A Bayesian analysis of quantal bioassay experiments incorporating historical controls via Bayes factors.

Stat Med. 2017 May 30;36(12):1907-1923

Authors: León Novelo LG, Womack A, Zhu H, Wu X

Abstract
This paper addresses model-based Bayesian inference in the analysis of data arising from bioassay experiments. In such experiments, increasing doses of a chemical substance are given to treatment groups (usually rats or mice) for a fixed period of time (usually 2 years). The goal of such an experiment is to determine whether an increased dosage of the chemical is associated with increased probability of an adverse effect (usually presence of adenoma or carcinoma). The data consists of dosage, survival time, and the occurrence of the adverse event for each unit in the study. To determine whether such relationship exists, this paper proposes using Bayes factors to compare two probit models, the model that assumes increasing dose effects and the model that assumes no dose effect. These models account for the survival time of each unit through a Poly-k type correction. In order to increase statistical power, the proposed approach allows the incorporation of information from control groups from previous studies. The proposed method is able to handle data with very few occurrences of the adverse event. The proposed method is compared with a variation of the Peddada test via simulation and is shown to have higher power. We demonstrate the method by applying it to the two bioassay experiment datasets previously analyzed by other authors. Copyright © 2017 John Wiley & Sons, Ltd.

PMID: 28106916 [PubMed - indexed for MEDLINE]

Long-term (52-week) safety and efficacy of Sacubitril/valsartan in Asian patients with hypertension.

Hypertens Res. 2017 May;40(5):472-476

Authors: Supasyndh O, Sun N, Kario K, Hafeez K, Zhang J

Abstract
Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD. The sacubitril/valsartan dose was uptitrated to 400 mg QD if BP was uncontrolled (>140/90 mm Hg) after 4 weeks. Subsequently, in patients with uncontrolled BP, treatment was intensified every 4 weeks with amlodipine 5-10 mg followed by hydrochlorothiazide 6.25-25 mg. Of the 341 patients enrolled, 7 (2.1%) discontinued the study drug due to adverse events (AEs). The incidence of AEs and serious AEs were 63.9 and 3.8%, respectively, and no deaths were reported in this study. The most frequent AEs were nasopharyngitis (18.2%) and dizziness (8.8%). Events that were potentially indicative of low BP were infrequent. One patient reported mild transient angioedema (lasting 2.5 h) that resolved without treatment but led to study drug discontinuation. The sacubitril/valsartan-based regimen provided clinically significant mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-24.7/-16.2 mm Hg). The overall BP control, msSBP and msDBP response rates were 75.3, 90.6 and 87.6%, respectively. Long-term use of sacubitril/valsartan was generally safe and well-tolerated in patients with hypertension and provided significant BP reductions from baseline.

PMID: 27853163 [PubMed - indexed for MEDLINE]

Assessment of Drug Therapy-Related Issues in an Outpatient Heart Failure Population and the Potential Impact of Pharmacist-Driven Intervention.

J Pharm Pract. 2017 Jun;30(3):318-323

Authors: Dempsey JT, Matta LS, Carter DM, Stevens CA, Stevenson LW, Desai AS, Cheng JW

Abstract
BACKGROUND: The Ambulatory Cardiac Triage, Intervention, and Education (ACTIVE) infusion unit is an outpatient center that aims to provide heart failure (HF) patients with comprehensive multidisciplinary interventions.
OBJECTIVE: To describe the patient population served in ACTIVE and to document the prevalence of comorbidities and drug therapy-related issues (DRIs) in order to define the most effective role of a pharmacist in the unit.
METHODS: Patients who have been interviewed by a pharmacist in ACTIVE were included. Comprehensive medical and medication profile reviews were performed. Patient comorbidities were documented, and DRIs were classified.
RESULTS: Sixty patients were included. Most prevalent cardiac comorbidities included hypertension (73%) and hyperlipidemia (62%). Top 3 noncardiac comorbidities included chronic kidney disease (60%), diabetes (50%), and obesity (35%). The prevalence of DRI was reported as follows: (1) needs additional/alternative therapy (untreated indication [37] or suboptimal therapeutic choice [46]), (2) wrong drug (major drug-drug interaction [90], contraindication [11], or duplicate therapy [1]), (3) suboptimal dosing (17), (4) dose exceeds recommended maximum (9), and (5) adverse drug reaction (93). In 63 (22%) of the DRIs, a pharmacist made recommendations to modify the regimen.
CONCLUSION: The prevalence of DRI is high even among HF patients managed in a subspecialty cardiovascular practice. Pharmacists in this setting play a vital role in more effectively resolving DRI.

PMID: 27080398 [PubMed - indexed for MEDLINE]

Does low-dose methotrexate deserve more respect from clinicians?

JAAPA. 2017 May;30(5):12-15

Authors: Luu B, Rodway GW

Abstract
Medical errors associated with low-dose methotrexate may be life-threatening. Prescribers should be cognizant of the medication's toxicities and the persistent challenges in preventing adverse events. This article reviews the properties of methotrexate and its common drug-drug interactions. Best practices from the Institute for Safe Medication Practices, aimed at reducing methotrexate errors, are highlighted.

PMID: 28441215 [PubMed - indexed for MEDLINE]

Drug-associated pulmonary arterial hypertension.

Clin Toxicol (Phila). 2018 Mar 06;:1-9

Authors: McGee M, Whitehead N, Martin J, Collins N

Abstract
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence.
OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension.
METHODS: A systematic search was conducted using PubMed covering the period September 1970- 2017. The search term utilized was "drug induced pulmonary hypertension". This resulted in the identification of 853 peer-reviewed articles including case reports. Each paper was then reviewed by the authors for its relevance. The majority of these papers (599) were excluded as they related to systemic hypertension, chronic obstructive pulmonary disease, human immunodeficiency virus, pulmonary fibrosis, alternate differential diagnosis, treatment, basic science, adverse effects of treatment, and pulmonary hypertension secondary to pulmonary embolism. Agents affecting serotonin metabolism (and related anorexigens): Anorexigens, such as aminorex, fenfluramine, benfluorex, phenylpropanolamine, and dexfenfluramine were the first class of medications recognized to cause pulmonary arterial hypertension. Although most of these medications have now been withdrawn worldwide, they remain important not only from a historical perspective, but because their impact on serotonin metabolism remains relevant. Selective serotonin reuptake inhibitors, tryptophan, and lithium, which affect serotonin metabolism, have also been implicated in the development of pulmonary arterial hypertension. Interferon and related medications: Interferon alfa and sofosbuvir have been linked to the development of pulmonary arterial hypertension in patients with other risk factors, such as human immunodeficiency virus co-infection. Antiviral therapies: Sofosbuvir has been associated with two cases of pulmonary artery hypertension in patients with multiple risk factors for its development. Its role in pathogenesis remains unclear. Small molecule tyrosine kinase inhibitors: Small molecule tyrosine kinase inhibitors represent a relatively new class of medications. Of these dasatinib has the strongest evidence in drug-induced pulmonary arterial hypertension, considered a recognized cause. Nilotinib, ponatinib, carfilzomib, and ruxolitinib are newer agents, which paradoxically have been linked to both cause and treatment for pulmonary arterial hypertension. Monoclonal antibodies and immune regulating medications: Several case reports have linked some monoclonal antibodies and immune modulating therapies to pulmonary arterial hypertension. There are no large series documenting an increased prevalence of pulmonary arterial hypertension complicating these agents; nonetheless, trastuzumab emtansine, rituximab, bevacizumab, cyclosporine, and leflunomide have all been implicated in case reports. Opioids and substances of abuse: Buprenorphine and cocaine have been identified as potential causes of pulmonary arterial hypertension. The mechanism by which this occurs is unclear. Tramadol has been demonstrated to cause severe, transient, and reversible pulmonary hypertension. Chemotherapeutic agents: Alkylating and alkylating-like agents, such as bleomycin, cyclophosphamide, and mitomycin have increased the risk of pulmonary veno-occlusive disease, which may be clinically indistinct from pulmonary arterial hypertension. Thalidomide and paclitaxel have also been implicated as potential causes. Miscellaneous medications: Protamine appears to be able to cause acute, reversible pulmonary hypertension when bound to heparin. Amiodarone is also capable of causing pulmonary hypertension by way of recognized side effects.
CONCLUSIONS: Pulmonary arterial hypertension remains a rare diagnosis, with drug-induced causes even more uncommon, accounting for only 10.5% of cases in large registry series. Despite several agents being implicated in the development of PAH, the supportive evidence is typically limited, based on case series and observational data. Furthermore, even in the drugs with relatively strong associations, factors that predispose an individual to PAH have yet to be elucidated.

PMID: 29508628 [PubMed - as supplied by publisher]

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

NPJ Syst Biol Appl. 2018;4:10

Authors: Cordes H, Thiel C, Baier V, Blank LM, Kuepfer L

Abstract
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis, which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

PMID: 29507756 [PubMed]

New low-dose liquid pilocarpine formulation for treating dry mouth in Sjögren's syndrome: clinical efficacy, symptom relief, and improvement in quality of life.

J Pharm Health Care Sci. 2018;4:4

Authors: Watanabe M, Yamada C, Komagata Y, Kikuchi H, Hosono H, Itagaki F

Abstract
Background: Patients with Sjögren's syndrome (SS) typically present clinically with xerostomia (dry mouth) because of progressive damage to the exocrine glands. We developed a new, low-dose pilocarpine/sodium alginate (LPA) solution with pilocarpine hydrochloride to inhibit systemic adverse effects by administering via the oral mucosa. The purpose of this study was to assess its stability, safety, and efficacy.
Methods: The pilocarpine concentration in an LPA liquid formulation was measured 3, 7, 14, and 28 days after preparation to assess its stability. A prospective clinical trial was undertaken to assess the efficacy and safety of the LPA solution as a symptomatic treatment for dry mouth in SS. Patients (n = 24) with clinically significant xerostomia were enrolled after providing written informed consent. Whole-mouth salivary flow rate was measured twice; immediately before and 60 min after LPA application. Symptoms were assessed by questionnaire with visual analog scales or checkboxes before the first application (baseline), and then once daily for 7 days.
Results: The pilocarpine content 3, 7, 14, and 28 days after preparation showed no marked change, confirming its stability. Salivary flow was significantly increased from 0.076 ± 0.092 g/30 s to 0.122 ± 0.140 g/30 s 60 min after LPA administration (P < 0.001). Dry mouth and thirstiness showed significant improvement compared with that of baseline (P ≤ 0.01). The only adverse effect was sweating, and no serious drug-related adverse events were reported.
Conclusions: This new, low-dose pilocarpine formulation was well-tolerated and resulted in significant improvements in symptoms of dry mouth and other xerostomic conditions in patients with SS.
Trial registration: The study approval number in the institution; 08-068-2. Registered January 19, 2009. UMIN000029307. Registered 27 September 2017 (retrospectively registered).

PMID: 29507747 [PubMed]

Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

Biol Pharm Bull. 2017;40(6):824-829

Authors: Chisaki Y, Aoji S, Yano Y

Abstract
In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug-ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (≤69 years old) and elderly (≥70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug-ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1-702.9). In total, 27 drug-ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug-ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting.

PMID: 28566626 [PubMed - indexed for MEDLINE]

Adverse effects of levamisole in cocaine users: a review and risk assessment.

Arch Toxicol. 2017 Jun;91(6):2303-2313

Authors: Brunt TM, van den Berg J, Pennings E, Venhuis B

Abstract
The immunomodulatory adjuvant and antihelminth levamisole is increasingly used as an adulterant in cocaine worldwide. An accumulating body of clinical and toxicological literature has appeared since 2010 describing neutropenia, agranulocytosis, leukoencephalopathy and vasculitis in cases associated with levamisole-adulterated cocaine. Mostly, neutropenia and agranulocytosis were reported, characterized by a decimation of neutrophils. A large proportion of cases also involved vasculopathy, characterized by pronounced black and purple skin purpura with cutaneous necrosis. Females are more susceptible for both agranulocytosis and vasculitis. Another complication reported with levamisole-adulterated cocaine is leukoencephalopathy, a disabling and potentially fatal neurological disorder caused by cerebral demyelination. In this review, all adverse effects associated with therapeutic levamisole and levamisole-adulterated cocaine are described. In addition, this review provides an update of the pharmacology of levamisole, its metabolism, including toxic metabolites and metabolites that are relevant for levamisole's addition to cocaine. Special emphasis is put on the immunopathology and the dose-effect relationship of chronic levamisole exposure. Finally, a risk assessment is provided based on the current level of levamisole adulteration in street cocaine, the dose range calculated per gram and the pattern of chronic exposure in heavy or dependent users.

PMID: 28314885 [PubMed - indexed for MEDLINE]

DTNI: a novel toxicogenomics data analysis tool for identifying the molecular mechanisms underlying the adverse effects of toxic compounds.

Arch Toxicol. 2017 Jun;91(6):2343-2352

Authors: Hendrickx DM, Souza T, Jennen DGJ, Kleinjans JCS

Abstract
Unravelling gene regulatory networks (GRNs) influenced by chemicals is a major challenge in systems toxicology. Because toxicant-induced GRNs evolve over time and dose, the analysis of global gene expression data measured at multiple time points and doses will provide insight in the adverse effects of compounds. Therefore, there is a need for mathematical methods for GRN identification from time-over-dose-dependent data. One of the current approaches for GRN inference is Time Series Network Identification (TSNI). TSNI is based on ordinary differential equations (ODE), describing the time evolution of the expression of each gene, which is assumed to be dependent on the expression of other genes and an external perturbation (i.e. chemical exposure). Here, we present Dose-Time Network Identification (DTNI), a method extending TSNI by including ODE describing how the expression of each gene evolves with dose, which is supposed to depend on the expression of other genes and the exposure time. We also adapted TSNI in order to enable inclusion of time-over-dose-dependent data from multiple compounds. Here, we show that DTNI outperforms TSNI in inferring a toxicant-induced GRN. Moreover, we show that DTNI is a suitable method to infer a GRN dose- and time-dependently induced by a group of compounds influencing a common biological process. Applying DTNI on experimental data from TG-GATEs, we demonstrate that DTNI provides in-depth information on the mode of action of compounds, in particular key events and potential molecular initiating events. Furthermore, DTNI also discloses several unknown interactions which have to be verified experimentally.

PMID: 28032149 [PubMed - indexed for MEDLINE]

Net Reclassification Index and Integrated Discrimination Index Are Not Appropriate for Testing Whether a Biomarker Improves Predictive Performance.

Toxicol Sci. 2017 Mar 01;156(1):11-13

Authors: Burch PM, Glaab WE, Holder DJ, Phillips JA, Sauer JM, Walker EG

Abstract
One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing.

PMID: 27815493 [PubMed - indexed for MEDLINE]

Non-adherence to medication regimens among older African-American adults.

BMC Geriatr. 2017 Jul 25;17(1):163

Authors: Bazargan M, Smith J, Yazdanshenas H, Movassaghi M, Martins D, Orum G

Abstract
BACKGROUND: Despite concerns about racial differences on adherence to prescribed medication rigimens among older adults, current information about nonadherence among underserved elderly African Americans with co-morbidities is limited. This study examines the association between adherence to drug regimens and an array of medication-related factors, including polypharmacy, medication regimen complexity, use of Potentially Inappropriate Medications (PIM), and knowledge about the therapeutic purpose and instructions of medication use.
METHODS: Four-hundred African Americans, aged 65 years and older, were recruited from South Los Angeles. Structured, face-to-face interviews and visual inspection of participants' medications were conducted. From the medication container labels, information including strength of the drug, expiration date, instructions, and special warnings were recorded. The Medication Regimen Complexity Index (MRCI) was measured to quantify multiple features of drug regimen complexity. The Beers Criteria was used to measure the PIM use.
RESULTS: Participants reported taking an average of 5.7 prescription drugs. Over 56% could not identify the purpose of at least one of their medications. Only two-thirds knew dosage regimen of their medications. Thirty-five percent of participants indicated that they purposely had skipped taking at least one of their medications within last three days. Only 8% of participants admitted that they forgot to take their medications. The results of multivariate analysis showed that co-payment for drugs, memory deficits, MRCI, and medication-related knowledge were all associated with adherence to dosage regimen of medications. Participants with a higher level of knowledge about therapeutic purpose and knowledge about dosage regimen of their medications were seven times (CI: 4.2-10.8) more likely to adhere to frequency and dose of medications. Participants with a low complexity index were two times (CI: 1.1-3.9) more likely to adhere to the dosage regimen of their medications, compared with participants with high drug regimen complexity index.
CONCLUSIONS: While other studies have documented that non-adherence remains an important issue among older adults, our study shows that for underserved elderly African Americans, these issues are particularly striking. A periodic comprehensive assessment of all medications that they use remains a critical initial step to identify medication related issues. Assessment of their disease and medication related knowledge (e.g., therapeutic purposes, side-effects, special instructions, etc.) and their ability to follow complicated medication regimens and modification of their drug regimens requires inter-professional collaboration.

PMID: 28743244 [PubMed - indexed for MEDLINE]

Concurrent use of alcohol interactive medications and alcohol in older adults: a systematic review of prevalence and associated adverse outcomes.

BMC Geriatr. 2017 Jul 17;17(1):148

Authors: Holton AE, Gallagher P, Fahey T, Cousins G

Abstract
BACKGROUND: Older adults are susceptible to adverse effects from the concurrent use of medications and alcohol. The aim of this study was to systematically review the prevalence of concurrent use of alcohol and alcohol-interactive (AI) medicines in older adults and associated adverse outcomes.
METHODS: A systematic search was performed using MEDLINE (PubMed), Embase, Scopus and Web of Science (January 1990 to June 2016), and hand searching references of retrieved articles. Observational studies reporting on the concurrent use of alcohol and AI medicines in the same or overlapping recall periods in older adults were included. Two independent reviewers verified that studies met the inclusion criteria, critically appraised included studies and extracted relevant data. A narrative synthesis is provided.
RESULTS: Twenty studies, all cross-sectional, were included. Nine studies classified a wide range of medicines as AI using different medication compendia, thus resulting in heterogeneity across studies. Three studies investigated any medication use and eight focused on psychotropic medications. Based on the quality assessment of included studies, the most reliable estimate of concurrent use in older adults ranges between 21 and 35%. The most reliable estimate of concurrent use of psychotropic medications and alcohol ranges between 7.4 and 7.75%. No study examined longitudinal associations with adverse outcomes. Three cross-sectional studies reported on falls with mixed findings, while one study reported on the association between moderate alcohol consumption and adverse drug reactions at hospital admission.
CONCLUSIONS: While there appears to be a high propensity for alcohol-medication interactions in older adults, there is a lack of consensus regarding what constitutes an AI medication. An explicit list of AI medications needs to be derived and validated prospectively to quantify the magnitude of risk posed by the concurrent use of alcohol for adverse outcomes in older adults. This will allow for risk stratification of older adults at the point of prescribing, and prioritise alcohol screening and brief alcohol interventions in high-risk groups.

PMID: 28716004 [PubMed - indexed for MEDLINE]

[Prevalence of potentially inappropriate drug prescription in the elderly].

Rev Calid Asist. 2016 Sep-Oct;31(5):279-84

Authors: Fajreldines A, Insua J, Schnitzler E

Abstract
INTRODUCTION: One of the causes of preventable adverse drug events (ADES) in older patients constitutes inappropriate prescription of drugs (PIM). The PIM is where risks exceed the clinical benefit. Several instruments can be use to measure this problem, the most used are: a) Beers criteria; b) Screening tool to Older People Potentially inappropriate Prescription (STOPP); c) Screening tool to Alert Doctors to Right Appropriate indicated Treatments (START); d) The Medication Appropriateness Index (MAI). This study aims to assess the prevalence of PIM, in a population of older adults in three clinical scopes of university hospital.
MATERIAL AND METHODS: cross sectional study of 300 cases from a random sample of fields: hospitalization (n=100), ambulatory (n=100) and emergency (n=100), all patients over 65 years old or more who where treated at our hospital.
RESULTS: 1355 prescription drugs were analized, finding patients hospitalized (PIM) of 57.7%, 55%, 26%, and 80% according to Beers, in ambulatory 36%, 36.5%, 5% and 52% with the same tools and in emergency 35%, 35%, 6% y 52% with the same tools. Was found significant association the PIM with polipharmacy with Beers, STOPP and MAI.
CONCLUSIONS: results can be compare to world literature (26-80% vs 11-73.1%). The STOPP-START used in an integrated manner would be best estimating the problem of PIM.

PMID: 26970837 [PubMed - indexed for MEDLINE]

Ceftriaxone combination therapy versus respiratory fluoroquinolone monotherapy for community-acquired pneumonia: A meta-analysis.

Am J Emerg Med. 2018 Feb 27;:

Authors: Zhang YQ, Zou SL, Zhao H, Zhang MM, Han CL

Abstract
BACKGROUND: The goal of this study was to investigate whether ceftriaxone combination therapy is associated with better clinical outcomes than respiratory fluoroquinolone monotherapy for adults with community-acquired pneumonia (CAP). We conducted a meta-analysis of published studies.
METHODS: Using the PubMed, EMBASE, and Cochrane Library databases, we performed a literature search of available randomized controlled trials (RCTs) published as original articles before September 2017.
RESULTS: Nine RCTs, involving 1520 patients, were included in the meta-analysis. The pooled relative risks (RRs) for the efficacy of ceftriaxone combination therapy versus respiratory fluoroquinolones monotherapy were 0.96 (95% CI: 0.92-1.01), based on clinically evaluable populations, and 0.93 (95% CI: 0.88-0.99) based on intention-to-treat (ITT) populations. No statistically significant differences were observed in microbiological treatment success (pooled RR=0.99, 95% CI: 0.90-1.09), although drug-related adverse events were significantly lower with ceftriaxone combination therapy than with respiratory fluoroquinolones monotherapy (pooled RR=1.27, 95% CI: 1.04-1.55).
CONCLUSIONS: Current evidence showed that the efficacy of ceftriaxone combination therapy was similar to respiratory fluoroquinolone monotherapy for hospitalized CAP patients, and was associated with lower drug-related adverse events.

PMID: 29499898 [PubMed - as supplied by publisher]

Safety assessment of sorafenib in Chinese patients with unresectable hepatocellular carcinoma: subgroup analysis of the GIDEON study.

BMC Cancer. 2018 Mar 02;18(1):247

Authors: Ye SL, Yang J, Bie P, Zhang S, Chen X, Liu F, Liu L, Zhou J, Dou K, Hao C, Shao G, Xia Q, Chen Y, Yang J, Deng X, Liu Y, Yuan Y, Fu Z, Nakajima K, Lv Z

Abstract
BACKGROUND: This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients.
METHODS: A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0.
RESULTS: Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug-related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib.
CONCLUSION: Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation.
TRIAL REGISTRATION: ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008.

PMID: 29499662 [PubMed - in process]

Potential associations between atazanavir exposure and clinical outcome: a pharmacokinetic sub-study from the MODAt randomized trial.

New Microbiol. 2018 Mar 02;41(1)

Authors: Colella E, Cattaneo D, Galli L, Baldelli S, Clementi E, Galli M, Lazzarin A, Castagna A, Rusconi S, Spagnuolo V

Abstract
The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100mg] versus ATV/ritonavir triple therapy [ATV/r 300/100mg+2NRTIs]. A chromatographic method coupled with tandem mass spectrometry was applied to analyze ATV plasma concentrations in a pharmacokinetic sub-study from the MODAt trial. Mixed linear models were used to examine the ATV plasma concentration trend during follow-up and to assess the association between ATV plasma concentrations trajectories with the study arm or the occurrence of treatment failure or drug-related adverse events or the grading of baseline total bilirubin (<3 vs ≥3). The analyses were performed using SAS Software, release 9.4 (SAS Institute, Cary, NC, USA). Overall, ATV plasma Ctrough concentration did not vary during follow-up (slope: +0.75 ng/mL/week, 95%CI: -0.97 to 2.47, p=0.387); trajectories did not differ between study arms 2 (p=0.527). The unadjusted model-based means (95%CI) of ATV Ctrough during follow-up were 835 (95%CI: 657-1012) ng/ml in the ATV/r monotherapy arm as compared to 911 (95%CI: 740-1082) ng/mL in the ATV/r triple therapy arm (p=0.621). Mean ATV Ctrough was similar in subjects with or without adverse events (AEs). Subjects treated with ATV/r monotherapy showed significantly higher ATV concentrations as compared to subjects without adverse events or treated with ATV/r triple therapy. ATV concentrations were associated with the grading of baseline total bilirubin and the occurrence of drug-related AEs but not with HCV infection. Our findings showed a lack of association between ATV concentrations and treatment failure both in ATV/r monotherapy and triple therapy. Conversely, these data emphasized that ATV concentrations are associated with the development of side-effects in both subjects treated with ATV/r monotherapy and subjects treated with ATV/r triple therapy.

PMID: 29498742 [PubMed - as supplied by publisher]

Comparison of efficacy of haloperidol and olanzapine in the treatment of delirium.

Indian J Psychiatry. 2017 Oct-Dec;59(4):451-456

Authors: Jain R, Arun P, Sidana A, Sachdev A

Abstract
Objective: Till date, typical antipsychotic haloperidol is the treatment of choice for delirium. But, due to higher side effects with haloperidol, newer atypical antipsychotics (e.g., olanzapine) are increasingly being used in the treatment of delirious patients. The aim of the current research was to study the efficacy and tolerability of haloperidol and olanzapine in the treatment of delirium.
Materials and Methods: This was an open-label, randomized controlled study carried out in a tertiary care hospital at Chandigarh, India. A total of 100 patients admitted in medicine, surgery, and orthopedic wards and diagnosed as having delirium on Confusion Assessment Method scale were included in the study. Patients were given either haloperidol (1-4 mg/day either orally or by nasogastric tube) or olanzapine (2.5-10 mg/day either orally or by nasogastric tube). Severity of delirium and pattern of symptom improvement were assessed by Memorial Delirium Assessment Scale (MDAS). Extrapyramidal side effects were assessed by Simpson-Angus Scale.
Results: There was an improvement in delirium severity in both groups with treatment. Mean daily dose of haloperidol and olanzapine used per patient was 2.10 and 5.49 mg, respectively, and the mean duration of treatment in olanzapine group and haloperidol group was 3.57 days and 3.37 days, respectively. There was no significant difference in the mean duration of treatment in both groups. At the end of study period, the MDAS scores in olanzapine and haloperidol groups were 8.43 and 8.00, respectively, and the difference was not significant statistically with P = 0.765. Five patients experienced drug-related mild side effects.
Conclusion: Low-dose haloperidol and olanzapine were equally efficacious and well tolerated in delirium.

PMID: 29497187 [PubMed - in process]

Finding balance: Optimizing medication prescribing in older patients.

Cleve Clin J Med. 2018 02;85(2):136-137

Authors: Sponsler KC, Mixon AS

PMID: 29425084 [PubMed - indexed for MEDLINE]

Risk Factors for Chemotherapy-Related Toxicity and Adverse Events in Elderly Thai Cancer Patients: A Prospective Study.

Oncology. 2018;94(3):149-160

Authors: Phaibulvatanapong E, Srinonprasert V, Ithimakin S

Abstract
OBJECTIVES: To assess factors predisposing to severe chemotherapy-related toxicity and adverse events (AEs) and dose modification in aging cancer patients.
METHODS: Cancer patients aged ≥70 years scheduled to receive the first cycle of a new chemotherapy regimen were enrolled. On the day of starting chemotherapy, demographic data, performance status (PS), and geriatric parameters were recorded. AEs and chemotherapy modification were recorded. Quality of life (QOL) was assessed at baseline and 3 months after starting chemotherapy or at the end of chemotherapy.
RESULTS: We included 151 patients (mean age, 76.4 years) with gastrointestinal (47%), lung (24%), breast (9%), or genitourinary (6%) cancer. All-grade and severe AEs occurred in 83 and 42% of patients, respectively; 51.6% of patients required chemotherapy modification due to toxicities. A higher incidence of severe AEs (71% vs. 39%, p = 0.01) and poorer QOL was found in patients with PS 2 than in those with PS 0-1. Patients with PS 2 or who received palliative-intent chemotherapy or had multiple comorbidities were more likely to discontinue chemotherapy because of toxicity.
CONCLUSIONS: PS remains a key predictor of chemotherapy-related toxicity in elderly patients. PS 2 was correlated with higher incidence of severe AEs, premature treatment discontinuation, and worsening QOL after treatment.

PMID: 29212082 [PubMed - indexed for MEDLINE]