For many years obesity was believed to be a condition of overeating that could be resolved through counseling and short term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long-term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/ naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP- 1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in phase III trials for obesity and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide (Ac-Arg-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys-NH2, disulfide Cys2-Cys8), is a melanocortin-4 receptor agonist which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues. (Drugs. 2018 Jul; 78(11): 1113–1132.)
Month: November 2020
Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.
Terpenes are a class of natural compounds with strong permeation-enhancing potential and have been generally recognized as safe (GRAS) adjuvants with relatively low and transient irritation. For example, the acyclic monoterpene alcohols citronellol, geraniol, and linalool, enhanced the permeation of ondansetron, caffeine and haloperidol, respectively. The cyclic monoterpenes borneol, carveol, menthol, and limonene were reported as enhancers for ibuprofen, curcumin, indomethacin, and valsartan, respectively. In addition, sesquiterpene farnesol increased the permeation of haloperidol. (Sci Rep. 2019; 9: 14617.)
One-pot conversion of alkyl aldehydes into substituted propanoic acids via Knoevenagel condensation with Meldrum’s acid
Reaction of a range of alkyl aldehydes and Meldrum’s acid in triethylammonium formate (TEAF) at 100 °C generates substituted propanoic acids in a single step. (Tetrahedron Letters.,Volume 51, Issue 38, 22 September 2010, Pages 4972-4974.)