Klumpers L.E.,Center for Human Drug Research |
Fridberg M.,7TM Pharma |
De Kam M.L.,Center for Human Drug Research |
Little P.B.,7TM Pharma |
And 4 more authors.
British Journal of Clinical Pharmacology | Year: 2013
Aim Cannabinoid receptor type 1 (CB1) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 was studied in humans. Methods This was a double-blind, randomized, placebo-controlled, crossover study. On occasions 1-4, 24 healthy subjects received 5 × 4 mg THC with TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic (PD) effects were assessed frequently. Pharmacokinetics (PK) and PD were quantified using population PK-PD modelling. Results The TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 showed an estimated terminal half-life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [-26.70% [90% confidence interval (CI) -40.9, -12.6%]; -7.10%, (90%CI -18.1, 5.3%); -7.30%, (90% CI -11.5%, -3.0%) respectively] and TM38837 500 mg [-22.10% (90% CI -34.9, -9.4%); -12.20% (90% CI -21.6%, -1.7%); -8.90% (90% CI -12.8%, -5.1%) respectively]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM38837 as a peripherally selective CB 1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects. © 2013 The British Pharmacological Society.
Bellmann-Sickert K.,University of Leipzig |
Elling C.E.,7TM Pharma |
Madsen A.N.,Copenhagen University |
Little P.B.,7TM Pharma |
And 6 more authors.
Journal of Medicinal Chemistry | Year: 2011
The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y2 and hY4 receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity. © 2011 American Chemical Society.
Kulahin N.,Copenhagen University |
Kulahin N.,Hagedorn Institute |
Grunnet L.G.,Hagedorn Research Institute |
Grunnet L.G.,Copenhagen University |
And 11 more authors.
FEBS Letters | Year: 2011
Biological activity of the neural cell adhesion molecule (NCAM) depends on both adhesion and activation of intra-cellular signaling. Based on in vitro experiments with truncated extra-cellular domains, several models describing homophilic NCAM trans- and cis-interactions have been proposed. However, cis-dimerization in living cells has not been shown directly and the role of the cytoplasmic part in NCAM dimerization is poorly understood. Here, we used the bioluminescence resonance energy transfer (BRET2) technique to directly demonstrate that full-length NCAM cis-homodimerizes in living cells. Based on BRET250 values we suggest that the intra-cellular part of NCAM inhibits cis-dimerization, an effect mainly dependent on the palmitoylation sites. © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
News Article | November 30, 2016
Globally, obesity is a public health problem. Obesity is a genetic and chronic metabolic disease involving accumulation of excessive or abnormal fat in the body. It contributes to risk of chronic conditions such as cancer, hypertension, cardiovascular diseases, diabetics, obstructive sleep apnea, ventilatory failure, renal failure and asthma. According to a World Health Organization (WHO) report published in 2014, around 3.4 million adults in the world die each year due to obesity related issues. Increasing prevalence of obesity among children and adults is posing a threat and developing nations. Effective intervention strategies such as increased physical activity, behavioral and dietary changes are commonly used to control and prevent obesity. Obesity has a major impact on population longevity and health related expense. Request TOC (desk of content material), Figures and Tables of the report: http://www.persistencemarketresearch.com/toc/3381 North America dominates the global market for anti-obesity prescription due to increasing prevalence of obesity and lifestyle associated diseases. Asia followed by the Europe are expected to show high growth rates in the next five years in the global anti-obesity prescription market. China and India are expected to be the fastest growing anti-obesity prescription markets in Asia-Pacific region. Some of the key driving forces for anti-obesity prescription market in emerging countries are large pool of patients, increased government funding and improving healthcare infrastructure. In recent times there is increased use of anti-obesity prescription due to increasing obesity endemic. Sedentary lifestyle and junk food habits, increasing healthcare expenditure and rise in aging population are some of the key factors driving the growth for global anti-obesity prescription market. In addition, increasing healthcare awareness is also fuelling the growth of the global anti-obesity prescription market. However, side effects of anti-obesity drugs, high drug development cost and strict regulatory framework are some of the major factors restraining the growth for the global anti-obesity prescription market. New researches for discovery of novel drugs for treatment of obesity would develop opportunity for the global anti-obesity prescription market. However, unfavorable reimbursements policies could lead a challenge for the global anti-obesity prescription market. Some of the major companies operating in the global anti-obesity prescription market are 7TM Pharma, Zydus Cadila, Akrimax Pharmaceuticals, Zealand Pharma, Arrowhead Research, Arena Pharmaceuticals, Inc., Compellis Pharmaceuticals, Yungjin Pharm, Alpex Pharma SA and Bridge BioResearch.