Current opinion in investigational drugs最新文献

The PI3K/Akt/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target for therapeutic intervention in this pathway. The discovery of the involvement of rapamycin-insensitive mTOR complex 2 (mTORC2) in the activation of Akt, combined with the limited clinical antitumor activity of mTOR complex 1 (mTORC1)-directed rapamycin analogs, have led to the discovery of ATP-competitive selective inhibitors of the mTOR kinase that inhibit the function of both mTORC1 and mTORC2. This review describes progress in the identification of selective and novel inhibitors of mTORC1/2, focusing on the profile of inhibitors that are in clinical development.

Clinical trials of vitamin D supplementation published from 2000 to 2009 are reviewed, with an emphasis on changes in serum calcium levels. In these trials, vitamin D supplementation often resulted in modest increases in serum calcium levels, but rarely caused hypercalcemia. Although hypercalcemia is considered to be the only toxicity of vitamin D, many prospective studies have demonstrated associations between high normocalcemia (serum calcium levels that are high but fall within the normal reference range) and premature mortality, predominantly from cardiovascular disease. These findings suggest that high normocalcemia may represent a more sensitive index of the long-term toxicity associated with vitamin D supplementation than hypercalcemia. Therefore, efforts to chemoprevent diseases with vitamin D must consider the potential health risks associated with high normocalcemia.

Clinically, 5-fluorouracil (5-FU) and its derivatives, platinum-based agents and gemcitabine (GEM) are used as key treatments for unresectable or recurrent biliary cancer. A phase III clinical trial has demonstrated that treatment with GEM plus CDDP prolongs the survival of patients with biliary cancer compared with treatment with GEM alone. Moreover, promising results are also being reported against molecular targets, particularly with inhibitors of EGFR. In addition, the development of novel drugs based on biological markers might be important for the treatment of biliary cancer. In the future, a paradigm shift from disease-specific drug development to biomarker-oriented investigations may be applicable for rare diseases such as biliary cancer.

Patients at high risk for developing breast cancer and those with early stage breast cancer may have treatment options in addition to systemic therapy for the prevention and treatment of this disease in the near future. Methods of intraductal diagnosis and treatment of breast cancer, including nipple aspiration, ductal lavage and ductoscopy, are discussed in this review. Advances in this field include improvements in equipment and techniques, more reliable biomarker assessment and improved targeted therapies. As a result of these advances, intraductal treatment in high-risk populations is being investigated in clinical trials.

Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus that can lead to visual impairment and blindness. There is no approved pharmacological treatment for DR; however, laser therapy, steroids and anti-VEGF agents appear to provide some benefit. Hyperglycemia, advanced glycation end products, growth factors, and elevated levels of circulating and vitreous cytokines and chemokines can all trigger an inflammatory response of the retinal vasculature. Features of DR can include diabetic macular edema, microhemorrhage, loss of capillaries, development of avascular areas and the vitreo-retinal proliferation of neovessels. The kallikrein-kinin system (KKS) has long been recognized as a key player of inflammatory processes in various organs. Intravitreally administered recombinant plasma kallikrein has been demonstrated to produce retinal vascular leakage and hemorrhage, while both kinin B1 and B2 receptor agonists have induced retinal edema. Furthermore, kallikrein inhibitors and peptide-based B1 receptor antagonists could reduce or block retinal vascular permeability in diabetic rats. In a diabetic rat model, FOV-2304 (Fovea Pharmaceuticals SA), a non-peptide selective B1 receptor antagonist, consistently blocked retinal vascular permeability, inhibited leukocyte adhesion and abolished the retinal mRNA expression of several inflammatory mediators. Although additional studies are required to investigate the role of the KKS in early capillary loss and late-stage neovascularization processes, the blockade of the KKS is a promising therapeutic strategy for DR.

Laquinimod, a second-generation quinoline-3-carboxamide, is being developed by Active Biotech AB and Teva Pharmaceutical Industries Ltd for the treatment for relapsing-remitting multiple sclerosis (RRMS). Laquinimod has demonstrated significant activity in suppressing experimental autoimmune encephalomyelitis, an animal model of RRMS. In phase I and II clinical trials, the drug was well tolerated, with some hints of efficacy in small numbers of patients with RRMS. While the mechanism of action of the drug is unknown, it likely involves Th1 to Th2/Th3 immune deviation, promotion of the synthesis and release of neurotrophic factors, and other possible neuroprotective effects. Two phase III clinical trials are ongoing and, if successful, will lead to the approval of the first oral immunomodulatory drug for suppressing multiple sclerosis disease activity.

A subpopulation of nociceptive primary sensory neurons expresses six different transient receptor potential (TRP) ion channels of the vanilloid (V1, V2, V3 and V4), melastatin (M8) and ankyrin (A1) subtypes. TRPV1 mediates the tussive action of capsaicin, which is widely used in cough provocation studies. The upregulation of TRPV1 expression and function has been reported in asthma and other inflammatory conditions. TRPA1 is targeted by a series of byproducts of oxidative and nitrative stress, including acrolein, 4-hydroxy-2-nonenal and hydrogen peroxide. Proinflammatory neuropeptides are released from nociceptive nerve terminals after TRPV1/TRPA1 stimulation, thereby causing airway neurogenic inflammation. In addition, the early inflammatory response to cigarette smoke is mediated entirely by neuronal TRPA1. TRPV1 and TRPA1 antagonists may therefore represent potential antitussive and anti-inflammatory therapeutics for respiratory airway diseases.

The main goals for developing effective treatments for pediatric asthma are to improve the quality of life of children with asthma by reducing symptoms and the frequency of exacerbations, to allow undisturbed sleep and performance of daily activities, and to ensure a more healthy adult future. Despite advances in modern medical care and the introduction of effective therapies, such as inhaled corticosteroids, poor asthma control exists in clinical practice. This lack of control can be attributed to two primary factors: (i) poor compliance and adherence to treatment; and (ii) poor efficiency of inhalation drug delivery, resulting from the inability of young children to correctly use inhalers that were designed for adults. Both the FDA and EMEA have mandated pediatric testing regulations for drugs indicated for pediatric use and established incentives for the development of such agents; however, there are no inhalers on the market that have been specifically designed to meet the unique needs of children because most inhalers were developed for adults and then used for the treatment of children following minor modifications. Significant effort needs to be invested in the area of pediatric asthma to increase the availability of high-quality, patient-centric medication and delivery systems.

CB-01-05-MMX (LMW Heparin MMX), being developed by Cosmo Pharmaceuticals SpA, is a novel oral parnaparin sodium formulation for the potential treatment of ulcerative colitis. At the time of publication, clinical trial data were limited and the mechanism of action had not been elucidated. However, in one phase I and one phase IIb trial in patients with left-sided ulcerative colitis, CB-01-05-MMX had an acceptable safety profile and was not associated with bleeding complications, which is a known side effect of unfractionated heparin and low molecular weight heparin compounds previously evaluated for the treatment of ulcerative colitis. Evaluable efficacy data from the phase IIb trial revealed significant improvements in the clinical activity index values in the CB-01-05-MMX group, but this was not accompanied by mucosal healing. More research, including placebo-controlled trials in patients with left-sided ulcerative colitis and trials in patients with pancolitis, would determine the role of CB-01-05-MMX in the current spectrum of available medications for this condition.

Gout is a commonly occurring medical condition that can lead to significant morbidity. Therapies available for the treatment of both acute and chronic gouty arthritis have not changed significantly since the 1960s. Although these treatments are well established, they are often contraindicated in the presence of various different comorbidities, including diabetes, renal insufficiency, hypertension and gastrointestinal disease, all of which can occur frequently in patients with gout. Therefore, new treatments are needed. This review describes recent advances in therapeutics for gout, including drugs designed to reduce levels of urate and to inhibit acute or chronic inflammation. While some of these strategies are currently available, others are undergoing regulatory evaluation or are at earlier stages of development.