Risk of Recurrence of Adverse Events Following Immunization: A Systematic Review.

Pediatrics. 2017 Sep;140(3):

Authors: Zafack JG, De Serres G, Kiely M, Gariépy MC, Rouleau I, Top KA, Canadian Immunization Research Network

Abstract
CONTEXT: Reimmunizing patients who had an adverse event following immunization (AEFI) is sometimes a challenge because there are limited data on the risk and severity of AEFI recurrence.
OBJECTIVE: To summarize the literature on the risk of AEFI recurrence.
DATA SOURCES: PubMed, Embase, and Cochrane library.
STUDY SELECTION: We included articles in English or French published before September 30, 2016. Articles were selected if they estimated the risk of AEFI recurrence in at least 5 individuals. Studies with experimental vaccines were excluded.
DATA EXTRACTION: Data on study design, setting, population, vaccines, and AEFI recurrence were extracted.
RESULTS: Twenty-nine articles were included. Among patients with a history of hypotonic hyporesponsive episode (n = 398), anaphylaxis (n = 133), or seizures (n = 60) who were reimmunized, events recurred in 0% to 0.8%. Allergic-like events recurred in 30 of 594 reimmunized patients. Fever recurred in 0% to 84% of 836 reimmunized patients, depending on the vaccine and dose number. Among children with extensive limb swelling after the fourth dose of diphtheria-tetanus-acellular pertussis vaccine, recurrence was higher when the fifth dose was given withthe full-antigen formulation (78%) compared with the reduced-antigen formulation (53%, P = .02) LIMITATIONS: Many studies, included few patients, and those with severe AEFIs were often not reimmunized.
CONCLUSIONS: Despite vaccines being administered to millions of people annually, there are few studies in which researchers evaluated AEFI recurrence. Published studies suggest that reimmunization is usually safe. However in these studies, severe cases were often not reimmunized.

PMID: 28847985 [PubMed - indexed for MEDLINE]

Methodological and Ethical Issues in Pediatric Medication Safety Research.

Pediatrics. 2017 Sep;140(3):

Authors: Carpenter D, Gonzalez D, Retsch-Bogart G, Sleath B, Wilfond B

Abstract
In May 2016, the Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill convened the PharmSci conference to address the topic of "methodological and ethical issues in pediatric medication safety research." A multidisciplinary group of experts representing a diverse array of perspectives, including those of the US Food and Drug Administration, children's hospitals, and academia, identified important considerations for pediatric medication safety research and opportunities to advance the field. This executive summary describes current challenges that clinicians and researchers encounter related to pediatric medication safety research and identifies innovative and ethically sound methodologies to address these challenges to improve children's health. This article addresses 5 areas: (1) pediatric drug development and drug trials; (2) conducting comparative effectiveness research in pediatric populations; (3) child and parent engagement on study teams; (4) improving communication with children and parents; and (5) assessing child-reported outcomes and adverse drug events.

PMID: 28778857 [PubMed - indexed for MEDLINE]

Weight Loss in Patients with Dementia: Considering the Potential Impact of Pharmacotherapy.

Drugs Aging. 2017 Jun;34(6):425-436

Authors: Franx BAA, Arnoldussen IAC, Kiliaan AJ, Gustafson DR

Abstract
Unintentional body weight loss is common in patients with dementia and is linked to cognitive impairment and poorer disease outcomes. It is proposed that some dementia medications with market approval, while aiming to improve cognitive and functional outcomes of a patient with dementia, are associated with reported body weight or body mass index loss. This review presents evidence in the published literature on body weight loss in dementia, describes selected theories behind body weight loss, evaluates the potential impact of approved dementia pharmacotherapies on body weight, considers the potential role for medical foods, understands the potential influence of treatments for neuropsychiatric symptoms and signs, and finally, summarizes this important area.

PMID: 28478593 [PubMed - indexed for MEDLINE]

Potentially Inappropriate Antihypertensive Prescriptions to Elderly Patients: Results of a Prospective, Observational Study.

Drugs Aging. 2017 Jun;34(6):453-466

Authors: Márquez PHP, Torres OH, San-José A, Vidal X, Agustí A, Formiga F, López-Soto A, Ramírez-Duque N, Fernández-Moyano A, Garcia-Moreno J, Arroyo JA, Ruiz D, Potentially Inappropriate Prescription in Older Patients in Spain (PIPOPS) Investigators’ Project

Abstract
INTRODUCTION: Previous studies of antihypertensive treatment of older patients have focused on blood pressure control, cardiovascular risk or adherence, whereas data on inappropriate antihypertensive prescriptions to older patients are scarce.
OBJECTIVES: The aim of the study was to assess inappropriate antihypertensive prescriptions to older patients.
METHODS: An observational, prospective multicentric study was conducted to assess potentially inappropriate prescription of antihypertensive drugs, in patients aged 75 years and older with arterial hypertension (HTN), in the month prior to hospital admission, using four instruments: Beers, Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START) and Assessing Care of Vulnerable Elders 3 (ACOVE-3). Primary care and hospital electronic records were reviewed for HTN diagnoses, antihypertensive treatment and blood pressure readings.
RESULTS: Of 672 patients, 532 (median age 85 years, 56% female) had HTN. 21.6% received antihypertensive monotherapy, 4.7% received no hypertensive treatment, and the remainder received a combination of antihypertensive therapies. The most frequently prescribed antihypertensive drugs were diuretics (53.5%), angiotensin-converting enzyme inhibitors (ACEIs) (41%), calcium antagonists (32.2%), angiotensin receptor blockers (29.7%) and beta-blockers (29.7%). Potentially inappropriate prescription was observed in 51.3% of patients (27.8% overprescription and 35% underprescription). The most frequent inappropriately prescribed drugs were calcium antagonists (overprescribed), ACEIs and beta-blockers (underprescribed). ACEI and beta-blocker underprescriptions were independently associated with heart failure admissions [beta-blockers odds ratio (OR) 0.53, 95% confidence interval (CI) 0.39-0.71, p < 0.001; ACEIs OR 0.50, 95% CI 0.36-0.70, p < 0.001].
CONCLUSION: Potentially inappropriate prescription was detected in more than half of patients receiving antihypertensive treatment. Underprescription was more frequent than overprescription. ACEIs and beta-blockers were frequently underprescribed and were associated with heart failure admissions.

PMID: 28432600 [PubMed - indexed for MEDLINE]

Clinical Relevance of Differences in Glomerular Filtration Rate Estimations in Frail Older People by Creatinine- vs. Cystatin C-Based Formulae.

Drugs Aging. 2017 Jun;34(6):445-452

Authors: Jacobs A, Benraad C, Wetzels J, Rikkert MO, Kramers C

Abstract
BACKGROUND: The risk of incorrect medication dosing is high in frail older people. Therefore, accurate assessment of the glomerular filtration rate is important.
OBJECTIVE: The objective of this study was to compare the estimated glomerular filtration rate using creatinine- and cystatin C-based formulae, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in frail older people. We hypothesized that frailty determines the difference between the creatinine- and cystatin C-based formulae.
METHODS: The mean difference between CKD-EPI creatinine and cystatin C was determined using (cross-sectional) data of 55 patients (mean age 73 years) admitted to a psychiatric ward for older adults. The level of agreement of these estimations was assessed by a Bland-Altman analysis. In all patients, the Rockwood's Frailty Index was derived and correlated with the mean difference between CKD-EPI creatinine and cystatin C.
RESULTS: The mean difference between CKD-EPI creatinine (mean 71.2 mL/min/1.73 m(2)) and CKD-EPI cystatin C (mean 57.6 mL/min/1.73 m(2)) was 13.6 mL/min/1.73 m(2) (p < 0.0001). The two standard deviation limit in the Bland-Altman plot was large (43.2 mL/min/1.73 m(2)), which represents a low level of agreement. The Frailty Index did not correlate with the mean difference between the creatinine- and cystatin C-based glomerular filtration rate (Pearson correlation coefficient 0.182, p = 0.184).
CONCLUSIONS: There was a significant gap between a creatinine- and cystatin C-based estimation of glomerular filtration rate, irrespective of frailty. The range of differences between the commonly used estimated glomerular filtration rate formulae might result in clinically relevant differences in drug prescription and differences in chronic kidney disease staging.

PMID: 28405944 [PubMed - indexed for MEDLINE]

Adapting Cancer Immunotherapy Models for the Real World.

Trends Immunol. 2016 Jun;37(6):354-63

Authors: Klevorn LE, Teague RM

Abstract
Early experiments in mice predicted the success of checkpoint blockade immunotherapy in cancer patients. However, these same animal studies failed to accurately predict many of the limitations and toxicities of treatment. One of the likely reasons for this discrepancy is the nearly universal use of young healthy mice, which stand in stark contrast to diverse patient populations varying in age, weight, diet, and hygiene. Because these variables impact immunity and metabolism, they also influence outcomes during immunotherapy and should be incorporated into the study design of preclinical experiments. Here, we discuss recent findings that highlight how efficacy and toxicity of cancer immunotherapy are affected by patient variation, and how distinct host environments can be better modeled in animal studies.

PMID: 27105824 [PubMed - indexed for MEDLINE]

Polyethylene Glycol 3350 With Electrolytes vs Polyethylene Glycol 4000 for Constipation: A Randomized, Controlled Trial.

J Pediatr Gastroenterol Nutr. 2017 Sep 12;:

Authors: Bekkali NLH, Hoekman DR, Liem O, Bongers MEJ, van Wijk MP, Zegers B, Pelleboer RA, Verwijs W, Koot BGP, Voropaiev M, Benninga MA

Abstract
OBJECTIVES: The long-term efficacy and safety of polyethylene glycol (PEG) in constipated children are unknown, and a head-to-head comparison of the different PEG formulations is lacking. We aimed to investigate non-inferiority of PEG3350 with electrolytes (PEG3350+E) compared to PEG4000 without electrolytes (PEG4000).
METHODS: In this double-blind trial, children aged 0.5 - 16 years with constipation, defined as a defecation frequency of < 3 times per week, were randomized to receive either PEG3350 + E or PEG4000. Primary outcomes were change in total sum score (TSS) at week 52 compared to baseline, and dose range determination. TSS was the sum of the severity of 5 constipation-symptoms rated on a 4-point scale (0 - 3). Non-inferiority margin was a difference in TSS of ≤1.5 based on a 95%-CI. Treatment success was defined as a defecation frequency of ≥3 per week with < 1 episode of fecal incontinence.
RESULTS: Ninety-seven subjects were included, of whom 82 completed the study. Mean reduction in TSS was -3.81 (95%-CI:-4.96 - -2.65) and -3.74 (95%-CI:-5.08 - -2.40), for PEG3350 + E and PEG4000, respectively. Non-inferiority criteria were not met (maximum difference between groups: -1.81 - 1.68). Daily sachet use was: 0 - 2 years: 0.4 - 2.3 and 0.9 - 2.1; 2 - 4y 0.1 - 3.5 and 1.2 - 3.2; 4 - 8y 1.1 - 2.8 and 0.7 - 3.8; 8 - 16y 0.6 - 3.7 and 1.0 - 3.7, in PEG3350 + E and PEG4000, respectively. Treatment success after 52 weeks was achieved in 50% and 45% of children, respectively (p = 0.69). Rates of adverse events were similar between groups, and no drug-related serious adverse events occurred.
CONCLUSIONS: Non-inferiority regarding long-term constipation-related symptoms of PEG3350 + E compared to PEG4000 was not demonstrated. However, analysis of secondary outcomes suggests similar efficacy and safety of these agents.

PMID: 28906317 [PubMed - as supplied by publisher]

Microbiota-Derived Uremic Retention Solutes: Perpetrators of Altered Nonrenal Drug Clearance in Kidney Disease.

Expert Rev Clin Pharmacol. 2017 Sep 14;:

Authors: Prokopienko AJ, Nolin TD

Abstract
INTRODUCTION: Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas Covered: This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert Commentary: Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.

PMID: 28905671 [PubMed - as supplied by publisher]

Benefit-Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis.

Drugs. 2017 Sep 13;:

Authors: Comi G, Hartung HP, Bakshi R, Williams IM, Wiendl H

Abstract
Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit-risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.

PMID: 28905255 [PubMed - as supplied by publisher]

Drug-drug interactions in pediatric oncology patients.

Pediatr Blood Cancer. 2017 Jul;64(7):

Authors: Balk TE, van der Sijs IH, van Gelder T, Janssen JJB, van der Sluis IM, van Leeuwen RWF, Engels FK

Abstract
BACKGROUND: Drug-drug interactions (DDIs) can negatively affect pharmacotherapy. However, pediatric DDI studies are scarce. We undertook an exploratory study to investigate prevalence and clinical relevance of DDIs between cytostatic and noncytostatic drugs in outpatient pediatric oncology patients.
PROCEDURE: After informed consent and inclusion, the following information was collected: currently prescribed noncytostatic and cytostatic drugs, comorbidities, and use of over-the-counter (OTC) drugs, complementary and alternative medicines (CAMs), and dietary supplements. All medication was screened for DDIs according to two databases: Micromedex(®) Solutions and the Dutch drug database G-Standard. The researcher presented DDIs with an associated potential for adverse outcome and a proposal for intervention to three independent experts. If the experts considered a DDI to be potentially clinically relevant and requiring intervention, the physician was notified.
RESULTS: Seventy-three patients were included (median age 8.9 years). A total of 67 different DDIs were counted (66 in Micromedex(®) Solutions, 14 in G-Standard, and 13 DDIs in both databases). The medication reviews resulted in 35 interventions related to 11 different DDIs. The majority of DDIs concerned noncytostatic drugs (25/35) and one third occurred between cytostatic and noncytostatic drugs (10/35). The use of QTc-interval-prolonging drugs resulted in one intervention. The use of OTC drugs, CAM, or dietary supplements did not lead to DDIs.
CONCLUSIONS: This study resulted in a selection of 11 potentially clinically relevant DDIs for 73 outpatients in our pediatric oncology department. Interventions were formulated in close collaboration between physicians and clinical pharmacists. Future research should focus on assessing DDIs concerning QTc-interval prolongation.

PMID: 28205376 [PubMed - indexed for MEDLINE]

Successful treatment of donor-derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens.

Transpl Infect Dis. 2017 Apr;19(2):

Authors: Shah AP, Cameron A, Singh P, Frank AM, Fenkel JM

Abstract
We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)-negative donor to three HCV-negative recipients-two renal transplants and one liver. Both renal recipients underwent standard deceased-donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39-year-old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV-infected male partner. Recipient 1 was a 45-year-old man with a history of end-stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62-year-old woman with a history of end-stage renal disease caused by hypertension and insulin-dependent diabetes. Recipient 3 was a 42-year-old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post-transplant follow-up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor-derived HCV in transplant recipients.

PMID: 28060446 [PubMed - indexed for MEDLINE]

Comparative Effectiveness of Hands-on Versus Computer Simulation-Based Training for Contrast Media Reactions and Teamwork Skills.

J Am Coll Radiol. 2017 Jan;14(1):103-110.e3

Authors: Wang CL, Chinnugounder S, Hippe DS, Zaidi S, O'Malley RB, Bhargava P, Bush WH

Abstract
PURPOSE: To assess the performance of interprofessional teams of radiologists, technologists, and nurses trained with high-fidelity hands-on (HO) simulation and computer-based (CB) simulation training for contrast reaction management (CR) and teamwork skills (TS).
METHODS: Nurses, technologists, and radiology residents were randomized into 11 teams of three (one of each). Six teams underwent HO training and five underwent CB training for CR and TS. Participants took written tests before and after training and were further tested using a high-fidelity simulation scenario.
RESULTS: HO and CB groups scored similarly on all written tests and each showed improvement after training (P = .002 and P = .018, respectively). During the final scenario test, HO teams tended to receive higher grades than CB teams on CR (95% versus 81%, P = .17) and made fewer errors in epinephrine administration (0/6 versus 2/5, P = .18). HO and CB teams scored similarly on TS (51% versus 52%, P = .66), but overall scores were lower for TS than for CR skills in both the HO (P = .03) and CB teams (P = .06). HO training was more highly rated than CB as an effective educational tool (P = .01) and for effectiveness at teaching CR and team communication skills (P = .02).
CONCLUSIONS: High-fidelity simulation can be used to both train and test interprofessional teams of radiologists, technologists, and nurses for both CR and TS and is more highly rated as an effective educational tool by participants than similar CB training. However, a single session of either type of training may be inadequate for mastering TS.

PMID: 27815053 [PubMed - indexed for MEDLINE]

World Workshop on Oral Medicine VI: a systematic review of medication-induced salivary gland dysfunction.

Oral Dis. 2016 Jul;22(5):365-82

Authors: Villa A, Wolff A, Narayana N, Dawes C, Aframian DJ, Lynge Pedersen AM, Vissink A, Aliko A, Sia YW, Joshi RK, McGowan R, Jensen SB, Kerr AR, Ekström J, Proctor G

Abstract
The aim of this paper was to perform a systematic review of the pathogenesis of medication-induced salivary gland dysfunction (MISGD). Review of the identified papers was based on the standards regarding the methodology for systematic reviews set forth by the World Workshop on Oral Medicine IV and the PRISMA statement. Eligible papers were assessed for both the degree and strength of relevance to the pathogenesis of MISGD as well as on the appropriateness of the study design and sample size. A total of 99 papers were retained for the final analysis. MISGD in human studies was generally reported as xerostomia (the sensation of oral dryness) without measurements of salivary secretion rate. Medications may act on the central nervous system (CNS) and/or at the neuroglandular junction on muscarinic, α-and β-adrenergic receptors and certain peptidergic receptors. The types of medications that were most commonly implicated for inducing salivary gland dysfunction were those acting on the nervous, cardiovascular, genitourinary, musculoskeletal, respiratory, and alimentary systems. Although many medications may affect the salivary flow rate and composition, most of the studies considered only xerostomia. Thus, further human studies are necessary to improve our understanding of the association between MISGD and the underlying pathophysiology.

PMID: 26602059 [PubMed - indexed for MEDLINE]

Improving Patient-Centered Care by Assessing Patient Preferences for Multiple Sclerosis Disease-Modifying Agents: A Stated-Choice Experiment.

Perm J. 2017;21:

Authors: Carlin CS, Higuera L, Anderson S

Abstract
CONTEXT: Long-term adherence to pharmaceutical treatment for multiple sclerosis (MS) is poor. A focus on patient preferences when determining the patient's therapeutic plan may improve this experience.
OBJECTIVE: To identify factors important to patients with MS when evaluating their options for pharmaceutical agents that deliver disease-modifying therapy.
DESIGN: Stated-choice experiment to a sample of patients with MS from privately and publicly insured enrollees in a regional health plan. The experiment presented each respondent with a set of 8 drug choices for MS, asking them to select their preferred disease-modifying agent (DMA). Each respondent was randomized to 1 of 6 possible sets of 8 drug choices, for a total of 48 drug pairings in the experiment. Each choice included 2 hypothetical DMAs and a "no drug" option. Drug attributes included dosage type and modality, efficacy, relapse risk, and drug side effects.
RESULTS: The "no drug" alternative was a stronger substitute than the alternative drug when the focal drug characteristics changed, and the most important drivers of choice were type of side effects and risk of severe relapse.
DISCUSSION: The heterogeneity of our sample and the inclusion of a "no drug" alternative in the DMA choice scenarios make this study an important contribution to this body of literature. The importance of the "no drug" alternative in our results is consistent with poor long-term adherence to DMAs.
CONCLUSION: Patient-centered MS therapy using DMAs should include discussion of side effects and relapse risk.

PMID: 28406788 [PubMed - indexed for MEDLINE]

Deprescribing: A narrative review of the evidence and practical recommendations for recognizing opportunities and taking action.

Eur J Intern Med. 2017 Mar;38:3-11

Authors: Reeve E, Thompson W, Farrell B

Abstract
Deprescribing can be defined as the process of withdrawal or dose reduction of medications which are considered inappropriate in an individual. The aim of this narrative review is to provide an overview of "deprescribing"; firstly discussing the potential benefits and harms followed by the barriers to and enablers of deprescribing. We also provide practical recommendations to recognise opportunities and strategies for deprescribing in practice. Studies focused on minimizing polypharmacy indicate that deprescribing may be associated with potential benefits including resolution of adverse drug reactions, improved quality of life and medication adherence and a reduction in drug costs. While the data on the benefits is inconsistent, deprescribing appears to be safe. There are, however, potential harms including return of medical conditions or symptoms and adverse drug withdrawal reactions which emphasise the need for the process to be supervised and monitored by a health care professional. Taking action on deprescribing can be facilitated by knowledge of potential barriers, implementing a deprescribing process (utilising developed tools and resources) and identifying opportunities for deprescribing through engaging with patients and caregivers and other health care professionals and considering deprescribing in a variety of populations. Important areas for future research include the suitability of deprescribing of certain medications in specific populations, how to implement deprescribing processes into clinical care in a feasible and cost effective manner and how to engage consumers throughout the process to achieve positive health and quality of life outcomes.

PMID: 28063660 [PubMed - indexed for MEDLINE]

Studies in a Murine Model Confirm the Safety of Griffithsin and Advocate Its Further Development as a Microbicide Targeting HIV-1 and Other Enveloped Viruses.

Viruses. 2016 Nov 17;8(11):

Authors: Kouokam JC, Lasnik AB, Palmer KE

Abstract
Griffithsin (GRFT), a lectin from Griffithsia species, inhibits human immunodeficiency virus-1 (HIV-1) replication at sub-nanomolar concentrations, with limited cellular toxicity. However, in vivo safety of GRFT is not fully understood, especially following parenteral administration. We first assessed GRFT's effects in vitro, on mouse peripheral blood mononuclear cell (mPBMC) viability, mitogenicity, and activation using flow-cytometry, as well as cytokine secretion through enzyme-linked immunosorbent assay (ELISA). Toxicological properties of GRFT were determined after a single subcutaneous administration of 50 mg/kg or 14 daily doses of 10 mg/kg in BALB/c mice. In the context of microbicide development, toxicity of GRFT at 2 mg/kg was determined after subcutaneous, intravaginal, and intraperitoneal administrations, respectively. Interestingly, GRFT caused no significant cell death, mitogenicity, activation, or cytokine release in mPBMCs, validating the usefulness of a mouse model. An excellent safety profile for GRFT was obtained in vivo: no overt changes were observed in animal fitness, blood chemistry or CBC parameters. Following GRFT treatment, reversible splenomegaly was observed with activation of certain spleen B and T cells. However, spleen tissues were not pathologically altered by GRFT (either with a single high dose or chronic doses). Finally, no detectable toxicity was found after mucosal or systemic treatment with 2 mg/kg GRFT, which should be further developed as a microbicide for HIV prevention.

PMID: 27869695 [PubMed - indexed for MEDLINE]

Parkinsonian monkeys with prior levodopa-induced dyskinesias followed by fetal dopamine precursor grafts do not display graft-induced dyskinesias.

J Comp Neurol. 2017 Feb 15;525(3):498-512

Authors: Kordower JH, Vinuela A, Chu Y, Isacson O, Redmond DE

Abstract
Clinical trials testing the hypothesis that fetal dopamine grafts would provide antiparkinsonian benefit in patients who had already developed side effects from their long-term use of L-dopa revealed, in some cases, the presence of dyskinesias even in the absence of L-dopa. The form, intensity, and frequency of these dyskinesias were quite variable, but their manifestation slowed the clinical development of cell replacement therapies. Rodent models of graft-induced dyskinesias (GIDs) have been proposed, but their accuracy in modeling GIDs has been questioned because they usually require amphetamine for their presentation. The present study attempted to model GIDs in parkinsonian monkeys and, for the first time, to test the effect of grafts on previously dyskinetic monkeys. Toward this end, monkeys were rendered parkinsonian with n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dyskinetic with levodopa. They then received intraputamenal grafts of fetal dopaminergic cells, control cerebellar cells, or vehicle bilaterally and were studied for 18 months. Dopaminergic cells were grafted in a manner designed to produce either "hot spot" or "widespread" striatal innervation. Although levodopa-induced dyskinesias could be elicited postoperatively, GIDs were never observed in any animal at any time after grafting. Grafted monkeys were also challenged with levodopa but did not show any greater responses to these challenges than before grafting. These studies support the development of future dopamine neuron cell transplantation therapy-based approaches, indicating that in relevant primate models with appropriate cell preparation methodology, with successful graft survival and putamenal dopamine innervation, there is no evidence of graft-induced dyskinesias. J. Comp. Neurol. 525:498-512, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 27418401 [PubMed - indexed for MEDLINE]

Palivizumab Prophylaxis Against Respiratory Syncytial Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A Multicenter, Post-Marketing Surveillance in Japan.

Paediatr Drugs. 2017 Sep 11;:

Authors: Kashiwagi T, Okada Y, Nomoto K

Abstract
OBJECTIVE: The aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome.
METHODS: In this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged ≤24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed.
RESULTS: Of 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (±standard deviation) number of doses was 5.3 (±2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization.
CONCLUSION: Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.

PMID: 28895096 [PubMed - as supplied by publisher]

Rethinking Adverse Drug Events.

Consult Pharm. 2017 Jul 01;32(7):372

Authors: Davidson HE

PMID: 28701248 [PubMed - indexed for MEDLINE]

Community Pharmacist Training-and-Communication Network and Drug-Related Problems in Patients With CKD: A Multicenter, Cluster-Randomized, Controlled Trial.

Am J Kidney Dis. 2017 Sep;70(3):386-396

Authors: Lalonde L, Quintana-Bárcena P, Lord A, Bell R, Clément V, Daigneault AM, Legris MÈ, Letendre S, Mouchbahani M, Jouini G, Azar J, Martin É, Berbiche D, Beaulieu S, Beaunoyer S, Bertin É, Bouvrette M, Charbonneau-Séguin N, Desrochers JF, Desforges K, Dumoulin-Charette A, Dupuis S, El Bouchikhi M, Forget R, Guay M, Lemieux JP, Morin-Bélanger C, Noël I, Ricard S, Sauvé P, Ste-Marie Paradis F

Abstract
BACKGROUND: Appropriate training for community pharmacists may improve the quality of medication use. Few studies have reported the impact of such programs on medication management for patients with chronic kidney disease (CKD).
STUDY DESIGN: Multicenter, cluster-randomized, controlled trial.
SETTING & PARTICIPANTS: Patients with CKD stage 3a, 3b, or 4 from 6 CKD clinics (Quebec, Canada) and their community pharmacies.
INTERVENTION: Each cluster (a pharmacy and its patients) was randomly assigned to either ProFiL, a training-and-communication network program, or the control group. ProFiL pharmacists completed a 90-minute interactive web-based training program on use of medications in CKD and received a clinical guide, patients' clinical summaries, and facilitated access to the CKD clinic.
OUTCOMES: Drug-related problems (primary outcome), pharmacists' knowledge and clinical skills, and patients' clinical attributes (eg, blood pressure and glycated hemoglobin concentration).
MEASUREMENTS: Drug-related problems were evaluated the year before and after the recruitment of patients using a validated set of significant drug-related problems, the Pharmacotherapy Assessment in Chronic Renal Disease (PAIR) criteria. Pharmacists' questionnaires were completed at baseline and after 1 year. Clinical attributes were documented at baseline and after 1 year using available information in medical charts.
RESULTS: 207 community pharmacies, 494 pharmacists, and 442 patients with CKD participated. After 1 year, the mean number of drug-related problems per patient decreased from 2.16 to 1.60 and from 1.70 to 1.62 in the ProFiL and control groups, respectively. The difference in reduction of drug-related problems per patient between the ProFiL and control groups was -0.32 (95% CI, -0.63 to -0.01). Improvements in knowledge (difference, 4.5%; 95% CI, 1.6%-7.4%) and clinical competencies (difference, 7.4%; 95% CI, 3.5%-11.3%) were observed among ProFiL pharmacists. No significant differences in clinical attributes were observed across the groups.
LIMITATIONS: High proportion of missing data on knowledge and clinical skills questionnaire (34.6%) and clinical attributes (11.1%).
CONCLUSIONS: Providing community pharmacists with essential clinical data, appropriate training, and support from hospital pharmacists with expertise in nephrology increases pharmacists' knowledge and reduces drug-related problems in patients with CKD who are followed up in clinics incorporating a multidisciplinary health care team.

PMID: 28663062 [PubMed - indexed for MEDLINE]