anti-adipogenic activity of CLN. In vitro results showed significant inhibition of adipogenesis in 3T3-L1 and C3H10T1/2 cell by CLN. It arrests the cell cycle in G1 phase of interphase and inhibits mitotic clonal expansion to regulate adipogenesis. CLN elicits insulin sensitizing effect in mature adipocytes. During extracellular flux assessment studies, it increases oxidative respiration and energy expenditure in adipocytes. In vivo, CLN reversed HFD-induced dyslipidemia as well as insulin resistance in C57BL/6 mice. It promoted the expression of genes involved in improved mitochondrial function and fatty acid oxidation in eWAT. CLN restored energy expenditure and increased the capacity of energy utilization in HFD fed mice. Taken together, the study indicated beneficial effects of CLN in combating obesity-associated metabolic complications.

[The assessment of renal function during the therapy of arterial hypertension with azilsartan medoxomil in patients with obesity or overweight and concomitant metabolic disorders].

AIM: To assess the influence of the therapy of arterial hypertension with azilsartan medoxomil on the renal function in overweight or obese patients with concomitant metabolic disorders. MATERIALS AND METHODS: An international multicenter observational nonintervention prospective study included 1945 patients, taking azilsartan medoxomil in accordance with approved prescribing information. The observation period reached 6 months. RESULTS: In patients with an initial glomerular filtration rate (GFR)60 ml/min/1.73 m2 or 60 ml/min/1.73 m2 mean change in systolic blood pressure after 6 months of therapy reached -32.511.1 and -30.413.6 mmHg, correspondingly, while the change in diastolic blood pressure was -13.78.8 and -14.29.4 mmHg, respectively. No decrease in renal function was observed. Moreover, in patients with an initial GFR60 ml/min/1.73 m2 GFR increased significantly (p0.001). CONCLUSION: Azilsartan medoxomil, prescribed as monotherapy or in free combinations, provided an effective control of blood pressure in patients with arterial hypertension with both normal or moderately reduced and initially significantly reduced renal function. High efficacy and acceptability of the drug was associated with a beneficial effect on renal function, which allows to consider azilsartan medoxomil as the drug of choice for the treatment of hypertension in patients with concomitant metabolic disorders.

A national study on prescribed medicine use in Australia on a typical day.

PURPOSE: To describe Australians' prescribed medicine use on a typical day (September 25, 2018). METHODS: We conducted a cross-sectional study using nationally representative dispensing claims data using the Australian Government Department of Human Services random 10% sample of all Australians eligible for prescription medicines subsidised through the Australian Pharmaceutical Benefits Scheme (PBS). Our main outcome measures were the number and proportion of people using at least one prescribed medicine and the specific medicine groups and classes on the day. We estimated the proportion of Australians using these medicines using the mid-year Australian population as the denominator. We quantified multiple medicine use by calculating the number and proportion of people experiencing polypharmacy (the use of 5 or more unique medicines) and hyper-polypharmacy (the use of 10 or more unique medicines). RESULTS: We found that 9.0 million Australians used at least one PBS medicine on September 25, 2018; equating to 27.5 million medicines in use across Australia. "Cardiovascular system", "nervous system" and "alimentary tract and metabolism" medicines comprised the top three medicine groups. Over 1.8 million people experienced polypharmacy on the day, accounting for 13.6 million dispensed medicines. 1 022 590 (45%) people aged ≥70 years old experienced polypharmacy and 188 930 (8%) experienced hyper-polypharmacy. CONCLUSIONS: Rates of polypharmacy were high, particularly in the people most susceptible to polypharmacy-related harm. Strategies to optimise the risk-benefit ratio of medicines and to reduce polypharmacy through "choosing wisely" and "de-prescribing" in this age group are needed. Australia's national data provides a benchmark to inform global medicine utilisation practices.

Biomedical Research Goes Viral: Dangers and Opportunities.

Researchers around the globe have been mounting, accelerating, and redeploying efforts across disciplines and organizations to tackle the SARS-CoV-2 outbreak. However, humankind continues to be afflicted by numerous other devastating diseases in increasing numbers. Here, we outline considerations and opportunities toward striking a good balance between maintaining and redefining research priorities.

Ten-Year Trends in Enrollment of Women and Minorities in Pivotal Trials Supporting Recent US Food and Drug Administration Approval of Novel Cardiometabolic Drugs.

Background In 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10-year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017. Methods and Results A list of new molecular entities was abstracted from publicly available data at Drugs@Fda. Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty-five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175-10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation-to-prevalence ratio, 0.52), heart failure (participation-to-prevalence ratio, 0.58), and acute coronary syndrome (participation-to-prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women (P=0.29) or underrepresented minorities (P=0.45) with the drug approval year. Conclusions Over the past decade (2008-2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.

Long-Term Dietary Supplementation with Yerba Mate Ameliorates Diet-Induced Obesity and Metabolic Disorders in Mice by Regulating Energy Expenditure and Lipid Metabolism.

This study evaluated whether long-term supplementation with dietary yerba mate has beneficial effects on adiposity and its related metabolic dysfunctions in diet-induced obese mice. C57BL/6J mice were randomly divided into two groups and fed their respective experimental diets for 16 weeks as follows: (1) control group fed with high-fat diet (HFD) and (2) mate group fed with HFD plus yerba mate. Dietary yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT, which may be linked to observed decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. Yerba mate also decreased levels of plasma lipids (free fatty acids, triglycerides, and total cholesterol) and liver aminotransferase enzymes, as well as the accumulation of hepatic lipid droplets and lipid content by inhibiting the activities of hepatic lipogenic enzymes, such as FAS and phosphatidate phosphohydrolase, and increasing fecal lipid excretion. Moreover, yerba mate decreased the levels of plasma insulin as well as the homeostasis model assessment of insulin resistance, and improved glucose tolerance. Circulating levels of gastric inhibitory polypeptide and resistin were also decreased in the mate group. These findings suggest that long-term supplementation of dietary yerba mate may be beneficial for improving diet-induced adiposity, insulin resistance, dyslipidemia, and hepatic steatosis.

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.

BACKGROUND: Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. METHODS: Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer's dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. RESULTS: A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. CONCLUSIONS: This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.

GetReal in mathematical modelling: a review of studies predicting drug effectiveness in the real world.

The performance of a drug in a clinical trial setting often does not reflect its effect in daily clinical practice. In this third of three reviews, we examine the applications that have been used in the literature to predict real-world effectiveness from randomized controlled trial efficacy data. We searched MEDLINE, EMBASE from inception to March 2014, the Cochrane Methodology Register, and websites of key journals and organisations and reference lists. We extracted data on the type of model and predictions, data sources, validation and sensitivity analyses, disease area and software. We identified 12 articles in which four approaches were used: multi-state models, discrete event simulation models, physiology-based models and survival and generalized linear models. Studies predicted outcomes over longer time periods in different patient populations, including patients with lower levels of adherence or persistence to treatment or examined doses not tested in trials. Eight studies included individual patient data. Seven examined cardiovascular and metabolic diseases and three neurological conditions. Most studies included sensitivity analyses, but external validation was performed in only three studies. We conclude that mathematical modelling to predict real-world effectiveness of drug interventions is not widely used at present and not well validated. © 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.

Effects of a caspase and a calpain inhibitor on resting energy expenditures in normal and hypermetabolic rats: a pilot study.

Several diseases induce hypermetabolism, which is characterized by increases in resting energy expenditures (REE) and whole body protein loss. Exaggerated protein degradation is thought to be the driving force underlying this response. The effects of caspase and calpain inhibitors on REE in physiological and hypermetabolic conditions, however, are unknown. Thus, we studied whether MDL28170 (calpain inhibitor) or z-VAD-fmk (caspase inhibitor) affect REE under physiological conditions and during hypermetabolism post-burn. Rats were treated five times weekly and observed for 6 weeks. Treatment was started 2 h (early) or 48 h (late) after burn. In normal rats, MDL28170 transiently increased REE to 130 % of normal during week 2-4. z-VAD-fmk reduced REE by 20-25 % throughout the observation period. Within 14 days after burns, REE increased to 130+/-5 %. Whereas MDL28170/early treatment did not affect REE, MDL28170/late transiently increased REE to 180+/-10 % of normal by week 4 post-burn. In contrast, with z-VAD-fmk/early REE remained between 90-110 % of normal post-burn. z-VAD-fmk/late did not affect burn-induced increases in REE. These data suggest that caspase cascades contribute to the development of hypermetabolism and that burn-induced hypermetabolism can be pharmacologically modulated. Our data point towards caspase cascades as possible therapeutic targets to attenuate hypermetabolism after burns, and possibly in other catabolic disease processes.

Medicinal plants in Brazil: Pharmacological studies, drug discovery, challenges and perspectives.

This review article focuses on pre-clinical and clinical studies with some selected Brazilian medicinal plants in different areas of interest, conducted by research groups in Brazil and abroad. It also highlights the Brazilian market of herbal products and the efforts of Brazilian scientists to develop new phytomedicines. This review is divided into three sections. The section I describes the Brazilian large biodiversity and some attempts of Brazilian scientists to assess the pharmacological profile of most plant extracts or isolated active principles. Of note, Brazilian scientists have made a great effort to study the Brazilian biodiversity, especially among the higher plants. In fact, more than 10,000 papers were published on plants in international scientific journals between 2011 and 2013. This first part also discussed the main efforts to develop new medicines from plants, highlighting the Brazilian phytomedicines market. Despite the large Brazilian biodiversity, notably with the higher plants, which comprise over 45,000 species (20-22% of the total worldwide), and the substantial number of scientific publications on medicinal plants, only one phytomedicine is found in the top 20 market products. Indeed, this market is still only worth about 261 million American dollars. This represents less than 5% of the global Brazilian medicine market. The section II of this review focus on the use of Brazilian plant extract and/or active principles for some selected diseases, namely: central nervous systems disorders, pain, immune response and inflammation, respiratory diseases, gastrointestinal tract and metabolic diseases. Finally, section III discusses in more details some selected Brazilian medicinal plants including: Cordia verbenacea, Euphorbia tirucalli, Mandevilla velutina, Phyllanthus spp., Euterpe oleracea, Vitis labrusca, Hypericum caprifoliatum and Hypericum polyanthemum, Maytenus ilicifolia, Protium kleinii and Protium heptaphylium and Trichilia catigua. Most of these publications are preliminary and only report the effects of crude extracts, both in vitro and in vivo studies. Only very few studies have been dedicated to investigate the mechanisms of action of isolated compounds. Likewise, studies on safety (toxicology), pharmacokinetic, and especially on well-conducted clinical trials are rare. In conclusion, in spite of the abundant Brazilian biodiversity and the thousands of academic publications on plants in international peer-reviewed scientific journals, few patents and medicines have been derived from such studies. Undoubtedly, great efforts must be made to improve the development of plant-derived medicine market in Brazil, especially by involving the partnership between academia and pharmaceutical companies.

VeroScience: applying nature's genius to help improve the human condition.

VeroScience is a biotechnology company in Tiverton, Rhode Island, focused on the development of therapies and products to improve human health. The company has a strong pipeline of metabolic disease products and therapies for immunological disorders. A major platform technology of the company, Circadian Neuroendocrine Resetting Therapy, is utilized as a generator of multiple therapeutic strategies to treat a variety of disease states. The circadian timed daily (morning) administration of Cycloset®, a quick release formulation of bromocriptine mesylate, a dopamine agonist, was developed for the treatment of type 2 diabetes using this platform technology.

Moderately overweight and obese patients in general practice: a population based survey.

BACKGROUND: Obesity is a main threat to public health in the Western world and is associated with diseases such as diabetes mellitus and coronary heart diseases. Up to now a minority of research studied the relation between obesity and the use of primary health care. In the Netherlands the general practitioner (GP) is the main primary health care provider. The objective of this article is to evaluate GP consultation and prescription of drugs in moderate and severely overweight (obese) persons in the Netherlands. METHODS: Data were used from a representative survey of morbidity in Dutch general practice in 2001. Our study sample consisted of 8,944 adult respondents (18+ years) who participated in an extensive health interview. Interview data were linked to morbidity and prescription registration data from 95 general practices where respondents were listed. Body mass index (BMI) was calculated using self-reported height and weight. Analyses were controlled for clustering within practices as well as for socio-demographic and life style characteristics. RESULTS: Obesity (BMI > or = 30 kg/m2) was observed in 8.9% of men and 12.4% of women; for moderate overweight (BMI 25-< 30 kg/m2) these percentages were 42.2% and 30.4% respectively. Obese men and women were more likely to consult their GP than persons without overweight. This especially holds for diseases of the endocrine system, the cardiovascular system, the musculoskeletal system, the gastro-intestinal system, and skin problems. Related to this, obese men and women were more likely to receive drugs for the cardiovascular system, the musculoskeletal system, alimentary tract and metabolism (including, for example, antidiabetics), and dermatologicals, but also antibiotics and drugs for the respiratory system. For moderately overweight men and women (BMI 25- < 30 kg/m2) smaller but significant differences were found for diseases of the endocrine system, the cardiovascular system, and the musculoskeletal system. CONCLUSION: Obesity increases the workload of Dutch general practitioners and the use of prescribed medication. The current increase in the prevalence of obesity will further increase the use of health care and related costs. Since a large majority of Dutch persons visit their GP over the course of one year, GPs' potential role in effective prevention strategies cannot be denied.

[Prescription drugs and the elderly: results of the Argento study]. / La prescrizione di farmaci nell'anziano: risultati dello studio Argento.

OBJECTIVE: To evaluate prescription drug use in the elderly and in particular, to determine the number and types of medications taken, whether and to what extent drugs that are contraindicated in this age group are being used, and what type of prescription check may be performed by primary care physicians. DESIGN: A survey was performed in a sample of non-institutionalised elderly subjects (= 65 years). These were selected by cluster sampling in 11 of 20 Italian regions and were interviewed in the home by trained interviewers using a standardised questionnaire. RESULTS: Eighty-seven percent of interviewed subjects reported that they had taken at least one medication in the previous year; higher frequencies were found in age groups= 75 years. The most common therapeutic classes of drugs used in all participating regions, in the previous week, were cardiovascular, gastrointestinal, metabolic (including drugs to treat diabetes) and nervous system. Among interviewed subjects, 45.3% reported using 4 or more different drugs, though wide regional differences were observed (Campania 60.5%, Bolzano 35.6%); 7.2 % were taking potentially inappropriate drugs while 2.3% were taking medications that may lead to potentially harmful interactions. In addition, 84.9% of subjects reported that their primary care physician regularly checked their drug prescriptions. CONCLUSIONS: The high frequency of prescription drug use observed in the elderly is a diffuse phenomenon, related to the worsening health conditions that inevitably accompany aging. Considering the extent of this phenomenon, care should be taken to improve qualitative (i.e. contraindications in the elderly, potential drug-interactions) and quantitative (high number of medications taken by the elderly) appropriateness in physician prescribing. In addition, special attention must be placed on regularly checking drug therapies in the elderly.

Reduced violent behavior following biochemical therapy.

UNLABELLED: Reduced violent behavior following biochemical therapy. We conducted an outcome study to measure the effectiveness of biochemical therapy for 207 consecutive patients presenting with a diagnosed behavior disorder. The treatment protocols were based on clinical evaluation and our past experience in the treatment of 8000 patients with behavior disorders at the Pfeiffer Treatment Center (PTC) over a 10-year period. Each test subject was screened for chemical imbalances previously found in high incidence in this population, including metal-metabolism disorders, methylation abnormalities, disordered pyrrole chemistry, heavy-metal overload, glucose dyscontrol, and malabsorption. The clinical procedure included a medical history, assay of 90 biochemical factors, and a physical examination. Standardized treatment protocols were applied for each imbalance that was identified. The frequencies of physical assaults and destructive episodes were determined using a standardized behavior scale before and after treatment, with follow-up ranging from 4 to 8 months. RESULTS: Seventy-six percent of the test subjects achieved compliance during the treatment period. The remaining 24% were reported to have discontinued the therapy. A reduced frequency of assaults was reported by 92% of the compliant assaultive patients, with 58% achieving elimination of the behavior. A total of 88% of compliant destructive patients exhibited a reduced frequency of destructive incidents and 53% achieved elimination of the behavior. Statistical significance was found for reduced frequency of assaults (t=7.74, p<0.001) and destructive incidents (t= 8.77, p<0.001). The results of this outcome study strongly suggest that individualized biochemical therapy may be efficacious in achieving behavioral improvements in this patient population.