Current opinion in investigational drugs最新文献

The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.

Asthma is an inflammatory disease of the airways, caused by various allergens and characterized by airway hyper-responsiveness to stimuli. Inflammatory responses have two phases: an early asthma response in which acute inflammation mediators, such as histamine, induce bronchospasm; and a late asthma response involving more chronic and complex local inflammation. Nitric oxide (NO) is an endogenous mediator with bronchodilating and anti-inflammatory properties that is downregulated in asthma as a result of local inflammation. The augmented availability of NO in the lungs may represent a plausible approach for the treatment of asthma; however, the mechanisms leading to the decreased expression of this molecule have not been fully elucidated, and demonstration of the therapeutic effects of NO-enhancing compounds in asthma requires further research.

Autotaxin (ATX) is an autocrine motility-stimulating factor and an extracellular enzyme that catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). Although ATX can also hydrolyze sphingosylphosphorylcholine (SPC) to sphingosine-1-phosphate (S1P), the major source of extracellular S1P originates from the intracellular phosphorylation of sphingosine by sphingosine kinases (SphKs). LPA and S1P are well-characterized bioactive lysophospholipid mediators, which have critical roles in multiple cellular processes through binding and activating GPCRs. These two lipids have been implicated in various physiological (eg, cell growth, differentiation, migration and survival) and pathological (eg, angiogenesis, metastasis and autoimmunity) processes. The roles of LPA and S1P in autoimmune diseases, including rheumatoid arthritis (RA), have recently emerged. This review discusses recent findings suggesting that the LPA- and S1P-induced cellular functions of synoviocytes from patients with RA may contribute to the pathophysiology of the disease by exacerbating the disease process. ATX and the lysophospholipid mediators are potential targets for the treatment of patients with RA.

It is widely accepted that T-helper 2 cell (Th2) cytokines play an important role in the maintenance of asthma and allergy. Emerging evidence has highlighted the role of IL-13 in the pathogenesis of these diseases. In particular, IL-13 is involved in the regulation of IgE synthesis, mucus hypersecretion, subepithelial fibrosis and eosinophil infiltration, and has been associated with the regulation of certain chemokine receptors, notably CCR5. Thus, targeting IL-13 and its associated receptors may be a therapeutic approach to the treatment of asthma and/or allergy. Pharmaceutical and biotechnology companies are researching various strategies, based on this approach, aimed at binding IL-13, increasing the level of the IL-13 decoy receptor, IL-13Ralpha2, or blocking the effect of the chemokine receptor CCR5. This review focuses on the therapeutic potential of anti-IL-13 agents and their role in the treatment of asthma and allergy.

Oralair Birch is a dissolving tablet being developed for sublingual immunotherapy (SLIT) of allergic rhinitis caused by birch pollen allergy. Oralair Birch is being developed by Stallergenes SA and Canadian licensee Paladin Labs Inc. Oralair Birch is a recombinant protein that is synthesized from the DNA coding region of Bet v 1a, the major birch pollen allergen. During preclinical characterization, Oralair Birch had comparable structural and biological properties to the natural Bet v 1 allergen. However, Oralair Birch was more homologous than the natural Bet v 1 allergen, making a greater level of quality control possible. The administration of SLIT in tablet formulation provides a more uniform dose compared with liquid drops and better local application, which might enhance local uptake into dendritic cells of the sublingual submucosa and efficacy. Using skin prick testing, the performance of recombinant Bet v 1 was comparable to the natural Bet v 1 allergen. The results of a dose-finding phase IIb/III clinical trial of Oralair Birch were positive, with the primary endpoint met by all three tested doses. A confirmatory phase III trial was planned for 2011. Oralair Birch is a very promising treatment option for patients with birch pollen allergic rhinitis.

In vitro and in vivo preclinical studies and phase I/II clinical trials have demonstrated that the retroviral-mediated transfer of the suicide gene HSV-thymidine kinase into donor T-cells prior to infusion (ie, a 2-week ex vivo process including activation, retroviral transduction and selection of transduced cells), at the time of T-cell-depleted hematopoietic stem cell transplantation (HSCT) or as donor lymphocyte infusion after relapse, allows for the efficient control of donor T-cell alloreactivity. These donor suicide gene-modified T-cells (SGMTCs) can provide beneficial anti-leukemic, antiviral and immune reconstitution-facilitating effects to the recipient of an allogeneic HSCT. However, if the infused SGMTCs lead to GvHD, a severe complication of HSCT, these cells can be specifically depleted in vivo by the administration of the prodrug ganciclovir (GCV), without any associated immunosuppression. Limitations to this approach include a gene transfer-induced decrease in alloreactivity and antiviral reactivity, the immunogenicity of SGMTCs, and the development of GCV-resistant SGMTCs. However, major improvements that can prevent these limitations, such as introducing CD3/CD28 costimulation and immunomagnetic selection, have been applied to this approach, but further improvements are still required. The efficacy of suicide gene therapy as a safety control system allows the development of this strategy for gene therapy or immunotherapy approaches.

Diabetic kidney disease, or diabetic nephropathy, is the leading cause of kidney failure in developed countries and is projected to place an increasingly heavy burden on medical, social and economic systems worldwide. Existing therapies can slow, but do not stop, disease progression. Recent data from preclinical models and patients with diabetes emphasize the need for reducing excess metabolic flux through aldose reductase, an enzyme that plays a critical role in transducing the metabolic abnormalities that cause fibrosis in the diabetic kidney. The background and developmental history of aldose reductase inhibitors are reviewed briefly, as are metabolic, hemodynamic and genetic data linking aldose reductase to diabetic kidney disease. A new paradigm defining the pathogenic role of aldose reductase, the 'metabolic flux hypothesis', is presented, along with updated pharmacological goals for achieving success with this class of inhibitors in diabetic kidney disease.

Although the reconstitution of a functional beta-cell mass by transplantation of isolated islets can restore euglycemia in the absence of insulin treatment, a shortage of donor material is one of the factors preventing the general use of cell replacement therapy for the treatment of type 1 diabetes mellitus (T1DM). Advances in the directed differentiation of pluripotent stem cells toward beta-cells via the stepwise recapitulation of embryonic development have generated proof of concept demonstrating that stem cells may be an appropriate source of cells for the generation of therapeutic beta-cells. However, progress toward a clinical application of this technology is slow and challenging. This review highlights some of the critical issues impeding the translation of stem cell-based diabetes therapies to the clinic.

A new role for fatty acids as endocrine regulators of lipid and carbohydrate metabolism through the activation of their cognate receptors, GPCRs, has been discovered during the past decade. GPR43 is a GPCR that has been implicated in the regulation of fatty-acid and glucose homeostasis in adipose tissue and the intestines, thus having potential therapeutic relevance in the treatment of type 2 diabetes, insulin resistance and obesity. Ongoing drug discovery efforts are focused toward the development of a novel, potent and selective orthosteric or allosteric modulator that acts as an agonist for GPR43. This review summarizes data supporting a role for GPR43 in the pharmacological management of metabolic disorders.

Aprela, in development by Pfizer Inc, is a once-daily, orally administered, tissue-selective estrogen complex that contains the selective estrogen receptor modulator bazedoxifene (BZA) and conjugated equine estrogens (CE). Aprela was designed as an alternative to combination estrogen and progestin therapy to treat the vasomotor symptoms associated with menopause without the potential safety concerns associated with combination estrogen/progestin therapy, and with better tolerability. Both estrogens and BZA bind to estrogen receptors (ER)alpha and beta, but when BZA binds to an ER, the result may be an estrogen agonistic or antagonistic effect. In contrast, progestins antagonize the effects of estrogen in the uterus, but along with estrogen, stimulate breast tissue increasing the risk for breast cancer. In phase III clinical trials, Aprela significantly reduced the number and severity of vasomotor symptoms, reduced vaginal atrophy and increased bone mineral density. However, higher doses of BZA tended to attenuate these positive effects of CE. At the time of publication, there were no clinical data from women taking Aprela for > 2 years, and no definitive trials to determine the effects of Aprela on the risks for cardiovascular events, stroke, breast cancer, venous thromboembolism or cognitive function had been completed. Nevertheless, at the time of publication, Aprela was under consideration by the FDA for approval to treat vasomotor symptoms in postmenopausal women.