Inflammation-mediated Phenoconversion: A Potential Threat to COVID-19 Pharmacotherapy

One of the important hallmarks of coronavirus disease 2019 (COVID-19) is the existence of severe inflammatory responses. Many reports indicated that inflammatory mediators might suppress the biological functions of some drug metabolizing enzymes and transporters, and therefore result in a transient mismatch between their genotype and phenotype expressions, a phenomenon which is called phenoconversion. The incidence might be clinically relevant to the COVID-19 patients with comorbidities. The patients are treated with multiple drugs that are prone to be altered pharmacokinetically by inflammation-mediated phenoconversion, leading to the modification of their effectiveness and safety. In this review, we discuss the regulation of inflammatory responses during COVID-19 infection and the evidence as well as potential mechanisms of inflammation-mediated phenoconversion. We also provide possible clinical implications of such phenoconversion events as a potential threat in the management of COVID-19 patients

The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI):Co-medication of metoprolol and paroxetine or fluoxetine in the elderly

Purpose: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. Method: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (60years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. Results: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences=3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences=1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences=2320) than paroxetine/fluoxetine users (incidences=1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD=0.47) regardless whether they were prescribed paroxetine/fluoxetine. Conclusion: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation

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

Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel

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

Five years of antibiotic consumption for urinary tract infection patients in Indonesia’s Provincial Public Hospital

This retrospective study aimed to analyze antibiotic utilization and trends in urinary tract infection (UTI) patients without comorbidities at a Provincial Public Hospital in Indonesia. The data of 183 eligible patients who received antibiotics for UTI treatment from 2017 to 2021 were analyzed using the anatomical therapeutic chemical (ATC) classification system. Antibiotic utilization was measured in Defined Daily Dose (DDD) per 100 patient-days and Drug Utilization 90% (DU 90%) index. The study revealed fluctuating utilization, with 2018 (51.32 DDD/100 patient-days) and 2017 (37.22 DDD/100 patient-days) showing the highest and lowest antibiotic utilization, respectively. The most frequently prescribed antibiotics were ceftriaxone injection, cefixime oral, and levofloxacin injection, while ampicillin and amoxicillin oral were the least utilized. These findings provide valuable insights into antibiotic prescribing patterns for UTIs, highlighting fluctuating antibiotic utilization and the need for appropriate antibiotic stewardship strategies in primary care settings

Perbandingan Efektivitas Klinik Simvastatin dan Atorvastatin Terhadap Profil Lipid Darah: Studi Kasus di Rumah Sakit Universitas Hasanuddin

Simvastatin dan atorvastatin merupakan obat golongan statin yang bekerja dengan menghambat enzim HMG CoA reduktase. Tujuan penelitian ini adalah mengevaluasi efektivitas klinik simvastatin dan atorvastatin dalam mempengaruhi profil lipid darah pasien dislipidemia di Rumah Sakit Universitas Hasanuddin Makassar. Penelitian ini merupakan studi cross sectional menggunakan data rekam medik pasien dislipidemia yang menggunakan simvastatin 10 mg dan atorvastatin 20 mg selama periode 2017-2020. Efektivitas obat golongan statin dinilai dari perubahan nilai LDL, TC, TG, dan HDL sebelum dan setelah penggunaan obat. Analisis regresi linear digunakan untuk menilai perbedaan efek simvastatin dan atorvastatin terhadap parameter lipid darah. Dibandingkan dengan simvastatin, perbedaan efek atorvastatin terhadap nilai LDL, TC, TG dan HDL, berturut-turut adalah 12,11±20,60 (95% Cl: -28,90-53,21), -11,70±11,30 (95% Cl: -14,84-38,24),  -5,02±11,54 (95% Cl: -28,04-18,00) dan 0,42±4,04 (95% Cl: -7,65-8,48). Pasien yang menggunakan atorvastatin memiliki nilai akhir TC, HDL dan TG yang lebih baik dibandingkan simvastatin. Sementara pasien yang menggunakan simvastatin memiliki profil nilai akhir LDL yang lebih baik dibandingkan simvastatin. Hasil analisis statistik menunjukkan perbedaan yang tidak bermakna yang disebabkan karena terbatasnya jumlah pasien. Oleh karena itu, diperlukan studi dengan sampel yang lebih besar untuk melihat perbandingan efektivitas kedua jenis obat statin pada populasi pasien dislipidemia di Indonesia

STUDI PRAKLINIK EFEK SIMVASTATIN, ROSUVASTATIN, DAN FENOFIBRAT TERHADAP KADAR LAKTAT DEHIDROGENASE PADA TIKUS BETINA YANG DIINDUKSI KONTRASEPSI ORAL DAN DIET TINGGI LEMAK

Penggunaan pil kontrasepsi dapat menyebabkan peningkatan inflamasi yang terkait dengan resiko penyakit degeneratif pada wanita. Laktat dehidrogenase (LDH) merupakan biomarker peningkatan inflamasi dan kerusakan jaringan. Penelitian ini bertujuan mengetahui pengaruh pil kontrasepsi oral serta mengevaluasi efektivitas dari simvastatin, rosuvastatin, dan fenofibrat terhadap penurunan kadar LDH pada tikus betina (Rattus novergicus). Tikus (n=20) dibagi menjadi empat kelompok yaitu satu kelompok kontrol (pil kontrasepsi, pakan diet tinggi lemak dan NaCMC 0,5%), dan tiga kelompok perlakuan yang diberi pil kontrasepsi, pakan diet tinggi lemak dan obat uji: simvastatin (0,21 mg/kgBB), rosuvastatin (0,514 mg/kgBB) atau fenofibrat (8,246 mg/kgBB). Pemberian pil kontrasepsi dan pakan diet tinggi lemak dilakukan 30 hari.Pada hari ke-31, tikus diberi pengobatan sesuai kelompok perlakuan: kelompok kontrol diberikan plasebo (NaCMC), dan ketiga kelompok perlakuan, masing-masing diberikan obat uji simvastatin (0,21 mg/kgBB), rosuvastatin (0,51 mg/kgBB) serta fenofibrat (8,246 mg/kgBB) selama hari ke-30 hingga hari ke-60. Hasil menunjukkan bahwa pemberian pil kontrasepsi dan pakan diet tinggi lemak selama 30 hari menyebabkan peningkatan LDH pada semua kelompok tikus dan mencapai nilai signifikan pada kelompok simvastatin, rosuvastatin, dan fenofibrat (P<0,05). Setelah pemberian pengobatan selama 30 hari, kelompok simvastatin, rosuvastatin, maupun fenofibrat mengalami penurunan kadar LDH berturut-turut sebesar 25,8%, 27,1%, dan 27,9%. Penurunan kadar LDH dari ketiga jenis terapi tidak berbeda signifikan secara statistik. Dapat disimpulkan bahwa baik simvastatin, rosuvastatin maupun fenofibrat memiliki potensi menurunkan kadar LDH yang setara pada hewan model inflamasi sistemik yang diinduksi kontrasepsi oral dan diet tinggi lemak

Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction:A systematic review on CYP2C9, CYP2C19 and CYP2D6

Currently, most guidelines on drug-drug interaction (DDI) neither consider the potential effect of genetic polymorphism in the strength of the interaction nor do they account for the complex interaction caused by the combination of DDI and drug-gene interaction (DGI) where there are multiple biotransformation pathways, which is referred to as drug-drug-gene interaction (DDGI). In this systematic review, we report the impact of pharmacogenetics on DDI and DDGI in which three major drug-metabolizing enzymes - CYP2C9, CYP2C19 and CYP2D6 - are central. We observed that several DDI and DDGI are highly gene-dependent, leading to a different magnitude of interaction. Precision drug therapy should take pharmacogenetics into account when drug interactions in clinical practice are expected