First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers.

BMC Cancer. 2019 Mar 28;19(1):279

Authors: Fan Y, Li S, Ding X, Yue J, Jiang J, Zhao H, Hao R, Qiu W, Liu K, Li Y, Wang S, Zheng L, Ye B, Meng K, Xu B

Abstract
BACKGROUND: With poor prognosis and limited treatment options for advanced hepatocellular carcinoma (HCC), development of novel therapeutic agents is urgently needed. This single-arm phase I study sought to assess the safety and preliminary efficacy of icaritin in human as a potential oral immunotherapy in addition to the immune-checkpoint inhibitors.
METHODS: Eligible advanced HCC patients with Child-Pugh Class A or B were administered with a fixed oral dose of icaritin at either 600 or 800 mg b.i.d. The primary endpoint was safety, and the secondary endpoints included time-to-progression (TTP), overall survival (OS) and the clinical benefit rate (CBR). Icaritin treatment induced immune biomarkers and immune-modulating activities in myeloid cells were also explored.
RESULTS: No drug-related adverse events ≥ Grade 3 were observed in all 20 enrolled HCC patients. Among the 15 evaluable patients, 7 (46.7%) achieved clinical benefit, representing one partial response (PR, 6.7%) and 6 stable disease (SD, 40%). The median TTP was 141 days (range: 20-343 days), and the median OS was 192 days (range: 33-1036 days). Durable survival was observed in PR/SD patients with a median OS of 488 days (range: 72-773). TTP was significantly associated with the dynamic changes of peripheral neutrophils (p = 0.0067) and lymphocytes (p = 0.0337). Icaritin treatment induced changes in immune biomarkers-and immune-suppressive myeloid cells were observed.
CONCLUSIONS: Icaritin demonstrated safety profiles and preliminary durable survival benefits in advanced HCC patients, which were correlated with its immune-modulation activities and immune biomarkers. These results suggested the potential of icaritin as a novel oral immunotherapy for advanced HCC in addition to antibody-based PD-1/PD-L1 blockade therapies.
TRIAL REGISTRATION: Clinicaltrial.gov identifier. NCT02496949 (retrospectively registered, July 14, 2015).

PMID: 30922248 [PubMed - in process]

Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: a randomized controlled trial.

Pulm Pharmacol Ther. 2019 Mar 24;:

Authors: Watz H, Nagelschmitz J, Kirsten A, Pedersen F, van der Mey D, Schwers S, Bandel TJ, Rabe KF

Abstract
BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease.
METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501.
RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks.
CONCLUSIONS: 1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.

PMID: 30917927 [PubMed - as supplied by publisher]

Confidence and accuracy in identification of adverse drug reactions reported by outpatients.

Int J Clin Pharm. 2018 Dec;40(6):1559-1567

Authors: Kampichit S, Pratipanawatr T, Jarernsiripornkul N

Abstract
Background Patient reporting of adverse drug reactions (ADRs) could supplement the existing reporting system and contribute to early detection of ADRs. The confidence in ADR identification and their attribution of ADRs were limited to outpatients. Objective To determine the type and frequency of ADRs reported by outpatients, to evaluate confidence and accuracy in ADR identification as well as contributing factors. Setting University hospital in northeastern Thailand Method Cross-sectional study using questionnaires distributed to 500 outpatients who claimed to have experienced an ADR. Confidence in identifying ADRs was measured by visual analogue score (VAS), while accuracy of reported ADRs was determined using Naranjo algorithm and WHO criteria. Main outcome measure Number and type of ADRs, confidence rating and accuracy category. Results In total, 390 outpatients completed the questionnaire (response rate = 78.0%). Rash (19.0%), nausea/vomiting (7.4%), and dizziness (5.8%) were the top three reported ADRs. Sixty-one percent of respondents rated their level of confidence in identifying ADRs as high (VAS 9.2 ± 0.95), which was associated with having underlying diseases (OR 1.93), low number of reported symptoms (OR 0.38) and severe ADRs (OR 1.33). Causality assessment was classified as true ADRs in 90.0% and 88.9% of cases, using Naranjo algorithm and WHO criteria, respectively. Respondents with low number of reported symptoms (OR 0.27) and high level of confidence had greater accuracy in ADR identification (OR 1.11). Conclusion The outpatients reported a high proportion of potential ADRs with high confidence and accuracy. Patient reporting of ADRs has potential to support the pharmacovigilance system.

PMID: 30367372 [PubMed - indexed for MEDLINE]

Development of a tool for benchmarking of clinical pharmacy activities.

Int J Clin Pharm. 2018 Dec;40(6):1462-1473

Authors: Cillis M, Spinewine A, Krug B, Quennery S, Wouters D, Dalleur O

Abstract
Background Initiatives are needed to promote and evaluate clinical pharmacy. In this context, benchmarking could be useful. Objective To develop and validate a benchmarking tool for clinical pharmacy activities. Setting Six Belgian hospitals. Method A narrative literature review and two focus groups were performed to identify (1) clinical pharmacy benchmarking projects, (2) clinical pharmacy activities with a proven positive impact on the quality of care for patients, (3) quality indicators and (4) contextual factors to be included in the tool. Next, a Delphi survey and a test of the tool in practice led to content validation and usability of the benchmarking tool. Main Outcome Measure To identify quality indicators and contextual factors to be included in the tool. Results Three Delphi rounds were required (rounds 1-2: 9 participants, round 3: 8 participants). Ten quality indicators and 36 relevant contextual factors were selected. These 10 quality indicators represent 6 clinical pharmacy activities that demonstrated to improve patient outcomes: medication reconciliation at admission, patient monitoring, information provided to the health care team, patient education, discharge and transfer medication counselling, and adverse drug reaction monitoring. To collect the information needed to compose the quality indicators and to benchmark, the tool consists of three data collection instruments. An instruction manual accompanies the tool. Conclusion We have developed and validated a benchmarking tool, designed to identify and promote clinical pharmacy activities that demonstrated to improve patient outcomes. Future perspectives include the use of the tool on a national scale to identify the most efficient practices and their enablers and barriers.

PMID: 30242587 [PubMed - indexed for MEDLINE]

Relationship between adolescents' and their parents' attitudes toward medicines and awareness of the risk of medicines.

Int J Clin Pharm. 2018 Dec;40(6):1501-1510

Authors: Klimaszova Z, Fazekas T, Kuzelova M

Abstract
Background When they reach adolescence, children begin to independently use medicine without their parents' supervision, but parents usually still want to be involved in their drug therapy. Objective The aim of this study was to investigate how parental attitudes and awareness toward medicine relate to adolescents' attitudes and awareness. Setting Twelve secondary schools in different regions of the Slovak Republic. Method Adolescents and parents responded to a questionnaire, and the answers were paired and analysed. Parental and adolescents' attitudes toward medicines and awareness of the risk of medicines were measured using a five-point Likert scale. Main outcome measure The strength of the relationship between parents' and their adolescent children's level of agreement with statements about medicines. Results There were significant differences between parents᾽ and adolescents' mean Likert scores for statements about their attitudes toward medicines and their awareness of the risk of medicines (p < 0.05). Parents and adolescents were not fully aware of the risks of cough medicine (73.5% and 76.1%), antihistamines (32.7% and 52.1%), painkillers (33.6% and 47%) and combining medicines (25.2% and 40.4%). More than half of the parents and adolescents had a positive perception of the effectiveness of medication and believed that taking medicine would not hurt adolescents. Parents' and adolescents' responses to the statements were directly proportional (r = 0.94, p < 0.001). Conclusion The analysis revealed a relationship between Slovakian adolescents' and their parents' attitudes and awareness toward medicine; it highlighted areas of adolescents' and parents' education about the proper use of medications.

PMID: 30167969 [PubMed - indexed for MEDLINE]

Ask the experts: computational chemistry.

Future Med Chem. 2018 07;10(13):1521-1524

Authors: Matta CF, Hutter MC

PMID: 29992825 [PubMed - indexed for MEDLINE]

Quantitative Evaluation of Cytochrome P450 3A4 Inhibition and Hepatotoxicity in HepaRG 3-D Spheroids.

Int J Toxicol. 2018 Sep/Oct;37(5):393-403

Authors: Shin DS, Seo H, Yang JY, Joo J, Im SH, Kim SS, Kim SK, Bae MA

Abstract
Predicting drug-drug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics. In this study, we applied a human 3-D spheroid culture protocol using HepaRG cells combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess its ability to predict CYP3A4 inhibition. Levels of midazolam, a specific substrate of CYP3A4, were used to determine the long-term metabolic capacity of CYP3A4. Midazolam was decreased in the 3-D HepaRG culture system by ∼80% over 7 days, whereas its primary metabolite, 1-hydroxymidazolam, increased by ∼40%. Next, we assessed hepatotoxicity by determining the cytotoxicity of known hepatotoxicants in HepaRG spheroids, HepG2 cells, and primary human hepatocytes. Significant differences in cytotoxicity were detected in the system using 3-D HepaRG spheroids. These results suggest that 3-D HepaRG spheroids are a good model for prediction of CYP inhibition and hepatotoxicity in screening of early drug candidates.

PMID: 29923436 [PubMed - indexed for MEDLINE]

Development of a Phototoxicity Testing Strategy for Accurate Photosafety Evaluation of Pharmaceuticals Based on the Assessment of Possible Melanin-Binding Effects.

Int J Toxicol. 2018 Jul/Aug;37(4):296-307

Authors: Reinen J, van Sas P, van Huygevoort T, Rubio L, Scase K, Wenker M

Abstract
Drug-induced phototoxicity occurs when drugs absorb natural sunlight, leading to chemical reactions causing cellular damage. Distribution to light-exposed tissues is critical and is enhanced by binding to melanin. The International Council on Harmonization S10 guidance document on photosafety evaluation of pharmaceuticals states that although nonpigmented skin tends to be more sensitive than pigmented skin, pigmented skin models should be considered for drugs that bind significantly to melanin. In this study, an in vitro melanin-binding assay was evaluated as prescreening tool for animal model selection. Binding of various structurally diverse phototoxic drugs to synthetic melanin was investigated in vitro and the high-affinity binder sparfloxacin (SPX), moderate-affinity binder 8-methoxypsoralen (8-MOP), and low-affinity binder pirfenidone (PIF) were selected for in vivo studies. Pigmented Brown Norway (BN) rats were compared with nonpigmented Wistar Albino rats to evaluate their sensitivity for the assessment of phototoxicity and skin concentrations of the drugs were measured. For SPX, the onset of phototoxic symptoms was faster for BN rats and drug concentrations were significantly higher in skin of BN rats. For 8-MOP, both models showed comparable sensitivity and skin concentrations did not differ. For the low-affinity binder PIF, no phototoxic effects were observed and skin concentrations in both models were similar. A combined in vitro/in vivo approach was developed that can be applied for accurate photosafety evaluation of pharmaceuticals based on the assessment of possible melanin-binding effects. In view of the presented data, the pigmented model could be considered for compounds showing a high-affinity binding capacity in vitro.

PMID: 29898631 [PubMed - indexed for MEDLINE]

Mechanism-based Pharmacovigilance over the Life Sciences Linked Open Data Cloud.

AMIA Annu Symp Proc. 2017;2017:1014-1023

Authors: Kamdar MR, Musen MA

Abstract
Adverse drug reactions (ADR) result in significant morbidity and mortality in patients, and a substantial proportion of these ADRs are caused by drug-drug interactions (DDIs). Pharmacovigilance methods are used to detect unanticipated DDIs and ADRs by mining Spontaneous Reporting Systems, such as the US FDA Adverse Event Reporting System (FAERS). However, these methods do not provide mechanistic explanations for the discovered drug-ADR associations in a systematic manner. In this paper, we present a systems pharmacology-based approach to perform mechanism-based pharmacovigilance. We integrate data and knowledge from four different sources using Semantic Web Technologies and Linked Data principles to generate a systems network. We present a network-based Apriori algorithm for association mining in FAERS reports. We evaluate our method against existing pharmacovigilance methods for three different validation sets. Our method has AUROC statistics of 0.7-0.8, similar to current methods, and event-specific thresholds generate AUROC statistics greater than 0.75 for certain ADRs. Finally, we discuss the benefits of using Semantic Web technologies to attain the objectives for mechanism-based pharmacovigilance.

PMID: 29854169 [PubMed - indexed for MEDLINE]

Efficacy of Ginger in Ameliorating Acute and Delayed Chemotherapy-Induced Nausea and Vomiting Among Patients With Lung Cancer Receiving Cisplatin-Based Regimens: A Randomized Controlled Trial.

Integr Cancer Ther. 2018 09;17(3):747-754

Authors: Li X, Qin Y, Liu W, Zhou XY, Li YN, Wang LY

Abstract
Nausea and vomiting are among the most common and distressing side effects of chemotherapy. Additional antiemetic drugs are urgently needed to effectively manage and ameliorate chemotherapy-induced nausea and vomiting (CINV). The efficacy of ginger as an antiemetic modality for ameliorating CINV has not been established in previous studies. The aim of this study was to examine the efficacy of ginger, as an adjuvant drug to standard antiemetic therapy, in ameliorating acute and delayed CINV in patients with lung cancer receiving cisplatin-based regimens. In this randomized, double-blind, placebo-controlled clinical trial, 140 patients with lung cancer receiving cisplatin-based regimens were enrolled and allocated to receive either ginger root powder or a placebo. Ginger root powder was administered orally (0.5 g, 2 capsules per day, 0.25 g per capsule, every 12 hours) for 5 days beginning on the first day of chemotherapy. The incidence and severity of acute and delayed nausea and vomiting were assessed using the MASCC (Multinational Association for Supportive Care in Cancer) Antiemesis Tool (MAT). Adverse effects and patient adherence were also assessed in this study. No significant difference was observed between the ginger and control groups in the reduction of the incidence and severity of nausea and vomiting ( P > .05). No significant difference in adverse events was observed between the 2 groups ( P > .05). No study-treatment-related adverse events were observed in this study. As an adjuvant drug to standard antiemetic therapy, ginger had no additional efficacy in ameliorating CINV in patients with lung cancer receiving cisplatin-based regimens.

PMID: 29417850 [PubMed - indexed for MEDLINE]

Does serious consequential masking exist? An update.

Pharmacoepidemiol Drug Saf. 2017 06;26(6):727-729

Authors: Hauben M, Maignen F

PMID: 28573827 [PubMed - indexed for MEDLINE]

Liposomal paclitaxel versus docetaxel in induction chemotherapy using Taxanes, cisplatin and 5-fluorouracil for locally advanced nasopharyngeal carcinoma.

BMC Cancer. 2018 Dec 20;18(1):1279

Authors: Liu SL, Sun XS, Li XY, Chen QY, Lin HX, Wen YF, Guo SS, Liu LT, Xie HJ, Tang QN, Liang YJ, Yan JJ, Lin C, Yang ZC, Tang LQ, Guo L, Mai HQ

Abstract
BACKGROUND: We wished to evaluate the efficacy and safety of liposomal paclitaxel and docetaxel for induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC).
METHODS: A total of 1498 patients with newly-diagnosed NPC between 2009 and 2017 treated with IC plus concurrent chemotherapy were included in our observational study. Overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and grade-3-4 toxicities were compared between groups using propensity score matching (PSM).
RESULTS: In total, 767 patients were eligible for this study, with 104 (13.6%) and 663 (86.4%) receiving a liposomal paclitaxel-based and docetaxel-based taxanes, cisplatin and 5-fluorouracil (TPF) regimen, respectively. PSM identified 103 patients in the liposomal-paclitaxel group and 287 patients in the docetaxel group. There was no significant difference at 3 years for OS (92.2% vs. 93.9%, P = 0.942), PFS (82.6% vs. 81.7%, P = 0.394), LRFS (94.7% vs. 93.3%, P = 0.981) or DMFS (84.6% vs. 87.4%, P = 0.371) between the two groups after PSM. Significant interactions were not observed between the effect of chemotherapy regimen and sex, age, T stage, N stage, overall stage, or Epstein-Barr virus DNA level in the subgroup multivariate analysis. The prevalence of grade-3-4 leukopenia and neutropenia in the liposomal-paclitaxel group was significantly lower than that of the docetaxel group (P < 0.05 for all).
CONCLUSIONS: Compared with docetaxel, liposomal paclitaxel has identical anti-tumor efficacy, but causes fewer and milder adverse reactions in IC for NPC.

PMID: 30572856 [PubMed - indexed for MEDLINE]

Oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX-4) as a salvage chemotherapy in heavily-pretreated platinum-resistant ovarian cancer.

BMC Cancer. 2018 Dec 19;18(1):1267

Authors: Conteduca V, Gurioli G, Rossi L, Scarpi E, Lolli C, Schepisi G, Farolfi A, De Lisi D, Gallà V, Burgio SL, Menna C, Amadori A, Losi L, Amadori D, Costi MP, De Giorgi U

Abstract
BACKGROUND: The purpose of this study was to evaluate the clinical impact of oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-4) chemotherapy in terms of the response rate, progression-free/overall survival (PFS/OS) and safety profile in patients with heavily pretreated recurrent epithelial ovarian cancer.
METHODS: Clinical data were reviewed in 29 patients who received FOLFOX-4 as more than third-line chemotherapy, consisting of 85 mg/m2 of oxaliplatin, 200 mg/m2 of leucovorin, and bolus 400 mg/m2 on day 1 of 5-fluorouracil, followed by a 22-h infusion of 600 mg/m2 of 5-fluorouracil for 2 consecutive days every 3 weeks. We also compared the efficacy and toxicity of FOLFOX-4 with that of topotecan, a standard treatment, given at a dosage of 1.5 mg/m2 every three weeks in 26 patients.
RESULTS: The median age of enrolled patients was 60 years (range 33 to 85). A median of 4 cycles (range 1-17) of FOLFOX-4 were administered. Complete response and partial response were observed in one (3.5%) and 5 (17.2.2%) patients, respectively, while stable disease was reported in 8 (27.6%) patients. Among all patients, grade 3-4 anemia, neutropenia, and thrombocytopenia were observed in 0 (0%), 5 (17.2%), and 3 (10.3%) cases, respectively. Grade 3-4 fatigue was recorded in one (3.4%) patient and diarrhea in 2 (6.9%). Median PFS and OS were 2.8 months [95% confidence interval (CI) 1.7-4.9] and 6.2 months (95% CI 2.4-14.6), respectively. No significant differences in terms of efficacy and toxicity were observed between patients receiving FOLFOX-4 and those treated with topotecan.
CONCLUSIONS: The FOLFOX-4 regimen would seem to obtain similar survival rates to those of standard therapy with topotecan in platinum-resistant ovarian cancer. Further randomized trials are warranted to confirm our findings.

PMID: 30567527 [PubMed - indexed for MEDLINE]

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions.

Mol Immunol. 2018 09;101:488-499

Authors: Ramsbottom KA, Carr DF, Jones AR, Rigden DJ

Abstract
Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with the HLA-B*57:01 allele, and anti-epilepsy drug Carbamazepine with B*15:02, in both cases likely following the altered peptide repertoire model of interaction. Under this model, the drug binds directly to the antigen presentation region, causing different self peptides to be presented, which trigger an unwanted immune response. There is growing interest in searching for evidence supporting this model for other ADRs using bioinformatics techniques. In this study, in silico docking was used to assess the utility and reliability of well-known docking programs when addressing these challenging HLA-drug situations. The overall aim was to address the uncertainty of docking programs giving different results by completing a detailed comparative study of docking software, grounded in the MHC-ligand experimental structural data - for Abacavir and to a lesser extent Carbamazepine - in order to assess their performance. Four docking programs: SwissDock, ROSIE, AutoDock Vina and AutoDockFR, were used to investigate if each software could accurately dock the Abacavir back into the crystal structure for the protein arising from the known risk allele, and if they were able to distinguish between the HLA-associated and non-HLA-associated (control) alleles. The impact of using homology models on the docking performance and how using different parameters, such as including receptor flexibility, affected the docking performance were also investigated to simulate the approach where a crystal structure for a given HLA allele may be unavailable. The programs that were best able to predict the binding position of Abacavir were then used to recreate the docking seen for Carbamazepine with B*15:02 and controls alleles. It was found that the programs investigated were sometimes able to correctly predict the binding mode of Abacavir with B*57:01 but not always. Each of the software packages that were assessed could predict the binding of Abacavir and Carbamazepine within the correct sub-pocket and, with the exception of ROSIE, was able to correctly distinguish between risk and control alleles. We found that docking to homology models could produce poorer quality predictions, especially when sequence differences impact the architecture of predicted binding pockets. Caution must therefore be used as inaccurate structures may lead to erroneous docking predictions. Incorporating receptor flexibility was found to negatively affect the docking performance for the examples investigated. Taken together, our findings help characterise the potential but also the limitations of computational prediction of drug-HLA interactions. These docking techniques should therefore always be used with care and alongside other methods of investigation, in order to be able to draw strong conclusions from the given results.

PMID: 30125869 [PubMed - indexed for MEDLINE]

Adverse Effects of Hypnotic Medications.

J Clin Sleep Med. 2017 06 15;13(6):839

Authors: Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN

PMID: 28454603 [PubMed - indexed for MEDLINE]

Clinical medication review tool for polypharmacy: Mapping approach for pharmacotherapeutic classifications.

Geriatr Gerontol Int. 2017 Nov;17(11):2025-2033

Authors: Mizokami F, Mizuno T, Mori T, Nagamatsu T, Endo H, Hirashita T, Ichino T, Akishita M, Furuta K

Abstract
AIM: Polypharmacy is an extremely important problem, because it increases the risk of adverse drug reactions. The aim of the current study was to create a clinical medication review tool to detect inappropriate medication use, and assess this new method with elderly Japanese patients.
METHODS: The new method involves optimizing prescription drugs from indications, based on the chronic disease-anatomical therapeutic class code list. The present study investigated the prevalence of potentially inappropriate medications in 5667 Japanese patients aged ≥65 years with polypharmacy (≥5 drugs) in comparison with the Beers criteria 2012.
RESULTS: We propose a new method called the Mapping Approach for Pharmacotherapeutic Classifications: (i) identify the chronic disease-anatomical therapeutic class code assigned to the prescription drugs; (ii) identify the chronic disease-anatomical therapeutic class code corresponding to the patient's chronic disease; (iii) compare the prescription drug and patient's chronic disease chronic disease-anatomical therapeutic class codes; and (iv) identify the appropriateness of medication use based on the comparison (appropriate use is defined as matching codes). The mean number of potentially inappropriate medications detected was significantly different between the mapping approach and Beers criteria 2012 (3.1 ± 2.6 vs 0.6 ± 0.8 drugs, respectively; P < 0.001).
CONCLUSIONS: The Mapping Approach for Pharmacotherapeutic Classifications is highly dependent on the chronic condition. Pharmacists should confirm the chronic condition with the treating physician before reducing a patient's medications. We hope this process will further influence prescribing patterns, and decrease the inappropriate use of medications and associated adverse drug reactions in older adults. Geriatr Gerontol Int 2017; 17: 2025-2033.

PMID: 28371121 [PubMed - indexed for MEDLINE]

Prevalence of and factors associated with therapeutic failure-related hospitalizations in the elderly.

Consult Pharm. 2014 Jun;29(6):376-86

Authors: Patel RS, Marcum ZA, Peron EP, Ruby CM

Abstract
OBJECTIVE: A therapeutic failure (TF) is defined as a failure to accomplish the goals of treatment attributable to inadequate therapy, a drug-drug interaction that results in a subtherapeutic level for a drug, or medication nonadherence. The objective of this study was to evaluate the prevalence of and factors associated with TF-related hospitalizations in older adults.
DESIGN: This investigation was a retrospective cohort study.
SETTING: This study was conducted within a university-based hospital setting.
PATIENTS: This investigation included patients with a primary care physician from the University of Pittsburgh Medical Center (UPMC) Senior Care Institute admitted to any UPMC hospital between September 1, 2011, and December 1, 2011.
INTERVENTIONS: Chart abstracts of patient records were screened for a TF using a validated tool called the Therapeutic Failure Questionnaire (TFQ). Covariate data were also obtained. Descriptive statistics and bivariate analyses using Fisher's exact tests were conducted to assess the association between the covariates and the primary outcome.
MAIN OUTCOME MEASURE(S): The primary outcome was the presence of a TF as measured by the TFQ. Secondary outcomes included associations between covariates and the presence of a TF.
RESULTS: Of the 93 hospitalizations screened, 57 met inclusion criteria, and 18% of hospitalizations were as a result of preventable TFs. On bivariate analyses, both congestive heart failure (P = 0.03) and dependency for medication management (P = 0.04) were significantly associated with occurrence of TF.
CONCLUSIONS: TFs are a potentially preventable cause of hospitalization in the elderly population and are commonly caused by omission of therapy.

PMID: 25202891 [PubMed - indexed for MEDLINE]

Assessment of proarrhythmic potential of drugs in optogenetically paced induced pluripotent stem cell-derived cardiomyocytes.

Toxicol Sci. 2019 Mar 26;:

Authors: Patel D, Stohlman J, Dang Q, Strauss DG, Blinova K

Abstract
BACKGROUND: Cardiac side-effects are one of the major reasons for failure of drugs during preclinical development. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been proposed as a model for predicting drug-induced arrhythmias under the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Field potential duration (FPD) in spontaneously-beating iPSC-CMs is commonly corrected for beating rate using formulas originally derived from the clinical QT-RR relationship that have not been thoroughly validated for use with iPSC-CMs.
METHODS AND RESULTS: In this study, channelrhodopsin-2 (ChR2) was expressed in iPSC-CMs allowing for recordings in both spontaneously-beating and optically-paced (0.8, 1, and 1.5 Hz pacing rate) iPSC-CMs using a microelectrode array system (Maestro, Axion Biosystems). After optimizing the intensity (>1 mW/mm2), duration (15 milliseconds) and frequency of the stimulating light pulses, we recorded iPSC-CMs' responses to 28 blinded CiPA compounds with clinically-characterized risk of causing ventricular arrhythmia (Torsade de Pointes or TdP). Drug-induced FPD prolongation data along with drug-induced arrhythmia-like events were used to build a logistic regression model, separating high or intermediate TdP risk drugs from low-or-no TdP risk drugs. The area under the receiver operator characteristic curve for drug TdP risk prediction was identical for spontaneously-beating and 0.8 Hz-paced iPSC-CMs (AUC=0.96; 95% CI [0.9,1]), while it was slightly lower for 1 and 1.5 Hz pacing (AUC= 0.88; 95% CI [0.76,1] and 0.93; 95% CI [0.84,1], respectively).
CONCLUSION: In this study, optical pacing did not offer substantial improvement in proarrhythmic risk prediction when compared to non-paced iPSC-CMs in the sample of 28 drugs.

PMID: 30912807 [PubMed - as supplied by publisher]

N,N'-diaryl-bishydrazones in a biphenyl platform: Broad spectrum antifungal agents.

Eur J Med Chem. 2019 Feb 15;164:273-281

Authors: Thamban Chandrika N, Dennis EK, Shrestha SK, Ngo HX, Green KD, Kwiatkowski S, Deaciuc AG, Dwoskin LP, Watt DS, Garneau-Tsodikova S

Abstract
N,N'-Diaryl-bishydrazones of [1,1'-biphenyl]-3,4'-dicarboxaldehyde, [1,1'-biphenyl]-4,4'-dicarboxaldehyde, and 4,4'-bisacetyl-1,1-biphenyl exhibited excellent antifungal activity against a broad spectrum of filamentous and non-filamentous fungi. These N,N'-diaryl-bishydrazones displayed no antibacterial activity in contrast to previously reported N,N'-diamidino-bishydrazones and N-amidino-N'-aryl-bishydrazones. The leading candidate, 4,4'-bis((E)-1-(2-(4-fluorophenyl)hydrazono)ethyl)-1,1'-biphenyl, displayed less hemolysis of murine red blood cells at concentrations at or below that of a control antifungal agent (voriconazole), was fungistatic in a time-kill study, and possessed no mammalian cytotoxicity and no toxicity with respect to hERG inhibition.

PMID: 30597328 [PubMed - indexed for MEDLINE]

Reevaluation of the post-marketing safety of Xuebijing injection based on real-world and evidence-based evaluations.

Biomed Pharmacother. 2019 Jan;109:1523-1531

Authors: Wang C, Shi QP, Ding F, Jiang XD, Tang W, Yu ML, Cheng JQ

Abstract
AIMS: To determine the causes of adverse reactions associated with Xuebijing injection and provide medical evidence for its safe and rational post-marketing use in clinical practice.
MATERIALS AND METHODS: We used prospective nested case-control and prescription sequence analysis designs. Using data from the Hospital Information System, patients exhibiting trigger signals after receiving Xuebijing injection were classified as suspected allergic patients. Logistic regression analysis was performed on the risk factors associated with Xuebijing-induced allergic reactions. Randomized controlled and cohort studies on adverse drug reactions to Xuebijing injection were screened from databases and the results were subjected to meta-analysis.
RESULTS: The overall incidence of allergic reactions or anaphylaxis tended to increase with dosage and patient's age. Moreover, compared with Xuebijing alone, co-administration of Xuebijing with other drugs or agents (including Ringer's sodium acetate solution, reduced glutathione, aspirin-DL-lysine, and torasemide) increased the risk of adverse reactions. The use of glucose as a vehicle also provoked a greater incidence of allergic reactions than that by the use of 0.9% w/v sodium chloride as a vehicle. Adverse reactions occurred more frequently in patients receiving indicated dosages than in those receiving off-label dosages.
CONCLUSIONS: Adverse reactions to Xuebijing injections were correlated with vehicle type, dosage, age, and drug combination. There was no clear association between patient's condition at admission and suspected adverse reactions to Xuebijing injection. Factors influencing the adverse reactions to Xuebijing injection must be fully considered in clinical practice.

PMID: 30551404 [PubMed - indexed for MEDLINE]