Fexinidazole optimization: enhancing anti-leishmanial profile, metabolic stability and hERG safety.

The lack of adequate anti-leishmanial therapies has led to the continued suffering of millions of people from developing nations. Moreover, optimism for a therapeutic intervention by fexinidazole was dashed due to the inability to maintain cures and control unwanted side effects. To solve these shortcomings, the structural elements of fexinidazole responsible for anti-leishmanial activity and toxicities were explored.

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates.

The tale of abate in antibiotics continued defense mechanisms that chaperone the rise of drug-defying superbugs-on the other hand, the astray in antibacterial drug discovery and development. Our salvation lies in circumventing the genesis of resistance. Considering the competitive advantages of antibacterial chemotherapeutic agents equipped with multiple warheads against resistance, the development of hybrids has rejuvenated.

Challenges and Opportunities for Drug Discovery in Developing Countries: The Example of Cutaneous Leishmaniasis.

The current drug discovery paradigm has failed to address the treatment need for diseases of high priority to developing countries. Cutaneous leishmaniasis is a good example of such diseases with virtually no new effective drug developed in the past 70 years. The past two decades had witnessed relatively increased attention toward neglected diseases by stimulating pharmaceutical industries through introductions of Priority Review Vouchers (PRVs) and Product Development Partnerships (PDPs).

Indole: The After Next Scaffold of Antiplasmodial Agents?

Malaria remains a global public health problem due to the uphill fight against the causative parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action.

Simultaneous quantification of acidic and basic flupirtine metabolites by supercritical fluid chromatography according to European Medicines Agency validation.

Supercritical fluid chromatography (SFC) holds the potential to become an orthogonal method to HPLC/UHPLC in xenobiotic metabolism studies, due to its outstanding capacity to simultaneously separate highly similar (as HPLC) and physicochemically different analytes (problematic using HPLC). Paucity of guideline-conform validation, however, has been a major obstacle to clinical application of SFC, even in cases where biotransformation yields chemically dissimilar metabolites that require more than one HPLC method for comprehensive analysis. Here, a method based on supercritical fluid chromatography coupled to single quadrupole MS detection was developed to simultaneously quantify the divisive analgesic flupirtine and its acidic and basic metabolites, represented by 4-fluorohippuric acid (4-FHA) and the active metabolite D-13223 respectively, using custom-made synthetic internal standards.

Flupirtine and retigabine as templates for ligand-based drug design of K7.2/3 activators.

Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy.

Sulfide Analogues of Flupirtine and Retigabine with Nanomolar K 7.2/K 7.3 Channel Opening Activity.

The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones.

Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on K7.2/K7.3 Channel Opening Activity.

Neuronal voltage-gated potassium channels K7.2/K7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands.

Interconnection of sulfides and sulfoxides in medicinal chemistry.

Aromatic heterocycles with basic nitrogen atoms as well as carboxylic acid derivatives are the dominating chemical space in the universe of drug-like molecules. These established and exceedingly evaluated structural motifs have to be combined with elements of diversity in order to chart less well-explored galaxies of chemical space and to be able to tackle seemingly undruggable targets. Flat scaffolds should be replaced by shapely molecular cores.

Synthesis and potassium K7 channel opening activity of thioether analogues of the analgesic flupirtine.

Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug-induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.

Health related quality of life of HIV/AIDS patients on highly active anti-retroviral therapy at a university referral hospital in Ethiopia.

Background: Highly active antiretroviral therapy improves the longevity of patients living with HIV/AIDS. We conducted the study in order to assess health related quality of life of HIV/AIDS patients and the association of socio-demographic and disease related variables with health related quality of life.

Methods: Health facility based cross-sectional study among 400 HIV/AIDS patients taking highly active anti-retroviral therapy from Gondar University referral hospital was conducted.

Pattern and predictors of medicine use among households in Gondar Town, northwestern Ethiopia: a community-based medicine utilization study.

Background: Medicine use can be influenced by several factors. Health managers need specific information about irrational use of medicines, in order to identify opportunities to enhance rational use of medicines in their communities. This study aimed to assess the pattern and factors associated with household medicine use in Gondar town, northwestern Ethiopia.

Self-reported and actual involvement of community pharmacists in patient counseling: a cross-sectional and simulated patient study in Gondar, Ethiopia.

Background: Community pharmacists play a crucial role in reducing medication related health problems and improving the patient's overall wellbeing. Evidence suggests that community pharmacist led counseling services result in a better clinical and self-reported outcome, including a higher level of satisfaction and quality of life.

Objective: This study aims to document self-reported and actual levels of community pharmacists' involvement in the provision of patient counseling and barriers that limit their involvement in such services.

A household survey of medicine storage practices in Gondar town, northwestern Ethiopia.

Background: Household surveys are crucial to get accurate information on how medicines are acquired, and used by consumers, as they provide the best evidence in the area. The objective of this study was to document household medicine storage practices in Gondar town, northwestern Ethiopia.

Methods: A cross-sectional household survey was conducted from April 5 to May 6, 2015.

Extent of dispensing prescription-only medications without a prescription in community drug retail outlets in Addis Ababa, Ethiopia: a simulated-patient study.

Purpose: This study was aimed at assessing the extent of dispensing prescription-only medications without a prescription in community drug retail outlets (CDROs) of Addis Ababa, Ethiopia.

Methods: A descriptive cross-sectional observational study design was used to sample 31 pharmacies, 25 drug stores, and two rural drug vendors from August 11, 2015, to October 21, 2015, through a simple random sampling method. A simulated-patient method of visit was implemented to collect data.

Synthesis, characterization and in silico biological activity of some 2-(N,N-dimethyl guanidinyl)-4,6-diaryl pyrimidines.

Introduction: As pyrimidine is a basic nucleus in DNA and RNA, it has been found to be associated with diverse biological activities. Pyrimidine derivatives were reported to possess anticonvulsant, antimicrobial, anti-inflammatory, antitumor, and antihistaminic. Recently, our team reported the anti-inflammatory and antimicrobial evaluation of some pyrimidines.

Satisfaction of clients with the services of an outpatient pharmacy at a university hospital in northwestern Ethiopia: a cross-sectional study.

Background: Evaluation of patient/client satisfaction with pharmacy services as a crucial part of the health services through appropriate studies is important. This will help identify specific areas of the service which need improvement in realizing high quality pharmacy services in general and enhance the positive changes in the current pharmaceutical services provision in Ethiopia. The current study aimed at assessing the level of client satisfaction with the services of the outpatient pharmacy of Gondar University Referral Hospital (GURH) in northwestern Ethiopia.

Assessment of the structural and process aspects of pharmaceutical care at a university hospital in Ethiopia.

Objective: To assess the structural and process components of the pharmaceutical care at Gondar University Referral Hospital (GURH).

Materials And Methods: An institution-based cross-sectional study was conducted on all the four pharmacies at GURH from October 1 to December 31, 2013. By adopting data collection instruments from a previously done study, the structural aspects of the pharmacies were assessed using an observation checklist and the process of pharmaceutical care delivery using a self-administered questionnaire.

Clients' expectations from and satisfaction with medicine retail outlets in Gondar town, northwestern Ethiopia: a cross-sectional study.

Purpose: The aim of this study was to assess clients' level of expectation from and satisfaction with medicine retail outlets (MROs) in Gondar town, northwestern Ethiopia.

Patients And Methods: An institutions-based cross-sectional study was conducted from April 20 to May 5, 2014, by sampling five pharmacies and eight drug stores through simple random sampling. Clients, 424, who came to the MROs during the study period were included in the study.