Early investigational drugs for hearing loss.
Ontology highlight
ABSTRACT:
SUBMITTER: Mukherjea D
PROVIDER: S-EPMC5488860 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IntroductionIschemic heart disease (IHD) is a major cause of death and disability among Western countries and angina pectoris is the most prevalent symptomatic manifestation. Strategies to improve management of chronic stable angina are a priority. Areas covered: A comprehensive review was conducted using the Medline and Cochrane databases as well as the clinical trial databases in the United States and Europe. Traditional therapies for angina will be discussed. This review particularly emphasizes investigational therapies for angina (including pharmacological agents, cell and gene based therapies, and herbal medications). Expert opinion: There has been renewed interest in older anti-angina agents (e.g., perhexiline, amiodarone, and phosphodiestrase-5 inhibitors). Other anti-inflammatory agents (e.g., allopurinol and febuxostat) are currently undergoing evaluation for angina therapy. Therapeutic angiogenesis continues to face some challenges. Future trials should evaluate the optimum patient population that would benefit from this form of therapy.
| S-EPMC5228503 | biostudies-literature
Project description:INTRODUCTION:Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy. Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K+-channels, the late Na+-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca2+-activated K+-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development. Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.
| S-EPMC6324729 | biostudies-literature
Project description:IntroductionThe development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients.Areas coveredMultiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field.MethodologyPublished studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included.ConclusionMany ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
| S-EPMC9589453 | biostudies-literature
Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is a significant burden to society. With continual expansion of our understanding of the disease, novel therapies are emerging as potential therapeutics to either halt or reverse progression of the disease.This paper aims to provide an overview of current drug therapies aimed at targeting the tau protein. With this protein known to be a noted pathologic finding of the disease, trials of therapeutics aimed at this protein have been under investigation. This article is based on data obtained from PubMed searches, TauRx, ALZFORUM, and Clinicaltrials.gov with search terms including: anti-tau, tau therapeutic agents in AD, Phase 0, I, II, III trials in AD, monoclonal antibodies and vaccines.Broad-based treatments that target tau, including microtubule stabilization and tau aggregation inhibitors, appear to be of greatest promise. Immunotherapy appears to be relatively safe and efficacious but narrow whereas protein kinase inhibition has not demonstrated clinical benefit to date.
| S-EPMC5502785 | biostudies-other
Project description:Introduction: The armamentarium of antileishmanial drugs is small. It is further being threatened by the development of resistance and decreasing sensitivity to the available drugs. The development of newer drugs is sorely needed. Areas covered: The authors have based their review on a literature search performed using PubMed. The article specifically looks at investigational drugs, which have demonstrated, at the very least, in vitro and in vivo activities against the leishmania species that cause visceral leishmaniasis. Specifically, the authors review the nitroimidazole compound fexinidazole, which is one of the few drugs which have reached Phase II trials. The article also discusses the R enantiomer of (S)-PA-824, which has shown good antileishmanial activity. Finally, the article also highlights the many novel delivery systems and oral formulations of amphotericin B, which are both cheap and less toxic and are currently under investigation. Expert opinion: Very few new drugs have reached the clinic for this neglected tropical disease and there is an urgent need for new efficacious therapeutics. The authors believe that support from public-private partnerships would help in enabling the prompt development of drug candidates that could potentially make the clinic.
| S-EPMC4262729 | biostudies-other
Project description:Cyclodextrins are a family of cyclic oligosaccharides with widespread usage in medicine, industry and basic sciences owing to their ability to solubilize and stabilize guest compounds. In medicine, cyclodextrins primarily act as a complexing vehicle and consequently serve as powerful drug delivery agents. Recently, uncomplexed cyclodextrins have emerged as potent therapeutic compounds in their own right, based on their ability to sequester and mobilize cellular lipids. In particular, 2-hydroxypropyl-?-cyclodextrin (HP?CD) has garnered attention because of its cholesterol chelating properties, which appear to treat a rare neurodegenerative disorder and to promote atherosclerosis regression related to stroke and heart disease. Despite the potential health benefits, use of HP?CD has been linked to significant hearing loss in several species, including humans. Evidence in mice supports a rapid onset of hearing loss that is dose-dependent. Ototoxicity can occur following central or peripheral drug delivery, with either route resulting in the preferential loss of cochlear outer hair cells (OHCs) within hours of dosing. Inner hair cells and spiral ganglion cells are spared at doses that cause ~85% OHC loss; additionally, no other major organ systems appear adversely affected. Evidence from a first-to-human phase 1 clinical trial mirrors animal studies to a large extent, indicating rapid onset and involvement of OHCs. All patients in the trial experienced some permanent hearing loss, although a temporary loss of function can be observed acutely following drug delivery. The long-term impact of HP?CD use as a maintenance drug, and the mechanism(s) of ototoxicity, are unknown. ?-cyclodextrins preferentially target membrane cholesterol, but other lipid species and proteins may be directly or indirectly involved. Moreover, as cholesterol is ubiquitous in cell membranes, it remains unclear why OHCs are preferentially susceptible to HP?CD. It is possible that HP?CD acts upon several targets-for example, ion channels, tight junctions (TJ), membrane integrity, and bioenergetics-that collectively increase the sensitivity of OHCs over other cell types.
| S-EPMC5676048 | biostudies-literature
Project description:We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 208?T >C transition causing an amino-acid substitution (70S-P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P<0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared with those of untreated mice. Thus, the erl mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27-P90) makes this model ideal for screening and validating otoprotective drugs.
| S-EPMC3000876 | biostudies-literature
Project description:IntroductionDespite substantial improvements in standards of care, the most common aggressive pediatric and adult high-grade gliomas (HGG) carry uniformly fatal diagnoses due to unique treatment limitations, high recurrence rates and the absence of effective treatments following recurrence. Recent advancements in our understanding of the pathophysiology, genetics and epigenetics as well as mechanisms of immune surveillance during gliomagenesis have created new knowledge to design more effective and target-directed therapies to improve patient outcomes.Areas coveredIn this review, the authors discuss the critical genetic, epigenetic and immunologic aberrations found in gliomas that appear rational and promising for therapeutic developments in the presence and future. The current state of the latest therapeutic developments including tumor-specific targeted drug therapies, metabolic targeting, epigenetic modulation and immunotherapy are summarized and suggestions for future directions are offered. Furthermore, they highlight contemporary issues related to the clinical development, such as challenges in clinical trials and toxicities.Expert opinionThe commitment to understanding the process of gliomagenesis has created a catalogue of aberrations that depict multiple mechanisms underlying this disease, many of which are suitable to therapeutic inhibition and are currently tested in clinical trials. Thus, future treatment endeavors will employ multiple treatment modalities that target disparate tumor characteristics personalized to the patient's individual tumor.
| S-EPMC5674816 | biostudies-literature
Project description:Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and do not interfere with its antitumoral activity. Many therapies have been successful in preclinical work, but only a few have shown any protection in the clinic, and none have been approved by the FDA. This review summarizes the clinical and preclinical studies of the most effective small-molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field.
| S-EPMC6043375 | biostudies-literature
Project description:IntroductionSensorineural hearing loss affects a high percentage of the population. Ototoxicity is a serious and pervasive problem in patients treated with cisplatin. Strategies to ameliorate ototoxicity without compromising on antitumor activity of treatments are urgently needed. Similar problems occur with aminoglycoside antibiotic therapy for infections. Noise-induced hearing loss affects a large number of people. The use of ear protection is not always possible or effective. The prevention of hearing loss with drug therapy would have a huge impact in reducing the number of people with hearing loss from these major causes.Areas coveredThis review discusses significant research findings dealing with the use of protective agents against hearing loss caused by cisplatin, aminoglycoside antibiotics and noise trauma. The efficacy in animal studies and the application of these protective agents in clinical trials that are ongoing are presented.Expert opinionThe reader will gain new insights into current and projected future strategies to prevent sensorineural hearing loss from cisplatin chemotherapy, aminoglycoside antibiotic therapy and noise exposure. The future appears to offer numerous agents to prevent hearing loss caused by cisplatin, aminoglycoside antibiotics and noise. Novel delivery systems will provide ways to guide these protective agents to the desired target areas in the inner ear and circumvent problems with therapeutic interference of antitumor and antibiotics agents as well as minimize undesired side effects.
| S-EPMC3395201 | biostudies-literature