Telepharmacy in Indonesia: Navigating Knowledge, Perception, and Readiness Among 6,000 Pharmacists and Related Sociodemographic Determinants.

Introduction: Telepharmacy can improve the delivery of pharmaceutical care services to patients. However, there are limited data regarding the knowledge, perceptions, and readiness (KPR) for telepharmacy in Indonesia. In this cross-sectional survey study, we assessed KPR and associated factors among Indonesian pharmacists, aiming to implement telepharmacy services in the future. Methods: Eligible participants were recruited from all provinces of Indonesia through a 24-item instrument. KPR scores were classified as low, moderate, and high. Sociodemographic characteristics and KPR of participants were summarized using descriptive statistics. Bivariate/multivariate ordinal logistic regression analyses were conducted to identify independent determinants of KPR. An adjusted odds ratio (AOR) with a 95% confidence interval (CI) was calculated for each determinant. Results: A total of 6,059 pharmacists provided responses. Overall, 58.28% had a high knowledge score, and 63.51% expressed moderate perceptions toward telepharmacy services. Moreover, 70.21% showed a moderate level of readiness. Gender (male; AOR: 1.21 [95% CI: 1.06-1.39]), stable internet access (AOR: 0.75 [95% CI: 0.64-0.86]), and central region (AOR: 1.13 [95% CI: 0.99-1.29]) were significantly associated with perception toward telepharmacy. Readiness was significantly associated with age (17-25 years; AOR: 0.73 [95% CI: (0.60-0.89]), gender (male; AOR: 0.83 [95% CI: 0.72-0.95]), stable internet access (AOR: 0.75 [95% CI: 0.64-0.89]), education level (master/doctoral; AOR: 1.33 [95% CI: 1.06-1.67]), and central region (AOR: 1.29 [95% CI: 1.12-1.49]). Interestingly, knowledge levels were not significantly correlated with specific factors. Conclusions: Participants demonstrated high knowledge, without significant influencing factors. However, they showed moderate perceptions and readiness levels, influenced by sociodemographic factors, including gender, age, education level, internet access, and regional disparities. Therefore, targeted interventions (e.g., telepharmacy training and regional outreach) are imperative to enhancing perceptions and readiness, fostering the effective integration of telepharmacy services, and advancing pharmaceutical care in Indonesia.

Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis.

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

Favipiravir does not improve viral clearance in mild to moderate COVID-19 - A systematic review and meta-analysis of randomized controlled trials.

Purpose: Favipiravir has been used in the therapy of COVID-19, including patients with mild to moderate symptoms in certain countries. The aim of our systematic review and meta-analysis was to investigate its efficacy and safety in mild-to-moderate COVID-19 infections. Methods: The PubMed, Embase, Web of Science, and Cochrane databases were systematically reviewed for articles reporting the results of randomized controlled trials published until January 6, 2023, resulting in the identification of 20 eligible studies. Results: There were no significant differences in viral clearance time (HR = 1.20, p = 0.09) compared to those without favipiravir therapy. However, in the subgroup analyses, favipiravir treatment significantly increased viral clearance by 59 % (HR = 1.59, p < 0.01) and 42 % (HR = 1.42, p < 0.01], I2 = 20 %) compared to the comparator group in patients with moderate severity of COVID-19 and in the inpatient care setting, respectively. Favipiravir had no beneficial effects in the case of patients with mild symptoms and treated in ambulatory care. Conclusions: The use of favipiravir is questionable in the treatment of outpatients with COVID-19 with mild symptoms. Moderate beneficial effects in the case of patients with moderate symptoms and inpatients should be treated with care due to the limitations of the analysed trials.

Characteristics, knowledge, attitude, and practice of pharmacy personnel in supporting tuberculosis treatment: A multicenter cross-sectional study in a high-burden tuberculosis country.

BACKGROUND: Positive roles of community pharmacy in tuberculosis (TB) care have been widely reported. However, the actual practice of supporting TB treatment is not optimal yet. OBJECTIVES: We analyzed the current practice of community pharmacy personnel and its factors in supporting the successful treatment of TB patients in Indonesia, aiming to develop strategies for effective and sustainable TB practice models for the community pharmacy. METHODS: We performed a cross-sectional survey in 3 areas representing Indonesia's eastern, central, and western parts. Development and validation of the questionnaire were conducted to assess 4 domains, that is, characteristics, knowledge, attitudes, and practice of community pharmacy personnel in supporting the successful treatment of TB patients. Data were collected with purposive convenience sampling using online and offline questionnaires. Descriptive analyses were used to summarize factors in each domain, while binary logistic regression was used to analyze the associated factors of the practice. RESULTS: Thirty-five questionnaire items indicated a valid instrument, and the study successfully included 844 participants who comprised pharmacists (n = 473, 56%) and pharmacy assistants (n = 371, 44%). Although most of the knowledge items were correctly answered by more than 60% of the participants, items related to TB signs, risk groups, drug regimens, and medicine uses were still less than 60%. This was in line with exposure to updated TB training in only 51% of the participants (n = 426). Most of the participants had a positive attitude toward their professional role (n = 736, 87%), capability (n = 646, 77%), and consequences (n = 655, 78%) in supporting TB treatment. However, this was not aligned with the actual practice of supporting TB treatment, intensively performed by only 1.3% of participants (n = 11). We identified several factors associated with the practice, that is, a pharmacy assistant background (P < 0.05), short working time (P < 0.05), experience in TB training (P < 0.001), and a positive attitude (P < 0.001). CONCLUSION: This study highlighted a limited number of community pharmacy personnel intensively practicing as TB treatment supporters in Indonesia. An interventional package considering the identified factors is needed to develop effective and sustainable practices in the real world.

Development and Validation of the Knowledge, Attitude, and Practice Questionnaire for Community Pharmacy Personnel in Tuberculosis Case Detection, Drug Monitoring, and Education: A Study from Indonesia.

Background: Validated and standardized structured questionnaires based on psychometric analysis are extremely limited, particularly for assessing community pharmacy personnel's knowledge, attitude, and practice (KAP) in tuberculosis (TB) case detection, drug monitoring, and education. We, therefore, developed and validated a questionnaire to assess the KAP of community pharmacy personnel in TB case detection, drug monitoring, and community education. Methods: This study was conducted in two phases. First, we developed the questionnaire, which included framework development, item generation, individual item content validity index (I-CVI), item screening, and pre-testing. Second, we validated the questionnaire with 400 participants using various analyses, including participant analysis, confirmatory factor analysis (CFA), adjusted goodness-of-fit index (AGFI), comparative fit index (CFI), non-normed fit index (NNFI), root mean square error of approximation (RMSEA), and standardized root mean square residual (SRMR). We determined the reliability test using Cronbach's alpha and test-retest reliability using Pearson's correlation. Results: In the development phase, we defined 63 items that comprised 18 sociodemographic, 18 knowledge, 18 attitude, and 9 practice items. Across the 63 items, the I-CVI scores of sociodemographic and KAP items were one each. The CFA model parameter values were X2/df= 2.28; AGFI = 0.95; CFI = 0.99; NNFI = 0.98; RMSEA = 0.06; and SRMR = 0.03 (p < 0.05 for all). Cronbach's alpha coefficients of KAP items were 0.75, 0.91, and 0.95, respectively. The test-retest reliability coefficients of KAP were 0.84, 0.55, and 0.91, respectively (p < 0.01). Conclusion: This study indicates that the developed questionnaire is a valid and reliable instrument for assessing the KAP of community pharmacy personnel for TB case detection, drug monitoring, and community education in Indonesia. Community pharmacy personnel can support TB notification and treatment by assessing their prospective roles in surveys using this questionnaire, enabling TB eradication in 2030.

Knowledge, Attitudes, and Perceptions of Tuberculosis in Indonesia: A Multi-Center Cross-Sectional Study.

Introduction: Tuberculosis (TB) is still a persistent health challenge in Indonesia and ranks high on the list of factors causing morbidity and mortality. Improving knowledge, attitudes, and perceptions (KAP) of the general community about TB can help to control the disease. Purpose: This study aimed to examine the KAP about TB in Indonesian society and investigate their sociodemographic determinants. Participants and Methods: An online cross-sectional survey in 34 provinces in Indonesia was carried out in June 2022. The scores of KAP were classified as low, moderate, and high. Bivariate and multivariate ordinal logistic regression were applied to identify the potential sociodemographic determinants of KAP. Adjusted odds ratio and 95% confidence interval (CI) for each determinant were provided. Results: Among the 3205 participants, 56.4%, 91%, and 38% had high scores on knowledge, attitude, and perception, respectively. Independent determinants of high knowledge were age (26-35 years; adjusted odds ratio: 1.53 [95% CI: 1.19-1.97]), marital status (married; adjusted odds ratio: 1.18 [95% CI: 1.00-1.39]), and salary (middle income; adjusted odds ratio: 0.76 [95% CI: 0.63-0.93]). Independent factors associated with high scores in attitude and perception were the residence location (village; adjusted odds ratio: 0.76 [95% CI: 0.59-0.98]) and the occupation type (civil servant; adjusted odds ratio: 1.53 [95% CI: 1.09-2.13]), respectively. Conclusion: Most Indonesians have a high knowledge and good attitude, although they have a moderate perception toward TB. Improving public awareness and health education with the right strategies is critical to reducing the country's TB burden.

Solid lipid nanoparticles cyclodextrin-decorated incorporated into gellan gum-based dry floating in situ delivery systems for controlled release of bioactive compounds of safflower (Carthamus tinctorius. L): A proof of concept study in biorelevant media.

Safflower (Carthamus tinctorius L.) has been explored as a source of natural antioxidant. However, quercetin 7-O-beta-D-glucopyranoside and luteolin 7-O-beta-D-glucopyranoside, as its bioactive compounds, possessed poor aqueous solubility, limiting its efficacy. Here, we developed solid lipid nanoparticles (SLNs) decorated with hydroxypropyl beta-cyclodextrin (HPßCD) incorporated into dry floating gel in situ systems to control the release of both compounds. Using Geleol® as a lipid matrix, SLNs were <200 nm in size with >80 % of encapsulation efficiency. Importantly, following the decoration using HPßCD, the stability of SLNs in gastric environment was significantly improved. Furthermore, the solubility of both compounds was also enhanced. The incorporation of SLNs into gellan gum-based floating gel in situ provided desired flow and floating properties, with <30 s gelation time. The floating gel in situ system could control the release of bioactive compounds in FaSSGF (Fasted-State Simulated Gastric Fluid). Furthermore, to assess the effect of food intake on release behavior, we found that the formulation could show a sustained release pattern in FeSSGF (Fed-State Simulated Gastric Fluid) for 24 h after being released in FaSGGF for 2 h. This indicated that this combination approach could be a promising oral delivery for bioactive compounds in safflower.

Antibiotic use in elderly patients in ambulatory care: A comparison between Hungary and Sweden.

Background: The elderly use antibiotics frequently due to their increasing infection susceptibility. Given the high and increasing proportion of elderly in the population, their antibiotic use is substantial. Objective: This study aimed to compare antibiotic use in the elderly in the ambulatory care sector between Hungary and Sweden. Methods: This retrospective, descriptive, cross-national, comparative study included antibacterial use data from the Hungarian National Health Insurance Fund and the Swedish eHealth Agency. Antibiotic use (anatomical therapeutical chemical: J01) was expressed as the number of prescriptions/1000 inhabitants/year or month and was further stratified by age and sex. Results: Antibiotic exposure was higher in the Hungarian elderly population (649.8 prescriptions/1000 inhabitants/year) compared to its Swedish counterparts (545.0 prescriptions/1000 inhabitants/year). Hungary had a similar scale of antibacterial exposure across all elderly age subgroups, with different trends in males and females, while Sweden had a stepwise increase in antibiotic exposure by age in both sexes. The seasonal fluctuation was high in Hungary and reached a peak of 80.7 prescriptions/1000 inhabitants/month in January 2017, while even antibiotic use was detected throughout the year in Sweden. The pattern of antibiotic use in the elderly considerably differed between the two countries. Penicillin and beta-lactamase combinations, such as co-amoxiclav, were more frequently used in Hungary than in Sweden (19.08% vs 1.83% of corresponding total ambulatory antibiotic use). Likewise, quinolones were more commonly used in Hungary than in Sweden (34.53% vs. 9.98). The elderly in Sweden were mostly prescribed narrow spectra penicillins (26.71% vs. 0.29% in Hungary). Conclusion: This cross-national comparison revealed important differences in all aspects of antibiotic use in the elderly between the two countries. The identical scale and pattern of antibiotic use cannot be anticipated due to the poorer health status of the Hungarian elderly population. However, the substantial differences indicate some room for improvement in the antibiotic prescription for the Hungarian elderly.

The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis.

Synephrine has been used to promote weight loss; however, its safety and efficacy have not been fully established. The goals of our study were to give an overview of the safety and efficacy of p-synephrine, to systematically evaluate its efficacy regarding weight loss and to assess its safety, focusing on its cardiovascular side effects in a meta-analysis. PubMed, the Cochrane Library, Web of Science and Embase were searched for relevant studies. Only placebo-controlled, human clinical trials with synephrine intervention were included in the meta-analysis. The meta-analysis was reported according to the PRISMA guidelines using the PICOS format and taking into account the CONSORT recommendations. Altogether, 18 articles were included in the meta-analysis. Both systolic and diastolic blood pressure (DBP) increased significantly after prolonged use (6.37 mmHg, 95% CI: 1.02-11.72, p = 0.02 and 4.33 mmHg, 95% CI: 0.48-8.18, p = 0.03, respectively). The weight loss in the synephrine group was non-significant after prolonged treatment, and it did not influence body composition parameters. Based on the analyzed clinical studies, synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss. Further studies are needed to confirm evidence of its safety and efficacy.

Knowledge, attitude and practice of community pharmacy personnel in tuberculosis patient detection: a multicentre cross-sectional study in a high-burden tuberculosis setting.

INTRODUCTION: Control of tuberculosis (TB) is hampered by suboptimal case detection and subsequent delays in treatment, which is worsened by the COVID-19 pandemic. The community pharmacy is reported as the place for first aid medication among patients with TB. We, therefore, analysed knowledge, attitude and practice (KAP) on TB patient detection (TBPD) of community pharmacy personnel, aiming to find innovative strategies to engage community pharmacies in TBPD. METHODS: A multicentre cross-sectional study was performed in four areas of Indonesia's eastern, central and western parts. Pharmacists and pharmacy technicians who worked in community pharmacies were assessed for their characteristics and KAP related to TBPD. Descriptive analysis was used to assess participant characteristics and their KAP, while multivariable regression analyses were used to analyse factors associated with the KAP on TBPD. RESULTS: A total of 1129 participants from 979 pharmacies, comprising pharmacists (56.6%) and pharmacy technicians (43.4%), were included. Most participants knew about TB. However, knowledge related to TB symptoms, populations at risk and medication for TB were still suboptimal. Most participants showed a positive attitude towards TBPD. They believed in their professional role (75.1%), capacity in TB screening (65.4%) and responsibility for TBPD (67.4%). Nevertheless, a lack of TBPD practice was identified in most participants. Several factors significantly associated with performing the TBPD practice (p<0.05), such as TB training experience (p<0.001), provision of a drug consultation service (p<0.001), male gender (p<0.05), a positive attitude towards TBPD (p<0.001), short working hours (p<0.001) and central city location of the pharmacy (p<0.05). CONCLUSIONS: Most participants had good knowledge and attitude, which did not translate into actual TBPD practice. We identified that TB educational programmes are essential in improving the KAP. A comprehensive assessment is needed to develop effective strategies to engage the community pharmacy in TBPD activities.

Development and validation of a high-performance liquid chromatography method for levothyroxine sodium quantification in plasma for pre-clinical evaluation of long-acting drug delivery systems.

Levothyroxine (LEVO) sodium is an FDA-approved drug that is used to treat underactive thyroid (hypothyroidism) and other conditions. It is generally used as a thyroid-stimulating hormone administered orally. However, this approach has some drawbacks such as this drug should be taken every day 30 min to 1 h prior to breakfast with an empty stomach, moreover, some food interactions must be monitored. Thus, alternative innovative approaches capable of providing sustained LEVO release should be developed. Our research was designed to establish a simple quantitative determination method for LEVO in rat plasma for pre-clinical evaluation of long acting formulations using a high-performance liquid chromatography method, to validate the analytical method according to ICH guidelines and to characterise its pharmacokinetic behavior in rats. After simple protein precipitation with acetonitrile, LEVO was eluted on a Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with a particle size of 3.5 µm using a mobile phase of water and acetonitrile at a ratio of 65 : 35% v/v, including 0.1% v/v of trifluoracetic acid. The calibration standards used for plasma ranged between 0.5-1000 ng mL-1 with a correlation coefficient (r2) of ≥0.998. The limit of detection was 0.44 ng mL-1 and the lower limit of quantitation was 1.33 ng mL-1. The extraction recovery of LEVO in rat plasma samples by this method was between 80 and 85%. The method was selective, sensitive, accurate and precise for detecting and quantifying LEVO in a pharmacokinetic study carried out in rats for pre-clinical evaluation of long acting formulations. The validated HPLC method meets the ICH established requirements and therefore offers a wide range of potential applications in pre-clinical therapeutic drug monitoring, pharmacokinetics and toxicology.

Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine.

This work aimed to develop a subcutaneous implant for prolonged delivery of LEVO to treat hypothyroidism. This could overcome challenges with patient compliance and co-administration and could improve treatment of this condition. For this purpose, implants were produced by solvent casting mixtures of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG) and LEVO sodium. These implants contained mixtures of PCL of differing molecular weight, PEG and different LEVO sodium loadings (20% or 40% w/w). SEM images confirmed that the drug was evenly dispersed throughout the implant. In vitro release rates ranging from 28.37 ± 1.19 - 78.21 ± 19.93 µg/day and 47.39 ± 8.76 - 98.92 ± 4.27 µg/day were achieved for formulations containing 20% and 40% w/w drug loading, respectively. Implants containing higher amounts of low molecular weight PCL and 40% w/w of LEVO showed release profiles governed by zero order kinetics. On the other hand, implants containing higher amounts of high molecular weight PCL showed a release mechanism governed by Fickian diffusion. Finally, two representative formulations were tested in vivo. These implants were capable of providing detectable LEVO levels in plasma during the entire duration of the experiments (4 weeks) with LEVO plasma levels ranging between 5 and 20 ng/mL.

Albendazole Nanocrystal-Based Dissolving Microneedles with Improved Pharmacokinetic Performance for Enhanced Treatment of Cystic Echinococcosis.

Cystic echinococcosis (CE) is a zoonosis caused by Echinococcus spp., affecting both humans and animals' lives. Current treatment of CE by oral administration of albendazole (ABZ) is hampered by several limitations. The poor aqueous solubility and the rapid metabolism of ABZ in the liver are the main issues, leading to lack of efficacy of the treatment. In the present study, we developed a nanocrystalline (NC) formulation of ABZ to be delivered intradermally using dissolving microneedles (DMNs). The NC formulation was developed using milling in an ultrasmall-scale device. Following several screenings, Pluronic F127 was selected as a suitable stabilizer, producing NCs with around 400 nm in size with narrow particle distribution. The crystallinity of ABZ was maintained as observed by DSC and XRD analysis. The NC approach was able to improve the dissolution percentage of ABZ by approximately three-fold. Furthermore, the incorporation of NCs into DMNs using the combination of poly(vinylpyrrolidone) and poly(vinyl alcohol) formed sharp needles with sufficient mechanical strength and insertion properties. Dermatokinetic studies revealed that >25% of ABZ was localized in the dermis of excised neonatal porcine skin up to 48 h after DMN administration. In in vivo pharmacokinetic studies, the AUC and relative bioavailability values of ABZ delivered by NC-loaded DMNs were found to be significantly higher than those obtained after oral administration of coarse suspension of ABZ or ABZ-NCs, as well as DMNs delivering coarse ABZ as indicated by the relative bioavailability values of >100%. Therefore, the combination approach developed in this study could maintain the systemic circulation of ABZ, which could be possibly caused by avoiding the first-pass metabolism in the liver. This could be beneficial to improve the efficacy of ABZ in CE treatment.

Pharmaceutical Prospects of Bee Products: Special Focus on Anticancer, Antibacterial, Antiviral, and Antiparasitic Properties.

Bee products have long been used in traditional healing practices to treat many types of disorders, including cancer and microbial-related diseases. Indeed, several chemical compounds found in bee products have been demonstrated to display anticancer, antibacterial, antiviral, and antiparasitic properties. With the improvement of research tools and in view of recent advances related to bee products, this review aims to provide broad yet detailed insight into the pharmaceutical prospects of bee products such as honey, propolis, bee pollen, royal jelly, bee bread, beeswax, and bee venom, in the domain of cancer and infectious disease management. Available literature confirms the efficacy of these bee products in the alleviation of cancer progression, inhibition of bacterial and viral proliferation, and mitigation of parasitic-related symptoms. With such potentials, bioactive components isolated from the bee products can be used as an alternative approach in the long-run effort to improve humans' health at a personal and community level.

Impact of Drug-Gene-Interaction, Drug-Drug-Interaction, and Drug-Drug-Gene-Interaction on (es)Citalopram Therapy: The PharmLines Initiative.

We explored the association between CYP2C19/3A4 mediated drug-gene-interaction (DGI), drug-drug-interaction (DDI) and drug-drug-gene-interaction (DDGI) and (es)citalopram dispensing course. A cohort study was conducted among adult Caucasians from the Lifelines cohort (167,729 participants) and linked dispensing data from the IADB.nl database as part of the PharmLines Initiative. Exposure groups were categorized into (es)citalopram starters with DGI, DDI and DDGI. The primary outcome was drug switching and/or dose adjustment, and the secondary was early discontinuation after the start of (es)citalopram. Logistic regression modeling was applied to estimate adjusted odd ratios with their confidence interval. We identified 316 (es)citalopram starters with complete CYP2C19/3A4 genetic information. The CYP2C19 IM/PM and CYP3A4 NM combination increased risks of switching and/or dose reduction (OR: 2.75, 95% CI: 1.03-7.29). The higher effect size was achieved by the CYP2C19 IM/PM and CYP3A4 IM combination (OR: 4.38, 95% CI: 1.22-15.69). CYP2C19/3A4 mediated DDIs and DDGIs showed trends towards increased risks of switching and/or dose reduction. In conclusion, a DGI involving predicted decreased CYP2C19 function increases the need for (es)citalopram switching and/or dose reduction which might be enhanced by co-presence of predicted decreased CYP3A4 function. For DDI and DDGI, no conclusions can be drawn from the results.

Prevalence and Accuracy of Information on CYP2D6, CYP2C19, and CYP2C9 Related Substrate and Inhibitor Co-Prescriptions in the General Population: A Cross-Sectional Descriptive Study as Part of the PharmLines Initiative.

BACKGROUND: Drug-drug interaction (DDI) is one of the main contributors to adverse drug reactions and therefore, it is important to study its frequency in the population. We aimed to investigate frequency and concordance on CYP2D6, CYP2C19, and CYP2C9 (CYP2D6/2C19/2C9)-mediated potential DDIs at the Lifelines cohort and linked data from the pharmacy database IADB.nl. METHODS: As part of the University of Groningen PharmLines Initiative, data were collected on CYP2D6/2C19/2C9-related substrate/inhibitors from entry questionnaires of Lifelines participants and linked information from the pharmacy database IADB.nl. CYP2D6/2C19/2C9 related co-prescriptions were divided based on the type of drugs i.e. chronically used medication (CM) or occasionally used medication (OM). This resulted in the combination of two chronically used drugs (CM-CM), chronically and occasionally used medication (CM-OM), and two occasionally used drugs (OM-OM). To measure the agreement level, cohen's kappa statistics and test characteristics were used. Results were stratified by time window, gender, and age. RESULTS: Among 80,837 medicine users in the Lifelines, about 1-2 per hundred participants were exposed to a CYP2D6/2C19/2C9-mediated potential DDI. Overall, the overlapping time window of three months produced the highest mean kappa values between the databases i.e. 0.545 (95% CI:0.544-0.545), 0.512 (95% CI:0.511-0.512), and 0.374 (95% CI:0.373-0.375), respectively. CM-CM had a better level of agreement (good) than CM-OM (fair to moderate) and OM-OM combination (poor to moderate). The influence of gender on concordance values was different for different CYPs. Among older persons, agreement levels were higher than for the younger population. CONCLUSIONS: CYP2D6/2C19/2C9-mediated potential DDIs were frequent and concordance of data varied by time window, type of combination, sex and age. Subsequent studies should rather use a combination of self-reported and pharmacy database information.

SARS-CoV-2 reinfection and implications for vaccine development.

Coronavirus disease 2019 (COVID-19) pandemic continues to constitute a public health emergency of international concern. Multiple vaccine candidates for COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have entered clinical trials. However, some evidence suggests that patients who have recovered from COVID-19 can be reinfected. For example, in China, two discharged COVID-19 patients who had recovered and fulfilled the discharge criteria for COVID-19 were retested positive to a reverse transcription polymerase chain reaction (RT-PCR) assay for the virus. This finding is critical and could hamper COVID-19 vaccine development. This review offers literature-based evidence of reinfection with SARS-CoV-2, provides explanation for the possibility of SARS-CoV-2 reinfection both from the agent and host points of view, and discusses its implication for COVID-19 vaccine development.

Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients.

BACKGROUND: Guidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug-drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure. OBJECTIVES: (i) To review DDIs related to frequently prescribed ABs among COPD patients from observational and clinical studies. (ii) To improve AB prescribing safety in clinical practice by structuring DDIs according to comorbidities of COPD. METHODS: We conducted a systematic review by searching PubMed and Embase up to 8 February 2018 for clinical trials, cohort and case-control studies reporting DDIs of ABs used for COPD. Study design, subjects, sample size, pharmacological mechanism of DDI and effect of interaction were extracted. We evaluated levels of DDIs and quality of evidence according to established criteria and structured the data by possible comorbidities. RESULTS: In all, 318 articles were eligible for review, describing a wide range of drugs used for comorbidities and their potential DDIs with ABs. DDIs between ABs and co-administered drugs could be subdivided into: (i) co-administered drugs altering the pharmacokinetics of ABs; and (ii) ABs interfering with the pharmacokinetics of co-administered drugs. The DDIs could lead to therapeutic failures or toxicities. CONCLUSIONS: DDIs related to ABs with clinical significance may involve a wide range of indicated drugs to treat comorbidities in COPD. The evidence presented can support (computer-supported) decision-making by health practitioners when prescribing ABs during COPD exacerbations in the case of co-medication.

The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine.

AIM: Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI. METHOD: Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087). RESULTS: We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol-related side effects. In a case-control study, the DDI was not significantly associated with bradycardia. CONCLUSION: Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta-blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol-related side effects is necessary.

Effects of prophylactic antibiotics on patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials.

Background: As bacterial infections provoke exacerbations, COPD patients may benefit from prophylactic antibiotics. However, evidence regarding their overall benefit-risk profile is conflicting. Objectives: To update previous evidence and systematically evaluate the beneficial effects and side effects of prophylactic antibiotics in stable COPD patients. Methods: Several databases were searched up to 26 April 2017 for randomized controlled trials (RCTs) on prophylactic antibiotics in stable COPD patients. The primary outcomes were exacerbations and quality of life. Duration and schedule of antibiotics were considered in subgroup analyses. Results: Twelve RCTs involving 3683 patients were included. Prophylactic antibiotics significantly reduced the frequency of exacerbations [risk ratio (RR) 0.74, 95% CI 0.60-0.92] and the number of patients with one or more exacerbations (RR 0.82, 95% CI 0.74-0.90). Erythromycin and azithromycin appeared the most effective, with the number needed to treat ranging from four to seven. Quality of life was also significantly improved by prophylactic antibiotics (mean difference -1.55, 95% CI -2.59 to -0.51). Time to first exacerbation was prolonged in six studies, with one conflicting result. Neither the rate of hospitalization nor the rate of adverse events was significantly changed. Furthermore, no significant changes were observed in lung function, bacterial load and airway inflammation. However, antibiotic-resistant isolates were significantly increased (OR 4.49, 95% CI 2.48-8.12). Conclusions: Prophylactic antibiotics were effective in preventing COPD exacerbations and improving quality of life among stable patients with moderate to severe COPD. The choice of prophylactic antibiotics should be analysed and considered case by case, especially for long and continuous use.