Showing papers in "Journal of Clinical Pharmacy and Therapeutics in 2015"

Trends in pharmacists' medication order review in French hospitals from 2006 to 2009: analysis of pharmacists' interventions from the Act-IP© website observatory.

Abstract: Summary What is known and objectives The French Society of Clinical Pharmacy has developed a website, named Act-IP©, enabling hospital pharmacists to document and analyse pharmacists' interventions (PIs) proposed during medication order review when a drug-related problem is detected. This study analyses PIs documented in Act-IP© and assesses factors associated with physicians' acceptance of PIs. Methods PIs documented into Act-IP© over a 30-month period were analysed. Independent predictors of physicians' acceptance were assessed using multiple logistic regression. Results and discussion A total of 34 522 PIs were registered by 201 pharmacists working in 59 hospitals. PIs were mostly related to ‘dose adjustment’ (25%), ‘drug discontinuation’ (20%) and ‘drug switch’ (19%). Of the 43 343 medications involved, 28% targeted drugs acting on the central nervous system, 17% anti-infective drugs and 16% cardiovascular drugs. Sixty-eight per cent of PIs were accepted by physicians (15% refusals and 17% non-assessable). Physicians' acceptance was significantly associated with 1/ drug group: antineoplastics and immunomodulators (OR = 2·29, CI 95[1·94–2·69]), anti-infectives (OR = 1·19, CI 95 [1·11–1·28]); 2/ type of intervention: drug switch (OR = 1·54, CI 95 [1·43–1·65]), drug discontinuation (OR = 1·38, CI 95 [1·29–1·48]), administration modality optimization (OR = 1·19, CI 95 [1·11–1·29]), addition of a new drug (OR = 1·12, CI 95 [1·00–1·24]); 3/ ward specialty: paediatrics (OR = 1·83, CI 95 [1·24–2·70]) and intensive care (OR = 1·34, CI 95 [1·10–1·64]); 4/ level of pharmacist integration in the ward: higher when the pharmacist is regularly in the ward compared with occasionally (OR = 0·74, CI 95 [0·70–0·79]) or never (OR = 0·68, CI 95 [0·60–0·75]) present. What is new and conclusion This study highlights the role of routine pharmacist review of medication orders to prevent drug-related problems and gives new insights for a successful collaboration between physicians and pharmacists.

Phytocannabinoids and epilepsy

Abstract: SUMMARY What is known and objective: Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids. Methods: Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy. Results and discussion: Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration. What is new and conclusion: Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

Effects of coenzyme Q10 supplementation on metabolic profile in diabetes: a systematic review and meta-analysis.

Abstract: Summary What is known and objective CoenzymeQ10 (CoQ10), or ubiquinone, is an endogenous enzyme cofactor produced by most human cells. It is a potent antioxidant and is necessary for energy production in mitochondria. Diabetes mellitus is a chronic disease with multiple metabolic abnormalities, principally resulting from the inflammation and oxidative stress associated with mitochondrial dysfunctions. Clinical trials of the effects of supplementary CoQ10 on metabolic control in diabetes have reported inconsistent results. We undertook a systematic review and meta-analysis of randomized controlled trials to assess the effects of CoQ10 supplementation on glycaemic control, lipid profile and blood pressure in patients with diabetes. Methods A systematic search was conducted on MEDLINE, The Cochrane Library, CINAHL, NCCAM, Web of Science, Scopus, ClinicalTrials.gov and historical search of reference lists of relevant articles. The bibliographic databases were searched from inception to February 2015. We included randomized, placebo-controlled trials of CoQ10 in diabetes lasting at least 12 weeks. HbA1c or fasting plasma glucose had to be reported. Primary outcome was glycemic control, and secondary outcomes were lipid profile and blood pressure. Treatment effect was estimated with mean difference. Results and discussion Seven trials were included in the meta-analysis, involving 356 patients. Neither CoQ10 alone nor CoQ10 plus fenofibrate improved glycemic control. In addition, CoQ10, alone or in combination with fenofibrate, did not alter LDL-C, HDL-C and blood pressure. Triglycerides levels were significantly reduced with CoQ10 (mean difference −0·26 mmol/L, 95% CI −0·05 mmol/L to −0·47 mmol/L, P = 0·02) and CoQ10 plus fenofibrate (mean difference −0·72 mmol/L, 95% CI −0·32 mmol/L to −1·12 mmol/L, P = 0·0004). CoQ10 plus fenofibrate also effectively reduced total cholesterol (mean difference: −0·45 mmol/L, 95% CI −0·06 mmol/L to −0·84 mmol/L, P = 0·02). What is new and conclusions CoQ10 supplementation has no beneficial effects on glycemic control, lipid profile or blood pressure in patients with diabetes. However, it may reduce triglycerides levels. Due to limited data availability, well-powered and well-designed randomized controlled trials are needed to clearly determine the effect of CoQ10 on metabolic profile in diabetes. Dosage effects should also be explored.

Medicines can affect thermoregulation and accentuate the risk of dehydration and heat-related illness during hot weather

Abstract: WHAT IS KNOWN AND OBJECTIVE: Hot days are increasingly common and are often associated with increased morbidity and mortality, especially in the elderly. Most heat-related illness and heat-related deaths are preventable. COMMENT: Medicines may accentuate the risk of dehydration and heat-related illness, especially in elderly people taking multiple medicines, through the following mechanisms: diuresis and electrolyte imbalance, sedation and cognitive impairment, changed thermoregulation, reduced thirst recognition, reduced sweat production, and hypotension and reduced cardiac output. WHAT IS NEW AND CONCLUSION: Commonly used medicines that may significantly increase the risk include diuretics, especially when combined with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), anticholinergics and psychotropics. Initiation of individualized preventive measures prior to the start of the hot weather season, which includes a review of the patient and their medicines to identify thermoregulatory issues, may reduce the risk of heat-related illness or death. Language: en

Impact of pharmacist intervention on antibiotic use and prophylactic antibiotic use in urology clean operations.

Abstract: SummaryWhat is known and objective The use of prophylactic antibiotics in clean operations was routine in China before 2011. Along with the appeal for using antibiotics rationally by WHO in 2011, China launched a national special rectification scheme on clinical use of antibiotics from April that year. The scheme, aimed at achieving rational use of antibiotics, made pharmacists part of the responsible medical team. Our objective was to describe the impacts of pharmacist intervention on the use of antibiotics, particularly in urology clean operations. Methods Pharmacists participated in antibiotic stewardship programmes of the hospital and urological clinical work and conducted real-time interventions at the same time from 2011 to 2013. Data on the use of antibiotics between 2010 and 2013 in urology were collected. Results Comparison of the 2013 data with those of 2010 showed that antibiotic use density [AUD= DDDs*100/(The number of patients who were treated the same period*Average days in hospital). DDDs = Total drug consumption (g)/DDD. DDD is the Defined Daily Dose] decreased by 57·8(58·8%); average antibiotic cost decreased by 246·94 dollars; the cost of antibiotics as a percentage of total drug cost decreased by 27·7%; the rate of use of antibiotics decreased from 100% to 7·3%. What is new and conclusion The study illustrates how an antibiotic stewardship programme with pharmacist participation including real-time interventions can promote improved antibiotic-prescribing and significantly decrease costs.

Kawasaki disease: a comprehensive review of treatment options.

Abstract: Summary What is known and objective Kawasaki disease (KD) is an acute self-limiting systemic vasculitis with specific predilection for the coronary arteries that affects previously healthy young infants and children. It is the leading cause of childhood-acquired heart disease in the developed world. Although the stimulus for the cascade of inflammation in KD is unknown, prompt treatment within 10 days of symptom onset has been shown to improve clinical outcomes and reduce the risk of coronary artery complications. Standard initial therapy is intravenous immunoglobulin (IVIG) and aspirin. Non-responders to initial therapy remain a challenge. This present review summarizes the treatment options for initial and refractory KD, including the role of steroids and other immunosuppressive therapies. Methods Literature search using PubMed database to identify pharmacologic studies in KD using the terms Kawasaki disease, intravenous immunoglobulin, refractory, corticosteroids, infliximab, cyclosporine, methotrexate, high risk from January 1988–May 2015 was performed. Bibliographies of selected references were also evaluated for relevant articles. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated. Results and discussion Initial IVIG therapy results in rapid resolution of clinical symptoms in 80–90% of patients and has been shown to reduce the risk of coronary disease. Although concomitant aspirin remains the standard of care for the initial management of KD, the evidence to support its efficacy in improving coronary artery outcomes are lacking. Initial therapy with corticosteroids in addition to intravenous immunoglobulin and aspirin improves outcomes in patients in Japan. However, identifying patients at high risk who may benefit from additional corticosteroids in heterogeneous populations has been challenging. Therapeutic options for non-responders to initial therapy are also challenging given the paucity of data. Patients who fail to respond to the first dose of IVIG will most often receive a second dose. Patients who fail to respond to two doses of IVIG present a unique challenge as the appropriate treatment remains uncertain. Although their effectiveness remains unproven, treatment with infliximab, cyclosporine or methotrexate may be considered in those patients who fail multiple doses of IVIG and steroids. What is New and Conclusion The role of steroids in high-risk non-Japanese patients is unclear, with the biggest challenge being early identification of patients at high risk of developing adverse coronary artery outcomes. Limited data evaluating other immunosuppressive agents are available and should be reserved for patients failing two doses of IVIG. Although recent advances in research have broadened our understanding of the epidemiology, genetic susceptibility and pathogenesis of KD, the aetiology of KD remains unclear. Ongoing research will help determine more precise pathogenesis and may assist in developing a diagnostic test as well as identifying new targets for more precise treatment interventions.

Systematic review of topical amitriptyline for the treatment of neuropathic pain.

Abstract: Summary What is known and objective Neuropathic pain is a common disorder for which patients seek treatment. The most common causes of neuropathic pain are diabetes, herpetic infection and chemotherapy-induced neuropathy. Oral administration of amitriptyline has traditionally been used for treating neuropathic pain; however, it has dose-related anticholinergic effects, which may limit its use in some individuals. Pharmacotherapeutic agents that are commonly used to treat neuropathic pain include antidepressants, anticonvulsants, opioids and opioid-like substances, and topical medications. The objective of this paper is to review the effectiveness of topical amitriptyline in patients with neuropathic pain. Methods We utilized the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to provide a systematic and transparent reporting method. The literature search was performed using PubMed (1966 through October 2014) applying the MeSH ‘amitriptyline’ and ‘drug administration, topical’ and ‘neuropathy’. Web of Science (1945 through October 2014) was searched using the text words ‘amitriptyline’ and ‘neuropathy’. Bibliographies of retrieved articles were scanned for relevant articles. Cochrane databases were also searched for methods to treat neuropathic pain. Broad subject headings, including ‘neuropathic pain’, were used to search the database for review articles. All data sources in English and in humans were considered for inclusion. Results and discussion Topical application of amitriptyline has the theoretical advantage of local effects with fewer systemic side effects. The clinical trials and case reports describing the use of topical amitriptyline we reviewed show mixed results concerning the efficacy and the presence of adverse reactions. Controlled clinical trials reveal that topical amitriptyline is not effective in treating neuropathic pain. The uncontrolled clinical trials did support efficacy of topical amitriptyline; however, the data from these trials may be biased due to the nature of the study design. Finally, there have been several case reports that claim patients achieved pain relief with the use of topical amitriptyline. Data from these cases are limited due to the fact that there were no controls to which the amitriptyline treatments could be compared, and the majority of the patients in these cases were on other analgesics. What is new and conclusion Although there are reports that describe the benefits of topical amitriptyline for neuropathic pain, data from evidence-based controlled clinical trials do not support efficacy in patients who use topical amitriptyline for neuropathic pain control.

The pharmacokinetic/pharmacodynamic rationale for administering vancomycin via continuous infusion.

Abstract: Summary What is known and objective Vancomycin is administered via intermittent infusion (II) almost exclusively in the United States, whereas continuous infusion (CI) dosing methods are used regularly in many European countries. The purpose of this literature analysis is to review current evidence regarding the advantages and disadvantages of CI vancomycin in relation to II, based on the pharmacokinetic and pharmacodynamic aspects of dosing and monitoring therapy, and to identify current practices of CI vancomycin dosing. Methods Medline, Cochrane and GoogleScholar databases were searched using vancomycin as a MeSH term, along with continuous and infusion in all fields, which identified 136 citations. A second search added the terms intermittent and survey, producing nine additional articles. All articles that reported an assessment of CI or II vancomycin administration in adult patients, based on clinical, pharmacokinetic, cost or monitoring considerations, were identified. A total of 43 publications were determined to be suitable for final analysis and possible inclusion in the report. Results and discussion A meta-analysis of six studies concluded that CI vancomycin was associated with a lower relative risk of kidney injury than II therapy, although other studies reported equivocal findings. The results of several clinical studies suggest that CI vancomycin produces clinical outcomes that are comparable to II. Current vancomycin consensus guidelines promote aggressive dosing to achieve trough levels of 10–15 or 15–20 mg/L, but also include recommendations to target a daily area under the curve (AUC24) to minimum inhibitory concentration (MIC) ratio of at least 400. Because vancomycin is a non-concentration-dependent antibiotic, it might be more prudent to monitor steady-state serum concentrations (Css) during a CI rather than trough concentrations during II, due to the questionable correlation between measured trough concentration and AUC. From a pharmacokinetic/pharmacodynamic perspective, vancomycin dosing and monitoring practices associated with CI offer potentially greater reliability than II. A major disadvantage of CI involves the possibility of having to intravenously co-administer another drug that might not be compatible with vancomycin. What is new and conclusion Continuous infusion vancomycin therapy offers the advantage of Css monitoring, thus avoiding the variabilities associated with the timing of trough levels. Current CI practices include a loading dose of 15–20 mg/kg followed by an infusion of 10–40 mg/kg/day based on the patient's renal function, with a target Css of about 20–30 mg/L. An alternative approach to weight-based (mg/kg) CI dosing is to calculate the dose from an estimation of the patient's vancomycin clearance (in L/h), derived from creatinine clearance (CrCl) via the equation (CrCl∙0·041) + 0·22. The daily dose is then determined by multiplying vancomycin clearance (in L/h) by the desired AUC24. A new CI vancomycin dosing chart includes clearance-based dosing recommendations for Css values ranging from 17·5 to 27·5 mg/L or AUC24 values ranging from 420 to 660 mg h/L. Although sufficient data already exist to support the use of CI vancomycin as a reasonable therapeutic alternative to II, there is still much to learn about administering the drug in this fashion.

Using pictograms to assist caregivers in liquid medication administration: a systematic review.

Abstract: Summary What is known and objective It has been reported that more than 80% of out-of-hospital medication errors among the young children involve liquid formulations. The usefulness of pictorial aids to improve communication of medication instructions has not been extensively investigated for child health. The objective of this study was to determine the effectiveness of pictorial aids used to assist caregivers in the administration of liquid medications. Methods MEDLINE, CINAHL, PsycINFO, ScienceDirect, Scopus and the Cochrane Library were searched for articles published up to February 2015. Studies that used pictorial aids with liquid medications and measured at least one of the following outcomes were included: dosing accuracy, comprehension of medication instructions, recall of information and adherence of caregivers. Two authors independently selected studies, extracted data and assessed methodological quality of studies using the Cochrane Collaboration's tool. Results and discussion Five experimental studies (four hospital based and one community based) with a total of 962 participants were included. A wide range of liquid formulations were studied, including both prescription and over-the-counter medications. The existing findings suggest that pictographic interventions reduced dosing errors, enhanced comprehension and recall of medication instructions and improved adherence of caregivers. Incorporating pictorial aids into verbal medication counselling or text-based instructions was more beneficial than using the single approach alone. Mixed results were identified for the relationship between health literacy of caregivers and effectiveness of pictorial aids. What is new and conclusion The evidence remains limited due to the small number of studies found and variations in methodological quality. This review suggests that pictorial aids might be potential interventions, but more high-quality studies are needed to support the routine use of any pictogram-based materials with liquid medications in the clinical settings.

Adherence to controller asthma medications: 6-month prevalence across a US community pharmacy chain.

Abstract: Summary What is known and objective Non-adherence to controller asthma medications is an important public health problem It is estimated to occur in 30–70% of individuals and is a significant risk factor for asthma morbidity and mortality The aim of this study was to determine the level of adherence, as indicated by refill rates, to controller asthma medications in a community pharmacy setting Methods Secondary analyses of a community pharmacy dispensing database in 15 locations throughout Utah Results and discussion The dispensing records of 2193 patients who received controller medications for asthma in a 12-month period, and had a minimum of 6-month potential coverage (180 days) from the date of their first receipt of a controller medication in that period, were examined Using standard metrics to gauge adherence, the proportion of days covered (PDC) and the medication possession ratio (MPR), the average coverage for controller asthma medications across a 6-month period (180 days) was poor, averaging less than 50% of days’ availability Standard cut-offs (≥80% medication availability) indicated that only 14–16% of patients had ‘satisfactory’ adherence over their 6-month follow-on period Females and older patients had significantly greater satisfactory adherence Medication adherence was significantly greater with inhaled corticosteroid (ICS)–long-acting β2-agonist (LABA) combinations than with ICS alone What is new and conclusion This study confirms the considerable scope of the asthma therapy non-adherence problem Therefore, it is imperative to conduct survey-based research linked directly to pharmacy-based dispensing data to derive patient behavioural, attitudinal and environmental factors that may contribute to the issue, and then pilot and evaluate interventions for change

Evaluation of the appropriateness of dosing, indication and safety of rivaroxaban in a community hospital.

Abstract: Summary What is known and objective For over 50 years, warfarin was the only oral anticoagulant approved in the United States. In 2011, the Food and Drug Administration (FDA) approved rivaroxaban. Since its introduction, rivaroxaban has served as an alternative to warfarin to minimize drug interactions and avoid drug monitoring. The objective of this study was to evaluate the appropriateness of rivaroxaban dosing, indication and safety in a community hospital and to identify areas for improvement in its use. Methods This single-centre, retrospective review evaluated patients who received at least one dose of rivaroxaban between November 2011 and July 2013. The primary outcome included appropriateness of the first day of therapy based on indication and renal function per FDA-approved dosing recommendations for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) and for the treatment or prevention of venous thromboembolism (VTE). The secondary outcome included incidence of major bleeding or non-major clinically relevant bleeding. Results and discussion Of the 445 patients evaluated, 36·9% of patients treated for NVAF and 12·4% treated for VTE were on an inappropriate regimen. Major bleeding within 12 months occurred in 3·5% of patients treated for NVAF, 1·2% for VTE and 0% for off-label indications with a similar trend for non-major clinically relevant bleeding (3·8%, 1·8% and 0%, respectively). What is new and conclusion Though offering potential advantages over warfarin, the use of rivaroxaban should be monitored to increase appropriateness of therapy and improve patient safety. Therapeutic interchanges, pharmacist-directed interventions and other initiatives can be implemented to ensure appropriate use.

EPICC study: evaluation of pharmaceutical intervention in cancer care

Abstract: Summary What is known and objectives In cancer care, clinical pharmacists contribute to improving prevention and management of drug-related problems (DRPs). The 3-year EPICC study (Evaluation of Pharmaceutical Intervention in Cancer Care) aimed to collect and analyse pharmaceutical interventions (PIs) in oncology. Methods The free online version of the French Society of Clinical Pharmacy (SFPC) coding system, ACT-IP, was used, supplemented by a standardized dedicated cancer-care decision tree. Results A total of 29 589 medication orders (77 004 anticancer drug preparations) were analysed. Eight hundred and ninety-four PIs were recorded. ACT-IP identified 54·1% of DRPs as concerning over- or underdosage. The standardized dedicated cancer-care decision tree identified the three principal causes of dosage problems: 50·2% due to miscalculation, 20% to omission of dose adjustment and 12% to poor choice of antineoplastic regimen. About 13·8% of DRPs were adverse effects and 3·9% were drug–drug interactions. The decision tree showed that 22% of adverse events could be circumvented by a switch within the same drug family and 72% of drug–drug interactions would have led to increased neoplastic toxicity. Discussion Pharmaceutical analysis of prescription forms contributes to medication safety in cancer care, and the present dedicated decision tree highlights additional information about DRPs and PIs. The DRP rate (3% of prescriptions) was consistent with the literature. The pharmacist has a role to play in optimizing the management of patients with cancer in terms of dose adjustment, drug toxicity management, improvement of administration and drug–drug interactions. What is new and conclusion This study, highlighting PIs in cancer care, is the first of this scale in terms of number of prescriptions analysed (nearly 30 000). Results demonstrated the specificity of DRPs and PIs for patients with cancer and the value of a dedicated coding system in cancer care.

The association between HLA-DQB1 polymorphism and antituberculosis drug-induced liver injury: a Case-Control Study.

Abstract: Summary What is known and objective Research on genetic factors associated with antitubercular drug-induced liver injuries (ATLI) has been reported. However, most of the research has focused on genetic polymorphisms of genes encoding metabolic enzymes, including NAT2, GST and CYP450. It is probable that the immune system also contributes to the onset of drug adverse effects. A few small studies have explored the possible association of HLA genes with drug-induced liver injuries (DILI), but more supportive evidence from larger studies or prospective cohort designs is needed. We aim to explore the possible association of HLA-DQB1 gene polymorphisms with ATLI in a case–control study. Methods A case–control study design was used. ATLI was recorded in a prospectively followed-up cohort of patients receiving antituberculosis treatment. Identified cases were matched with control tuberculosis patients within the same cohort but with no adverse effects in 1 : 1 ratio. We used the sequence-based typing method to determine the HLA-DQB1 genotypes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Results and discussion Eighty-nine cases were included in this case–control study. HLA-DQB1 typing was successful for 177 subjects. No association between frequency of HLA-DQB1 genotypes and ATLI was statistically significant in univariate analyses. Multivariate analysis using the conditional logistic regression model revealed that the individuals with two DQB1*05 alleles were at higher risk of ATLI than control subjects. The OR was 5·28 adjusted for use of liver protective drugs and weight (10/88 VS 2/88, 95% CI: 1·134-24·615, P = 0·034). Analysis according to the liver injury type showed that both mixed liver injury patients and cholestatic/mixed liver injury patients had higher proportions of DQB1*05 : 02 alleles (P values were 0·028 and 0·005, respectively). What is new and conclusion This study suggests that ATLI was more likely in subjects of HLA-DQB1*05/*05 genotype. Further studies are needed to verify this association.

Delta opioid agonists: a concise update on potential therapeutic applications

Abstract: Summary What is known and objective The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators – thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes (PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor (DOR). We present a concise update on the status of progress and opportunities of this approach. Methods A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from www.clinicaltrials.com. Results and discussion DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others.

The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: a retrospective analysis

Abstract: SummaryWhat is known and objective Linezolid (LZD) is an oxazolidinone antibiotic that is active against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The major adverse effect related to its use in humans is reversible myelosuppression, which mostly manifests as thrombocytopenia. This retrospective study was conducted to identify risk factors that might contribute towards the development of thrombocytopenia due to intravenous administration of LZD. Method Patients who were administered LZD between January 2008 and March 2013 were included. Thrombocytopenia was defined as a decrease in platelet count of ≥10 × 104 cell/μL from baseline or of ≥30%. Results A total of 47 patients were included in this study. These patients were divided into two groups: 22 patients (46·8%) were assigned to a non-thrombocytopenia group and 25 patients (53·2%) to a thrombocytopenia group. Multivariate logistic regression analysis revealed significant intergroup differences in duration of LZD treatment [odds ratio (OR) = 1·278; 95% confidence interval (CI) = 1·068–1·529; P = 0·007] and white blood cell (WBC) count (>12000 cells/μL; OR = 10·399; 95% CI = 1·667–64·882; P = 0·012). What is new and conclusions This finding suggests that duration of LZD treatment and WBC count (>12000 cells/μL) are risk factors associated with thrombocytopenia resulting from LZD administration.

Comparison of two databases to detect potential drug–drug interactions between prescriptions of HIV/AIDS patients in critical care

Abstract: Summary What is known and objective Adverse drug events (ADE), common and underestimated in ICU patients, have direct consequences on length of stay, mortality and hospital costs. Critically ill patients with HIV/AIDS are at a high risk of ADE because of their need for multiple drug therapies. ADE can be prevented, especially by the identification of potentially harmful drug–drug interactions (DDIs). Electronic databases are useful tools for the investigation of DDIs to avoid potential ADEs, thereby increasing patient safety. The purpose of this study was to compare the classification and severity rating of potential adverse drug interactions seen in the prescriptions for patients with HIV/AIDS in two databases, one with free access (Drugs.com™) and another requiring payment for access (Micromedex®). Methods A cross-sectional retrospective study of the prescriptions issued for 40 ICU HIV/AIDS patients on mechanical ventilation, admitted for more than 48 h, in a referral hospital for infectious diseases in Rio de Janeiro, Brazil, was undertaken. One prescription was reviewed each week for each patient from the second day after admission. A list of all drug–drug interactions was generated for each patient using the two drug–drug interactions databases. The weighted kappa index was estimated to assess the agreement between the classifications of DDIs identified by both databases and qualitative assessment made of any discordant classification of recorded drug–drug interactions. Results and discussion Of the 106 prescriptions analysed, Micromedex® and Drugs.com identified 347 and 615 potential DDIs, respectively. A predominance of moderate interactions and pharmacokinetic interactions was observed. The agreement between the databases regarding the severity rating was only 68·3%. The weighted kappa of 0·44 is considered moderate. Better agreement (82·4%) was observed in the classification of mechanism of interaction, with a weighted kappa of 0·61. What is new and Conclusion DDIs are common between the prescriptions of patients with HIV/AIDS admitted to the ICU. Although both databases were able to identify the clinically relevant DDIs, we observed a significant discrepancy in the classification of the severity of DDIs in the two bases. The free access database could serve as an alternative to the identification of DDIs in resource-limited settings; however, there is a need for better evidence-based assessments for your use on clinical management of more serious DDIs.

A comparison of propofol vs. dexmedetomidine for sedation, haemodynamic control and satisfaction, during esophagogastroduodenoscopy under conscious sedation.

Abstract: SummaryWhat is known and objective Esophagogastroduodenoscopy (EGD) is a common diagnostic procedure which requires sedation for most patients. We undertook a prospective, randomized, double-blinded study to compare the effect of propofol vs. dexmedetomidine on the sedation of outpatients during EGD. Methods Prior to the procedure, outpatients received either propofol at 0·6 mg/kg, with additional doses of 10–20 mg until the Observer's Assessment of Alertness/Sedation Scale (OAA/S) score reached 2–4, or dexmedetomidine at a loading dose of 1 μg/kg over a 10-min period followed by a 0·5 μg/kg/h infusion until the OAA/S score reached 2–4. Vital signs, sedation level, adverse events, patients' and endoscopist's satisfaction score, and an evaluation of the recovery time were assessed. Results and discussion Negligible haemoglobin oxygen saturation (SpO2) and respiratory rate variations were observed in both groups, although respiratory depression occurred in two cases (5·9%) in the propofol group. Mean arterial pressure (MAP) in the propofol group decreased during the procedure compared with baseline (P 0·05). Three cases (9·1%) in the dexmedetomidine group were delayed because of dizziness, bradycardia and nausea. There was a higher satisfaction score among patients in the propofol group (P 0·05). What is new and conclusion Propofol and dexmedetomidine provide a relatively satisfactory level of sedation without clinically notable adverse effects during EGD. In addition, patients preferred propofol administration for the deeper sedation and rapid recovery, and dexmedetomidine exhibited minimal adverse effects on respiratory function.

Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression.

Abstract: Summary What is known and objective The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. Comment Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose–response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. What is new and conclusion It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders.

Who gets dipyrone (metamizole) in Germany? Prescribing by age, sex and region.

Abstract: Summary What is known and objective Metamizole (dipyrone) is an analgesic that has been the focus of considerable controversy regarding its safety. Because of potentially life-threatening blood disorders such as agranulocytosis, it has been withdrawn in many countries but not in Germany, where prescribing even increased over recent years. We aimed to evaluate prescribing of metamizole in Germany with respect to age, sex and regional variations. Methods Using data of a statutory health insurance, we analysed a cohort of 1·7 million persons who were insured at least 1 day in each quarter of 2009. Outcome of interest was the outpatient prescription prevalence, for example the proportion of persons receiving at least one prescription of metamizole. Results and discussion A total of 6·8% received metamizole with a higher prescribing prevalence in females (7·8% vs. 6·0%). The prevalence increased with age up to 26·7% in persons ≥85 years (men: 21·1%; and women: 30·4%). We found large regional variations with higher prevalences in the northern part of Germany. Most of the prescriptions were issued by general practitioners (78·9%). 58·3% were liquid oral formulations with considerable regional variations ranging between 32·3% in Mecklenburg-West Pomerania and 67·3% in North Rhine-Westphalia. Overall, liquid oral forms are much more often prescribed in the western than in the eastern part of Germany. What is new and conclusion Metamizole – a drug with a relatively narrow indication – is often prescribed in Germany with relevant differences by age, sex and region. Qualitative studies should clarify reasons for this. Further quantitative research should investigate small-area variations, indications and treatment durations.

Evaluation of prescribing and patient use of target-specific oral anticoagulants in the outpatient setting.

Abstract: SummaryWhat is known and objective Pharmacist-managed anticoagulation programmes have been shown to improve appropriate use of warfarin, but few programmes have included the new target-specific oral anticoagulants (TSOACs) in their protocols. A greater understanding of TSOAC prescribing, monitoring and administration is needed to identify common errors in the current outpatient practice. The objective of this study is to assess the rate of errors related to prescribing, baseline monitoring and patient administration of TSOACs. Methods A retrospective chart review was conducted to identify patients on TSOAC therapy in each of four outpatient practice sites. Data were abstracted to include TSOAC indication, dosage and frequency prescribed, pertinent past medical history, and laboratory monitoring obtained at the time of TSOAC initiation. In addition, patients were contacted by telephone to assess TSOAC adherence, storage, administration and incidence of adverse events. Results and discussion A total of 395 patients were included in the evaluation. Prescribers did not obtain baseline laboratory values within 1 week before or after the time of TSOAC initiation for a majority of study patients. At the time of TSOAC initiation, two patients had abnormally elevated alanine aminotransferase, six had elevated total bilirubin, and 43 had low haemoglobin. A majority (61%) of study patients were prescribed an appropriate TSOAC dose based upon their indication and renal function; however, dosing accuracy could not be determined for all patients as baseline serum creatinine was not obtained by prescribers for 148 patients (37%) at the time of prescribing. TSOACs were dosed inappropriately according to baseline serum creatinine in six patients, and two patients receiving treatment for venous thromboembolism were maintained on a high dose of rivaroxaban for an inappropriate duration. A total of 157 (40%) patients were available by phone and agreed to answer questions regarding their current TSOAC use. Twenty-four patients (23%) reported taking rivaroxaban inappropriately without food, and six patients (14%) endorsed inappropriate storage of dabigatran. Ten patients (6%) reported missing at least one TSOAC dose per week, and 25 (16%) described minor bleeding with their TSOAC. What is new and conclusion Inappropriate prescribing, monitoring and administration of TSOACs occurred frequently in patients not formally enrolled in an anticoagulation monitoring programme. These results indicate a need for more thorough patient education at the time of TSOAC initiation, as well as improved prescriber education regarding recommended TSOAC dosing and monitoring.

Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS).

Abstract: SummaryWhat is known and objective Febuxostat is recommended as an alternative drug for gouty patients with a history of allopurinol hypersensitivity or carrying the HLA-B*5801 allele. Case summary An 81-year-old man with the medical history of gout presented to our clinic with generalized rashes for 2 days. After taking febuxostat for 2 days, he developed generalized skin rash with high fever. Laboratory tests showed elevated liver enzymes and acute kidney injury. What is Known and Objective This is the first identified case of febuxostat-associated DRESS. Febuxostat should be withdrawn immediately when DRESS is observed to avoid further serious complications.

The recommended dose of ertapenem poses a potential risk for central nervous system toxicity in haemodialysis patients - case reports and literature reviews.

Abstract: What is known and objective Dosage adjustment of 500 mg ertapenem daily is recommended for patients with advanced kidney disease. 30% of ertapenem is cleared by a session of haemodialysis (HD). However, because most published carbapenems studies have excluded patients on dialysis, little is known about the dosing of ertapenem to avoid central nervous system (CNS) toxicity in regular HD patients. We report of four patients who developed CNS toxicity in such patients. Case summary The 4 HD patients developed unexplained CNS toxicity manifested as seizures, hallucination and cognitive dysfunction after receiving 3-7 consecutive recommended doses of ertapenem. Their symptoms of CNS toxicity were completely resolved within 8 days after discontinuation of ertapenem. In one of our presented cases, we demonstrated the very high level of plasma ertapenem accumulating with several consecutive doses. Cognitive function gradually recovered in line with a corresponding decline in blood level of ertapenem. What is new and conclusions This is the first report of ertapenem-associated CNS toxicity in patients on regular HD and utilizing the plasma ertapenem concentration to demonstrate the causal relationship. The recommended dosage of 500 mg ertapenem daily may be still too high in regular HD patients, especially in Asians, owing to their relatively small body size. An increased awareness of ertapenem-associated CNS toxicity would avoid unnecessary examinations, hospitalization, and potentially catastrophic complications.

Celecoxib for the treatment of mild-to-moderate depression due to acute brucellosis: a double-blind, placebo-controlled, randomized trial.

Abstract: What is known and objectiveDepression is a debilitating complication of brucellosis and how best to treat this is a matter of debate. Inflammatory processes are involved in the pathogenesis of both brucellosis and depression. Therefore, we hypothesized that celecoxib could be beneficial for the treatment of depression due to brucellosis. MethodsForty outpatients with depression due to brucellosis with a Hamilton Depression Rating Scale score (HDRS) <19 participated in a randomized, double-blind, placebo-controlled trial and underwent 8weeks of treatment with either celecoxib (200mg bid) or placebo as an adjunctive to antibiotic therapy. Patients were evaluated using HDRS at baseline and weeks 4 and 8. Result and discussionRepeated-measures analysis demonstrated significant effect for time x treatment interaction on the HDRS score F (143, 5741)=3722, P<0001. Significantly greater response to treatment occurred in the celecoxib group than in the placebo group at the study end 10 patients (50%) vs. no patient (0%), respectively, P<0001. No serious adverse event was observed. What is new and conclusionCelecoxib is a safe and effective treatment for depression due to brucellosis when compared with placebo.

Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients

Abstract: Summary What is known and objective Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI. Methods In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment. Results and discussion The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8·89; 95% CI 1·36–57·93, P < 0·05), compared with those of wild-type CC genotype. What is new and conclusion The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene.

A systematic review of the efficacy and tolerability of hydroxyethylrutosides for improvement of the signs and symptoms of chronic venous insufficiency.

Abstract: Summary What is known and objective Rutoside (rutin; quercetin rutinoside) is a glycoside found in various plant products, including apples, citrus fruits and cranberries. Hydroxyethylrutosides (HR) are semisynthetic derivatives sold as standardized products for the treatment of chronic venous insufficiency (CVI). Commercially available products include Relvene® (France), Venoruton® (Switzerland) and Paroven® (United Kingdom). However, the evidence for their efficacy is inconclusive. The aim of this systematic review was to evaluate the evidence of efficacy and tolerability of hydroxyethylrutosides for CVI. Methods We searched electronic databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL, and publisher databases, conference proceedings and references lists for randomized controlled trials published in English and non-English languages. We also performed hand searches for additional trials. We included all trials that assessed the effectiveness of HR for CVI. Comparisons include HR (with or without compression bandaging) vs. placebo (with or without compression bandaging) or HR vs. compression bandaging alone. Two review authors independently selected studies, extracted data and assessed risks of bias in the included trials. Results and discussion The search identified 1474 records. Only 15 trials involving 1643 participants met our inclusion criteria. A meta-analysis based on similar studies that compared HR with placebo showed that HR significantly reduced symptoms of pain (SMD −1·07, 95% CI −1·44 to −0·70), symptoms of heavy legs (OR 0·50; 95% CI 0·28–0·91) and cramps (SMD −1·07, 95% CI −1·45 to −0·69). No serious adverse effect due to HR was reported. What is new and conclusion The findings showed that HR produced modest improvements in several symptoms of CVI. However, all the included trials were of limited quality, and therefore, better-quality trials are still required to draw firm conclusions on the usefulness of HR for CVI.

Conceptualizing and measuring potentially inappropriate drug therapy

Abstract: Summary What is known and objective Elderly people are the principal consumers of prescription drugs. The more the medication used by the patient, the greater the likelihood there is of the patient being subjected to potentially inappropriate drug therapy (PIDT). PIDT has been measured in the literature with both implicit and explicit tools. The purpose of this review was to assess the use of tools to detect PIDT in various studies and to determine which terms are used to refer to PIDT in practice. Methods A systematic review was conducted according to the following steps: the first was identification. In this step, studies were selected from different combinations of the descriptors ‘aged’, ‘elderly’, ‘inappropriate prescribing’ and ‘drug utilization’ in three different languages, using the Embase, Medline, Scielo, Scopus and Web of Science databases. Second, the papers that satisfied the inclusion criteria for data extraction were carefully examined by three evaluators to determine the tools used and terms that referred to PIDT. Results and discussion From the combinations of keywords, 8610 articles were found. At the end of the selection process, 119 of the articles complied with the specified criteria. The degree of agreement among evaluators was moderate for the study titles (κ1 = 0·479) and substantial for abstracts (κ2 = 0·647). With respect to the PIDT evaluation criteria used by the studies, 27·7% used two criteria. Of the 27 evaluation criteria identified, the Beers criteria were used by 82·3% of the studies. More than 50 different terms to identify PIDT were found in the literature. What is new and conclusion This review is the first study to conceptualize and discuss terms that refer to PIDT. At present, there is no consensus regarding terms used to refer to PIDT, with over 50 different terms currently in use. This review shows an increase in the number of articles aimed at evaluating PIDT using implicit and explicit tools.

A model-based meta-analysis of the influence of factors that impact adherence to medications.

Abstract: Summary What is known and objective Several studies have investigated factors that may influence adherence for a given disease. The influence of disease on adherence has received limited attention. Less work has been conducted to investigate the influence of other factors in conjunction with disease on adherence. The aim of this study was to determine the independent influence of disease and other factors on adherence. Methods A literature search was conducted to retrieve adherence studies using medication event monitoring system devices. Studies were categorized into different therapeutic areas. Only the two most commonly studied therapeutic areas were selected. Pseudopatient-level data were extracted from each study. The extracted data were analysed using a model-based meta-analysis technique. Univariate and multivariate models were developed. Model selection was based on a likelihood ratio test and visual plots. Results The most commonly studied therapeutic areas were HIV and hypertension. The most commonly recorded adherence criterion was percentage of prescribed doses taken per day. Based on this adherence criterion, ultimately, 24 HIV papers and 12 hypertension papers were included for data extraction. The statistically significant factors were disease, age and dosing regimen. The independent influences of each factor on adherence were as follows: an increase in adherence of approximately 8% per 10-year increase of age, a 15–19% reduction from once to thrice daily dosing and that patients with HIV were 5% more adherent than those with hypertension. What is new and conclusion Although the influence of disease on adherence was significant, it was of limited clinical significance in the diseases studied here. Adherence appears to improve with age and decline with more frequent dosing. Additionally, the influence of dosing regimen wanes with increasing age. These results should be treated as exploratory and require prospective assessment.

Drug-drug interaction between isavuconazole and tacrolimus: a case report indicating the need for tacrolimus drug-level monitoring.

Abstract: SummaryWhat is known and objective Despite the known significant drug–drug interaction between isavuconazole and tacrolimus, there are no recommendations on dose adjustment when these drugs are given concomitantly. We report on a patient with a mediastinal Aspergillus fumigatus infection resistant to posaconazole and describe how she was successfully managed with tacrolimus therapeutic drug-level monitoring. Case summary Our patient presented with a mediastial Aspergillus fumigatus infection, 2 years after lung transplantation. A. fumigatus was resistant to posaconazole, and the patient had intolerance to voriconazole shown by elevated transaminases. The patient was given isavuconazole with drug-level monitoring. She was managed successfully with no adverse events. Tacrolimus concentration continued to increase after more than 2 weeks of therapy and required a further reduction to 72% of the usual dose to maintain the target concentrations over a 8-week period. What is new and conclusion When isavuconazole is given to patients on tacrolimus, the dose of the latter will need considerable reduction. We would suggest an initial 50% reduction and recommend close weekly monitoring of tacrolimus concentration. Further dose decreases of 25–50% may be required.

Impact of common ABCB1 polymorphism on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites.

Abstract: SUMMARY What is known and objective: The reasons of clopidogrel (CLP) resistance are still unclear The response to CLP may be influenced by both genetic and non-genetic factors Among genetic factors, common polymorphisms in the gene coding glycoprotein-P (P-gp, MDR1 and ABCB1) are considered as potential determinants of the efficacy of CLP treatment The aim of this study was to evaluate the influence of ABCB1 3435C>T genetic polymorphism on the pharmacokinetics and pharmacodynamics of CLP and its metabolites: diastereoisomers of thiol metabolite (the inactive H3 and the active H4) and inactive carboxylic derivative Methods: The study group included 42 patients undergoing elective coronary angiography and percutaneous coronary intervention The plasma concentrations of CLP and its metabolites were measured by a validated HPLC-MS/MS method Wholeblood aggregation was determined with Multiplate analyzer For evaluation of ABCB1 3435C>T polymorphism, PCR-RFLP method was applied Results and discussion: It was found that Exposition to the unchanged CLP, measured by AUC0–t of the drug, was significantly lower (P = 0� 012) in TT homozygotes comparing to that observed in CC and CT genotypes, although no correlation was found between platelet aggregation and ABCB1 genetic polymorphism What is new and conclusion: Our findings show that the presence of 3435C>T allele has an impact on CLP pharmacokinetics but not on the drug pharmacodynamics Therefore, the 3435C>T genotype may not be the primary determinant influencing the pharmacokinetics of the active H4 metabolite and antiplatelet effect of the drug

A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia

Abstract: Summary What is known and objective Fibromyalgia is a painful disease affecting 1–2% of the United States population. Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and milnacipran, are well studied and frequently used for treating this disorder. However, efficacy data are limited for the SNRI venlafaxine despite its use in nearly a quarter of patients with fibromyalgia. Accordingly, we systematically reviewed the efficacy of venlafaxine for treatment of fibromyalgia. Methods PubMed, Web of Science and the Cochrane Database were searched using the terms ‘venlafaxine’ and ‘fibromyalgia’. Results were classified as primary studies or review articles based on abstract review. References of review articles were evaluated to ensure no primary studies evaluating venlafaxine were overlooked. All clinical studies that investigated venlafaxine for the treatment of fibromyalgia were included and graded on strength of evidence. Results and discussion Five studies met the inclusion criteria, including 4 open-label cohort studies and 1 randomized, controlled trial. Study durations ranged from 6 weeks to 6 months, and study sizes ranged from 11 to 102 participants. Four of the five published studies reported improvement in at least one outcome. Generally consistent improvements were observed in pain-related outcome measures, including the Fibromyalgia Impact Questionnaire (range, 26–29% reduction; n = 2 studies), Visual Analog Scale (range, 36–45% reduction; n = 2 studies), McGill Pain Questionnaire (48% reduction; n = 1 study) and Clinical Global Impression scale (51% had significant score change; n = 1 study). However, the few studies identified were limited by small sample size, inconsistent use of outcomes and methodological concerns. What is new and conclusion Studies assessing the efficacy of venlafaxine in the treatment of fibromyalgia to date have been limited by small sample size, inconsistent venlafaxine dosing, lack of placebo control and lack of blinding. In the context of these limitations, venlafaxine appears to be at least modestly effective in treating fibromyalgia. Larger randomized controlled trials are needed to further elucidate the full benefit of venlafaxine.