The Role of the Pharmacist in the Treatment of Patients with Infantile Hemangioma Using Propranolol.

Adv Ther. 2016 Oct;33(10):1831-1839

Authors: Castaneda S, Melendez-Lopez S, Garcia E, De la Cruz H, Sanchez-Palacio J

Abstract
INTRODUCTION: Infantile hemangiomas (IH) are the most common benign vascular tumors of childhood, with an incidence of 5-10% during the first year of age. Propranolol is considered the first-line treatment for this condition. Potentially there is a high probability of negative results to therapy, because in many countries there are no treatment protocols or propranolol formulations appropriate for the pediatric population. The objective of the present study was to evaluate the impact of pharmacist interventions such as detecting, analyzing, and solving problems presented during treatment with propranolol in patients with IH.
METHODS: An open observational prospective study was performed over 25 months in a group of pediatric patients diagnosed with infantile hemangioma treated with propranolol. Pharmacist participation consisted of development of an extemporaneous formulation and counseling the child's parents. At each visit to the pharmacy service, family members were interviewed, detecting and classifying problems related to treatment.
RESULTS: Sixty-three children with IH were treated during the period under review. Patient ages ranged from 3 to 11 months old; 64% were female and 36% were male. Forty-nine problems in 30 patients were detected, principally inadequate dose (18.4%), non-adherence to treatment (16.3%), side effects (14.3%), and wrong administration (14.3%). Of the problems detected, 81.6% were resolved. Interventions by the pharmacist in 27 patients were intensive counseling on adherence to therapy (20%), detection of adverse effects (11.4%), and adjustment of the dose (22.9%). In 95.2% of patients a good response to treatment was obtained compared with 77.2% reported in European studies without pharmacist intervention.
CONCLUSION: It seems that pharmacist participation increases adherence to treatment and reduces the likelihood of adverse effects, allowing for safe and effective therapy in patients with IH.

PMID: 27461120 [PubMed - indexed for MEDLINE]

Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study.

J Clin Oncol. 2017 Aug 24;:JCO2017733675

Authors: Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, Mehnert JM, Algazi A, van Brummelen EMJ, Saraf S, Thanigaimani P, Cheng JD, Hansen AR

Abstract
Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.

PMID: 28837405 [PubMed - as supplied by publisher]

Keratitis in association with herpes zoster and varicella vaccines.

Drugs Today (Barc). 2017 Jul;53(7):393-397

Authors: Grillo AP, Fraunfelder FW

Abstract
The objective of this review was to collect reports of keratitis in association with herpes zoster virus (HZV) or varicella zoster virus (VZV) vaccines. HZV vaccination is intended for at-risk adult populations and VZV vaccination is intended for all pediatric patients. We reviewed the literature and reports of keratitis in association with herpes zoster or varicella vaccine from the National Registry of Drug-Induced Ocular Side Effects and the World Health Organization. Twenty-four cases of unilateral keratitis in association with VZV vaccines were collected from the adverse reaction databases and literature. In most cases, the onset of keratitis occurred within days of vaccination and resolved with topical steroid eye drops and oral acyclovir. Data suggest that keratitis in association with herpes zoster or varicella vaccine is rare, is usually self-limited or resolves with treatment. The mechanism may be the persistence of viral antigens in the cornea after VZV vaccination or herpes zoster ophthalmicus. This reaction is probable, given the plausible biological mechanism, the temporal relationship between vaccination and keratitis, and overall patterns of presentation after vaccination.

PMID: 28837183 [PubMed - in process]

Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

Hypertension. 2017 Jul;70(1):183-191

Authors: Chiasson VL, Pakanati AR, Hernandez M, Young KJ, Bounds KR, Mitchell BM

Abstract
The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4(+)/FoxP3(+) regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.

PMID: 28584011 [PubMed - indexed for MEDLINE]

Medication Regimen Complexity in Long-Term Care Facilities and Adverse Drug Events-Related Hospitalizations.

Consult Pharm. 2017 May 01;32(5):281-284

Authors: Tam SHY, Hirsch JD, Watanabe JH

Abstract
Adverse drug events (ADE) are a leading cause of mortality in the United States. Recent studies have demonstrated a high level of complex medication regimens in institutionalized residents. Evidence of the relationship between medication regimen complexity (MRC) and ADE-related rehospitalizations or emergency department (ED) visits is evolving. Therefore, there is a demand for better characterization and study of MRC as an objective identifier to quickly screen and prioritize high-risk patients for follow-up medication management therapy. This manuscript will serve as a brief summary review of the current findings regarding the relationship between MRC and hospital readmission and ED usage and provide strategies for pharmacists to more efficiently evaluate complex medication regimens and optimize therapies.

PMID: 28483008 [PubMed - indexed for MEDLINE]

Dangers of Nonprescription Medicines: Educating and Counseling Older Adults.

Consult Pharm. 2017 May 01;32(5):269-280

Authors: Kinsey JD, Nykamp D

Abstract
OBJECTIVE: To provide a review for health care providers regarding appropriate education and counseling for older adults involving commonly used nonprescription medicines with potential for adverse effects, drug-drug interactions, or toxicity when incorrectly selected or overused.
DATA SOURCES: A literature search was performed using MEDLINE and PUBMED to locate relevant articles. DAILYMED was used for manufacturer dosage recommendations. Additionally, peer-reviewed textbooks were consulted for evidence-based standards of care.
STUDY SELECTION/DATA EXTRACTION: Articles were reviewed and selected for inclusion based on relevance to the subject and accuracy of information provided. Articles chosen were published between March 2008 and December 2016. Additionally, several textbook chapters providing information for nonprescription medicines chosen for evaluation in this review were used.
DATA SYNTHESIS: Nonprescription medicines are accessible and widely used by older adults. Polypharmacy and drug duplication are concerns because of negative outcomes. Given the accessibility and knowledge of pharmacists, they are often asked questions regarding nonprescription medicines.
CONCLUSION: Pharmacists have a duty and responsibility to commit to lifelong learning and to provide appropriate education and counseling on the use of nonprescription medicines. This will help decrease overall health care costs and potential negative problems associated with polypharmacy among older adults that include adverse effects, toxicity, and drug-drug interactions.

PMID: 28483007 [PubMed - indexed for MEDLINE]

Neda Leonard: Filling a Void.

Consult Pharm. 2017 May 01;32(5):256-257

Authors:

PMID: 28483005 [PubMed - indexed for MEDLINE]

Don't Make Things Harder Than They Need to Be.

Consult Pharm. 2017 May 01;32(5):246

Authors: Davidson HE

PMID: 28483004 [PubMed - indexed for MEDLINE]

Impact of early in-hospital medication review by clinical pharmacists on health services utilization.

PLoS One. 2017;12(2):e0170495

Authors: Hohl CM, Partovi N, Ghement I, Wickham ME, McGrail K, Reddekopp LN, Sobolev B

Abstract
BACKGROUND: Adverse drug events are a leading cause of emergency department visits and unplanned admissions, and prolong hospital stays. Medication review interventions aim to identify adverse drug events and optimize medication use. Previous evaluations of in-hospital medication reviews have focused on interventions at discharge, with an unclear effect on health outcomes. We assessed the effect of early in-hospital pharmacist-led medication review on the health outcomes of high-risk patients.
METHODS: We used a quasi-randomized design to evaluate a quality improvement project in three hospitals in British Columbia, Canada. We incorporated a clinical decision rule into emergency department triage pathways, allowing nurses to identify patients at high-risk for adverse drug events. After randomly selecting the first eligible patient for participation, clinical pharmacists systematically allocated subsequent high-risk patients to medication review or usual care. Medication review included obtaining a best possible medication history and reviewing the patient's medications for appropriateness and adverse drug events. The primary outcome was the number of days spent in-hospital over 30 days, and was ascertained using administrative data. We used median and inverse propensity score weighted logistic regression modeling to determine the effect of pharmacist-led medication review on downstream health services use.
RESULTS: Of 10,807 high-risk patients, 6,416 received early pharmacist-led medication review and 4,391 usual care. Their baseline characteristics were balanced. The median number of hospital days was reduced by 0.48 days (95% confidence intervals [CI] = 0.00 to 0.96; p = 0.058) in the medication review group compared to usual care, representing an 8% reduction in the median length of stay. Among patients under 80 years of age, the median number of hospital days was reduced by 0.60 days (95% CI = 0.06 to 1.17; p = 0.03), representing 11% reduction in the median length of stay. There was no significant effect on emergency department revisits, admissions, readmissions, or mortality.
LIMITATIONS: We were limited by our inability to conduct a randomized controlled trial, but used quasi-random patient allocation methods and propensity score modeling to ensure balance between treatment groups, and administrative data to ensure blinded outcomes ascertainment. We were unable to account for alternate level of care days, and therefore, may have underestimated the treatment effect in frail elderly patients who are likely to remain in hospital while awaiting long-term care.
CONCLUSIONS: Early pharmacist-led medication review was associated with reduced hospital-bed utilization compared to usual care among high-risk patients under 80 years of age, but not among those who were older. The results of our evaluation suggest that medication review by pharmacists in the emergency department may impact the length of hospital stay in select patient populations.

PMID: 28192477 [PubMed - indexed for MEDLINE]

Worldwide withdrawal of medicinal products because of adverse drug reactions: a systematic review and analysis.

Crit Rev Toxicol. 2016 Jul;46(6):477-89

Authors: Onakpoya IJ, Heneghan CJ, Aronson JK

Abstract
We have systematically identified medicinal products withdrawn worldwide because of adverse drug reactions, assessed the level of evidence used for making the withdrawal decisions, and explored the patterns of withdrawals over time. We searched PubMed, the WHO database of withdrawn products, and selected texts. We included products that were withdrawn after launch from 1950 onwards, excluding non-human and over-the-counter medicines. We assessed the levels of evidence on which withdrawals were based using the Oxford Center for Evidence Based Medicine Levels of Evidence. Of 353 medicinal products withdrawn from any country, only 40 were withdrawn worldwide. Anecdotal reports were cited as evidence for withdrawal in 30 (75%) and deaths occurred in 27 (68%). Hepatic, cardiac, and nervous system toxicity accounted for over 60% of withdrawals. In 28 cases, the first withdrawal was initiated by the manufacturer. The median interval between the first report of an adverse drug reaction that led to withdrawal and the first withdrawal was 1 year (range 0-43 years). Worldwide withdrawals occurred within 1 year after the first withdrawal in any country. In conclusion, the time it takes for drugs to be withdrawn worldwide after reports of adverse drug reactions has shortened over time. However, there are inconsistencies in current withdrawal procedures when adverse drug reactions are suspected. A uniform method for establishing worldwide withdrawal of approved medicinal products when adverse drug reactions are suspected should be developed, to facilitate global withdrawals. Rapid synthesis of the evidence on harms should be a priority when serious adverse reactions are suspected.

PMID: 26941185 [PubMed - indexed for MEDLINE]

Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

J Clin Oncol. 2017 Aug 23;:JCO2017723064

Authors: Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, Gomella LG, Kamat AM, Lotan Y, Svatek RS, Bivalacqua TJ, Grubb RL, Krupski TL, Lerner SP, Woods ME, Inman BA, Milowsky MI, Boyd A, Treasure FP, Gregory G, Sawutz DG, Yla-Herttuala S, Parker NR, Dinney CPN

Abstract
Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10(11) vp/mL, n = 21; 3 × 10(11) vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd--IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

PMID: 28834453 [PubMed - as supplied by publisher]

Outcome of cancer-related seizures in patients treated with lacosamide.

Acta Neurol Scand. 2017 Aug 22;:

Authors: Toledo M, Molins A, Quintana M, Santamarina E, Martinez-Ricarte F, Martínez-Saez E, Salas-Puig J

Abstract
OBJECTIVES: Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients.
MATERIALS AND METHODS: Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy.
RESULTS: Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events.
CONCLUSION: Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio-/chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus.

PMID: 28832891 [PubMed - as supplied by publisher]

The Marginal Costs of Adverse Drug Events Associated With Exposures to Anticoagulants and Hypoglycemic Agents During Hospitalization.

Med Care. 2017 Sep;55(9):856-863

Authors: Spector WD, Limcangco R, Furukawa MF, Encinosa WE

Abstract
BACKGROUND: Anticoagulants and hypoglycemic agents are 2 of the most challenging drug classes for medical management in the hospital resulting in many adverse drug events (ADEs).
OBJECTIVE: Estimating the marginal cost (MC) of ADEs associated with anticoagulants and hypoglycemic agents for adults in 5 patient groups during their hospital stay and the total annual ADE costs for all patients exposed to these drugs during their stay.
RESEARCH DESIGN AND SUBJECT: Data are from 2010 to 2013 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases and Medicare Patient Safety Monitoring System (MPSMS). Deidentified patients were linked using probabilistic matching in the same hospital and year for 5 patient groups. ADE information was obtained from the MPSMS using retrospective structured record review. Costs were derived using HCUP cost-to-charge ratios. MC estimates were made using Extended Estimating Equations controlling for patient characteristics, comorbidities, hospital procedures, and hospital characteristics. MC estimates were applied to the 2013 HCUP National Inpatient Sample to estimate annual ADE costs.
RESULTS: Adjusted MC estimates were smaller than unadjusted measures with most groups showing estimates that were at least 50% less. Adjusted anticoagulant ADE costs added >45% and Hypoglycemic ADE costs added >20% to inpatient costs. The 2013 hospital cost estimates for ADEs associated with anticoagulants and hypoglycemic agents were >$2.5 billion for each drug class.
CONCLUSIONS: This study demonstrates the importance of accounting for confounders in the estimation of ADEs, and the importance of separate estimates of ADE costs by drug class.

PMID: 28742544 [PubMed - indexed for MEDLINE]

An assessor-blinded, randomized comparison of efficacy and tolerability of switching from olanzapine to ziprasidone and the combination of both in schizophrenia spectrum disorders.

J Psychiatr Res. 2017 Feb;85:59-65

Authors: Wang HH, Cai M, Wang HN, Chen YC, Zhang RG, Wang Y, McAlonan GM, Bai YH, Wu WJ, Guo L, Zhang YH, Tan QR, Zhang ZJ

Abstract
BACKGROUND: Ziprasidone (ZIP) is often used with olanzapine (OLZ) in 'switch' and combination therapy but empirical evidence to support these strategies is limited.
OBJECTIVE: This study was therefore designed to compare the efficacy and tolerability of switching from OLZ to ZIP, the combination of both medications, and OLZ and ZIP monotherapy, in patients with schizophrenia spectrum disorders (SSD).
METHODS: In this 12 week open-label, assessor-blinded randomized trial, 148 patients with SSD who had not used antipsychotics for at least 3 months were assigned to ZIP (n = 49) or OLZ monotherapy (n = 31); OLZ for 4 weeks then a switch to ZIP (OLZ/ZIP, n = 35); or combination therapy (OLZ + ZIP, n = 33). The severity of psychosis and abnormal involuntary movements was evaluated at baseline, 1, 2, 4, 8, and 12 weeks using standard instruments. Baseline-to-endpoint changes in weight gain and metabolic measures were compared.
RESULTS: The efficacy of both OLZ/ZIP and OLZ + ZIP was comparable OLZ monotherapy and better than ZIP monotherapy in reducing overall psychotic and negative symptoms at most 8 and 12 week measurement points. Changes in weight gain, glucose, and lipid measures did not differ between OLZ/ZIP and OLZ + ZIP, but were markedly higher following OLZ monotherapy. The OLZ + ZIP group had the lowest overall incidence of adverse events and extrapyramidal symptoms of all the treatment regimens.
CONCLUSIONS: We conclude that combining ZIP and OLZ at the outset of treatment is superior to switching from OLZ to ZIP in terms of improving psychotic symptoms and limiting movement side effects without increasing the risk of metabolic syndrome.

PMID: 27837658 [PubMed - indexed for MEDLINE]

[Pharmacovigilance in Germany : It is about time].

Internist (Berl). 2016 Jun;57(6):616-23

Authors: Douros A, Schaefer C, Kreutz R, Garbe E

Abstract
BACKGROUND: Pharmacovigilance is defined as the activities relating to the detection, assessment, and prevention of adverse drug reactions (ADRs). Although its beginnings in Germany date back more than 50 years, a stagnation in this field has been observed lately.
OBJECTIVES: Different tools of pharmacovigilance will be illustrated and the reasons for its stagnation in Germany will be elucidated.
CURRENT DATA: Spontaneous reporting systems are an important tool in pharmacovigilance and are based on reports of ADRs from treating physicians, other healthcare professionals, or patients. Due to several weaknesses of spontaneous reporting systems such as underreporting, media bias, confounding by comorbidity or comedication, and due to the limited quality of the reports, the development of electronic healthcare databases was publicly funded in recent years so that they can be used for pharmacovigilance research. In the US different electronic healthcare databases were merged in a project sponsored by public means resulting in more than 193 million individuals. In Germany the establishment of large longitudinal databases was never conceived as a public duty and has not been implemented so far. Further attempts to use administrative healthcare data for pharmacovigilance purposes are severely restricted by the Code of Social Law (Section 75, Book 10). This situation has led to a stagnation in pharmacovigilance research in Germany.
CONCLUSIONS: Without publicly funded large longitudinal healthcare databases and an amendment of Section 75, Book 10, of the Code of Social Law, the use of healthcare data in pharmacovigilance research in Germany will remain a rarity. This could have negative effects on the medical care of the general population.

PMID: 27224991 [PubMed - indexed for MEDLINE]

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A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout.

Ann Rheum Dis. 2017 Sep;76(9):1522-1528

Authors: Stamp LK, Chapman PT, Barclay ML, Horne A, Frampton C, Tan P, Drake J, Dalbeth N

Abstract
OBJECTIVES: To determine the efficacy and safety of allopurinol dose escalation using a treat-to-target serum urate (SU) approach.
METHODS: A randomised, controlled, parallel-group, comparative clinical trial was undertaken. People with gout receiving at least creatinine clearance (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL were recruited. Participants were randomised to continue current dose (control) or allopurinol dose escalation for 12 months. In the dose escalation group, allopurinol was increased monthly until SU was <6 mg/dL. The primary endpoints were reduction in SU and adverse events (AEs).
RESULTS: 183 participants (93 control, 90 dose escalation) were recruited. At baseline, mean (SD) urate was 7.15 (1.6) mg/dL and allopurinol dose 269 mg/day. 52% had CrCL<60 mL/min. Mean changes in SU at the final visit were -0.34 mg/dL in the control group and -1.5 mg/dL in the dose escalation group (p<0.001) with a mean difference of 1.2 mg/dL (95% CI 0.67 to 1.5, p<0.001). At month 12, 32% of controls and 69% in the dose escalation had SU <6 mg/dL. There were 43 serious AEs in 25 controls and 35 events in 22 dose escalation participants. Only one was considered probably related to allopurinol. Five control and five dose escalation participants died; none was considered allopurinol related. Mild elevations in LFTs were common in both groups, a few moderate increases in gamma glutamyl transferase (GGT) were noted. There was no difference in renal function changes between randomised groups.
CONCLUSIONS: Higher than CrCL-based doses of allopurinol can effectively lower SU to treatment target in most people with gout. Allopurinol dose escalation is well tolerated.
TRIAL REGISTRATION NUMBER: ANZCTR12611000845932; Results.

PMID: 28314755 [PubMed - indexed for MEDLINE]

Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naïve HIV-positive patients receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan.

PLoS One. 2017;12(2):e0171596

Authors: Wu PY, Cheng CY, Liu CE, Lee YC, Yang CJ, Tsai MS, Cheng SH, Lin SP, Lin DY, Wang NC, Lee YC, Sun HY, Tang HJ, Hung CC

Abstract
OBJECTIVES: Two nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) plus 1 non-NRTI (nNRTI) remain the preferred or alternative combination antiretroviral therapy (cART) for antiretroviral-naive HIV-positive patients in Taiwan. The three most commonly used nNRTIs are nevirapine (NVP), efavirenz (EFV) and rilpivirine (RPV). This study aimed to determine the incidences of hepatotoxicity and skin rashes within 4 weeks of initiation of cART containing 1 nNRTI plus 2 NRTIs.
METHODS: Between June, 2012 and November, 2015, all antiretroviral-naive HIV-positive adult patients initiating nNRTI-containing cART at 8 designated hospitals for HIV care were included in this retrospective observational study. According to the national HIV treatment guidelines, patients were assessed at baseline, 2 and 4 weeks of cART initiation, and subsequently every 8 to 12 weeks. Plasma HIV RNA load, CD4 cell count and aminotransferases were determined. The toxicity grading scale of the Division of AIDS (DAIDS) 2014 was used for reporting clinical and laboratory adverse events.
RESULTS: During the 3.5-year study period, 2,341 patients initiated nNRTI-containing cART: NVP in 629 patients, EFV 1,363 patients, and RPV 349 patients. Rash of any grade occurred in 14.1% (n = 331) of the patients. In multiple logistic regression analysis, baseline CD4 cell counts (per 100-cell/μl increase, adjusted odds ratio [AOR], 1.125; 95% confidence interval [95% CI], 1.031-1.228) and use of NVP (AOR, 2.443; 95% CI, 1.816-3.286) (compared with efavirenz) were independently associated with the development of skin rashes. Among the 1,455 patients (62.2%) with aminotransferase data both at baseline and week 4, 72 (4.9%) developed grade 2 or greater hepatotoxicity. In multiple logistic regression analysis, presence of antibody for hepatitis C virus (HCV) (AOR, 2.865; 95% CI, 1.439-5.704) or hepatitis B surface antigen (AOR, 2.397; 95% CI, 1.150-4.997), and development of skin rashes (AOR, 2.811; 95% CI, 1.051-7.521) were independently associated with the development of hepatotoxicity.
CONCLUSIONS: The baseline CD4 cell counts and use of NVP were associated with increased risk of skin rashes, while hepatotoxicity was independently associated with HCV or hepatitis B virus coinfection, and development of skin rashes in antiretroviral-naïve HIV-positive Taiwanese patients within 4 weeks of initiation of nNRTI-containing regimens.

PMID: 28222098 [PubMed - indexed for MEDLINE]

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool.

PLoS One. 2017;12(1):e0169393

Authors: Bracken LE, Nunn AJ, Kirkham JJ, Peak M, Arnott J, Smyth RL, Pirmohamed M, Turner MA

Abstract
AIM: To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings.
METHODS: The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist).
MAIN OUTCOME MEASURES: Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories.
RESULTS: Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'.
CONCLUSION: Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

PMID: 28046035 [PubMed - indexed for MEDLINE]

Risk Factors for Initiation of Potentially Inappropriate Medications in Community-Dwelling Older Adults with and without Alzheimer's Disease.

Drugs Aging. 2017 Jan;34(1):67-77

Authors: Hyttinen V, Taipale H, Tanskanen A, Tiihonen J, Tolppanen AM, Hartikainen S, Valtonen H

Abstract
BACKGROUND: Various criteria have been created to define potentially inappropriate medications (PIMs) to help improve the quality and safety of medicine use in older patients. Individuals with Alzheimer's disease (AD) may be at higher risk of adverse drug events associated with PIMs (such as falls).
OBJECTIVE: Our objective was to determine the risk factors for PIM initiation in a nationwide cohort of community dwellers aged ≥65 years with and without AD.
METHODS: The Finnish nationwide MEDALZ cohort includes all patients diagnosed with AD in 2005-2011 (n = 70,718) and two comparison individuals without AD (non-AD) matched for age, sex and region of residence for each person with AD. After a 1-year washout period for PIM use and exclusion of those aged <65 years, we included 50,494 patients with AD and 106,306 comparison subjects. PIM use was defined according to Finnish criteria.
RESULTS: Subjects without AD initiated PIMs more frequently than those with AD (16.4 vs. 12.2%, respectively; p < 0.001). The most common PIMs were muscle relaxants and urinary antispasmodics. Older individuals (aged ≥75 years) were less likely to initiate PIMs. In the AD group, women were less likely to initiate PIMs than men. More comorbidities were associated with PIM initiation, especially in the non-AD group. The use of opioids or psychotropic medicines was associated with PIM initiation in both cohorts. Regional differences between university hospital districts were observed.
CONCLUSION: PIM initiation was dependent on patient characteristics and possibly also some healthcare system-related factors such as differing regional treatment practices. It is important that medicines prescribed to the older vulnerable population are assessed regularly to avoid adverse effects and ensure safe pharmacotherapy, especially in those with multiple comorbidities.

PMID: 27838819 [PubMed - indexed for MEDLINE]