Current opinion in investigational drugs最新文献

Leishmaniasis is a parasitic disease that is endemic to American, African, Asian and southern European countries. More than 350 million individuals in 88 countries are at risk of infection from this neglected tropical disease. No effective vaccinations are available against leishmaniasis, and control of the disease relies entirely on toxic drug treatments, some of which were developed as early as the 1940s. As parasite resistance becomes more prevalent, there is increasing concern that currently used drugs will soon become ineffective treatments. Consequently, an urgent need exists to develop new classes of compounds that are active against drug-resistant strains of Leishmania. This review summarizes research aimed at investigating the potential development of antimicrobial peptide-based antileishmanial agents.

Cyclophilins (Cyps) constitute one of the three families of peptidyl prolyl isomerase enzymes. CypA is the prototypical member of the Cyp family and is the predominant Cyp expressed in human cells. Recent studies indicate that CypA has an essential role in supporting HCV-specific RNA replication and protein expression. CypA interacts with several virally expressed proteins, including the non-structural (NS) proteins NS2, NS5A and NS5B, and may regulate diverse activities ranging from polypeptide processing to viral assembly. The introduction of non-immunosuppressive Cyp inhibitors into clinical trials confirms that Cyp inhibition is a valid strategy for developing novel therapeutics for the treatment of chronic HCV infection. This review describes the cyclophilin protein family and the potential roles played by cyclophilins in supporting HCV RNA replication and protein expression, as well as the initial clinical results obtained with a novel series of non-immunosuppressive cyclophilin inhibitors that established the clinical proof of concept for this emerging class of therapeutic agents.

Parenteral vaccination is generally considered to be the most effective form of therapy for protection against infectious diseases. In recent years, vaccination at mucosal surfaces and combinatorial vaccination strategies that link immunostimulatory molecules to antigens have been developed to enhance vaccine efficacy. Prominent among immunological enhancement strategies are the bacterial A and B toxins, which include the cholera toxin (CT)A and CTB subunits. In contrast to the toxic CTA subunit, the non-toxic CTB subunit displays both carrier and immunostimulatory properties. When linked to pathogen antigens, CTB can impart immunostimulatory properties that are characteristic of the linked antigen. Vaccination strategies have also been broadened to include 'self' proteins applied for the immunological suppression of autoimmunity. When CTB is linked to an autoantigen, the outcome might be considered paradoxical. In type 1 diabetes, self proteins become strongly immunosuppressive, while cancer CTB-autoantigen fusion proteins may exert a strong inflammatory response. This review discusses the immunostimulatory and immunosuppressive roles played by the CTB subunit in vaccine protection and therapy against infectious and autoimmune diseases.

Improvements in the treatment of HIV infection and in the advancement of combination antiretroviral therapy (cART) have led to an increase in the number of individuals with HIV who are surviving to an older age. Preventing the development of neurocognitive abnormalities has become an increasingly important issue in this aging patient population, which is already at risk for cognitive impairment as a result of the neuropathological effects of HIV. cART has been critical in reducing the overall severity of HIV-associated neurocognitive disorders (HAND), but numerous challenges remain, as the prevalence of HAND continues to be high. There are several key areas in which treatment could be improved to reduce the incidence and severity of HAND. The use of well-tolerated cART medications that are able to penetrate the blood-brain barrier hold particular promise, as these agents may enable increased viral suppression in the parenchyma and may reduce neurocognitive dysfunction. In addition, the improved treatment of comorbid medical conditions that are common in patient populations with HIV (eg, HCV, liver failure and metabolic syndrome) is critical, as several of these conditions are known to have a significant effect on neural functions. Various research approaches indicate that the development of agents that control free radicals, neurotoxicity, proinflammatory processes and apoptosis may also have substantial potential in this field.

Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed.

Patients with serious infections requiring parenteral antimicrobial therapy are usually hospitalized for treatment. For certain conditions, however, administration of parenteral antibiotics outside the hospital setting may be safe, efficacious, convenient for patients and cost-beneficial. Outpatient parenteral antimicrobial therapy (OPAT) was developed in the US initially and its use has expanded globally during the past three decades. A wide variety of infections are amenable to treatment by OPAT. Once-daily agents such as ceftriaxone or teicoplanin and, more recently, antimicrobials such as ertapenem or daptomycin have been used for OPAT. The use of higher doses and less-frequent dosing of existing agents is being explored, and exciting new developments include the emergence of agents with broader-spectrum activity against drug-resistant organisms and the use of antifungal agents in the OPAT setting. Future prospects in OPAT include the use of more recently launched drugs such as telavancin, as well as drugs in development, including dalbavancin (Durata Therapeutics Inc) and omadacycline (PTK-0796; Novartis AG/PARATEK Pharmaceuticals Inc). This review outlines recent developments in, and future prospects for, the antimicrobial agents used in OPAT.

Potent antiretroviral therapy (ART) has transformed HIV infection into a chronic manageable disease, but drug resistance remains a common problem that limits the effectiveness and clinical benefits of treatment. With increasing experience with ART, the understanding of viral dynamics of HIV improved, and researchers learned how challenging HIV can be to control. With new-class and new-generation drugs, it is hoped that the lessons learned will be useful for limiting drug resistance and optimizing the use of ART for long-term management of HIV infection.

Treatment of HIV-1-infected individuals is often complicated by the development of antiretroviral resistance, and novel antiretroviral agents with unique mechanisms of action and resistance profiles are needed to address this issue. CCR5 inhibitors represent a new class of antiretroviral agents that block the CCR5 receptor and prevent HIV-1 recognition and entry into CD4+ macrophages and T-cells. Tobira Therapeutics Inc is developing cenicriviroc (TBR-652, formerly TAK-652), a potent inhibitor of CCR5-tropic HIV-1 replication. Cenicriviroc has good oral bioavailability, a long t1/2 that allows once-daily dosing, and has demonstrated excellent antiviral potency with minimal toxicity in in vitro studies and phase I clinical trials. Encouraging efficacy results have been reported from phase II clinical trials in patients with CCR5-tropic HIV-1. The drug is also an inhibitor of the CCR2 receptor, which is known to be associated with inflammatory-related disease states, leading to Tobira initiating a phase I clinical trial in patients with rheumatoid arthritis. Cenicriviroc is a promising CCR5 inhibitor with potentially important anti-inflammatory effects, and warrants further investigation.

Danoprevir (ITMN-191; RG-7227), under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, 'IFN-free' clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naïve patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns. In a phase IIb trial in treatment-naïve patients with HCV-1 infection, danoprevir plus pegylated IFNalpha2a and ribavirin resulted in undetectable levels of HCV-RNA in the majority of patients, without any evidence of viral resistance; however, the high-dose danoprevir arm was prematurely terminated because of grade 4 ALT elevations. Phase I trials have also demonstrated that ritonavir boosting improved the pharmacokinetic profile of danoprevir; therefore, at the time of publication, a phase IIb trial to evaluate ritonavir-boosted, low-dose danoprevir in combination with RG-7128 was planned.

Vacc-4x is being developed by Bionor Immuno AS as a therapeutic vaccine to be used in conjunction with antiretroviral therapies by individuals infected with HIV. The vaccine is comprised of four synthetic peptides describing sequences from within the highly conserved HIV core protein p24, which are thought to induce T-cell-mediated responses. Vacc-4x was assessed in 51 patients infected with HIV in one phase I and one phase II clinical trial and was demonstrated to be safe and generally well tolerated with no significant adverse events. Promisingly, the vaccine was reported to induce cell-mediated immunity, with a third of vaccinees eligible for follow-up remaining off antiretroviral therapy and being essentially symptom-free 4 years after treatment. Nonetheless, without the inclusion of a placebo group, the data will be looked upon with a degree of skepticism in the scientific community. A phase IIb, placebo-controlled clinical trial to address this issue is currently ongoing, with data expected to become available by the end of 2010. If Vacc-4x vaccinees demonstrate significantly better responses than the placebo group in this trial, the prospects for Vacc-4x could be highly promising.