Safety of cetirizine ophthalmic solution 0.24% for the treatment of allergic conjunctivitis in adult and pediatric subjects.

Clin Ophthalmol. 2019;13:403-413

Authors: Malhotra RP, Meier E, Torkildsen G, Gomes PJ, Jasek MC

Abstract
Purpose: The studies reported here aimed to assess the safety and tolerability of cetirizine ophthalmic solution 0.24%, a new topical ophthalmic medication approved by the US Food and Drug Administration for the treatment of ocular itching associated with allergic conjunctivitis.
Patients and methods: Three clinical studies evaluated cetirizine ophthalmic solution 0.24% administration: a Phase I prospective, single-center, open-label, pharmacokinetic (PK) study (N=11) evaluating single-dose administration and twice-daily (BID) administration for 1 week in healthy adults, and two Phase III, multi-center, randomized, double-masked, vehicle-controlled, parallel-group studies evaluating the safety and tolerability in adult and pediatric populations (2-18 years of age) for up to 6 consecutive weeks. The first safety and tolerability study evaluated cetirizine BID (study 1, N=512), while the second study examined cetirizine three times daily (TID) (study 2, N=516). Each study assessed best corrected visual acuity, slit-lamp biomicroscopy, IOP, dilated ophthalmoscopy, treatment-emergent adverse events, vital signs, urine pregnancy test, and physical examination (general health, head, eyes, ears, nose, and throat). The PK study also measured hematology, blood chemistry, and urinalysis, while the two Phase III studies additionally assessed corneal endothelial cell counts (ECC) and ECC density in a subset of subjects (via specular microscopy), and drug administration tolerability.
Results: Bilateral administration of cetirizine ophthalmic solution 0.24% resulted in low systemic exposure in the PK study and was associated with a low incidence of mild adverse events. There were no drug-related severe or serious adverse events. The tolerability scores between the active and vehicle groups were comparable, demonstrating high comfort in the administration of cetirizine ophthalmic solution 0.24%.
Conclusion: Cetirizine ophthalmic solution 0.24% dosed BID or TID demonstrated an acceptable safety profile and was well-tolerated when administered to subjects aged ≥2 years.

PMID: 30858690 [PubMed]

Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: A prospective pilot study.

Int J Mycobacteriol. 2019 Jan-Mar;8(1):89-92

Authors: Lang SM, Ortmann J, Rostig S, Schiffl H

Abstract
Background: Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy.
Methods: Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity.
Results: Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects.
Conclusion: Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.

PMID: 30860185 [PubMed - in process]

77 Long-term Valbenazine Treatment in Patients with Schizophrenia/Schizoaffective Disorder or Mood Disorder and Tardive Dyskinesia.

CNS Spectr. 2019 Feb;24(1):214-215

Authors: Lindenmayer JP, Marder SR, Singer C, Comella C, Farahmand K, Burke J, Jimenez R, Siegert S

Abstract
BACKGROUND: Patients treated with antipsychotics, regardless of psychiatric diagnosis, are at risk for developing tardive dyskinesia (TD), a potentially debilitating drug-induced movement disorder. Valbenazine (INGREZZA; VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat TD in adults. Data from KINECT 4 (NCT02405091) were analyzed to evaluate the long-term effects of VBZ in adults with schizophrenia/schizoaffective disorder (SZD) or mood disorder (MD) and moderate or severe TD.
METHODS: KINECT 4 included open-label treatment (48weeks) followed by washout (4weeks). Entry requirements included: moderate or severe TD, qualitatively assessed at screening by a blinded, external reviewer; DSM diagnosis of SZD or MD; psychiatric stability (Brief Psychiatric Rating Scale score <50). Stable concomitant psychiatric medications were allowed. Dosing was initiated at 40mg, with escalation to 80mg at Wk4 if participants had a Clinical Global Impression of Change-TD score of ≥3 (minimally improved to very much worse) and tolerated 40mg. A reduction to 40mg was allowed if 80mg was not tolerated (80/40mg); participants unable to tolerate 40mg were discontinued. Safety was the primary focus, but the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1-7) was used to evaluate changes in TD. Mean changes from baseline (BL) in AIMS total score (rated by on-site investigators) were analyzed descriptively. Safety assessments included treatment-emergent adverse events (TEAEs) and psychiatric scales (Positive and Negative Syndrome Scale [PANSS], Calgary Depression Scale for Schizophrenia [CDSS], Montgomery-Åsberg Depression Rating Scale [MADRS], Young Mania Rating Scale [YMRS], and Columbia-Suicide Severity Rating Scale [C SSRS]).
RESULTS: Of 163 participants in the analyses, 103 completed the study. Adverse events (n=26) was the most common reason for discontinuation. Analyses included 119 participants with SZD (40mg=37; 80mg=76; 80/40mg=6) and 44 with MD (40mg=8; 80mg=31; 80/40mg=5). At Wk48, mean improvements from BL in AIMS total score were: SZD (40mg, -10.1; 80mg,-10.7); MD (40mg, 10.2; 80mg: -11.6). AIMS total scores at Wk52 (end of washout) indicated a return toward BL levels. Compared to SZD, the MD subgroup had a higher incidence of any TEAE (84% vs 61% [all doses]) but fewer TEAEs leading to discontinuation (7% vs 18%). Urinary tract infection was the most common TEAE in the MD subgroup (18%); somnolence and headache were most common in the SZD subgroup (7% each). Psychiatric status remained stable from BL to Wk48: SZD (PANSS positive, -0.7, PANSS negative, -0.6; CDSS, -0.7); MD (MADRS, -0.3; YMRS, -0.3). Most participants (95%) had no change in C-SSRS score during the study.
CONCLUSION: Sustained and clinically meaningful TD improvements were observed with VBZ, regardless of primary psychiatric diagnosis. VBZ was generally well tolerated and no notable changes in psychiatric status were observed.Funding Acknowledgements: Supported by Neurocrine Biosciences, Inc.

PMID: 30859992 [PubMed - in process]

Enhancing Pharmacovigilance Capabilities in the EU Regulatory Network: The SCOPE Joint Action.

Drug Saf. 2018 12;41(12):1285-1302

Authors: Radecka A, Loughlin L, Foy M, de Ferraz Guimaraes MV, Sarinic VM, Di Giusti MD, Lesicar M, Straus S, Montero D, Pallos J, Ivanovic J, Raine J

Abstract
In November 2013, a team of European regulators initiated the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Funded by the Health Programme of the European Union, and with contributions from the involved Member States, SCOPE gathered information and expertise on how regulators in Member States run their national pharmacovigilance systems to meet the requirements of the pharmacovigilance legislation that came into effect in June 2012. The SCOPE project evaluated then-current practices and developed tools to further improve the skills and capability in the pharmacovigilance network. The project was divided into eight separate work streams, five of which concentrated on pharmacovigilance topics-collecting information on suspected adverse drug reactions, identifying and managing safety issues (signals), communicating risk and assessing risk minimisation measures, supported by effective quality management systems. The other three work streams focused on the functional aspects-coordination, communication and evaluation of the project. Through the project, SCOPE delivered guidance, training in key aspects of pharmacovigilance, and tools and templates to support best practice. The deliverables provide practical guidance that those working in the European national competent authorities can take to strengthen their national systems. The SCOPE outputs can be useful for other stakeholders involved in pharmacovigilance activities, including the pharmaceutical industry, healthcare professionals, patient and consumer organisations, and academia.

PMID: 30128638 [PubMed - indexed for MEDLINE]

Management of Immune Checkpoint Inhibitor Toxicities: A Review and Clinical Guideline for Emergency Physicians.

J Emerg Med. 2018 10;55(4):489-502

Authors: Hryniewicki AT, Wang C, Shatsky RA, Coyne CJ

Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) are a novel class of drugs used in cancer immunotherapy that are becoming more commonly used among advanced-stage cancers. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs).
OBJECTIVES: We conducted a review of relevant primary research and clinical guidelines in oncology, pharmacology, and other literature, and synthesized this information to address the needs of the emergency physician in the acute management of irAEs.
DISCUSSION: Although the antitumor effects of immunotherapies are desirable, the inhibition of immune checkpoints may also lead to loss of peripheral tolerance and a subsequent unleashing of the immune system on nontumor cells, leading to unintended tissue damage, which manifests as multisystem organ dysfunction. This tissue damage can affect nearly every organ system, with the dermatologic, gastrointestinal, endocrine, and pulmonary systems being the most commonly affected. Treatment may range drastically, depending on the severity of the irAE, starting with supportive care and moving toward high-dose steroids and additional immune modulators such as infliximab or intravenous immunoglobulin.
CONCLUSION: With the increasing success and popularity of ICIs, emergency physicians will inevitably encounter increasing numbers of patients on these medications as well as the associated side effects. It is important that emergency physicians become aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications.

PMID: 30120013 [PubMed - indexed for MEDLINE]

Mouse Population-Based Approaches to Investigate Adverse Drug Reactions.

Drug Metab Dispos. 2018 11;46(11):1787-1795

Authors: Mosedale M

Abstract
Genetic variation is now recognized as a key factor in the toxicity of pharmaceutical agents. However, genetic diversity is not present in standard nonclinical toxicology models, and small clinical studies (phase I/II) may not include enough subjects to identify toxicity liabilities associated with less common susceptibility factors. As a result, many drugs pass through preclinical and early clinical studies before safety concerns are realized. Furthermore, when adverse drug reactions are idiosyncratic in nature, suggesting a role for rare genetic variants in the toxicity susceptibility, even large clinical studies (phase III) are often underpowered (due to low population frequency and/or small effect size of the risk factor) to identify associations that may be used for precision medicine risk mitigation strategies. Genetically diverse mouse populations can be used to help overcome the limitations of standard nonclinical and clinical studies and to model toxicity responses that require genetic susceptibility factors. Furthermore, mouse population-based approaches can be used to: 1) identify sensitive strains that can serve as a screening tool for next-in-class compounds, 2) identify genetic susceptibility factors that can be used for risk mitigation strategies, and 3) study mechanisms underlying drug toxicity. This review describes genetically diverse mouse populations and provides examples of their utility in investigating adverse drug response. It also explores recent efforts to adapt mouse population-based approaches to in vitro platforms, thereby enabling the incorporation of genetic diversity and the identification of genetic risk factors and mechanisms associated with drug toxicity susceptibility at all stages of drug development.

PMID: 30045843 [PubMed - indexed for MEDLINE]

Assessment of the Utility of Social Media for Broad-Ranging Statistical Signal Detection in Pharmacovigilance: Results from the WEB-RADR Project.

Drug Saf. 2018 12;41(12):1355-1369

Authors: Caster O, Dietrich J, Kürzinger ML, Lerch M, Maskell S, Norén GN, Tcherny-Lessenot S, Vroman B, Wisniewski A, van Stekelenborg J

Abstract
INTRODUCTION AND OBJECTIVE: Social media has been proposed as a possibly useful data source for pharmacovigilance signal detection. This study primarily aimed to evaluate the performance of established statistical signal detection algorithms in Twitter/Facebook for a broad range of drugs and adverse events.
METHODS: Performance was assessed using a reference set by Harpaz et al., consisting of 62 US Food and Drug Administration labelling changes, and an internal WEB-RADR reference set consisting of 200 validated safety signals. In total, 75 drugs were studied. Twitter/Facebook posts were retrieved for the period March 2012 to March 2015, and drugs/events were extracted from the posts. We retrieved 4.3 million and 2.0 million posts for the WEB-RADR and Harpaz drugs, respectively. Individual case reports were extracted from VigiBase for the same period. Disproportionality algorithms based on the Information Component or the Proportional Reporting Ratio and crude post/report counting were applied in Twitter/Facebook and VigiBase. Receiver operating characteristic curves were generated, and the relative timing of alerting was analysed.
RESULTS: Across all algorithms, the area under the receiver operating characteristic curve for Twitter/Facebook varied between 0.47 and 0.53 for the WEB-RADR reference set and between 0.48 and 0.53 for the Harpaz reference set. For VigiBase, the ranges were 0.64-0.69 and 0.55-0.67, respectively. In Twitter/Facebook, at best, 31 (16%) and four (6%) positive controls were detected prior to their index dates in the WEB-RADR and Harpaz references, respectively. In VigiBase, the corresponding numbers were 66 (33%) and 17 (27%).
CONCLUSIONS: Our results clearly suggest that broad-ranging statistical signal detection in Twitter and Facebook, using currently available methods for adverse event recognition, performs poorly and cannot be recommended at the expense of other pharmacovigilance activities.

PMID: 30043385 [PubMed - indexed for MEDLINE]

Adverse Drug Reactions Among Patients Initiating Second-Line Antiretroviral Therapy in South Africa.

Drug Saf. 2018 12;41(12):1343-1353

Authors: Onoya D, Hirasen K, van den Berg L, Miot J, Long LC, Fox MP

Abstract
INTRODUCTION: Understanding the occurrence of antiretroviral (ARV)-related adverse events (AEs) among patients receiving second-line antiretroviral therapy (ART) is important in preventing switches to more limited and expensive third-line regimens.
OBJECTIVE: This study aimed to estimate the rates and examine predictors of AEs among adult HIV-1-infected patients receiving second-line ART in the Right to Care (RTC) clinical cohort in South Africa.
METHODS: This was a cohort study of HIV-1-infected adult patients (≥ 18 years of age) initiating standard second-line ART in South Africa from 1 April 2004 to 10 January 2016. Our primary outcome was the development of an AE within 24 months of initiating second-line therapy. We used Kaplan-Meier survival analysis to determine AE incidence in the first 24 months of second-line ART. Predictors of AEs were modelled using a Cox proportional hazards model.
RESULTS: A total of 7708 patients initiated second-line ART, with 44.5% developing at least one AE over the first 24 months of second-line treatment. The highest AE incidence was observed among patients receiving abacavir (ABC) + lamivudine (3TC) + ritonavir-boosted lopinavir/atazanavir (LPVr/ATVr) (52.7/100 person-years (PYs), 95% confidence interval (CI): 42.9-64.8), while patients initiated on a tenofovir (TDF) + emtricitabine (FTC)/3TC + LPVr regimen had the lowest rate of AEs (26.4/100 PYs, 95% CI: 24.9-28.3). Clinical predictors of AEs included experiencing AEs when receiving first-line ART (adjusted hazard ratio (aHR) 2.3, 95% CI: 1.9-2.8), lower CD4 cell count (0-199 vs. ≥ 350 cells/mm3; aHR 1.4, 95% CI: 1.4-1.8), and switching to second-line therapy from an ABC-base first-line regimen (ABC + 3TC + efavirenz/nevirapine [EFV/NVP] vs. TDF + 3TC/FTC + EFV/NVP; aHR 3.4, 95% CI: 1.1-11.1).
CONCLUSIONS: The rates of AEs were lowest among patients receiving a TDF-based second-line regimen. Patients with poorer health at the time of switch were at higher risk of AEs when receiving second-line ART and may require closer monitoring to improve the durability of second-line therapy.

PMID: 30043384 [PubMed - indexed for MEDLINE]

Drugs policy will not change as long as UK government refuses to acknowledge the need for change.

BMJ. 2018 Jun 20;361:k2604

Authors: Robertson R, McAuley A, Macleod J, Strang J, McCallum A

PMID: 29925647 [PubMed - indexed for MEDLINE]

Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications.

Aliment Pharmacol Ther. 2018 02;47(3):332-345

Authors: Le Bastard Q, Al-Ghalith GA, Grégoire M, Chapelet G, Javaudin F, Dailly E, Batard E, Knights D, Montassier E

Abstract
BACKGROUND: Global prescription drug use has been increasing continuously for decades. The gut microbiome, a key contributor to health status, can be altered by prescription drug use, as antibiotics have been repeatedly described to have both short-term and long-standing effects on the intestinal microbiome.
AIM: To summarise current findings on non-antibiotic prescription-induced gut microbiome changes, focusing on the most frequently prescribed therapeutic drug categories.
METHODS: We conducted a systematic review by first searching in online databases for indexed articles and abstracts in accordance with PRISMA guidelines. Studies assessing the intestinal microbiome alterations associated with proton pump inhibitors (PPIs), metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, statins and antipsychotics were included. We only included studies using culture-independent molecular techniques.
RESULTS: Proton pump inhibitors and antipsychotic medications are associated with a decrease in α diversity in the gut microbiome, whereas opioids were associated with an increase in α diversity. Metformin and NSAIDs were not associated with significant changes in α diversity. β diversity was found to be significantly altered with all drugs, except for NSAIDs. PPI use was linked to a decrease in Clotridiales and increase in Actinomycetales, Micrococcaceae and Streptococcaceae, which are changes previously implicated in dysbiosis and increased susceptibility to Clostridium difficile infection. Consistent results showed that PPIs, metformin, NSAIDs, opioids and antipsychotics were either associated with increases in members of class Gammaproteobacteria (including Enterobacter, Escherichia, Klebsiella and Citrobacter), or members of family Enterococcaceae, which are often pathogens isolated from bloodstream infections in critically ill patients. We also found that antipsychotic treatment, usually associated with an increase in body mass index, was marked by a decreased ratio of Bacteroidetes:Firmicutes in the gut microbiome, resembling trends seen in obese patients.
CONCLUSIONS: Non-antibiotic prescription drugs have a notable impact on the overall architecture of the intestinal microbiome. Further explorations should seek to define biomarkers of dysbiosis induced by specific drugs, and potentially tailor live biotherapeutics to counter this drug-induced dysbiosis. Many other frequently prescribed drugs should also be investigated to better understand the link between these drugs, the microbiome and health status.

PMID: 29205415 [PubMed - indexed for MEDLINE]

Detecting Hypoglycemia Incidents Reported in Patients' Secure Messages: Using Cost-Sensitive Learning and Oversampling to Reduce Data Imbalance.

J Med Internet Res. 2019 Mar 11;21(3):e11990

Authors: Chen J, Lalor J, Liu W, Druhl E, Granillo E, Vimalananda VG, Yu H

Abstract
BACKGROUND: Improper dosing of medications such as insulin can cause hypoglycemic episodes, which may lead to severe morbidity or even death. Although secure messaging was designed for exchanging nonurgent messages, patients sometimes report hypoglycemia events through secure messaging. Detecting these patient-reported adverse events may help alert clinical teams and enable early corrective actions to improve patient safety.
OBJECTIVE: We aimed to develop a natural language processing system, called HypoDetect (Hypoglycemia Detector), to automatically identify hypoglycemia incidents reported in patients' secure messages.
METHODS: An expert in public health annotated 3000 secure message threads between patients with diabetes and US Department of Veterans Affairs clinical teams as containing patient-reported hypoglycemia incidents or not. A physician independently annotated 100 threads randomly selected from this dataset to determine interannotator agreement. We used this dataset to develop and evaluate HypoDetect. HypoDetect incorporates 3 machine learning algorithms widely used for text classification: linear support vector machines, random forest, and logistic regression. We explored different learning features, including new knowledge-driven features. Because only 114 (3.80%) messages were annotated as positive, we investigated cost-sensitive learning and oversampling methods to mitigate the challenge of imbalanced data.
RESULTS: The interannotator agreement was Cohen kappa=.976. Using cross-validation, logistic regression with cost-sensitive learning achieved the best performance (area under the receiver operating characteristic curve=0.954, sensitivity=0.693, specificity 0.974, F1 score=0.590). Cost-sensitive learning and the ensembled synthetic minority oversampling technique improved the sensitivity of the baseline systems substantially (by 0.123 to 0.728 absolute gains). Our results show that a variety of features contributed to the best performance of HypoDetect.
CONCLUSIONS: Despite the challenge of data imbalance, HypoDetect achieved promising results for the task of detecting hypoglycemia incidents from secure messages. The system has a great potential to facilitate early detection and treatment of hypoglycemia.

PMID: 30855231 [PubMed - in process]

Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia.

Ther Adv Hematol. 2019;10:2040620719826444

Authors: Molica M, Scalzulli E, Colafigli G, Foà R, Breccia M

Abstract
There are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig®) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug.

PMID: 30854182 [PubMed]

Medication-related dental implant failure: Systematic review and meta-analysis.

Clin Oral Implants Res. 2018 Oct;29 Suppl 16:55-68

Authors: Chappuis V, Avila-Ortiz G, Araújo MG, Monje A

Abstract
OBJECTIVES: The aim of this systematic review was to investigate the association between the intake of systemic medications that may affect bone metabolism and their subsequent impact on implant failures.
MATERIAL AND METHODS: Electronic and manual literature searches were conducted. Implant failure (IF) was the primary outcome, while biological/mechanical and the causes/timing associated with IF were set as secondary outcomes. Meta-analyses for the binary outcome IF and odds ratio were performed to investigate the association with medications.
RESULTS: A final selection of 17 articles was screened for qualitative assessment. As such, five studies focused on evaluating the association of implant failure and non-steroidal anti-inflammatory drugs (NSAIDs), two on selective serotonin reuptake inhibitors (SSRIs), two on proton pump inhibitors (PPIs), seven on bisphosphonates (BPs), and one on anti-hypertensives (AHTNs). For PPIs, the fixed effect model estimated a difference of IF rates of 4.3%, indicating significantly higher IF rates in the test compared to the control group (p < 0.5). Likewise, for SSRIs, the IF was shown to be significantly higher in the individuals taking SSRIs (p < 0.5) as estimated a difference of 7.5%. No subset meta-analysis could be conducted for AHTNs medications as only one study fulfilled the inclusion criteria, which revealed an increased survival rate of AHTN medication. None of the other medications yielded significance.
CONCLUSIONS: The present systematic review showed an association of PPIs and SSRIs with an increased implant failure rate. Hence, clinicians considering implant therapy should be aware of possible medication-related implant failures.

PMID: 30328197 [PubMed - indexed for MEDLINE]

An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs.

PLoS One. 2018;13(10):e0204648

Authors: Hosomi K, Fujimoto M, Ushio K, Mao L, Kato J, Takada M

Abstract
Different computational approaches are employed to efficiently identify novel repositioning possibilities utilizing different sources of information and algorithms. It is critical to propose high-valued candidate-repositioning possibilities before conducting lengthy in vivo validation studies that consume significant resources. Here we report a novel multi-methodological approach to identify opportunities for drug repositioning. We performed analyses of real-world data (RWD) acquired from the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) and the claims database maintained by the Japan Medical Data Center (JMDC). These analyses were followed by cross-validation through bioinformatics analyses of gene expression data. Inverse associations revealed using disproportionality analysis (DPA) and sequence symmetry analysis (SSA) were used to detect potential drug-repositioning signals. To evaluate the validity of the approach, we conducted a feasibility study to identify marketed drugs with the potential for treating inflammatory bowel disease (IBD). Primary analyses of the FAERS and JMDC claims databases identified psycholeptics such as haloperidol, diazepam, and hydroxyzine as candidates that may improve the treatment of IBD. To further investigate the mechanistic relevance between hit compounds and disease pathology, we conducted bioinformatics analyses of the associations of the gene expression profiles of these compounds with disease. We identified common biological features among genes differentially expressed with or without compound treatment as well as disease-perturbation data available from open sources, which strengthened the mechanistic rationale of our initial findings. We further identified pathways such as cytokine signaling that are influenced by these drugs. These pathways are relevant to pathologies and can serve as alternative targets of therapy. Integrative analysis of RWD such as those available from adverse-event databases, claims databases, and transcriptome analyses represent an effective approach that adds value to efficiently identifying potential novel therapeutic opportunities.

PMID: 30300381 [PubMed - indexed for MEDLINE]

Call For Help! The Importance of Role Delineation in a Standardized Contrast Media Emergency Response Protocol.

Curr Probl Diagn Radiol. 2019 Mar - Apr;48(2):111-113

Authors: Loving V, Johnston B, Valencia E, Dupras S, Blackhurst K, Rush J, Johnson R, Figuli M

Abstract
With the use of intravenous contrast in medical imaging, radiologists and radiology personnel will inevitably encounter adverse events at their imaging facilities. At our institution, the stress of these emergency scenarios led to disorderly and unsafe responses by the staff. We present a quality improvement project, where our team addressed these unsafe emergency responses. Through explicit role delineation and standardization, we created an effective and efficient emergency response protocol that was replicable throughout our healthcare organization.

PMID: 30121160 [PubMed - indexed for MEDLINE]

Comprehensive pharmaceutical care to prevent drug-related readmissions of dependent-living elderly patients: a randomized controlled trial.

BMC Geriatr. 2018 06 04;18(1):135

Authors: Lenssen R, Schmitz K, Griesel C, Heidenreich A, Schulz JB, Trautwein C, Marx N, Fitzner C, Jaehde U, Eisert A

Abstract
BACKGROUND: Elderly patients are vulnerable to adverse drug reactions (ADRs). Drug-related readmissions (DRRs) can be a major consequence of ADR. Therefore, this study aimed to investigate the effects of a ward-based, comprehensive pharmaceutical care service on the occurrence of DRRs as the endpoint in dependent-living elderly patients.
METHODS: A randomized, controlled trial was performed at a German University Hospital. Patients fulfilling the following criteria were eligible: admission to a cooperating ward, existing drug therapy at admission, 65 years of age and older, home-care or nursing home residents in ambulatory care, and a minimum hospital stay of three days. Patients received either standard care (control group) or pharmaceutical care (intervention group). Follow-up consultations were conducted for each patient at 1, 8, 26, and 52 weeks after discharge. The time to DRR was defined as the primary outcome measure and was analysed using the log-rank test. The Cox-proportional hazard model was used for risk factor analysis.
RESULTS: Sixty patients (n = 31 intervention group, n = 29 control group) participated in the study. For patients in the intervention group, the median time to DRR was prolonged; however, the level of statistical significance was not reached (log-rank test P = 0.068; HR = 3.28, P = 0.086). When the risk factors 'age' or 'length of stay on the ward' were added to the Cox proportional hazard model, patients in the control group exhibited a significantly higher risk of experiencing a DRR than patients of the intervention group (HR = 4.62; P = 0.028 including age and HR = 5.76; P = 0.033 including length of stay on the ward).
CONCLUSIONS: Our findings demonstrate the successful implementation of ward-based, comprehensive pharmaceutical care for dependent-living elderly. Despite a low participation rate, which led to an underpowered study, the results provide a preliminary efficacy signal and effect size estimates to power a definitive trial.
TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01578525 , prospectively registered April 13, 2012.

PMID: 29898670 [PubMed - indexed for MEDLINE]

Validation of pharmacist-physician collaboration in psychiatry: 'the Eichberger-model'.

Int J Clin Pharm. 2018 Oct;40(5):1001-1004

Authors: Hahn M, Ritter C, Roll SC

Abstract
Background Collaboration between physicians and pharmacists can increase medication safety. In the "Eichberger model" a clinical pharmacist is employed and working full time in a psychiatric hospital. Objective The aim of this study was to determine the expected type of expertise from a clinical pharmacist in psychiatry and the acceptance of the pharmacist's recommendations. Method All email requests to the clinical pharmacist from January 1st to April 30th 2015 were screened retrospectively and type of requester and content of request were extracted. Maintenance rate of drug therapy was analyzed by reviewing patient charts 2 weeks after medication prescription. Results A total of 147 requests were included. 85 (57.8%) requests were from attending physicians and 62 (42.2%) from residents. 82.1% of all physicians were contacting the clinical pharmacist during the study period. Most common reasons for requests were: appropriate drug selection (31.3%), drug interactions (25.2%), possible adverse drug events (17%) and switching drugs (12.2%). The acceptance rate by the physicians was 100%, with an implementation and maintenance rate of both 98.6%. Conclusion We found a high acceptance level of the pharmacist's recommendations. The pharmacist's skills were requested by the majority of physicians and included a in a large variety of specific questions. A pharmacist can play an important role to optimize patient care in collaboration with the physician in psychiatry.

PMID: 29796963 [PubMed - indexed for MEDLINE]

Gadolinium-Based Contrast Agent-Related Toxicities.

CNS Drugs. 2018 03;32(3):229-240

Authors: Pasquini L, Napolitano A, Visconti E, Longo D, Romano A, Tomà P, Espagnet MCR

Abstract
In recent years, gadolinium-based contrast agents have been associated with different types of toxicity. In particular, nephrogenic systemic fibrosis, a progressive sclerotic-myxedematous systemic disease of unknown etiology, is related to gadolinium-based contrast agent administration in patients with kidney dysfunction. More recently, evidence of magnetic resonance signal intensity changes on pre-contrast T1-weighted images after multiple gadolinium-based contrast agent administrations resulted in the hypothesis of gadolinium brain accumulation in patients with normal renal function, subsequently confirmed in pathological samples. However, there is limited current data and further investigations are necessary before drawing definite conclusions on the clinical consequences of gadolinium-based contrast agent accumulation in human tissues and particularly in the brain. Gadolinium-based contrast agent-related toxicity appears connected to molecular stability, which varies together with the pharmacokinetic properties of the compound and depends on the individual characteristics of the subject. During a lifetime, the physiological changes occurring in the human body may influence its interaction with gadolinium-based contrast agents: the integrity and developmental stage of the organs has an effect on the dynamics of gadolinium-based contrast agent distribution and excretion, thus leading to different possible mechanisms of deposition and toxicity. Therefore, the aim of this work is to discuss the pharmacokinetics and pharmacodynamics of gadolinium-based contrast agents, with a special focus on the brain, and to explore potential predominant gadolinium-based contrast agent-related toxicity in two cornerstone periods of the human life cycle: fetal/neonatal and adulthood/aged.

PMID: 29508245 [PubMed - indexed for MEDLINE]

Unusual Milk Colors.

Breastfeed Med. 2018 04;13(3):172-173

Authors: Anderson PO

PMID: 29485895 [PubMed - indexed for MEDLINE]

Patterns of relapse after upfront bortezomib therapy in AL amyloidosis.

Amyloid. 2017 03;24(sup1):60-61

Authors: Basset M, Milani P, Russo F, Lavatelli F, Nuvolone M, Foli A, Perlini S, Palladini G, Merlini G

PMID: 28434342 [PubMed - indexed for MEDLINE]