Annual Review of Medicine

▪ Abstract  The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases.

▪ Tóm tắt  RU486 (mifepristone) đã chứng minh là một tác nhân kháng progesterone và kháng glucocorticosteroid rất hiệu quả ở người. Cơ chế hoạt động liên quan đến các thụ thể nội bào của các hormone bị đối kháng (progesterone và glucocorticosteroid). Ở mức độ phân tử, các đặc điểm quan trọng nhất là độ bám dính cao với thụ thể, sự tương tác của nhóm phenylaminodimethyl tại vị trí 11β với một vùng cụ thể của túi liên kết thụ thể, và sự khác biệt về chuyển dạng do RU486 gây ra trong miền liên kết ligand. Những đặc điểm này có những hệ quả ở các bước chức năng của thụ thể so với các agonist. Tuy nhiên, lý luận không thể bị giới hạn ở sự tương tác giữa RU486 và thụ thể, và, chẳng hạn, có khả năng chuyển từ tính chất đối kháng sang hoạt động agonist, tùy thuộc vào sự can thiệp của các con đường tín hiệu khác. Mong muốn có các dẫn xuất chỉ có một trong hai tính chất đối kháng (kháng progestin, kháng glucocorticosteroid) mặc dù có sự tương đồng giữa cấu trúc steroid, các thụ thể liên quan và các cơ chế phản ứng trong các tế bào mục tiêu. Về mặt lâm sàng, phương pháp RU486 cộng với prostaglandin đã sẵn sàng để được sử dụng trên quy mô lớn và gần như tiện lợi và an toàn như bất kỳ phương pháp phá thai y tế nào. Việc sử dụng sớm RU486 như một phương pháp tránh thai ngay khi một người phụ nữ lo sợ về một thai kỳ không mong muốn sẽ giúp giảm bớt vấn đề phá thai. Nghiên cứu bây giờ nên được tiến hành để xác định một phương pháp ngừa thai hiệu quả và thuận tiện với RU486 hoặc các antiprogestin khác. Tính hữu ích của RU486 cho các chỉ định sản khoa, bao gồm việc hỗ trợ sinh khó, cần được đánh giá nhanh chóng. Các thử nghiệm phụ khoa, đặc biệt trong u xơ tuyến, cũng nên được tiếp tục một cách hệ thống. Các kết quả rất sơ bộ thu được với các khối u, bao gồm ung thư vú, chỉ ra rằng cần có thêm các nghiên cứu.

▪ Abstract  GnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes.

This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.

▪ Abstract  Platelet-inhibitory drugs are of proven benefit to individuals who suffer from atherosclerotic cardiovascular disease. Despite substantial effort to identify more potent platelet-inhibitory agents, aspirin, an irreversible inhibitor of platelet cyclooxygenase activity, remains the standard against which other drugs are judged. Drugs that appear to be at least as efficacious as aspirin in specific clinical settings include the thienopyridines ticlopidine and clopidogrel, specific inhibitors of ADP-stimulated platelet function, and the phosphodiesterase 3 inhibitor cilostazol. Ligand binding to the platelet integrin αIIbβ3 (GPIIb-IIIa), a prerequisite for platelet thrombus formation, has been a prominent target for drug development. Currently, three types of αIIbβ3 antagonists are available: the monoclonal antibody Fab fragment abciximab, cyclic peptides based on the Arg-Gly-Asp (RGD) or related amino acid motifs, and RGD-based peptidomimetics. The efficacy of each type of αIIbβ3 antagonist in the setting of acute coronary artery disease has been confirmed in multicenter clinical trials.

Obesity is perhaps the most significant public health problem facing the United States today. Obese patients are at increased risk for numerous medical problems, which can adversely affect surgical outcome. However, these risks have not uniformly translated into increased or prohibitive operative morbidity and mortality in this population. With appropriate perioperative precautions and monitoring, the incidence of serious cardiovascular and pulmonary complications can be minimized. Obese patients can be treated as safely and effectively as their normal weight counterparts under most circumstances and should not be denied surgical treatment for any disorder when surgery constitutes the most appropriate therapy. When indicated, surgical treatment should be considered for patients with clinically severe obesity, since currently it appears to offer the best long-term results for weight control and amelioration of comorbidity.

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.

Nanomedicine, the application of nanotechnology to medicine, enabled the development of nanoparticle therapeutic carriers. These drug carriers are passively targeted to tumors through the enhanced permeability and retention effect, so they are ideally suited for the delivery of chemotherapeutics in cancer treatment. Indeed, advances in nanomedicine have rapidly translated into clinical practice. To date, there are five clinically approved nanoparticle chemotherapeutics for cancer and many more under clinical investigation. In this review, we discuss the various nanoparticle drug delivery platforms and the important concepts involved in nanoparticle drug delivery. We also review the clinical data on the approved nanoparticle therapeutics as well as the nanotherapeutics under clinical investigation.

Solid tumors derived from epithelial tissues (carcinomas) are responsible for 90% of all new cancers in Europe, and the main four tumor entities are breast, prostate, lung, and colon cancer. Present tumor staging is mainly based on local tumor extension, metastatic lymph node involvement, and evidence of overt distant metastasis obtained by imaging technologies. However, these staging procedures are not sensitive enough to detect early tumor cell dissemination as a key event in tumor progression. Many teams have therefore focused on the development of sensitive assays that allow the specific detection of single tumor cells or small amounts of cell-free tumor DNA in the peripheral blood of cancer patients. These methods allow the detection and characterization of early metastatic spread and will provide unique insights into the biology of metastatic progression of human tumors, including the effects of therapeutic interventions.