Effect of Multi-Dose Dispensing on Medication Regimen Complexity: A Real-World Study.

(1) Background: Older patients frequently require dosing aids, such as multi-dose medication dispensing (MMD) when they experience medication regimen complexity (MRC) with increased drug use. However, the evaluations of the efficacy of MMD alterations remain limited. (2) Methods: A total of 1120 patients were included in the study who were discharged from hospital during the study period of January to March 2019. The Medication Regimen Complexity Index (MRCI) score, a validated 65-item tool in Korea (MRCI-K), was used to quantify MRC. The original MRCI-K scores, representing the typical administration based on prescription information, were compared to recalculated MRCI-K scores measured following MMD during the hospital dispensing period. Differences in MRCI-K across the top four wards based on the numbers of discharge prescription medications were assessed, and the overall scores were categorized into quartiles to identify MMD's impact within each group. We confirmed the effect of MMD based on the patient's admission diagnosis depending on MRCI. (3) Results: The mean (standard deviation) of original MRCI scores was 26.2 (13.4), which decreased to 18.9 (8.8) after applying MMD. The decrease in MRCI scores after MMD was statistically significant in all four wards, with the Orthopedic Surgery ward showing the biggest decrease. The patients with MRCI scores in the highest quartile group demonstrated the greatest improvement as a result of the implementation of MMD. Respiratory diseases exhibited the highest baseline MRCI scores due to formulation complexity, and ear, nose, and throat patients demonstrated the most significant reduction in MRC after MMD, depending on the diagnostic criteria at administration. (4) Conclusions: We confirmed the reduction in MRC after applying MMD, as a significant decrease in MRCI-K scores. This study highlights the need to deliver effective pharmacist-led services to identify patients who would benefit from MMD.

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia.

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed. Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States). Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 to meet the target trough range of 5-15 ng/mL. Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz®, 2 mg, 3 mg, and 5 mg.

Effect of Pharmacist-Led Intervention in Elderly Patients through a Comprehensive Medication Reconciliation: A Randomized Clinical Trial.

PURPOSE: Polypharmacy can cause drug-related problems, such as potentially inappropriate medication (PIM) use and medication regimen complexity in the elderly. This study aimed to investigate the feasibility and effectiveness of a collaborative medication review and comprehensive medication reconciliation intervention by a pharmacist and hospitalist for older patients. MATERIALS AND METHODS: This comprehensive medication reconciliation study was designed as a prospective, open-label, randomized clinical trial with patients aged 65 years or older from July to December 2020. Comprehensive medication reconciliation comprised medication reviews based on the PIM criteria. The discharge of medication was simplified to reduce regimen complexity. The primary outcome was the difference in adverse drug events (ADEs) throughout hospitalization and 30 days after discharge. Changes in regimen complexity were evaluated using the Korean version of the medication regimen complexity index (MRCI-K). RESULTS: Of the 32 patients, 34.4% (n=11/32) reported ADEs before discharge, and 19.2% (n=5/26) ADEs were reported at the 30-day phone call. No ADEs were reported in the intervention group, whereas five events were reported in the control group (p=0.039) on the 30-day phone call. The mean acceptance rate of medication reconciliation was 83%. The mean decreases of MRCI-K between at the admission and the discharge were 6.2 vs. 2.4, although it was not significant (p=0.159). CONCLUSION: As a result, we identified the effect of pharmacist-led interventions using comprehensive medication reconciliation, including the criteria of the PIMs and the MRCI-K, and the differences in ADEs between the intervention and control groups at the 30-day follow-up after discharge in elderly patients. TRIAL REGISTRATION: (Clinical trial number: KCT0005994).

Real-world experience of angiotensin receptor neprilysin inhibitor on the glucose-lowering effect.

We investigated the effect of angiotensin receptor neprilysin inhibitor (ARNI) on glycemic control in Korean patients. This retrospective cohort study was conducted at a single tertiary hospital. We compared the HbA1c level reduction between the ARNI and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in chronic heart failure patients with diabetes. We also examined whether the target HbA1c level was reached and the time to start insulin between the two groups. Over the study period, ARNI did not significantly lower the HbA1c level after adjusting confounding factors compared to ACEIs or ARBs. However, as a result of a simple comparison using Mann-Whitney U test, ARNI group showed significant decrease in HbA1c at 6, 12, and 24 months compared to ACEIs or ARBs group (p = 0.003, 0.009, and 0.026, respectively). The initiation of insulin was delayed in the ARNI group, but this difference was not significant based on the result of hazard ratio, but cumulative incidence was significantly lower in the ARNI group. In the real world, the blood glucose-control effects of ARNI were not superior to those of ACEIs or ARBs. However, long-term studies are needed as ARNI use increases to obtain more statistically significant results.

Eye, hepatobiliary, and renal disorders of erlotinib in patients with non-small-cell lung cancer: A meta-analysis.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.

Correction: Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study.

[This corrects the article DOI: 10.1371/journal.pone.0225599.].

Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: A retrospective, single-center study.

Glioblastoma multiforme (GBM) is a lethal and aggressive malignant tumor of the central nervous system. The World Health Organization classifies it as a grade IV astrocytoma. Controlling seizures is essential during GBM treatment because they are often present and closely associated with the quality of life of GBM patients. Some antiepileptic drugs (AEDs) exhibit antitumor effects and could decrease the mortality of patients with GBM. In this retrospective cohort study, we examined 418 patients treated with surgery, radiotherapy, and chemotherapy with temozolomide (TMZ) at Severance Hospital in South Korea, per the current protocol. Median overall survival (OS) was 21 months [95% confidence interval (CI): 18.1-23.9] in the levetiracetam (LEV) treatment group, whereas it was 16 months [95% CI: 14.1-17.9] in the group without LEV, exhibiting a statistically significant difference between the two groups (P < 0.001). Of nine AED groups, only LEV treatment [P = 0.001; hazard ratio (HR), 0.65; 95% CI: 0.51-0.83] exhibited a statistically significant difference in the OS, in the univariate analysis. In the risk analysis of the baseline characteristics, age, administration of LEV, and O6-methylguanine-DNA methyltransferase (MGMT) promoter status correlated with OS. The use of LEV in the group with a methylated MGMT promoter resulted in a positive impact on the OS [P = 0.006; HR, 0.174; 95% CI: 0.050-0.608], but the effect of LEV on the OS was not statistically significant in the unmethylated MGMT promoter group (P = 0.623). This study suggests that, compared with other AEDs, the administration of LEV may prolong the survival period in GBM patients with methylated MGMT promoters, who are undergoing chemotherapy with TMZ.

Utilization patterns of insulin for patients with type 2 diabetes from national health insurance claims data in South Korea.

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires long-term therapy and regular check-ups to prevent complications. In this study, insurance claim data from the National Health Insurance Service (NHIS) of Korea were used to investigate insulin use in T2DM patients according to the economic status of patients and their access to primary physicians, operationally defined as the frequently used medical care providers at the time of T2DM diagnosis. A total of 91,810 participants were included from the NHIS claims database for the period between 2002 and 2013. The utilization pattern of insulin was set as the dependent variable and classified as one of the following: non-use of antidiabetic drugs, use of oral antidiabetic drugs only, or use of insulin with or without oral antidiabetic drugs. The main independent variables of interest were level of income and access to a frequently-visited physician. Multivariate Cox proportional hazards analysis was performed. Insulin was used by 9,281 patients during the study period, while use was 2.874 times more frequent in the Medical-aid group than in the highest premium group [hazard ratio (HR): 2.874, 95% confidence interval (CI): 2.588-3.192]. Insulin was also used ~50% more often in the patients managed by a frequently-visited physician than in those managed by other healthcare professionals (HR: 1.549, 95% CI: 1.434-1.624). The lag time to starting insulin was shorter when the patients had a low income and no frequently-visited physicians. Patients with a low level of income were more likely to use insulin and to have a shorter lag time from diagnosis to starting insulin. The likelihood of insulin being used was higher when the patients had a frequently-visited physician, particularly if they also had a low level of income. Therefore, the economic statuses of patients should be considered to ensure effective management of T2DM. Utilizing frequently-visited physicians might improve the management of T2DM, particularly for patients with a low income.

Risk factors for linezolid-induced thrombocytopenia in patients without haemato-oncologic diseases.

This study aimed to describe the occurrence and to evaluate the predictive factors of thrombocytopenia caused by parenteral linezolid in hospitalised patients without haemato-oncologic diseases. Using electronic medical records, a retrospective safety evaluation was performed among all hospitalised adult patients who received parenteral linezolid therapy between January 2005 and June 2016. Of all identified 264 patients with an average age of 63.4 (SD 15.8) years, thrombocytopenia occurred at a rate of 29.2% after an average of 11.2 (SD 7.4) days of the initiation of linezolid therapy. Significant predictive factors for thrombocytopenia included the duration of linezolid therapy longer than or equal to 7 days (adjusted odds ratios [ORs] 7.25, 19.51 and 28.80; 95% confidence intervals [CIs] 1.92-27.38, 4.76-79.95 and 6.48-127.92 for 7-13 days, 14-20 days and ≥21 days, respectively; P < 0.01 for all values), baseline platelet count <150 × 103 /mm3 (adjusted OR, 5.08; 95% CI, 2.06-12.55; P < 0.001), creatinine clearance <30 mL/min (adjusted OR, 4.19; 95% CI, 1.59-11.06; P = 0.004) and concurrent low-dose aspirin therapy (adjusted OR, 2.99; 95% CI, 1.26-7.08; P = 0.013). Baseline platelet count less than 150 × 103 /mm3 was an independent predictor of early-onset (≤6 days) thrombocytopenia (adjusted OR, 5.07; 95% CI, 1.46-17.58; P = 0.011). Closer monitoring of platelet count is required in patients who receive parenteral linezolid therapy for 7 days or more, and have low baseline platelet counts or impaired renal function.

Fluorogenic reaction-based prodrug conjugates as targeted cancer theranostics.

Theranostic systems are receiving ever-increasing attention due to their potential therapeutic utility, imaging enhancement capability, and promise for advancing the field of personalized medicine, particularly as it relates to the diagnosis, staging, and treatment of cancer. In this Tutorial Review, we provide an introduction to the concepts of theranostic drug delivery effected via use of conjugates that are able to target cancer cells selectively, provide cytotoxic chemotherapeutics, and produce readily monitored imaging signals in vitro and in vivo. The underlying design concepts, requiring the synthesis of conjugates composed of imaging reporters, masked chemotherapeutic drugs, cleavable linkers, and cancer targeting ligands, are discussed. Particular emphasis is placed on highlighting the potential benefits of fluorogenic reaction-based targeted systems that are activated for both imaging and therapy by cellular entities, e.g., thiols, reactive oxygen species and enzymes, which are present at relatively elevated levels in tumour environments, physiological characteristics of cancer, e.g., hypoxia and acidic pH. Also discussed are systems activated by an external stimulus, such as light. The work summarized in this Tutorial Review will help define the role fluorogenic reaction-based, cancer-targeting theranostics may have in advancing drug discovery efforts, as well as improving our understanding of cellular uptake and drug release mechanisms.

Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis.

PURPOSE: Lapatinib is a tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and the epidermal growth factor receptor (EGFR/HER1), and there are concerns about its cardiac toxicity. Recent studies of lapatinib have reported cardiac adverse events; however, the results have been inconsistent among the studies. The aim of our study was to estimate the cardiac toxicity of lapatinib in patients with breast cancer and other HER2-positive cancers. METHODS: To evaluate the cardiotoxicity of lapatinib, the results of previous studies were quantitatively integrated using meta-analysis. Forty-five articles regarding cardiac adverse events, including left ventricular dysfunction, left ventricular ejection fraction (LVEF) decrease, arrhythmia, and other cardiac adverse events, were assessed. As a subgroup analysis in patients with breast cancer, 26 studies of lapatinib-induced cardiac adverse events were assessed. RESULTS: The overall incidence of cardiac adverse events was 2.70% (95% confidence interval [CI] 1.60-4.50%). The incidences of left ventricular dysfunction and LVEF decrease were 1.60% (95% CI 1.30-2.00%) and 2.20% (95% CI 1.30-3.60%), respectively. The overall incidence of cardiac adverse events was 3.00% (95% CI 1.50-6.10%) in patients with breast cancer, which was marginally higher than the rate in patients with all type of cancers. CONCLUSION: The overall incidence of lapatinib-induced cardiac toxicity was relatively low based on an indirect comparison with trastuzumab. However, careful monitoring of cardiac toxicity is still needed when patients are treated with lapatinib because the related risk factors have not been clearly identified.

Liposomal Texaphyrin Theranostics for Metastatic Liver Cancer.

Reported here is a new theranostic agent, 1, which consists of a Gd3+-texaphyrin core conjugated to a doxorubicin prodrug via a disulfide bond. Conjugate 1 was designed to undergo cleavage in the presence of glutathione (GSH), a species typically upregulated in cancer cells. As prepared, conjugate 1 displays no appreciable fluorescence. However, when exposed to excess GSH an increase in the fluorescence intensity at 592 nm is observed that is ascribed to release of free doxorubicin. To improve the solubility and enhance the tumor targeting of 1, it was loaded into folate-receptor-targeted liposomes to produce FL-1 (for folate liposome loaded with 1). As inferred from both fluorescence turn on studies and independent HPLC analyses, FL-1 was found to undergo selective uptake and cleavage to release free Dox in the KB and CT26 cell lines, which express folate receptors on the cell surface, relative to the HepG2 and NIH3T3 cell lines, which show low expression of those receptors. FL-1 was found to produce a greater antiproliferative effect in the case of the KB and CT26 cell lines as compared to that in the HepG2 and NIH3T3 cell lines. FL-1 was also found to provide enhanced magnetic resonance imaging in vivo under conditions of T1 contrast in the early stage of metastatic cancer progression. Finally, time-dependent tumor regrowth studies involving both subcutaneous and metastatic liver cancer mouse models revealed that FL-1 is capable of reducing the tumor burden in vivo.

Application of a drug-interaction detection method to the Korean National Health Insurance claims database.

Drug interactions (DIs) constitute a serious problem and are considered to contribute to 6-30% of all adverse events (AEs). The use of existing data, including claims data, is expected to be helpful in detecting unknown DIs by complementing conventional spontaneous reporting systems. In the present study, an 'Ω shrinkage measure' was applied to the Korean National Health claims database to test the potential of the claims database as a DI surveillance resource. A well-known DI between non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics was analyzed using the model. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes related to DIs were assigned to the AEs of the DIs: I50, I50.0, I50.1, I50.9, R60, R60.1, R60.9, and J81. An elevated occurrence of AEs versus the expected level was observed using a two-sided 95% lower credibility interval limit above zero, Ω025=0.245, which was the screening limit. The result was consistent with the actual DI between the two drugs. The finding indicates that the claims data have the potential to be used as a DI surveillance resource and that the Ω shrinkage measure may be a promising tool for detecting DIs in claims data.

Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials.

PURPOSE: This study aimed to investigate the neuroprotective effects of vitamin E for preventing chemotherapy-induced peripheral neuropathy (CIPN). METHODS: A comprehensive search from 1973 through July 2011 identified randomized controlled trials (RCTs) that reported the preventive effects of vitamin E on CIPN. The relative risk (RR) of CIPN with vitamin E supplementation, compared with placebo, was assessed with the Bayesian random effect model and expressed as RR with a 95 % credible-interval (CrI). Bayesian outcome probabilities were calculated as the probability (P) of RR < 1. RESULTS: Five RCTs, involving 319 patients, were identified. Upon pooling these RCTs, vitamin E supplementation (300 - 600 mg/day) had a significant effect on CIPN prevention (RR 0.43; 95 % CrI 0.10 - 1.00, P = 97.5 %). Subgroup analysis by chemotherapeutic agent type was only available for cisplatin and showed that vitamin E supplementation significantly reduced the incidence of CIPN (RR 0.26; 95 % CrI 0.06 - 0.89, P = 98.1 %). Furthermore, there were no adverse effects caused by vitamin E supplementation in any of the RCTs. CONCLUSION: Available data included in this meta-analysis show that vitamin E supplementation might significantly prevent CIPN. Currently, however, the data are insufficient to confidently conclude the true value. Large-scale, rigorously designed RCTs are needed to confirm the role of vitamin E supplementation in CIPN prevention.

Protective effects of Haematococcus astaxanthin on oxidative stress in healthy smokers.

Free radicals induced by cigarette smoking have been strongly linked to increased oxidative stress in vivo, contributing to the pathobiology of various diseases. This study was performed to investigate the effects of Haematococcus astaxanthin (ASX), which has been known to be a potent antioxidant, on oxidative stress in smokers. Thirty-nine heavy smokers (≥20 cigarettes/day) and 39 non-smokers were enrolled in this study. Smokers were randomly divided into three dosage groups to receive ASX at doses of 5, 20, or 40 mg (n=13, each) once daily for 3 weeks. Oxidative stress biomarkers such as malondialdehyde, isoprostane, superoxide dismutase, and total antioxidant capacity, and ASX levels in plasma were measured at baseline and after 1, 2, and 3 weeks of treatment. Compared with baseline, the plasma malondialdehyde and isoprostane levels decreased, whereas superoxide dismutase level and total antioxidant capacity increased in all ASX intervention groups over the 3-week period. In particular, isoprostane levels showed a significant dose-dependent decrease after ASX intake. The results suggest that ASX supplementation might prevent oxidative damage in smokers by suppressing lipid peroxidation and stimulating the activity of the antioxidant system in smokers.

Cytotoxic lignans from the stem bark of Magnolia officinalis.

Three new lignans, 4'-methoxymagndialdehyde ( 1), 4'-methoxymagnaldehyde B ( 2), and 4'-methoxymagnaldehyde E ( 3), were isolated from hexane- and EtOAc-soluble fractions of the stem bark of Magnolia officinalis, together with eight known compounds ( 4- 11). The structures of compounds 1- 3 were determined on the basis of spectroscopic and physicochemical data analysis. Compounds 1- 11 were tested in vitro for their cytotoxic activity against the K562, HeLa, and A549 cancer cell lines. Among the compounds tested, compound 1 showed the most potent cytotoxic activity against these cancer cell lines, with IC50 values of 3.9, 1.5, and 3.7 microg/mL, respectively.