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]

Bridging the boundaries between scientists and clinicians-mechanistic hypotheses and patient stories in risk assessment of drugs.

J Eval Clin Pract. 2017 Feb;23(1):114-120

Authors: Rocca E

Abstract
The cultural divide between scientists and clinicians has been described as undermining the advance of medical science, by hindering the production of practice-relevant research and of research-informed clinical decisions. Here, I consider the field of post-marketing risk assessment of drugs as an example of strict interdependence between basic biomedical research, clinical research, and clinical evaluation and show how it would benefit from a closer collaboration between scientists and clinicians. The risk assessment of drugs after their marketing relies on spontaneous adverse effect reports to drug agencies and on peer-reviewed case reports. I emphasize the importance of qualitative analysis of such reports for the improvement of mechanistic understanding of harmful effects of drugs. I argue that mechanistic explanations of drug effects are at least as important as determination of their frequency, in order to establish causation. An ideal risk assessment, then, verifies not only the frequency of undesired effects but also why and how the harm happens. For this purpose, the frequency or novelty of the unintended outcome, although contextually indicative, should not determine the epistemic value of a report. Details about the context that generated an unexpected outcome, instead, can offer the chance of improving causal understanding about how the intervention works. This is illustrated through examples from medical research. Mechanistic understanding is a domain of joint collaboration among (1) clinicians, in charge of detailed, qualitative reporting of patient stories about side effects, (2) qualitative clinical researchers, in charge of analyzing clinical contexts or harmful effects and formulating explanatory hypotheses, and (3) basic biomedical researchers, in charge of verifying such hypotheses. In addition, direct information flow can on one side focus clinicians' attention on knowledge gaps about drugs/effects where more research is needed, while on the other side create a more contextualized concept of mechanism among scientists.

PMID: 27538494 [PubMed - indexed for MEDLINE]

Cardiovascular Safety Assessment in Early-Phase Clinical Studies: A Meta-Analytical Comparison of Exposure-Response Models.

CPT Pharmacometrics Syst Pharmacol. 2016 Jun;5(6):324-35

Authors: Conrado DJ, Chen D, Denney WS

Abstract
Exposure-response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure-response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug-effect exposure-response models on vital signs and electrocardiogram (ECG) intervals, an individual-level model-based meta-analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross-validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross-validated drug-effect when considering all markers. A linear model was the most commonly selected to characterize drug-effect on all markers. We propose these models as a starting point assisting with CV safety exposure-response assessment in nondedicated small studies with healthy subjects.

PMID: 27318037 [PubMed - indexed for MEDLINE]

The implementation of medical monitoring programs following potentially hazardous exposures: a medico-legal perspective.

Clin Toxicol (Phila). 2017 Nov;55(9):956-969

Authors: Vearrier D, Greenberg MI

Abstract
CONTEXT: Clinical toxicologists may be called upon to determine the appropriateness of medical monitoring following documented or purported exposures to toxicants in the occupational, environmental, and medical settings.
METHODS: We searched the MEDLINE database using the Ovid(®) search engine for the following terms cross-referenced to the MeSH database: ("occupational exposures" OR "environmental exposures") AND ("physiologic monitoring" OR "population surveillance"). The titles and abstracts of the resulted articles were reviewed for relevance. We expanded our search to include non-peer-reviewed publications and gray literature and resources using the same terms as utilized in the MEDLINE search. There were a total of 48 relevant peer-reviewed and non-peer-reviewed publications. Publications excluded contained no information relevant to medical monitoring following potentially harmful toxicologic exposures, discussed only worker screening/surveillance and/or population biomonitoring, contained redundant information, or were superseded by more recent information. Approaches to medical monitoring: A consensus exists in the peer-reviewed medical literature, legal literature, and government publications that for medical monitoring to be a beneficial public health activity, careful consideration must be given to potential benefits and harms of the program. Characteristics of the exposure, the adverse human health effect, the screening test, and the natural history of the disease are important in determining whether an exposed population will reap a net benefit or harm from a proposed monitoring program. Broader interpretations of medical monitoring: Some have argued that medical monitoring programs should not be limited to exposure-related outcomes but should duplicate general preventive medicine efforts to improve public health outcomes although an overall reduction of morbidity, mortality and disability by modifying correctable risk factors and disease conditions. This broader approach is inconsistent with the targeted approach advocated by the Agency for Toxic Substances and Disease Registry and the United States Preventive Services Task Force and the bulk of the peer-reviewed medical literature. Medical monitoring in legal contexts: Numerous medical monitoring actions have been litigated. Legal rationales for allowing medical monitoring claims often incorporate some of the scientific criteria for the appropriateness of monitoring programs. In the majority of cases in which plaintiffs were awarded medical monitoring relief, plaintiffs were required to demonstrate both that the condition for which medical monitoring was sought could be detected early, and that early detection and treatment will improve morbidity and mortality. However, the treatment of medical monitoring claims varies significantly depending upon jurisdiction. Examples of large-scale, comprehensive medical monitoring programs: Large-scale, comprehensive medical monitoring programs have been implemented, such as the Fernald Medical Monitoring Program and the World Trade Center Health Program, both of which exceeded the scope of medical monitoring typically recommended in the peer-reviewed medical literature and the courts. The Fernald program sought to prevent death and disability due to non-exposure-related conditions in a manner similar to general preventive medicine. The World Trade Center Health Program provides comprehensive medical care for World Trade Center responders and may be viewed as a large-scale, federally--funded research effort, which distinguishes it from medical monitoring in a medico-legal context. Synthesis of public health approaches to medical monitoring: Medical monitoring may be indicated following a hazardous exposure in limited circumstances. General causation for a specific adverse health effect must be either established by scientific consensus through a formal causal analysis using a framework such as the Bradford-Hill criteria. The exposure must be characterized and must be of sufficient severity that the exposed population has a significantly elevated risk of an adverse health effect. Monitoring must result in earlier detection of the condition than would otherwise occur and must confer a benefit in the form of primary, secondary or tertiary prevention. Outcome tables may be of use in describing the potential benefits and harms of a proposed monitoring program.
CONCLUSIONS: In the context of litigation, plaintiffs may seek medical monitoring programs after documented or putative exposures. The role of the clinical toxicologist, in this setting, is to evaluate the scientific justifications and medical risks and assist the courts in determining whether monitoring would be expected to result in a net public health benefit.

PMID: 28644057 [PubMed - indexed for MEDLINE]

Trends in hospital admissions due to antidepressant-related adverse drug events from 2001 to 2011 in the U.S.

BMC Health Serv Res. 2017 Jan 19;17(1):51

Authors: Parihar HS, Yin H, Gooch JL, Allen S, John S, Xuan J

Abstract
BACKGROUND: Depression is a prevalent mental health disorder and the fourth leading cause of disability in the world as per the World Health Organization. Use of antidepressants can lead to adverse drug events (ADEs), defined as any injury resulting from medication use. This study aimed to examine changes in hospital admissions due to antidepressant-related ADEs (ArADEs) among different socio-demographic groups and changes in lengths of stay (LOS) and hospital charges in ArADE admissions from 2001 to 2011.
METHODS: The Healthcare Cost and Utilization Project database was used. ArADE admissions in different socio-demographic groups were examined including characteristics such as age, gender, rural/urban, and income. LOS and hospital charges for ArADE cases were compared between 2001 and 2011. Chi-square test and t test were used for statistical analyses.
RESULTS: There were 17,375 and 20,588 ArADE related admissions in 2001 and 2011, respectively. There was a 17.6% increase among the group of 18 to 64 years old and a 64.8% increase among the group of 65 years or older while the other age groups experienced decreased admission rates. Males and females had similar increases. Patients from the lower income areas experienced a two-fold increase while those from the higher income areas experienced a decrease. The mean LOS for all ArADE related admissions increased from 2.18 to 2.81 days and mean hospital charges increased from $8,456.2 to $21,572.5.
CONCLUSIONS: There was an increase in ArADE hospital admissions. The greater increase in ArADE admissions among elderly, urban or low-income patients should be noted and addressed by practitioners and policy makers. The large increase in hospital charges needs further research.

PMID: 28103930 [PubMed - indexed for MEDLINE]

Adverse outcome pathway development from protein alkylation to liver fibrosis.

Arch Toxicol. 2017 Apr;91(4):1523-1543

Authors: Horvat T, Landesmann B, Lostia A, Vinken M, Munn S, Whelan M

Abstract
In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.

PMID: 27542122 [PubMed - indexed for MEDLINE]

Hepatotoxicity by combination treatment of temozolomide, artesunate and Chinese herbs in a glioblastoma multiforme patient: case report review of the literature.

Arch Toxicol. 2017 Apr;91(4):1833-1846

Authors: Efferth T, Schöttler U, Krishna S, Schmiedek P, Wenz F, Giordano FA

Abstract
Glioblastoma multiforme (GBM) represents an aggressive tumor type with poor prognosis. The majority of GBM patients cannot be cured. There is high willingness among patients for the compassionate use of non-approved medications, which might occasionally lead to profound toxicity. A 65-year-old patient with glioblastoma multiforme (GBM) has been treated with radiochemotherapy including temozolomide (TMZ) after surgery. The treatment outcome was evaluated as stable disease with a tendency to slow tumor progression. In addition to standard medication (ondansetron, valproic acid, levetiracetam, lorazepam, clobazam), the patient took the antimalarial drug artesunate (ART) and a decoction of Chinese herbs (Coptis chinensis, Siegesbeckia orientalis, Artemisia scoparia, Dictamnus dasycarpus). In consequence, the clinical status deteriorated. Elevated liver enzymes were noted with peak values of 238 U/L (GPT/ALAT), 226 U/L (GOT/ASAT), and 347 U/L (γ-GT), respectively. After cessation of ART and Chinese herbs, the values returned back to normal and the patient felt well again. In the literature, hepatotoxicity is well documented for TMZ, but is very rare for ART. Among the Chinese herbs used, Dictamnus dasycarpus has been reported to induce liver injury. Additional medication included valproic acid and levetiracetam, which are also reported to exert hepatotoxicity. While all drugs alone may bear a minor risk for hepatotoxicity, the combination treatment might have caused increased liver enzyme activities. It can be speculated that the combination of these drugs caused liver injury. We conclude that the compassionate use of ART and Chinese herbs is not recommended during standard radiochemotherapy with TMZ for GBM.

PMID: 27519711 [PubMed - indexed for MEDLINE]

Diarrhea in Multiple Myeloma: A Review of the Literature.

Clin J Oncol Nurs. 2016 Aug 01;20(4):E100-5

Authors: Faiman B

Abstract
BACKGROUND: One of the most common and inadequately managed symptoms that patients with multiple myeloma (MM) experience as a result of cancer treatment is diarrhea. Diarrhea in patients with MM often is severe enough to warrant dose reduction, delays, or discontinuation of chemotherapy. Short-term diarrhea can occur as a side effect of drugs, such as bortezomib (Velcade®) or panobinostat (Farydak®). Late-onset diarrhea from lenalidomide (Revlimid®) can occur 17-24 months after the start of therapy. Treatment of diarrhea is often by dose reduction and discontinuation of the offending drug. However, the symptom fails to entirely resolve with these interventions and dose reductions place the individual at risk for disease progression. Best practices for diarrhea management in MM are poorly understood, but diarrhea symptoms impede patient adherence and undermine quality of life.
OBJECTIVES: The purpose of this article is to review the etiology of the symptom of diarrhea in people with cancer, specifically MM. Management strategies also are discussed.
METHODS: A comprehensive review of CINAHL®, MEDLINE®, and PubMed databases was performed using the search terms diarrhea, chemotherapy, multiple myeloma, and cancer. Research studies, guidelines, and papers from peer-reviewed publications were considered.
FINDINGS: Although general guidelines from the American Society of Clinical Oncology and Oncology Nursing Society exist that suggest best practices in the management of chemotherapy-induced diarrhea, best practices to identify and manage diarrhea symptoms in patients with MM are lacking.

PMID: 27441522 [PubMed - indexed for MEDLINE]