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Dengue virus (DENV) poses a significant global health challenge, with millions of cases each year. Developing effective antiviral drugs against DENV remains a major hurdle. Varenicline is a medication used to aid smoking cessation, with anti-inflammatory and antioxidant effects. In this study, varenicline was investigated for its antiviral potential against DENV. This study provides evidence of the antiviral activity of varenicline against DENV, regardless of the virus serotype or cell type used. Varenicline demonstrated dose-dependent effects in reducing viral protein expression, infectivity, and virus yield in Vero and A549 cells infected with DENV-1 and DENV-2, with EC50 values ranging from 0.44 to 1.66 μM. Time-of-addition and removal experiments demonstrated that varenicline had a stronger inhibitory effect on the post-entry stage of DENV-2 replication than on the entry stage, as well as the preinfection and virus attachment stages. Furthermore, cell-based trans-cleavage assays indicated that varenicline dose-dependently inhibited the proteolytic activity of DENV-2 NS2B-NS3 protease. Docking models revealed the formation of hydrogen bonds and van der Waals forces between varenicline and specific residues in the DENV-1 and DENV-2 NS2B-NS3 proteases. These results highlight the antiviral activity and potential mechanism of varenicline against DENV, offering valuable insights for further research and development in the treatment of DENV infection. [ABSTRACT FROM AUTHOR]

ABSTRACT Background: The issue of multidrug resistance (MDR) cancer is one of the major barriers to successful chemotherapy treatment. The ATP-binding cassette (ABC) efflux transporters play an important role in [...]

Background/purpose: With an increasing geriatric population, the need for effective management of chronic conditions and medication use in the elderly is growing. Medication use in the elderly presents significant challenges due to changes in pharmacodynamic and pharmacokinetic profiles. We aimed to examine the impact of a collaborative physician-pharmacist medication therapy management (MTM) program for polypharmacy elderly patients.Methods: Elderly patients with multiple chronic conditions on polypharmacy were enrolled in this prospective, randomized, and controlled study over 16 months of implementation. The intervention group consisted of patients randomized to a collaborative pharmacist-physician MTM program. They were monitored continuously by a clinical pharmacist, while patients in the control group received only usual care with follow-up assessment. Primary outcome was economic differences, measured in total medical expenditure. Secondary outcomes of clinical and humanistic effects were compared between the two groups.Results: The total number of enrolled patients was 87 and 91 in the MTM and usual groups, respectively. The difference-in-difference estimate on medical expenditure during the 16-month implementation period was $3,758,373 New Taiwan Dollars ($127,015 US Dollars) less than the usually care group. Impact was also seen in humanistic outcomes while lipid profiles and mortality trended toward improvement.Conclusion: The pharmacist-physician collaborative MTM program for polypharmacy elderly had significant cost savings and improvement in humanistic measures, demonstrating the importance of clinical pharmacists and MTM programs for elderly patients in Taiwan. The results suggest the possibility of clinical benefits, but the study was not substantially powered to find a statistical difference. [ABSTRACT FROM AUTHOR]

Background: Several case reports have indicated that tamoxifen induced acute pancreatitis (AP); but no pharmacoepidemiological data support the claim. Therefore, we investigated whether tamoxifen use is correlated with the risk of AP in patients with breast cancer. Methods: This population-based cohort study used the Taiwan National Health Insurance Research Database. A cohort of 22 005 patients aged ≥20 years with breast cancer from January 1, 2000 to December 31, 2009 was identified and the date of cancer diagnosis was set as the index date. The end point was developing AP during the follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated to determine the correlation between the risk of AP and tamoxifen use. Because the drug use varied over time, it was measured as a time-dependent covariate in the Cox proportional hazard model. The same approaches were applied in PS-matched cohorts. Results: After adjustment for covariates and medication use including fluorouracil and doxorubicin, the risk of AP was not significant between tamoxifen users and tamoxifen nonusers (adjusted HR = 0.94, 95% CI = 0.74–1.19) in the non-matching cohorts. The results revealed no dose–response trend between tamoxifen use and the risk of AP (adjusted HR = 0.98, 95% CI = 0.96–1.00). The comorbidities DM and gallstones were associated with a significantly increased risk of AP. Similar trends were observed in PS-matched cohorts. Conclusions: No significant correlation was observed between tamoxifen use and the risk of AP in patients with breast cancer. [ABSTRACT FROM AUTHOR]

Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp’s interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates. [ABSTRACT FROM AUTHOR]

Folium Sennae (FS), a popular laxative (Senna), contains polyphenolic anthranoids, whose conjugation metabolites are probable modulators of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). We suspected that the combined use of FS might alter the pharmacokinetics of various medicines transported by MRPs or BCRP. This study investigated the effect of FS on the pharmacokinetics of methotrexate (MTX), an anticancer drug and a probe substrate of MRPs/BCRP. Rats were orally administered MTX alone and with two dosage regimens of FS in a parallel design. The results show that 5.0 g/kg of FS significantly increased the AUC0–2880, AUC720–2880 and MRT of MTX by 45%, 102% and 42%, and the seventh dose of 2.5 g/kg of FS significantly enhanced the AUC720–2880 and MRT by 78% and 42%, respectively. Mechanism studies indicated that the metabolites of FS (FSM) inhibited MRP 2 and BCRP. In conclusion, the combined use of FS increased the systemic exposure and MRT of MTX through inhibition on MRP 2 and BCRP. [ABSTRACT FROM AUTHOR]

Antihypertensive drugs have been linked to new-onset diabetes (NOD); however, data on the effect of these drugs on the development of NOD in hypertensive patients has not been well determined in a clinical setting. The aim was to investigate the association between antihypertensive drugs and NOD in Taiwan. We conducted a retrospective study of hypertensive Taiwanese patients receiving antihypertensive drugs treatment between January 2006 and December 2011. Clinical information and laboratory parameters were collected by reviewing the medical records. We estimated the odds ratios (ORs) of NOD associated with antihypertensive drug use; nondiabetic subjects served as the reference group. A total of 120 NOD cases were identified in 1001 hypertensive patients during the study period. The risk of NOD after adjusting sex, age, baseline characteristics, and lipid profiles was higher among users of thiazide diuretics (OR, 1.65; 95% confidence interval (CI), 1.12-2.45) and nondihydropyridine (non-DHP) calcium channel blockers (CCBs) (OR, 1.96; 95% CI, 1.01-3.75) than among nonusers. Other antihypertensive drug classes were not associated with risk of NOD. Our results show that patients with hypertension who take thiazide diuretics and non-DHP CCBs are at higher risk of developing NOD than those who take other classes of antihypertensive drugs in Taiwan. [ABSTRACT FROM AUTHOR]

Background: Medication adherence is critical for patient treatment. This study involved evaluating how implementing Short Message Service (SMS) reminders affected patient medication adherence and related factors.Methods: We used a structured questionnaire to survey outpatients at three medical centers. Patients aged 20 years and older who were prescribed more than 7 days of a prescription medication were randomized into SMS intervention or control groups. The intervention group received daily messages reminding them of aspects regarding taking their medication; the control group received no messages. A phone follow-up was performed to assess outcomes after 8 days. Data were collected from 763 participants in the intervention group and 435 participants in the control group.Results: After participants in the intervention group received SMS reminders to take medication or those in the control group received no messages, incidences of delayed doses were decreased by 46.4 and 78.8% for those in the control and intervention groups, respectively. The rate of missed doses was decreased by 90.1% for participants in the intervention group and 61.1% for those in the control group. We applied logistic regression analysis and determined that participants in the intervention group had a 3.2-fold higher probability of having a decrease in delayed doses compared with participants in the control group. Participants in the intervention group also showed a 2.2-fold higher probability of having a decrease in missed doses compared with participants in the control group.Conclusions: Use of SMS significantly affected the rates of taking medicine on schedule. Therefore, daily SMS could be useful for reminding patients to take their medicine on schedule. [ABSTRACT FROM AUTHOR]

Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague-Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC 0-t and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC 0-t and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC 0-t and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.

Background: Since OpenAI released ChatGPT, with its strong capability in handling natural tasks and its user-friendly interface, it has garnered significant attention., Objective: A prospective analysis is required to evaluate the accuracy and appropriateness of medication consultation responses generated by ChatGPT., Methods: A prospective cross-sectional study was conducted by the pharmacy department of a medical center in Taiwan. The test data set comprised retrospective medication consultation questions collected from February 1, 2023, to February 28, 2023, along with common questions about drug-herb interactions. Two distinct sets of questions were tested: real-world medication consultation questions and common questions about interactions between traditional Chinese and Western medicines. We used the conventional double-review mechanism. The appropriateness of each response from ChatGPT was assessed by 2 experienced pharmacists. In the event of a discrepancy between the assessments, a third pharmacist stepped in to make the final decision., Results: Of 293 real-world medication consultation questions, a random selection of 80 was used to evaluate ChatGPT's performance. ChatGPT exhibited a higher appropriateness rate in responding to public medication consultation questions compared to those asked by health care providers in a hospital setting (31/51, 61% vs 20/51, 39%; P=.01)., Conclusions: The findings from this study suggest that ChatGPT could potentially be used for answering basic medication consultation questions. Our analysis of the erroneous information allowed us to identify potential medical risks associated with certain questions; this problem deserves our close attention., (©Hsing-Yu Hsu, Kai-Cheng Hsu, Shih-Yen Hou, Ching-Lung Wu, Yow-Wen Hsieh, Yih-Dih Cheng. Originally published in JMIR Medical Education (https://mededu.jmir.org), 21.08.2023.)

Pharmacogenetic (PGx) testing has not been well adopted in current clinical practice. The phenotypic distribution of clinically relevant pharmacogenes remains to be fully characterized in large population cohorts. In addition, no study has explored actionable PGx alleles in the East Asian population at a large scale. This study comprehensively analyzed 14 actionable pharmacogene diplotypes and phenotypes in 172,854 Taiwanese Han individuals by using their genotype data. Furthermore, we analyzed data from electronic medical records to investigate the effect of the actionable phenotypes on the individuals. The PGx phenotype frequencies were comparable between our cohort and the East Asian population. Overall, 99.9% of the individuals harbored at least one actionable PGx phenotype, and 29% of them have been prescribed a drug to which they may exhibit an atypical response. Our findings can facilitate the clinical application of PGx testing and the optimization of treatment and dosage individually., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Liu, Chou, Chang, Hsieh, Chang and Tsai.)

Background: This study explored the possible association between the use of proton pump inhibitors (PPIs) and the increased incidence of pneumonia in patients with type 2 diabetes mellitus (T2DM)., Methods: We selected 4940 patients with T2DM of whom 988 and 3952 were enrolled in PPI and propensity score-matched control cohorts, respectively. All patients were followed from the index date until admission with pneumonia, withdrawal from the National Health Insurance program or the end of 2013. The PPIs associated with risk of incident pneumonia were examined. Furthermore, we assessed the risk of pneumonia according to annual defined daily doses in the PPI cohort., Results: After a 14-year follow-up, the cumulative incidence of pneumonia in the PPI users was 11.4% higher than that in the controls (30.3% vs 18.9%). Compared to the controls, the PPI users had a 1.70-fold higher risk of pneumonia in the Cox proportional hazards model after adjustment for matched pairs. The risk of pneumonia increased with the annual PPI defined daily dose., Conclusion: The results of this population-based retrospective cohort study suggest that PPI use increased the risk of pneumonia in patients with T2DM. The effects were more prominent in patients administered higher doses of PPIs., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.

A combined deferasirox (DFX) and deferiprone (DFP) treatment protocol for relieving thalassemia patients' iron-overload was designed and the pharmacokinetic study was performed by LC-MS/MS. For this open-label, randomized trial, eight patients were recruited and randomly allocated to different treatment regimens: (A) monotherapy with single oral dose of DFX 30 mg/kg, (B) monotherapy with DFP 80 mg/kg/day, twice daily, (C) combined therapy with DFX and DFP (DFX 30 mg/kg for first dose, DFP 40 mg/kg 7 hours later, and DFP 40 mg/kg after another 7 h) and (D) concurrent therapy with DFX 30 mg/kg and DFP 80 mg/kg. Descriptive statistics evaluated pharmacokinetic parameters, AUC0-t, AUC0-inf, Cmax, Tmax, T1/2 and MRT. A positive pharmacokinetic drug interaction was observed in combined therapy. In case of DFX, combined therapy tallied about 2-fold larger than monotherapy in AUC, 1.5-fold larger in Cmax, 1 h longer in Tmax, but 1 h shorter in T1/2. Regarding DFP, most such parameters of combined therapy concurred with monotherapy. Conversely, negative drug interaction was observed in concurrent therapy. With DFX, concurrent therapy attained 1.2- to 2.2-fold lower than monotherapy in AUC0-t and Cmax, 0.6-h shorter in Tmax, and 3-fold longer in T1/2. With DFP, concurrent therapy proved approximately 2-fold larger than monotherapy in AUC and Cmax, 2.5-fold longer in T1/2, and 1.4-fold longer in MRT. Follow-up of subjects' clinical examinations and subjective symptoms showed no adverse events. Our findings showed the combined therapy had advantages, safe, convenient and painless for patients, over the existing concurrent therapy with deferoxamine (DFO) and DFX., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp's interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates.