Drugs of today最新文献

Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.

Aging populations worldwide are already increasing the frequency of diseases of the urinary tract, including not just malignancies such as prostate and bladder cancer, but also common diseases of the aging male, such as benign prostatic hyperplasia, as well as age-facilitated diseases of women, such as urinary incontinence. Upon this background, the European Association of Urology (EAU) 2012 congress opened the gates in Paris, with attendees from across Europe and beyond crowding the Palais des Congres, as well as the subway lines leading to it. Four hectic days of oral and moderated poster sessions began, where leading scientists and researchers presented and discussed the results of clinical and preclinical research into many areas of urology related with the treatment and management of patients. The following report reviews many of these findings presented during the meeting, with a most direct impact on the current and future treatment for urological diseases.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder characterized by developmentally inappropriate levels of inattention, hyperactivity and impulsivity. Although much evidence supports the use of psychostimulants as a first-line treatment in children and adolescents, up to 30% of patients may have an inadequate response to these medications. For these patients, addition of an α₂-adrenoceptor agonist can further improve ADHD symptoms. The α₂-adrenoceptor agonists may work in a synergistic fashion with stimulants through regulation of prefrontal cortex function. Early studies were completed with immediate-release clonidine (CLON-IR), which requires multiple daily doses and achieves a higher maximum concentration more rapidly than the more recently developed extended-release clonidine (CLON-XR). Pharmacokinetic properties of CLON-XR may be responsible for differences in efficacy and tolerability between the CLON-IR and CLON-XR formulations. Recent double-blind, placebo-controlled trials have shown that extended-release α₂-adrenoceptor agonists are safe and effective, both as monotherapy and as adjunctive treatment with stimulants. This review will focus on clonidine used in conjunction with stimulants to optimize treatment of ADHD.

Chronic constipation is a highly prevalent, heterogeneous disorder that significantly affects patients' lives. Nearly 15% of the U.S. population meets diagnostic criteria for chronic constipation (1). Chronic constipation reduces patients' quality of life and imposes a significant economic burden to the healthcare system (2, 3). A number of therapeutic options are currently available to treat symptoms of chronic constipation, although they are not universally successful (4, 5). Irritable bowel syndrome (IBS) is another common functional gastrointestinal disorder, with a prevalence rate estimated at up to 12% in the U.S. (6). Similar to chronic constipation, IBS imposes a significant impact on both the healthcare system and the individual patient (7-12). Currently, only one medication (lubiprostone) is approved by the U.S. Food and Drug Administration for the treatment of IBS with constipation (IBS-C), and is approved only for women (13). Although effective in many patients, it is not universally effective for the treatment of constipation symptoms in all patients with IBS-C. Other treatment options are therefore needed for those patients with chronic constipation and IBS-C who fail currently available therapies. This article will present information on the pharmacology and pharmacokinetics of linaclotide, a new agent designed to treat symptoms of both chronic constipation and IBS-C. Preclinical data, clinical studies and safety data will also be reviewed.

Lurasidone is a novel benzoisothiazol antipsychotic that has recently been approved for the treatment of schizophrenia in the U.S. Like many other second-generation antipsychotics, it has a high affinity for dopamine D(2) and serotonin 5-HT(2A) receptors as well as a high affinity for 5-HT(7) receptors. It has negligible affinity for α(1)-adrenoceptors, histamine H(1) receptors or muscarinic acetylcholine M(1) receptors. It has demonstrated efficacy in short-term trials versus placebo, two of which included an active comparator (olanzapine, quetiapine) assay arm. A short-term, head-to-head trial of lurasidone versus ziprasidone in chronic stable schizophrenia was also conducted. A long-term, 12-month risperidone-controlled study and open-label studies primarily investigated the safety and tolerability of lurasidone. Limited evidence of procognitive and antidepressant effects was seen although these need further corroboration. The incidence of extrapyramidal symptoms (excluding akathisia/restlessness) was greater with lurasidone (14.7%) than placebo (5.1%). Akathisia and somnolence were dose-related adverse events. Lurasidone appears to have relatively little effect on weight, plasma glucose or lipids to date. No evidence of QTc prolongation was seen and orthostatic hypotension was uncommon. Raised prolactin levels in short-term studies were dose-dependent, greater in females and occurred overall in 3.7 and 0.7% of lurasidone and placebo recipients, respectively.

XL-184 (cabozantinib) is a novel, small-molecule, multitargeted receptor tyrosine kinase inhibitor with particular activity against hepatocyte growth factor receptor (tyrosine-protein kinase Met), vascular endothelial growth factor receptor 2 (VEGFR-2) and proto-oncogene tyrosine-protein kinase receptor Ret. There is ample evidence of Met, VEGFR-2 and Ret signaling in several tumor types. Preclinical data suggest that XL-184 has activity in tumors derived from both epithelial and mesenchymal origins. Phase I and II clinical studies support significant antitumor activity, particularly in medullary thyroid cancer and cancers metastatic to the bone. This review will evaluate XL-184's preclinical pharmacology, pharmacokinetics, drug interactions and clinical activity in phase I through phase III studies.

Exenatide, a synthetic glucagon GLP-1 receptor agonist, belongs to a new class of agents approved as a treatment option in patients with poorly controlled type 2 diabetes not adequately controlled on oral antidiabetic agents. The principal mode of drug action includes enhanced glucose-dependent insulin secretion --the so called "incretin effect"-- suppression of glucagon and inhibition of endogenous glucose production. The potential to address these dysregulated pathways allows exenatide to be a valuable adjunct to existing treatment options for patients with poorly controlled type 2 diabetes. Clinical trials with twice-daily exenatide have shown significant improvements in glycemic control (HbA(1c) reductions of 0.8-1% across studies), progressive weight loss and low incidence of hypoglycemia. Common side effects include nausea and vomiting which usually subside after a few days of therapy and do not usually necessitate withdrawal of the drug. In recent months, a longer-acting, once-weekly preparation of exenatide, which is currently approved for use in Europe, has shown promise and phase III studies indicate that it may be more potent and efficacious than existing twice-daily preparations. Meanwhile, the results from long-term studies to assess cardiovascular benefits with exenatide therapy are eagerly awaited.

Alzheimer's disease (AD) is indeed a source of sadness weighing on all those who after sharing a full life now depend on each other for the most basic functions. Nevertheless, besides the dramatic impact it imposes on the life of sufferers and their caregivers, AD, as well as other forms of dementia that affect the elderly, but also younger patients, also incurs in substantial healthcare costs for patients, their families and others, including society at large. The progressive aging of the population largely depending on improved preventive and curative healthcare is progressively worsening the situation because of the increasing number of elderly people and the consequent increase in dementia sufferers. Effective and cost-effective treatments are thus required for reversing, improving or preventing these cognitive impairments. Fortunately, research has resulted in therapeutic opportunities that were reviewed during the 2011 Alzheimer's Association International Conference (AAIC) in Paris, and will be briefly reviewed in the following report.

Telaprevir, a hepatitis C virus (HCV) NS3/NS4A protease inhibitor, was recently approved by the U.S. Food and Drug Administration for the treatment of chronic HCV genotype 1 infection. When given in combination with pegylated interferon and ribavirin, it demonstrated improved efficacy over conventional pegylated interferon and ribavirin therapy. Improvement in efficacy was also noted in African American patients who traditionally respond less well to conventional anti-HCV treatment. While the role of telaprevir in the management of chronic HCV infection remains to be fully defined, its development and licensure represents an important milestone in anti-HCV therapeutics.