Investigational Drug Therapies for Overactive Bladder Syndrome: The Potential Alternatives to Anticolinergics

2009 ◽  
Vol 76 (3) ◽  
pp. 161-177 ◽  
Author(s):  
E. Sacco ◽  
F. Pinto ◽  
D. Tienforti ◽  
F. Marangi ◽  
A. Destito ◽  
...  
Keyword(s):  
Overactive Bladder ◽  
Clinical Stage ◽  
Rho Kinase ◽  
New Drugs ◽  
Investigational Drug ◽  
Search Terms ◽  
Investigational Drugs ◽  
Camp Metabolism ◽  
English Articles ◽  
Novel Drug

Background Overactive bladder is a high prevalent and quality of life affecting disease. The mainstay of the medical therapy is represented by antimuscarinic drugs, but their side effects markedly affect patient compliance and prompt studies on novel investigational drugs. Methods A systematic literature search of peer-reviewed papers and meeting abstracts published by December 2008 was performed. PubMed databank was searched for original English articles, by using the following search terms: “overactive bladder” or “detrusor overactivity” or “urinary incontinence” and “treatment”, alone and linked to any potential molecular target or novel drug cited in the literature. Results Effective alternative pharmacological treatments are currently scarce, but many new promising compounds are emerging which target key molecular pathways involved in micturition control. The most promising potential therapeutic targets include central nervous system GABAergic inhibitory pathway, dopaminergic and serotoninergic systems, b-adrenoceptors and cAMP metabolism, nonadrenergic-noncholinergic mechanisms such as purinergic and neuropeptidergic systems, vanilloid receptor, bladder sensory nervous terminals, nonneuronal bladder signalling systems including urothelium and interstitial cells, prostanoids, Rho-kinase and different subtypes of potassium and calcium channels. Conclusions Despite the enormous amount of new biologic insight, very few novel pharmacological therapies seems to have passed the proof-of-concept clinical stage. The ultimate clinical utility of new drugs will depend on the ability to exploit tissue-specific differences and disease-related changes in molecular expression/function and to improve storage phase dysfunctions without interfering with the emptying phase. Further preclinical investigations and controlled clinical trials are urgently needed in this challenging field.

scholarly journals Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1683
Author(s):  
Milagros Mateos-Olivares ◽  
Luis García-Onrubia ◽  
Fco. Javier Valentín-Bravo ◽  
Rogelio González-Sarmiento ◽  
Maribel Lopez-Galvez ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Macular Oedema ◽  
Standard Therapy ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Rho Kinase ◽  
Diabetic Macular Oedema ◽  
New Drugs ◽  
Anti Vegf

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

scholarly journals Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

2020 ◽  
Author(s):  
Meenakshisundaram Balasubramaniam ◽  
Robert Shmookler Reis
Keyword(s):  
Small Molecules ◽  
Drug Targeting ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Hiv Treatment ◽  
Investigational Drug ◽  
Docking Simulations ◽  
Investigational Drugs ◽  
Low Toxicity

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.

scholarly journals VP196 Impact Of Trial Registry Search Features On Searches In CT.gov/ICTRP

2017 ◽  
Vol 33 (S1) ◽  
pp. 240-241
Author(s):  
Elke Hausner ◽  
Marco Knelangen ◽  
Siw Waffenschmidt
Keyword(s):  
Clinical Trials ◽  
New Drugs ◽  
Health Conditions ◽  
Bibliographic Databases ◽  
Trial Registry ◽  
Search Queries ◽  
Search Terms ◽  
Advanced Search ◽  
Approved Drugs ◽  
Clinical Trials Registry

INTRODUCTION:In contrast to bibliographic databases, trial registries do not offer the option of formulating complex search queries, thus making targeted searches more difficult. However, ClinicalTrials.gov (CT.gov) and the International Clinical Trials Registry Platform (ICTRP) offer different search features that may help compensate this limitation. Our aim was to determine the importance of search features (for example, searches using synonyms or, additionally in CT.gov, automatic inclusion of further search fields) for trial registry searches.METHODS:We conducted a project called “Trial registry searches for studies of newly approved drugs” (1). One analysis investigated the question as to whether searches for different health conditions and interventions (new drugs) directly identified registry entries with the search terms entered or whether certain search features were responsible for this. We searched CT.gov and ICTRP for different conditions and interventions using the advanced search interface. For each search, we documented the synonyms listed in the two registries. We imported the registry entries into EndNote and evaluated whether the search terms used were available in the corresponding search fields (condition; intervention).RESULTS:For CT.gov, 96 registry entries on 18 interventions and 190 entries on 12 conditions were analysed. Of these, twenty-three (24 percent) entries for interventions and thirty-eight (20 percent) for conditions were identified by search features, not by search terms. For ICTRP, 32 entries on 10 interventions and 100 entries on 9 conditions were analysed. Of these, five (16 percent) entries for interventions and eight (8 percent) for conditions were identified by search features.CONCLUSIONS:Trial registry search features have an important impact on the sensitivity of searches. Many studies are not identified by the search terms entered, but by searches using synonyms and, additionally in CT.gov, by automatic inclusion of further search fields. Moreover, search features in CT.gov are more effective than in ICTRP – even though the same search terms are used, they consistently yield higher sensitivities.

scholarly journals Tropheryma whippleiCrystalline Keratopathy: Report of a Case and Updated Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Scott D. Schoenberger ◽  
Sumeer Thinda ◽  
Stephen J. Kim
Keyword(s):  
Signs And Symptoms ◽  
Tropheryma Whipplei ◽  
Extensive Literature ◽  
Whipple’S Disease ◽  
Whipple's Disease ◽  
Case Presentation ◽  
Search Terms ◽  
Crystalline Keratopathy ◽  
Extensive Literature Search ◽  
English Articles

Purpose. To report a case ofTropheryma whippleiinfection with crystalline keratopathy and review the recent literature on the presentation, diagnosis, and management of Whipple's disease.Methods. Detailed case presentation and extensive literature search of Pubmed for all years through February 2012 using the following search terms:Whipple's disease, Tropheryma whipplei, corneal deposits, crystalline keratopathy, and uveitis. Relevant articles were retrieved and analyzed. English abstracts were used for non-English articles. Cross-referencing was employed and reference lists from selected articles were used to identify additional pertinent articles.Results. Diagnosis of Whipple's disease remains challenging and untreated infection can result in mortality. Ocular signs and symptoms are usually nonspecific, but several independent cases have reported the presence of intraocular crystals or crystalline-like deposits.Conclusions. The presence of intraocular crystals or crystalline-like deposits may be an identifying feature of ocular Whipple’s disease.

What is the role of QTc prolongation assessment in new drugs development phase I oncology trials?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2006-2006
Author(s):  
G. Curigliano ◽  
C. Cipolla ◽  
C. Sessa ◽  
C. Noberasco ◽  
T. De Pas ◽  
...  
Keyword(s):  
Phase I ◽  
Qt Interval ◽  
Phase I Study ◽  
Qt Prolongation ◽  
New Drugs ◽  
Accurate Information ◽  
Investigational Drug ◽  
Qtc Interval ◽  
Qtc Prolongation ◽  
Qt Interval Prolongation

2006 Background: QT interval prolongation associated with “torsades de pointes” (TdP) has been a common cause of withdrawal from the market for several promising drugs. We determined the degree of QT prolongation in patients treated within a phase I study with a thioxanthone derivative known to have arrhythmogenic potential. Methods: Clinical data and serial ECGs from 31 patients with advanced tumors who received 86 courses of investigational drug were prospectively reviewed. The drug has been administered intravenously over 24 hours every 3 weeks. Patients have been on a 24 hour Holter monitor until 24 hours after infusion was complete. Three baseline ECGs were done and compared to those every 6 hours during therapy and once 6 hours after the infusion was complete. ECGs were read at a central lab according to a standard protocol. All QT measurements were then corrected for heart rate (QTc) using Bazett’s formula (QTc = QT interval divided by the square root of the R-R interval). Results: Overall,843 ECG tracings were obtained, all evaluable for analysis. No basal ECG showed significant abnormalities. Prolonged QT intervals developed in 2 patients without clinical symptoms (1 patient had intervals 500 milliseconds).In both cases it was associated with the maximum concentration of the drug. Compared with baseline, the QTc interval was prolonged by 30 to 60 milliseconds in 20% of total tracings, and by more than 60 milliseconds in 2% of ECGs. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course. Conclusions: The assessment of QTc prolongation was a major effort in this study but produced an accurate information about such event. In phase I study such an effort is justified when arrhythmogenicity is suspected. The timing of collection of ECGs should be guided by the available preclinical information about the pharmacokinetic profile of the drug. Nevertheless uncertainty remains regarding the specific relationship between the degree of QT prolongation and the risk of life-threatening arrhythmias. The decision to use the drug ultimately has to be based on an estimation of the perceived risk relative to expected benefits for patients. No significant financial relationships to disclose.

The emergence of new drugs for overactive bladder

2006 ◽  
Vol 11 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Rebecca J McCrery ◽  
Phillip P Smith ◽  
Rodney A Appell
Keyword(s):  
Overactive Bladder ◽  
New Drugs

Something old, something new: revisiting natural products in antibiotic drug discovery

2014 ◽  
Vol 60 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Gerard D. Wright
Keyword(s):  
Natural Products ◽  
New Drugs ◽  
Clinical Use ◽  
Antibiotic Resistant ◽  
Antibiotic Drug ◽  
New Antibiotics ◽  
Bacteria And Fungi ◽  
Antibiotic Discovery ◽  
Novel Drug ◽  
New Strategies

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an “apocalyptic” threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

EYE ON CHINA

2014 ◽  
Vol 18 (11) ◽  
pp. 16-22 ◽  
Keyword(s):  
Clinical Stage ◽  
Fruit Trees ◽  
New Drugs ◽  
Asia Pacific ◽  
Google Glass ◽  
Chinese Market ◽  
Manufacturing Facility ◽  
China Market ◽  
Representative Office ◽  
Colorectal Screening

Clinical Genomics signs Chinese colorectal screening deal. WuXi PharmaTech laboratory testing division expands in U.S. with acquisition of XenoBiotic Laboratories. Roche to invest 450 million Swiss Francs in new diagnostic manufacturing facility in China. SCYNEXIS, Inc. enters into agreement with Waterstone Pharmaceutical for the development and commercialization of treatment for viral diseases. Johnson & Johnson Innovation launches Asia Pacific Innovation Center. ScinoPharm and Nanjing King-friend Biochemical Pharmaceutical team up to jointly enter the Chinese market for new drugs. Ascletis gains exclusive China market rights from Presidio for clinical stage Hepatitis C virus inhibitor. Irvine Pharmaceutical Services opens an analytical facility in Hangzhou, China. Pioneering application of Google Glass by Renji Hospital. WuXi PharmaTech launches representative office in Israel, forms strategic collaboration with Pontifax. International Symposium on molecular biology of fruit trees held at Huazhong Agricultural University.

Are Investigational Drugs Getting you Down? One Hospital's Solution to the Increasing Number of Clinical Research Studies

2003 ◽  
Vol 38 (2) ◽  
pp. 140-143 ◽  
Author(s):  
Christine D. Sybert
Keyword(s):  
Clinical Research ◽  
Drug Acquisition ◽  
Investigational Drug ◽  
Clinical Research Center ◽  
Investigational Drugs ◽  
Part Time ◽  
Important Means ◽  
Acquisition Costs ◽  
Drug Studies ◽  
Clinical Drug

This article describes the process and results of employing an Investigational Drug Service Pharmacist (IDSP) to coordinate pharmacy support for clinical drug studies. In 1998, a Clinical Research Center (CRC) was established to coordinate all research at a 407-bed Baltimore teaching hospital, resulting in an increase in studies requiring pharmacy support. By the end of 1998, there was a backlog of nine studies awaiting review for feasibility and impact on pharmacy resources. A lack of communication between departments further impeded the process. In March 1999, a part-time pharmacist was hired to coordinate all drug studies; the pharmacist's salary was paid by the CRC. Primary responsibilities of the position were protocol review, staff education, and drug accountability. Dispensing was still handled by staff pharmacists. After three years, results were as follows: 72 studies were reviewed, 41 were opened for enrollment, 8 were in preparation, 16 were completed. Two studies alone have saved the pharmacy department over $80,000 in drug acquisition costs. The efforts of the IDSP have helped the CRC to more than double its growth, with gross income from studies of $533,712 in 2001 compared with only $237,663 in 1998. The IDSP has improved communication between the CRC and pharmacy and expedited study initiation. It has also made the CRC more attractive to prospective sponsors, since one pharmacist works directly with study coordinators. With more physicians interested in carrying out research and hospital budgets becoming tighter, the part-time IDSP position represents an important means of supporting these endeavors without increasing fiscal burdens.

Multi-objective Genetic Algorithm for De Novo Drug Design

2020 ◽  
Vol 16 ◽  
Author(s):  
R. Vasundhara Devi ◽  
S. Siva Sathya ◽  
S. Mohane Coumar
Keyword(s):  
Genetic Algorithm ◽  
Drug Design ◽  
De Novo ◽  
New Drugs ◽  
Weighted Sum ◽  
De Novo Drug Design ◽  
Multi Objective ◽  
Multi Objective Genetic Algorithm ◽  
Fragment Library ◽  
Novel Drug

Background: Genetic algorithm being a famous evolutionary algorithm, multiple objectives of drug design are solved using weighted sum approach. Objective: To design a computational tool for the de novo design of novel drug-like molecules to aid in the discovery of new drugs using Genetic algorithm and chemical fragment library and reference molecules. Method: Multi-objective optimization using genetic algorithm and weighted sum approach. Results: The drug-like molecules for the reference molecules such as Lidocaine, Furano-pyrimidine, Imatinib, Atorvastatin and Glipizide. Conclusion: The performance of the MOGADdrug tool is evaluated using 5 reference molecules and the designed molecules are compared with Zinc and Pubchem databases along with their docking investigations.

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