More than 25 years of genetic studies of clozapine-induced agranulocytosis.

Pharmacogenomics J. 2017 Jul;17(4):304-311

Authors: de With SAJ, Pulit SL, Staal WG, Kahn RS, Ophoff RA

Abstract
Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

PMID: 28418011 [PubMed - indexed for MEDLINE]

Association Between Psychotropic and Cardiovascular Iatrogenic Alerts and Risk of Hospitalizations in Elderly People Treated for Dementia: A Self-Controlled Case Series Study Based on the Matching of 2 French Health Insurance Databases.

J Am Med Dir Assoc. 2017 Jun 01;18(6):549.e1-549.e13

Authors: Zerah L, Boddaert J, Leperre-Desplanques A, Bonnet-Zamponi D, Verny M, Deligne J, Boelle PY

Abstract
BACKGROUND: Elderly people are at risk of repeated hospitalizations, some of which may be drug related and preventable. In 2011, a group of French healthcare experts selected 5 iatrogenic alerts (IAs), based on criteria identified in a literature search and from their professional experience, to assess the appropriateness of medication in elderly patients.
OBJECTIVES: Our objective was to examine the association between hospitalizations and IAs in elderly patients treated for Alzheimer disease who are particularly sensitive to adverse drug events.
DESIGN: A 2-year (January 1, 2011, to December 31, 2012) longitudinal national database study, with a study design similar to self-controlled case series, was performed to analyze data on drug prescriptions and hospitalization. IAs were defined as (1) long half-life benzodiazepine; (2) antipsychotic drugs in patients with Alzheimer disease; (3) co-prescription of 3 or more psychotropic drugs; (4) co-prescription of 2 or more diuretics; and (5) co-prescription of 4 or more antihypertensive drugs. Data were obtained by matching of 2 French National Health Insurance Databases.
SETTING: France.
PARTICIPANTS: All affiliates, aged ≥75 years, receiving treatment for Alzheimer disease, alive on January 1, 2011 were included.
MEASUREMENTS: We calculated the relative increase in the number of hospitalizations in patients with IAs. The analysis was performed over four 6-month periods.
RESULTS: A total of 10,754 patients were included. During the periods with IAs, hospitalization rates increased by 0.36/year compared with 0.23/year in the periods without for the same patient, and the number of hospitalizations doubled [proportional fold change = 1.9, 95% confidence interval (1.8, 2.1)]. We estimated that 22% [95% confidence interval (20%, 23%)] of all hospitalizations were associated with IAs, 80% of which were due to psychotropic IAs.
CONCLUSIONS: The IAs could be used as a simple and clinically relevant tool by prescribing physicians to assess the appropriateness of the prescription in elderly patients treated for Alzheimer disease.

PMID: 28330633 [PubMed - indexed for MEDLINE]

Gemcitabine as second-line chemotherapy after Folfirinox failure in advanced pancreatic adenocarcinoma: A retrospective study.

Dig Liver Dis. 2017 Jun;49(6):692-696

Authors: Viaud J, Brac C, Artru P, Le Pabic E, Leconte B, Bodère A, Pracht M, Le Sourd S, Edeline J, Lièvre A

Abstract
BACKGROUND: Pancreatic adenocarcinoma (PA) is diagnosed in most cases at an advanced stage requiring chemotherapy. Folfirinox is the standard first-line treatment. After Folfirinox failure, gemcitabine alone is routinely used as second-line therapy without data supporting this attitude.
AIM: Determine the response rate and outcome of patients with advanced PA treated with gemcitabine after Folfirinox failure.
METHODS: We retrospectively analyzed all consecutive patients treated with gemcitabine after Folfirinox failure for a locally advanced or metastatic PA between 2009 and 2015. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Response rate, control rate and tolerability were assessed.
RESULTS: 96 patients were included (male, 51%; median age, 62; performance status (PS) 0-1, 47%). Median duration on gemcitabine was 2.1 months. The overall disease control rate was 40%. Median OS was 3.7 months (95%CI: 2.5-5.2) and median PFS was 2.1 months (95%CI: 2.0-2.6). Reasons for treatment discontinuation were mostly progression (51%). Age at diagnosis and PS were independently associated with OS in multivariate analysis (HR of 1.86; p=0.0055 and 2.42; p<0.0001 respectively). 34 patients experienced a grade 3 adverse event.
CONCLUSIONS: This study suggests that gemcitabine is not beneficial to all patients failing on Folfirinox first-line therapy and should be restricted to young patients with good PS.

PMID: 28256401 [PubMed - indexed for MEDLINE]

Comprehensive Literature Review of Factors Influencing Medication Safety in Nursing Homes: Using a Systems Model.

J Am Med Dir Assoc. 2017 Jun 01;18(6):470-488

Authors: Al-Jumaili AA, Doucette WR

Abstract
OBJECTIVES: The objectives of this review were to identify the work system factors influencing medication safety measures [adverse drug events (ADEs), adverse drug reactions, or medication errors (MEs)], to determine the incidence of ADEs, and describe the most common ADEs in nursing homes (NHs).
METHODS: A comprehensive literature review was conducted using PubMed and CINAHL to identify studies investigating factors that influence ADEs, adverse drug reactions, and MEs in NHs and skilled nursing facilities. An initial search identified related studies over 3 decades (1985-2016). Studies were classified according to Systems Engineering Initiative for Patient Safety model factors.
RESULTS: Sixty studies were included in this review, which identifies 5 categories of work system factors affecting medication safety in NHs: persons (resident and staff), organization, tools and technology, tasks, and environment. The personal characteristics of NH residents included age, number and types of scheduled medications, and number and types of comorbidities. In addition, inadequate nursing staff medication knowledge and training are usually associated with administration MEs. Organizational factors include interprofessional collaboration, physician and pharmacist accessibility, and staff/resident ratio. A high staff number plays an essential role in preventing MEs and fracture incidents. The technology (barcode medication system) and tools (ME-reporting systems, ADE trigger tool, and potentially inappropriate medication criteria) can enhance the detection of MEs and ADEs. Workload and time pressure negatively impact NH staff task performance. Use of an ADE trigger tool by healthcare providers enhanced the ability to identify ADEs more than 50-fold over 6 months. Several environmental characteristics such as staff distraction and interruption negatively influence medication safety in NHs. The incidence rates of ADEs in NHs ranged from 1.89 to 10.8 per 100 resident-months. The most common ADEs were bleeding, thromboembolic events, hypoglycemia, falls, and constipation.
CONCLUSIONS: The Systems Engineering Initiative for Patient Safety model is a useful framework for investigating the factors contributing to ADEs. Multiple work-system factors affect the medication safety of NH residents. A comprehensive study is needed to quantify the influence of various work-system factors on ADEs in NHs.

PMID: 28242191 [PubMed - indexed for MEDLINE]

Review of targeted therapy in chronic lymphocytic leukemia: what a radiologist needs to know about CT interpretation.

Cancer Imaging. 2018 Apr 18;18(1):13

Authors: Gosangi B, Davids M, Somarouthu B, Alessandrino F, Giardino A, Ramaiya N, Krajewski K

Abstract
The last 5 years have been marked by profound innovation in the targeted treatment of chronic lymphocytic leukemia (CLL) and indolent lymphomas. Using CLL as a case study, we present a timeline and overview of the current treatment landscape for the radiologist, including an overview of clinical and radiological features of CLL, discussion of the targeted agents themselves, and the role of imaging in response and toxicity assessment. The goal is to familiarize the radiologist with multiple Food and Drug Administration (FDA)-approved targeted agents used in this setting and associated adverse events which are commonly observed in this patient population.

PMID: 29669600 [PubMed - in process]

Patients with platelet aggregation inhibitors in the dental office

Swiss Dent J. 2018 Apr 15;128(4):317-319

Authors: Yildirim A, Lübbers HT, Yildirim A

Abstract
Antiplatelet agents with the active ingredients acetylsalicylic acid (Aspirin® protect 100), clopidogrel (Iscover®, Plavix®), prasugrel (Efient®) or ticagrelor (Brilique™) prevent the clumping of platelets and thus the formation of small clots at constrictions of the coronary arteries or on the metal struts of stents in the coronary artery or in bypass grafts. Large-scale studies have shown that taken regularly, these drugs can extend life and help prevent heart attacks. Especially in patients with newly implanted stents, the combination of the above-mentioned agents prevents sudden complete occlusion of the vessel concerned. By paying careful attention to contraindications and pursuing the early detection of possible side effects, drug-induced complications can be prevented.

PMID: 29669404 [PubMed - in process]

Unexpected exacerbations following initiation of disease-modifying drugs in neuromyelitis optica spectrum disorder: Which factor is responsible, anti-aquaporin 4 antibodies, B cells, Th1 cells, Th2 cells, Th17 cells, or others?

Mult Scler. 2017 Aug;23(9):1300-1302

Authors: Kira JI

Abstract
Some disease-modifying drugs for multiple sclerosis, which mainly act on T cells, are ineffective for neuromyelitis optica spectrum disorder and induce unexpected relapses. These include interferon beta, glatiramer acetate, fingolimod, natalizumab, and alemtuzumab. The cases reported here suggest that dimethyl fumarate, which reduces the number of Th1 and Th17 cells and induces IL-4-producing Th2 cells, is also unsuitable for neuromyelitis optica spectrum disorder, irrespective of anti-aquaporin 4 IgG serostatus. Although oral dimethyl fumarate with manageable adverse effects is easy to initiate in the early course of multiple sclerosis, special attention should be paid for atypical demyelinating cases.

PMID: 28391741 [PubMed - indexed for MEDLINE]

Knowledge and characteristics of herbal supplement usage among community pharmacy customers in a Malaysian population.

Complement Ther Med. 2017 Dec;35:92-108

Authors: Yeong SW, Choong YC

Abstract
OBJECTIVES: We investigated the knowledge and characteristics of herbal supplement usage of the customers of community pharmacies in a Malaysian population.
DESIGN AND SETTING: Self-administered questionnaires (in English, Malay, or Chinese) were provided to customers at three community pharmacies in Malaysia (Ipoh, Perak). Questionnaire validation and translation validation were performed. A pilot study was conducted before actual questionnaire distribution. Informed consent was obtained from all participants.
RESULTS: Total number of participants was 270 (99 males and 171 females) with majority from the 31-50 age group (41.5%). Among the participants, 45.6% were herbal users. The most commonly used herbal supplements were evening primrose oil (17.9%), ginkgo biloba (13.0%), and milk thistle (8.5%). The participants seemed to have sufficient knowledge regarding herbal supplements including safety, quality, and indication of use from medical literature. Participants obtained information about herbal supplements from pharmacists (26.9%), package inserts (25.2%), friends (20.5%), and the Internet (13.3%) more often than from their doctors (9.8%). Most herbal users did not inform their doctors about their usage of herbal supplements (68.3%) or the side effects (61.5%). Herbal supplement users also tended to be women, >50-year-old, and those with higher monthly household incomes.
CONCLUSIONS: Community pharmacists have a vital role in educating their customers about the safe use of herbal supplements. The participants had sufficient knowledge about herbal supplement usage; therefore, customers of these community pharmacies may have benefitted from the advice of the pharmacists. Further studies could be carried out in future on the knowledge, skills and roles of community pharmacists in the safe use of herbal supplements.

PMID: 29154074 [PubMed - indexed for MEDLINE]

Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase®.

Pediatr Allergy Immunol. 2017 Nov;28(7):668-674

Authors: Meincke R, Pokladnikova J, Straznicka J, Meyboom RHB, Niedrig D, Russmann S, Jahodar L

Abstract
BACKGROUND: The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children.
OBJECTIVES: To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase® in children.
STUDY DESIGN: From the original VigiBase® extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions.
RESULTS: VigiBase® contained 2646 ICSRs with 14 860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12 years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%).
CONCLUSION: VigiBase® contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock.

PMID: 28846157 [PubMed - indexed for MEDLINE]

Acute kidney injury during treatment with high-dose cloxacillin: A report of 23 cases and literature review.

Int J Antimicrob Agents. 2018 Apr 14;:

Authors: Lavergne A, Vigneau C, Polard E, Triquet L, Rioux-Leclercq N, Tattevin P, Golbin L

Abstract
BACKGROUND: International guidelines recommend high-dose cloxacillin for endocarditis or osteoarticular infections due to meticillin-susceptible staphylococci. However, data on the tolerability of these regimens are scarce.
METHODS: We used the computerized registry of suspected drug-related adverse events in our institution. Cases of acute kidney injury (AKI), as defined by KDIGO, in patients receiving high-dose cloxacillin, were retrospectively reviewed. Data were collected from medical charts on a standardized questionnaire.
RESULTS: From 2009 to 2015, 23 consecutive patients (16 men, 7 women), with a median age of 75 years (interquartile range, IQR 66-80), fulfilled inclusion criteria. By the time of AKI diagnosis, patients were treated with a median cloxacillin dose of 12 g/day (IQR, 10-12), after a median duration of 7 days (IQR, 4-10). Most patients fulfilled RIFLE criteria for failure (n=20), with a median peak serum creatinine concentration of 339 µmol/L (IQR, 249-503). Urinalysis was suggestive of tubular disease in 7 patients, 3 had hypereosinophilia, and 8 had abnormal liver function tests. All patients presented at least one risk factor for AKI, including concomitant nephrotoxic drugs: gentamicin (n=19), diuretics (n=15), angiotensin-converting enzyme inhibitors (n=8), and angiotensin II receptor-blockers (n=6). Thirteen patients (57%) had cloxacilllin plasma concentrations >50 µg/mL. Thirteen patients (57%) had complete recovery of renal function.
CONCLUSIONS: AKI during high-dose cloxacillin treatment mostly occurs in elderly patients, with concomitant nephrotoxic drugs. The outcome is usually favorable after cloxacillin discontinuation. Therapeutic drug monitoring may decrease the risk of AKI in patients treated with high-dose cloxacillin.

PMID: 29665445 [PubMed - as supplied by publisher]

Introduction to Nephropharmacology for the Clinician: A New CJASN Series.

Clin J Am Soc Nephrol. 2018 Apr 16;:

Authors: Nolin TD, Perazella MA

PMID: 29661769 [PubMed - as supplied by publisher]

Optimization of drug therapy in elderly individuals admitted to a geriatric unit.

Clin Interv Aging. 2017;12:1691-1696

Authors: Piau A, Huet Y, Gallini A, Andre L, Vellas B, Nourhashemi F

Abstract
BACKGROUND: A substantial share of adverse drug events involves inappropriate prescribing (IP). Specialized geriatric units are supposed to pay particular attention to prescribing appropriateness and to promoting a higher prescribing quality.
OBJECTIVE: The objective of this study was to evaluate the reality of such assessment and optimization in real life (usual care) in a population of elderly individuals admitted to a geriatric unit.
METHOD: This is an observational study including all older patients admitted to an acute geriatric unit over a 6-month period. As part of usual care, the geriatrician is supposed to detect potentially inappropriate medication and potential prescribing omission using validated tools. The primary outcome was the prevalence rate of therapeutic modifications motivated by treatment optimization (stop, switch, or introduction). Multivariate logistic regression analyses were performed to identify the factors associated with therapeutic discontinuation.
RESULTS: A total of 216 patients were included. The mean age was 85.7 years. Included patients had an average of 7.2±3.3 drugs at admission and 5.8±2.7 at discharge. IP was highly prevalent in our study where about 63% of the patients had experienced at least one modification because of overuse. The most commonly discontinued medications were drugs used to treat gastroesophageal reflux disease and peptic ulcer disease and serotonin reuptake inhibitor antidepressants. The most commonly introduced medications were analgesics and warfarin. By using multivariate analysis, we found that patient age and number of drugs on admission were significantly associated with medication discontinuation during hospital stay.
CONCLUSION: In this real-life study of all patients admitted to a Geriatric Post Emergency Unit, 83% of the patients had a treatment modification during hospital stay. The most original result of our study is the clear reduction in polypharmacy during hospitalization.

PMID: 29066874 [PubMed - indexed for MEDLINE]

Effect of Herbal Medicines During Surgery.

Plast Surg Nurs. 2017 Jul/Sep;37(3):99

Authors: Powell A

PMID: 28858165 [PubMed - indexed for MEDLINE]

Target Safety Assessment: Strategies and Resources.

Methods Mol Biol. 2017;1641:213-228

Authors: Brennan RJ

Abstract
An in-depth evaluation of target safety is an invaluable resource throughout drug discovery and development. The goal of a target safety evaluation is to identify potential unintended adverse consequences of target modulation, and to propose a risk evaluation and mitigation strategy to shepherd compounds through the discovery and development pipeline, to confirm and characterize unavoidable on-target toxicities in a timely manner to assist in early program advancement decisions, and to anticipate, monitor, and manage potential clinical adverse events. The role of an experienced discovery toxicologist in synthesizing the available information into an actionable set of recommendations for a safety evaluation strategy is critical to its successful application in early discovery programs. This chapter presents a summary of some of the information types and sources that should be investigated, and approaches that can be taken to generate an early assessment of potential safety liabilities.

PMID: 28748467 [PubMed - indexed for MEDLINE]

Adverse drug reactions after intravenous rituximab infusion are more common in hematologic malignancies than in autoimmune disorders and can be predicted by the combination of few clinical and laboratory parameters: results from a retrospective, multicenter study of 374 patients.

Leuk Lymphoma. 2017 Nov;58(11):2633-2641

Authors: D'Arena G, Simeon V, Laurenti L, Cimminiello M, Innocenti I, Gilio M, Padula A, Vigliotti ML, De Lorenzo S, Loseto G, Passarelli A, Di Minno MND, Tucci M, De Feo V, D'Auria F, Silvestris F, Di Minno G, Musto P

Abstract
Rituximab is an effective treatment for CD20 + B-cell malignancies and autoimmune disorders. However, adverse drug reactions (ADRs) may occur after rituximab infusion, causing, in rare cases, its discontinuation. In this multicenter, retrospective study, among 374 patients treated with rituximab i.v., 23.5% experienced ADRs. Mean follow-up was 20.6 months (range 8-135). Overall, ADRs were significantly more frequent in non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemias (25-35.9%), than in autoimmune diseases (9.4-17.5%) (p < .0001). Grade 3-4 toxicity was observed in eight patients (2.1%), and in four of them (1% of all patients) definitive drug discontinuation was necessary. Interestingly, three groups of patients with different risk of developing ADR were identified, according to a predictive heat-map developed combining four parameters (splenomegaly, history of allergy, hemoglobin levels and gender) selected by multivariate analysis. This model may be useful in identifying patients at higher risk of ADRs, needing appropriate preventing therapies.

PMID: 28367662 [PubMed - indexed for MEDLINE]

Adverse drug reactions.

Dis Mon. 2017 Feb;63(2):49-53

Authors: Seagrave Z, Bamba S

PMID: 28034457 [PubMed - indexed for MEDLINE]

First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13).

Eur J Cancer. 2018 Apr 13;96:6-16

Authors: Wicki A, Brown N, Xyrafas A, Bize V, Hawle H, Berardi S, Cmiljanović N, Cmiljanović V, Stumm M, Dimitrijević S, Herrmann R, Prêtre V, Ritschard R, Tzankov A, Hess V, Childs A, Hierro C, Rodon J, Hess D, Joerger M, von Moos R, Sessa C, Kristeleit R

Abstract
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor.
PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).
RESULTS: Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed.
CONCLUSION: The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01940133.

PMID: 29660598 [PubMed - as supplied by publisher]

[Recurrent atypical hemolytic uremic syndrome after renal transplantation: treatment with eculizumab].

Medicina (B Aires). 2018;78(2):119-122

Authors: Latzke AB, Fernández P, Chiurchiu C, Sarmantano D, De Arteaga J, Douthat W, De la Fuente J

Abstract
Atypical hemolytic uremic syndrome (aHUS) is a rare entity. It is characterized by a thrombotic microangiopathy (nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure), with a typical histopathology of thickening of capillary and arteriolar walls and an obstructive thrombosis of the vascular lumen. The syndrome is produced by a genetic or acquired deregulation of the alternative pathway of the complement system, with high rates of end stage renal disease, post-transplant recurrence, and high mortality. Mutations associated with factor H, factor B and complement C3 show the worst prognosis. Even though plasma therapy is occasionally useful, eculizumab is effective both for treatment and prevention of post-transplant recurrence. We describe here an adult case of congenital aHUS (C3 mutation) under preventive treatment with eculizumab after renal transplantation, with neither disease recurrence nor drug-related adverse events after a 36-months follow-up.

PMID: 29659362 [PubMed - in process]

Longterm Safety and Efficacy of Adalimumab and Infliximab for Uveitis Associated with Juvenile Idiopathic Arthritis.

J Rheumatol. 2018 Apr 15;:

Authors: Cecchin V, Zannin ME, Ferrari D, Pontikaki I, Miserocchi E, Paroli MP, Bracaglia C, Marafon DP, Pastore S, Parentin F, Simonini G, De Libero C, Falcini F, Petaccia A, Filocamo G, De Marco R, La Torre F, Guerriero S, Martino S, Comacchio F, Muratore V, Martini G, Vittadello F, Zulian F

Abstract
OBJECTIVE: Anti-TNF-α agents have significantly changed the management of juvenile idiopathic arthritis (JIA). We evaluated the safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of JIA-associated uveitis in patients treated for ≥ 2 years.
METHODS: Patients with JIA-associated uveitis treated with IFX and ADA were managed by a standardized protocol and data were entered in the ORCHIDEA registry. At baseline, all patients were refractory to standard immunosuppressive treatment or were corticosteroid-dependent. Data recorded every 3 months were uveitis course, number/type of ocular flares and complications, drug-related adverse events (AE), and treatment switch or withdrawal. Data of patients treated for ≥ 2 years were analyzed by descriptive statistics.
RESULTS: Up to December 2014, 154 patients with ≥ 24 months followup were included in the study. Fifty-nine patients were treated with IFX and 95 with ADA. Clinical remission, defined as the absence of flares for > 6 months on treatment, was achieved in 69 patients (44.8%), with a better remission rate for ADA (60.0%) as compared to IFX (20.3%; p < 0.001). A significant reduction of flares was observed in all patients without difference between the 2 treatment modalities. The number of new ocular complications decreased in both groups but was lower for ADA (p = 0.015). No serious AE were recorded; 16.4% of patients experienced 35 minor AE and the incidence rate was lower with ADA than with IFX.
CONCLUSION: At the 2-year followup, ADA showed a better efficacy and safety profile than IFX for the treatment of refractory JIA-associated uveitis.

PMID: 29657140 [PubMed - as supplied by publisher]

Exploring the effect of end-binding proteins and microtubule targeting chemotherapy drugs on microtubule dynamic instability.

J Theor Biol. 2017 Sep 21;429:18-34

Authors: White D, Honoré S, Hubert F

Abstract
Microtubules (MTs) play a key role in normal cell development and are a primary target for many cancer chemotherapy MT targeting agents (MTAs). As such, understanding MT dynamics in the presence of such agents, as well as other proteins that alter MT dynamics, is extremely important. In general, MTs grow relatively slowly and shorten very fast (almost instantaneously), an event referred to as a catastrophe. These dynamics, referred to as dynamic instability, have been studied in both experimental and theoretical settings. In the presence of MTAs, it is well known that such agents work by suppressing MT dynamics, either by promoting MT polymerization or promoting MT depolymerization. However, recent in vitro experiments show that in the presence of end-binding proteins (EBs), low doses of MTAs can increase MT dynamic instability, rather than suppress it. Here, we develop a novel mathematical model, to describe MT and EB dynamics, something which has not been done in a theoretical setting. Our MT model is based on previous modeling efforts, and consists of a pair of partial differential equations to describe length distributions for growing and shortening MT populations, and an ordinary differential equation (ODE) system to describe the time evolution for concentrations of GTP- and GDP-bound tubulin. A new extension of our approach is the use of an integral term, rather than an advection term, to describe very fast MT shortening events. Further, we introduce an ODE system to describe the binding and unbinding of EBs with MTs. To compare simulation results with experiment, we define novel mathematical expressions for time- and distance-based catastrophe frequencies. These quantities help to define MT dynamics in in vivo and in vitro settings. Simulation results show that increasing concentrations of EBs work to increase time-based catastrophe while distance-based catastrophe is less affected by changes in EB concentration, a result that is consistent with experiment. We further describe how EBs and MTAs alter MT dynamics. In the context of this modeling framework, we show that it is likely that MTAs and EBs do not work independently from one another. Thus, we propose a mechanism for how EBs can work synergistically with MTAs to promote MT dynamic instability at low MTA dose.

PMID: 28645857 [PubMed - indexed for MEDLINE]