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. The adoption of antibiotic hybrid paradigm to macrocycles has advanced novel chemical entities to clinical trials. The multi-targeted TD-1792, for instance, retained potent antibacterial activities against multiple strains that are resistant to its constituent, vancomycin. Moreover, the antibiotic conjugation of rifamycins has provided hybrid clinical candidates with desirable efficacy and safety profiles. In 2020, the U.S. FDA has granted an orphan drug designation to TNP-2092, a conjugate of rifamycin and fluoroquinolone, for the treatment of prosthetic joint infections. DSTA4637S is a pioneer antibacterial agent under clinical development and represents a novel class of bacterial therapy, that is, antibody-antibiotic conjugates. DSTA4637S is effective against the notorious persistent S. aureus bacteremia, a revelation of the abracadabra potential of antibiotic hybrid approaches.

Indole: The After Next Scaffold of Antiplasmodial Agents?

Malaria remains a global public health problem due to the uphill fight against the causative Plasmodium 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 Plasmodium strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of Plasmodium through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.

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. In this context, it has been unheeded that phenyl rings in diaryl sulfides are less co-planar than in ethers and that the metabolic interconnection of sulfides and sulfoxides offers advantages that are unalike from the chemistry of amines and N-oxides in the CHN-O world. Moreover, σ-hole potentials increase with the polarizability of the atom N < P < O < S and do not only play a role in long-time overlooked halogen bonds. Examples for λ2 , λ4 , and λ6 S-based functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates, drug-targeting to parasites, and as basis for drug monitoring in sports are given and discussed.

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. A pre-tested semi-structured questionnaire, which was adopted from World Health Organization Quality of life brief instrument, was used. The data were then analyzed using SPSS version 20 software for Windows. RESULTS: The majority of the respondents reported to to have a good physical health (15.55). The World Health Organization clinical stage was found to be significantly associated with all the domains of health related quality of life. The current acute illness condition of the respondents, however, did not show significant association with any of the domains of health related quality of life. CONCLUSIONS: The six domains of health related quality of life were found to be moderate. The physical health and spirituality of the patients were relatively higher than their social relationship. Sex, age, educational status, residence and marital status showed significant association with at least one domain of health related quality of life.

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. METHODS: An interviewer-administered cross-sectional survey was conducted on 771 households, carried out between 5 April and 6 May 2015. The questionnaire contained items focusing on different aspects of medicine use in the households. The analysis involved descriptive summary and binary logistic regression test, which assessed association of independent variables with medicine use. RESULTS: Of the households interviewed, 22.4% (173/771) disclosed the presence of at least one chronic disease in the family; while 49.2% reported the use of medicine in the one month prior to the study. Almost all of the households (92.6%) reported a habit of discontinuing medicines, and 17.8% disclosed a practice of sharing medicines with household members and others. Level of education, presence of health professionals, and individuals with chronic illness in the households were linked to increased likelihood of reporting medicine use. Discarding leftover medicines with garbage (56.7%) was the principal means of disposal reported by the households. CONCLUSIONS: A high proportion of reported medicine use, together with problems such as sharing with other people and leaving medicines unfinished were found among the households in the study.

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. In the study, 809 households were surveyed from four sub-cities in the town selected through multistage sampling with 771 included in the final analysis. Data on the extent of storage, storage conditions, sources of medicines and their current status among others were collected through structured interviews and observations. The data were entered in to Epidata version 3.1, exported to and analyzed using Statistical Packages for Social Sciences (SPSS) version 21. RESULTS: Of the 771 households in the study, 44.2% stored medicines. Presence of family members with chronic illness(es) and higher levels of household incomes predicted higher likelihood of medicine storage. In the households which allowed observation of stored medicines (n = 299), a mean of 1.85 [SD = 1.09] medicines per household were found. By category, anti-infectives for systemic use (23.9%), medicines for alimentary tract and metabolism (19.2%) and those for cardiovascular system (17.7%) ranked top. Among individual medicines stored, diclofenac (10.7%), paracetamol (9.9%) and amoxicillin (8.0%) were on top of the list. Dispensaries (97.8%) and physicians (83.5%) were almost exclusive sources of medicines and advices/orders for medicines respectively. Nearly two-thirds of the medicines found were on use and a vast majority (76.5%) were stored in chests of drawers. Proportion of expired medicines was very low (3.14%). CONCLUSIONS: The use of physicians' and pharmacists' advice to get medicines; use of dispensaries as principal sources, large proportion of medicines being in use and very low proportion of expiry showed good practices. However, storage places of medicines were not purpose built. Encouraging good practices through continued medicine use education and advocating appropriate medicine storage in medicine cabinets is required to improve storage conditions and consequent use of medicines.

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. Requests of six tracer prescription-only medicines (amoxicillin + clavulanic acid capsule, amitriptyline, captopril, glibenclamide [also known as glyburide], omeprazole capsule, and sildenafil citrate) and upper respiratory tract infection were selected as the simulated clinical scenario. RESULTS: Amoxicillin-clavulanic acid capsule was dispensed when requested in 87.93% of the dispensaries. All of the CDROs dispensed omeprazole upon request. Sildenafil citrate (Viagra) was in stock in 96.55% of the CDROs, all of which issued the requested number of tablets without asking why or for whom the drug was needed. Amitriptyline, captopril, and glibenclamide (glyburide) were dispensed in 84.48%, 89.65%, and 87.93% of CDROs upon the provision of an empty container. Antibiotics were obtained from 75.86% of CDROs for presentation of upper respiratory tract infection symptoms. Among the dispensed antibiotics, the most common was amoxicillin (93.18%), followed by amoxicillin-clavulanic acid capsule (72.72%), and azithromycin (50%). Only 4.5% of the dispensaries asked about drug allergies, and 15.9% of the CDROs informed the simulated patient about the possible side effects of the drugs. CONCLUSION: This study revealed a very high rate of dispensing of prescription-only medicines without a prescription. Antimicrobials and drugs for chronic diseases were obtained with ease from almost all of the randomly sampled CDROs. Putting good dispensing practice into effect and adhering to the existing national laws and regulations regarding the same are necessary. It is also necessary to adopt a strong and explicit line of action, especially toward the irrational use of antibiotics.

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. OBJECTIVE: To synthesize, predict and evaluate biological activity of some 2-(N,N-dimethyl guanidinyl)-4,6-diaryl pyrimidines. EXPERIMENTAL: seven new pyrimidines were synthesized by following the standard procedures using substituted aromatic aldehydes, methyl ketones and metformin. After the biological activity was predicted using PASS, Molinspiration and Osiris property explorer, their anthelmintic activity was evaluated using Pheretima posthuma. The structural assignment of the title compounds (P1-7) has been made on the basis of elemental analysis, infrared, 1H-nuclear magnetic resonance and Mass spectral studies. RESULTS: All the synthesized compounds were found to obey Lipinski's rule. All the synthesized compounds scored good bioactivity values as GPCR ligands and kinase inhibitors. Among the test compounds, P5 was found to be more potent anthelmintic inducing paralysis in 36-48 minutes and death in 40-51 minutes. CONCLUSION AND RECOMMENDATION: The synthesized compound (P5) possessing methoxy group at position-4 of the benzene ring located at position-4 of pyrimidine exhibited good anthelmintic activity. The study revealed the necessity of synthesizing many more compounds with other substituents at position-4 of the benzene ring located at position-4 of pyrimidine.

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. METHODS: An institution-based cross-sectional study was conducted involving 400 clients who had prescriptions/orders filled at the outpatient pharmacy of the hospital during the period of 5th to 25th of November 2013. The data on the level of satisfaction of clients with the services of the outpatient pharmacy in the hospital was collected using a structured interview guide adopted from an instrument translated into Amharic and validated. The data collected was entered into and analyzed using Statistical Packages for Social Sciences (SPSS) version 16. RESULTS: The overall mean score the respondents gave to satisfaction with the pharmaceutical services was 2.48 out of a maximum of 5.00 score. The mean scores for all the individual parameters rated were less than 3.00. Maximum mean scores were given for parameters asking about the promptness of prescription medication service (2.99), and professionalism of the pharmacy staff (2.96) with the lowest being scored for information given to clients about the storage of medication (1.25), and explanations of possible side effects (1.27). Clients who were served free of fee recorded significantly higher level of satisfaction than those who paid. Higher levels of satisfaction were also reported among illiterates, older adults and those with no job compared to those with higher education, merchants and government employees. CONCLUSIONS: This study showed that the overall mean satisfaction level of clients of the outpatient pharmacy was low and it differed among different socio-demographic characteristics. Further research in to the reasons behind the low satisfaction should be done to provide appropriate solutions to improve the service.

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. The data collected was entered to and analyzed using Statistical Packages for Social Sciences (SPSS) version 16.0. RESULTS: none of the pharmacies had a private counseling room, fire extinguisher and meeting area. None of the pharmacy stores were equipped with fan and air ventilation system and had no cross aisles. The mean values for documentation, patient assessment and implementation of therapeutic objective were 12.14, 14.03 and 5.64 respectively. Many pharmacists (64.29%) did not participate in ward rotation with physicians. The overall pharmacy professionals' level of job satisfaction was found to be 2.77. CONCLUSION: There were gaps in the structure and the process of the provision of pharmaceutical care in GURH.

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. Data were collected using structured questionnaires measuring expectations and satisfaction of clients using a Likert scale of 1-5 through face-to-face interviews. RESULTS: Out of the total 424 interview encounters, 422 (99.5% response rate) questionnaires were included in the analysis, of which 61.1% were of males. The overall mean expectation of respondents toward MRO setting and services was 3.82 and that of satisfaction of the respondents was 3.02. More than three-quarters (76.8%) of the respondents expected medicines in affordable prices from MROs, but nearly half (44.8%) were not satisfied with it. Much more than half (58.5%) of the respondents were dissatisfied with the comfort and convenience of private counseling area. Also, nearly half (47.6%) of the respondents claimed that pharmacy professionals did not provide information regarding the storage condition of medications. There was statistically significant difference in overall expectation (t=2.707, P=0.007) and satisfaction (t=2.260, P=0.024) with the setting and services of MROs between respondents who claimed to know the difference between a pharmacy and a drug store and those who claimed they did not. CONCLUSION: Clients' expectation from MRO services was high, with average satisfaction. The overall expectation and satisfaction of the respondents toward MROs were lower in those who reported they did not know the difference between a pharmacy and a drug store than in those who claimed to know the difference. Supportive supervision by the town's health bureau on the MROs is recommended to help improve clients' satisfaction.