Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial.

Arterioscler Thromb Vasc Biol. 2019 Jan 31;:ATVBAHA118312328

Authors: Lorentz CU, Verbout NG, Wallisch M, Hagen MW, Shatzel JJ, Olson SR, Puy C, Hinds MT, McCarty OJT, Gailani D, Gruber A, Tucker EI

Abstract
Objective- Factor XI (FXI) contributes to thrombotic disease although playing a limited role in normal hemostasis. We generated a unique, humanized anti-FXI antibody, AB023, which blocks factor XIIa-mediated FXI activation without inhibiting FXI activation by thrombin or the procoagulant function of FXIa. We sought to confirm the antithrombotic activity of AB023 in a baboon thrombosis model and to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adult subjects. Approach and Results- In a primate model of acute vascular graft thrombosis, AB023 reduced platelet and fibrin accumulation within the grafts by >75%. To evaluate the safety of AB023, we performed a first-in-human study in healthy adult volunteers without any serious adverse events. Overall, 10 of 21 (48%) subjects experienced 20 treatment-emergent adverse events, with 7 of 16 (44%) subjects following active treatment and 3 of 5 (60%) subjects following placebo. AB023 did not increase bleeding or prothrombin times. Anticoagulation was verified by a saturable ≈2-fold prolongation of the partial thromboplastin time for over 1 month after the highest dose. Conclusions- AB023, which inhibits contact activation-initiated blood coagulation in vitro and experimental thrombus formation in primates, produced a dose-dependent duration of limited anticoagulation without drug-related adverse effects in a phase 1 trial. When put in context with earlier observations suggesting that FXI contributes to venous thromboembolism and cardiovascular disease, although contributing minimally to hemostasis, our data further justify clinical evaluation of AB023 in conditions where contact-initiated FXI activation is suspected to have a pathogenic role. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03097341.

PMID: 30700130 [PubMed - as supplied by publisher]

Clinically Significant Food-Drug Interactions.

Consult Pharm. 2018 Nov 01;33(11):649-657

Authors: Ased S, Wells J, Morrow LE, Malesker MA

Abstract
OBJECTIVE: Provide an up-to-date review for health care providers regarding clinically significant food-drug interactions and summarize recommendations for optimal medication administration in older adults and long-term care patients. DATA SOURCES: A literature search was performed using MEDLINE, PUBMED, and IPA abstracts to locate relevant articles published between January 1982 and July 2017. DAILYMED was used to identify manufacturer-specific medication administration recommendations. STUDY SELECTION AND DATA EXTRACTION: Articles were reviewed for inclusion based on their relevance to this subject matter and the integrity of the information provided. Additionally, the package labeling of included products was reviewed. DATA SYNTHESIS: The current recommendations for specific medication administration with regard to food are summarized descriptively. CONCLUSION: Clinically significant food-drug interactions are common and have been reported with multiple classes of medications. However, there are a limited number of studies examining food-drug interactions, and the majority of recommendations are made by product-specific manufacturers. Pharmacists should be aware of common food-drug interactions in the community, assisted living, long-term care, subacute care, and hospital settings. To optimize medication therapy and improve therapeutic outcomes, it is important for pharmacists and other health care providers to identify agents with potential for food-drug interactions and to understand the clinical relevance of such interactions.

PMID: 30458907 [PubMed - indexed for MEDLINE]

[How I manage drug therapy failure].

Rev Med Liege. 2018 Oct;73(10):488-491

Authors: Scheen AJ

Abstract
Drug therapy failure may occur with any medical intervention. It is badly accepted by both the physician and the patient. Drug failure may be attributed to the physician, the patient, the medication or the severity of the disease itself. Once drug failure is confirmed, causes should rapidly be identified in order to find a solution because several ones may often be offered.

PMID: 30335252 [PubMed - indexed for MEDLINE]

Increased risk of myocardial infarction with dabigatran etexilate: fact or fiction? A critical meta-analysis of over 580,000 patients from integrating randomized controlled trials and real-world studies.

Int J Cardiol. 2018 Sep 15;267:1-7

Authors: Wei AH, Gu ZC, Zhang C, Ding YF, Liu D, Li J, Liu XY, Lin HW, Pu J

Abstract
BACKGROUND: The question of whether the use of dabigatran etexilate is associated with a high risk of myocardial infarction (MI) remains unanswered owing to the lack of critical evidences.
METHODS: A comprehensive search of databases (Medline, Embase, Cochrane Library databases, and ClinicalTrials.gov Website) was performed for RCTs that reported MI events and observational nationwide database studies that reported adjusted hazard ratio (HR) with dabigatran treatment. Summary HRs and 95% confidence intervals (95% CI) were calculated using random-effects models. Cumulative meta-analysis was conducted for evaluating the results as a continuum, and subgroup analyses were undertaken on the basis of study type, indication, controls, and dosage.
RESULTS: Finally, 24 studies including 588,047 patients (44,856 patients in 14 RCTs and 543,191 patients in 10 observational database studies) met the inclusion criteria, among which 222,352 (37.8%) patients receiving dabigatran and 365,695 (62.2%) patients receiving placebo/other anticoagulants. In comparison to controls, no significant association was detected between the use of dabigatran and the higher risk of MI (HR: 0.97, 95% CI: 0.87-1.06; I2 for heterogeneity: 26.3%, P = 0.089). The results were consistent across the key subgroups (indication, controls, and dosage, Pinteraction > 0.05 for each), with the exception of study type (RCTs or database studies, Pinteraction = 0.046). Cumulative meta-analysis was not suggestive of a temporal trend in the effect of dabigatran on MI.
CONCLUSIONS: This meta-analysis confirms a low risk of MI in patients exposed to dabigatran, which seems to be validated when pooling over 580,000 patients from RCTs and real-world studies.

PMID: 29801762 [PubMed - indexed for MEDLINE]

Detection of drug safety signals from clinical trials data: Role of SUSARs.

Pharmacol Res. 2018 05;131:218-223

Authors: Perez C, Olivier P, Lortal B, Duranton S, Montastruc JL, Colin AL, Toulza E, Becker M, Hamy L, Crepin S, Roussillon C, Gimbert A, Petitpain N, Salvo F

Abstract
One of the main goals of safety management in clinical trials is to detect suspected unexpected serious adverse reactions (SUSARs). The unexpectedness concerns the nature, frequency or severity of an adverse reaction. Drug safety signals could thus be retrieved, and a study was performed to investigate whether SUSARs allow signal detection in pharmacovigilance. Data from six academic safety units were collected from 2005 to 2016. Characteristics of SUSARs were analysed and signals were identified i) by evaluating the presence of other causes, ii) by assessing the summary of product characteristics (SPC), iii) by searching for specific safety information in Pubmed and health agencies, and iv) by investigating the narrative of each case. Pharmacological plausibility was evaluated by compatible mechanism of reaction and time-to-onset. During the study period, 211 SUSARs were collected. They mostly concerned general disorders (26.1%) and protein kinase inhibitors (24.6%). After eliminating SUSARs with other causes or those considered as expected, 50 SUSARs (23.7%), involving a total of 115 drug-reaction pairs, concerned potential safety signals. Among these pairs, 12 (10.4%) were considered as pharmacologically plausible. This study indicates that one quarter of SUSARs collected in academic clinical trials refers to potential safety signals, especially for oncologic drugs. One tenth of drug-reaction pairs was considered to have a pharmacological plausibility and could merit further evaluation. This is the first study suggesting that SUSARs could be a source of safety signals and that their routine analysis should be complementary to spontaneous reporting.

PMID: 29444478 [PubMed - indexed for MEDLINE]

Dabigatran after Short Heparin Anticoagulation for Acute Intermediate-Risk Pulmonary Embolism: Rationale and Design of the Single-Arm PEITHO-2 Study.

Thromb Haemost. 2017 12;117(12):2425-2434

Authors: Klok FA, Ageno W, Barco S, Binder H, Brenner B, Duerschmied D, Empen K, Faggiano P, Ficker JH, Galiè N, Ghuysen A, Held M, Heydenreich N, Huisman MV, Jiménez D, Kozak M, Lang IM, Lankeit M, Münzel T, Petris A, Pruszczyk P, Quitzau K, Schellong S, Schmidt KH, Stefanovic BS, Verschuren F, Wolf-Puetz A, Meyer G, Konstantinides SV, PEITHO-2 Investigators

Abstract
Patients with intermediate-risk pulmonary embolism (PE) may, depending on the method and cut-off values used for definition, account for up to 60% of all patients with PE and have an 8% or higher risk of short-term adverse outcome. Although four non-vitamin K-dependent direct oral anticoagulants (NOACs) have been approved for the treatment of venous thromboembolism, their safety and efficacy as well as the optimal anticoagulation regimen using these drugs have not been systematically investigated in intermediate-risk PE. Moreover, it remains unknown how many patients with intermediate-high-risk and intermediate-low-risk PE were included in most of the phase III NOAC trials. The ongoing Pulmonary Embolism International Thrombolysis 2 (PEITHO-2) study is a prospective, multicentre, multinational, single-arm trial investigating whether treatment of acute intermediate-risk PE with parenteral heparin anticoagulation over the first 72 hours, followed by the direct oral thrombin inhibitor dabigatran over 6 months, is effective and safe. The primary efficacy outcome is recurrent symptomatic venous thromboembolism or death related to PE within the first 6 months. The primary safety outcome is major bleeding as defined by the International Society on Thrombosis and Haemostasis. Secondary outcomes include all-cause mortality, the overall duration of hospital stay (index event and repeated hospitalizations) and the temporal pattern of recovery of right ventricular function over the 6-month follow-up period. By applying and evaluating a contemporary risk-tailored treatment strategy for acute PE, PEITHO-2 will implement the recommendations of current guidelines and contribute to their further evolution.

PMID: 29212130 [PubMed - indexed for MEDLINE]

Regional Differences in Antithrombotic Treatment for Atrial Fibrillation: Insights from the GLORIA-AF Phase II Registry.

Thromb Haemost. 2017 12;117(12):2376-2388

Authors: Mazurek M, Huisman MV, Rothman KJ, Paquette M, Teutsch C, Diener HC, Dubner SJ, Halperin JL, Ma CS, Zint K, Elsaesser A, Lu S, Lip GYH, GLORIA-AF Investigators

Abstract
Introduction Although guideline-adherent antithrombotic therapy (ATT) for stroke prevention in atrial fibrillation (AF) is associated with lower mortality and thromboembolism, ATT uptake shows geographic variation worldwide. We aimed to assess thromboembolic risk and baseline ATT by geographic region and identify factors associated with prescription of ATT in a large, truly global registry of patients with recently diagnosed AF. Methods and Results Our analysis comprises 15,092 patients newly diagnosed with non-valvular AF at risk for stroke, enrolled in Phase II of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF). Global oral anticoagulation (OAC) use was 79.9%, being highest in Europe (90.1%), followed by Africa/Middle East (87.4%) and Latin America (85.3%), North America (78.3%) and Asia (55.2%). Among OAC users, vitamin K antagonists (VKAs) have been replaced by non-VKA OACs (NOACs) as the more prevalent OAC option in all regions, with highest use in North America (66.5%) and lowest in Asia (50.2%). In Asia, OAC was 80.4% in community hospitals but only 49.8% in university hospitals and 42.6% in specialist offices, and varied from 21.0% in China to 89.7% in Japan (NOACs at 5.8% in China and 83.3% in Japan). Globally, 76.5% of low-risk patients were prescribed ATT (46.1% OAC), whereas 17.7% high-risk patients were not anticoagulated (Europe 8.8%; North America 18.9%; Asia 42.4%). Conclusion Substantial inter- and intra-regional differences in ATT for stroke prevention in AF are evident in this global registry. While guideline-adherent ATT can be further improved, NOACs are the main contributor to high OAC use worldwide.

PMID: 29212125 [PubMed - indexed for MEDLINE]

Renal Function, Time in Therapeutic Range and Outcomes in Warfarin-Treated Atrial Fibrillation Patients: A Retrospective Analysis of Nationwide Registries.

Thromb Haemost. 2017 12;117(12):2291-2299

Authors: Bonde AN, Lip GYH, Kamper AL, Staerk L, Torp-Pedersen C, Gislason G, Olesen JB

Abstract
Patients with severely reduced renal function have been excluded from randomized controlled trials of oral anticoagulation in atrial fibrillation (AF). Warfarin treatment in this population is controversial and data on anticoagulation control and the impact on adverse outcomes are needed. By individual-level linkage of nationwide registries, we identified all patients discharged from hospitals with AF in Denmark between 1997 and 2011. Patients with available serum creatinine tests were categorized according to the estimated glomerular filtration rate (eGFR). Time in therapeutic range (TTR) was calculated using the Rosendaal method. The risk of stroke and bleeding was estimated using multivariable Cox regression analyses with eGFR and TTR estimated time dependently throughout follow-up. We identified 10,423 warfarin-treated AF patients with available international normalized ratio and creatinine tests; 5,527 with eGFR > 60 mL/min/1.73 m2, 4,524 with eGFR 30–60 mL/min/1.73 m2 and 372 with eGFR < 30 mL/min/1.73 m2. Median TTR was 66.7, 61.2 and 49.7% in patients with eGFR > 60, 30–59 and <30 mL/min/1.73 m2, respectively. A TTR < 70% was associated with a higher risk of stroke/thromboembolism (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.20–1.60) and bleeding (HR: 1.22; 95% CI: 1.05–1.42) among patients with eGFR of 30 to 59 and a trend towards higher risk of stroke/thromboembolism (HR: 1.24; 95% CI: 0.86–1.80) and bleeding (HR: 1.17; 95% CI: 0.83–1.65) among patients with eGFR < 30 mL/min/1.73 m2. In conclusion, warfarin-treated AF patients with reduced renal function have suboptimal anticoagulation control which was related to the risk of adverse outcomes.

PMID: 29212117 [PubMed - indexed for MEDLINE]

A Randomized, Double-Blinded, Placebo-Controlled, Dose-Escalation Phase 1 Study of Aerosolized Pirfenidone Delivered via the PARI Investigational eFlow Nebulizer in Volunteers and Patients with Idiopathic Pulmonary Fibrosis.

J Aerosol Med Pulm Drug Deliv. 2019 Jan 30;:

Authors: Khoo JK, Montgomery AB, Otto KL, Surber M, Faggian J, Lickliter JD, Glaspole I

Abstract
BACKGROUND: This clinical trial evaluated the pharmacokinetics and safety/tolerability of inhaled pirfenidone solution in volunteers and patients with idiopathic pulmonary fibrosis (IPF).
METHODS: Forty-four adults in six cohorts consented to receive single doses of a 12.5 mg/mL pirfenidone solution or placebo to assess tolerability and pharmacokinetics. Cohorts 1, 2, and 3 (normal healthy volunteers [NHV]) (n = 6 active; n = 2 placebo in each cohort) received 25, 50, and 100 mg pirfenidone, respectively. Cohort 4 (NHV) (n = 6 all active) received 100 mg of pirfenidone and underwent bronchoalveolar lavage (BAL) to measure epithelial lining fluid (ELF) pirfenidone concentrations. Cohort 5 (prior or current smokers with greater than 20 pack-year use) (n = 6 active; n = 2 placebo) and Cohort 6 (IPF patients) (n = 6 all active) received 100 mg of pirfenidone. All treatments were administered with an Investigational eFlow® Nebulizer System (PARI Pharma GmbH). Serial measures of urine and plasma pirfenidone were collected during the 24-hour postdose in all subjects.
RESULTS: Administration time ranged from 1.4 to 2 min/mL. No clinically relevant adverse effects on respiratory rate, spirometry, or oxygenation were observed. Drug-related adverse events were predominantly cough, n = 8/44 (one in IPF cohort), all mild, transient, and not dose limiting. Mean plasma pirfenidone Cmax levels in the 25, 50, 100 mg NHV, 100 mg smoker, and IPF cohorts were 202, 292, 802, 1370, 1016, and 1026 ng/mL, respectively. BAL cohort estimated ELF Cmax was 135.9 ± 54.5 μg/mL. In the BAL and IPF cohorts, 24-hour urine excretion of pirfenidone and metabolites data suggests similar alveolar deposition.
CONCLUSIONS: Aerosol pirfenidone was well tolerated in normal volunteers, smokers, and IPF patients. High ELF concentrations were achieved in NHV with a 100 mg nebulizer dose. The 100 mg nebulizer dose averaged a 15-fold lower systemic pirfenidone exposure than reported with oral administration of the licensed oral dose.

PMID: 30698487 [PubMed - as supplied by publisher]

Switching to paliperidone extended release in patients with schizophrenia dissatisfied with previous olanzapine treatment: Post hoc analysis of an open-label, prospective study.

Medicine (Baltimore). 2019 Jan;98(3):e13688

Authors: Si TM, Cai SL, Zhuo JM, Zhang LL

Abstract
OBJECTIVE: This post hoc analysis of an open-label, single-arm, multicenter study was designed to assess the efficacy, safety, and tolerability of paliperidone extended release (ER) in Chinese patients with non-acute schizophrenia, after switching from olanzapine.
METHODS: Patients with schizophrenia who were dissatisfied with prior olanzapine treatment switched to flexible paliperidone ER (3-12 mg/day) based on clinical judgment. Change from baseline to week 12 in Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint), PANSS subscale scores, response rate, Clinical Global Impression-Severity (CGI-S) score, personal and social performance (PSP) scores, patient satisfaction with treatment score, change in sleep quality, level of daytime sleepiness and safety were evaluated.
RESULTS: Out of 118 enrolled patients, 95 (81%) completed the study. Mean duration of study was 76.9 (23.85) days. The primary endpoint, mean (SD) PANSS total score changed significantly from baseline to endpoint (-19.6 [18.71], P <.0001). Secondary endpoints including PANSS subscale score, PSP, patient satisfaction and daytime drowsiness also significantly improved (P <.001). Most commonly reported (≥1%) treatment-emergent adverse events were akathisia (n = 14 [12%]) and insomnia (n = 9 [8%]).
CONCLUSIONS: Switching to flexible-dosed paliperidone ER in patients dissatisfied with prior olanzapine treatment achieved good efficacy and tolerability consistently over 12 weeks.

PMID: 30653088 [PubMed - indexed for MEDLINE]

Comparison of efficacy and safety of preventive measures used against canine leishmaniasis in southern European countries: Longitudinal retrospective study in 1647 client-owned dogs (2012-2016).

Vet Parasitol. 2018 Nov 15;263:10-17

Authors: Fernandez M, Tabar MD, Arcas A, Mateu C, Homedes J, Roura X

Abstract
The best preventive strategy for canine leishmaniasis is, to date, unknown. In the last few years, new preventive measures have become available in Europe, including vaccination against leishmaniasis and the use of domperidone. The objective of the present study was to evaluate the efficacy and safety of the different preventive measures available against leishmaniasis in client-owned dogs. A database search of medical records was carried out in 52 private veterinary practices located in endemic areas of canine leishmaniasis in Spain, Italy and Portugal. Healthy seronegative dogs were included in the study. Serology was repeated at least 6 months later, and was used to retrospectively classify dogs into healthy, infected or sick. A total of 1647 dogs were included in the study. The use of preventive measures in this population was widespread. The single most utilized measure was repellents alone in 45.7% of dogs, followed by the combination of repellents and vaccination in 23.0%, repellents and domperidone in 11.3%, vaccination alone in 4.2%, vaccination and domperidone in 2.7%, domperidone alone in 2.3%, and the combination of the three measures in 0.2% of dogs. No preventive measure was applied in 10.7% dogs. The incidence of clinical leishmaniasis in the group with no preventive treatment applied was 12.5%. In the groups where prevention was applied, the reported incidence was the following: 10.1% for the vaccination only group, 4.5% for repellents only group, 4.0% for repellents + vaccination group, and 0.5% for repellents + domperidone group. No dogs in the groups of domperidone, vaccination + domperidone, and combination of the three measures developed clinical leishmaniasis. All preventive measures resulted in a significantly lower incidence of leishmaniasis compared to not applying any measure, except for vaccination alone. The majority of preventive strategies used, with exception of vaccination alone, decreased the incidence of leishmaniasis significantly. Adverse events, mild and self-limiting in most of the cases, were reported in 5.2% of dogs and were significantly more common in dogs following vaccination. In conclusion, this is the first large-scale field study investigating the efficacy and safety of the preventive measures used routinely against leishmaniasis in client-owned dogs. Most preventive strategies used, with exception of vaccination alone, had some benefit over not applying any preventive. In this field study, the use of repellents showed a good degree of protection in dogs living in endemic areas of canine leishmaniasis. Although lower numbers of dogs are included, the use of domperidone appeared to provide additional protection. The role of vaccination and its combination with other preventive strategies needs further study.

PMID: 30389018 [PubMed - indexed for MEDLINE]

Amantadine-induced livedo reticularis in a child treated off label for neurobehavioral disorders.

Cutis. 2018 Sep;102(3):E8-E9

Authors: Helmandollar KJ, Hoverson KR, Meyerle JH

Abstract
We report the case of an 8-year-old boy who was taking amantadine off label for multiple childhood neurobehavioral disorders and subsequently developed livedo reticularis. Although this side effect is well-described in adult patients taking amantadine for Parkinson disease, it is now being seen in children as the off-label use of amantadine is expanded to this population.

PMID: 30372725 [PubMed - indexed for MEDLINE]

Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

Lancet HIV. 2018 07;5(7):e357-e365

Authors: Molina JM, Ward D, Brar I, Mills A, Stellbrink HJ, López-Cortés L, Ruane P, Podzamczer D, Brinson C, Custodio J, Liu H, Andreatta K, Martin H, Cheng A, Quirk E

Abstract
BACKGROUND: Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection.
METHODS: In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120.
FINDINGS: Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group.
INTERPRETATION: The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection.
FUNDING: Gilead Sciences.

PMID: 29925489 [PubMed - indexed for MEDLINE]

Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail.

Clin Microbiol Infect. 2018 Dec;24(12):1344.e1-1344.e4

Authors: Crespillo-Andújar C, Chamorro-Tojeiro S, Norman F, Monge-Maillo B, López-Vélez R, Pérez-Molina JA

Abstract
OBJECTIVE: To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole.
METHODS: We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs.
RESULTS: A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths.
CONCLUSIONS: Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.

PMID: 29906591 [PubMed - indexed for MEDLINE]

Dose-escalation strategies which use subgroup information.

Pharm Stat. 2018 09;17(5):414-436

Authors: Cotterill A, Jaki T

Abstract
Dose-escalation trials commonly assume a homogeneous trial population to identify a single recommended dose of the experimental treatment for use in future trials. Wrongly assuming a homogeneous population can lead to a diluted treatment effect. Equally, exclusion of a subgroup that could in fact benefit from the treatment can cause a beneficial treatment effect to be missed. Accounting for a potential subgroup effect (ie, difference in reaction to the treatment between subgroups) in dose-escalation can increase the chance of finding the treatment to be efficacious in a larger patient population. A standard Bayesian model-based method of dose-escalation is extended to account for a subgroup effect by including covariates for subgroup membership in the dose-toxicity model. A stratified design performs well but uses available data inefficiently and makes no inferences concerning presence of a subgroup effect. A hypothesis test could potentially rectify this problem but the small sample sizes result in a low-powered test. As an alternative, the use of spike and slab priors for variable selection is proposed. This method continually assesses the presence of a subgroup effect, enabling efficient use of the available trial data throughout escalation and in identifying the recommended dose(s). A simulation study, based on real trial data, was conducted and this design was found to be both promising and feasible.

PMID: 29900666 [PubMed - indexed for MEDLINE]

Potentially Inappropriate Medication Prescribing and Risk of Unplanned Hospitalization among the Elderly: A Self-Matched, Case-Crossover Study.

Drug Saf. 2018 10;41(10):959-968

Authors: Sato I, Yamamoto Y, Kato G, Kawakami K

Abstract
INTRODUCTION/OBJECTIVES: An association between potentially inappropriate medication (PIM) use and adverse events has been established. However, PIM criteria for elderly patients and medical circumstance vary in different countries. We investigated the association between PIM use according to Japanese guidelines and unplanned hospitalization among elderly patients.
DESIGN: A case-crossover study was conducted.
SETTING/PARTICIPANTS: We used the Japanese Medical Data Vision database of 17.9 million people from 270 acute care hospitals across Japan. Records from 247,897 patients aged ≥ 65 years with unscheduled admissions between January 2009 and December 2015 were analyzed.
MEASUREMENTS: We defined PIM use according to the Japanese Guidelines for Medical Treatment and Its Safety in the Elderly and used conditional logistic regression analysis to fit self-matched case-crossover models and compared each patient's PIM use over five case periods (1, 2, 4, 8, and 12 weeks) prior to each unplanned hospitalization.
RESULTS: We found the highest odds ratios (ORs) of unscheduled admission related to PIM use in the 1-week case period [OR 4.15; 95% confidence interval (CI) 4.05-4.25], followed by the 2-week (OR 3.01; 95% CI 2.95-3.07), 4-week (OR 3.91; 95% CI 3.83-4.00), 8-week (OR 2.00; 95% CI 1.96-2.05), and 12-week case periods (OR 1.48; 95% CI 1.44-1.51).
CONCLUSIONS: Elderly patients commonly used PIMs, especially antidiabetics and diuretics. PIM use was associated with a 1.5- to 4-fold increase in the ORs of unplanned hospitalization among them.

PMID: 29714005 [PubMed - indexed for MEDLINE]

Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species.

Mycoses. 2018 Jul;61(7):485-497

Authors: Marty FM, Cornely OA, Mullane KM, Ostrosky-Zeichner L, Maher RM, Croos-Dabrera R, Lu Q, Lademacher C, Oren I, Schmitt-Hoffmann AH, Giladi M, Rahav G, Perfect JR

Abstract
The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species.

PMID: 29611227 [PubMed - indexed for MEDLINE]

Efficacy and safety of sarolaner in the treatment of canine ear mite infestation caused by Otodectes cynotis: a non-inferiority study.

Vet Dermatol. 2018 Apr;29(2):100-e39

Authors: Becskei C, Cuppens O, Mahabir SP

Abstract
BACKGROUND: Various treatments are available for ear mite infestations in dogs.
OBJECTIVE: The efficacy of sarolaner was evaluated against ear mite infestation caused by Otodectes cynotis in dogs and compared with topical moxidectin/imidacloprid in a single-masked, multi-centre field study.
ANIMALS: Client-owned dogs with O. cynotis infestation were treated monthly with oral sarolaner (n = 163) or topical moxidectin/imidacloprid (n = 78).
METHODS: The presence of mites in the ear canals and the clinical signs associated with otoacariasis (including head shaking, pruritus/ear scratching, trauma or alopecia of the pinnae, and erythema, ulceration and debris in the ear canals) was evaluated on days 0, 14 and 30, and, if applicable, on day 60. Dogs were considered cured of mite infestation following one (on day 0) or two (on days 0 and 30) monthly treatments, if no live mites were found in either ear. Non-inferiority was evaluated at days 14 and 30.
RESULTS: Parasitological cure was achieved in 76.4%, 90.5% and 93.3% of the sarolaner-treated and in 53.9%, 63.5% and 66.7% of the moxidectin/imidacloprid-treated dogs on days 14, 30 and 60, respectively. At study completion, on day 60 at the latest, parasitological cure was achieved overall in 99.4% of sarolaner-treated and 87.8% of moxidectin/imidacloprid-treated cases. The parasitological cure rate for sarolaner was non-inferior to moxidectin/imidacloprid at days 14 and 30. The clinical signs of otoacariasis improved throughout the study in both groups. There were no treatment-related adverse events.
CONCLUSIONS: A single oral administration of sarolaner was safe and highly effective in the treatment of O. cynotis infestation in dogs.

PMID: 29392787 [PubMed - indexed for MEDLINE]

Prevalence of and Risk Factors for Extrapyramidal Side Effects of Antipsychotics: Results From the National FACE-SZ Cohort.

J Clin Psychiatry. 2019 Jan 08;80(1):

Authors: Misdrahi D, Tessier A, Daubigney A, Meissner WG, Schurhoff F, Boyer L, Godin O, Bulzacka E, Aouizerate B, Andrianarisoa M, Berna F, Capdevielle D, Chereau-Boudet I, D'Amato T, Dubertret C, Dubreucq J, Faget-Agius C, Lançon C, Mallet J, Passerieux C, Rey R, Schandrin A, Urbach M, Vidailhet P, Llorca PM, Fond G, FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) Group

Abstract
BACKGROUND: Extrapyramidal side effects (EPS) have been identified as a complication of antipsychotic treatment. Previous meta-analyses have investigated EPS prevalence and risk factors in randomized clinical trials with highly selected patients, but studies in real-world schizophrenia are missing.
OBJECTIVE: To examine the prevalence and clinical correlates associated with EPS in a nonselected national multicenter sample of stabilized patients with schizophrenia.
METHODS: Between 2010 and 2016, patients suffering from schizophrenia (DSM-IV-TR criteria) were recruited through the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) network and data were collected during a comprehensive 1-day-long standardized evaluation. The Simpson-Angus Scale and the Abnormal Involuntary Movement Scale were used to assess drug-induced parkinsonism (DIP) and tardive dyskinesia, respectively.
RESULTS: The overall prevalence of DIP and tardive dyskinesia was 13.2% and 8.3%, respectively, in this community-dwelling sample of 674 patients. DIP was associated with negative symptoms (Positive and Negative Syndrome Scale [PANSS] subscore) (adjusted odds ratio [aOR] = 1.102, P < .001), first-generation antipsychotic prescription (aOR = 2.038, P = .047), and anticholinergic drug administration (aOR = 2.103, P = .017) independently of sex, age, disorganization (PANSS disorganized factor), and antipsychotic polytherapy. Tardive dyskinesia was associated with PANSS disorganized factor (aOR = 1.103, P = .049) independently of sex, age, negative symptoms, excitation, first-generation antipsychotic prescription, and benzodiazepine and anticholinergic drug administration.
CONCLUSIONS: Our results indicate the high prevalence of EPS in a nonselected community-dwelling clinically stable sample of outpatients with schizophrenia. In the monitoring of antipsychotic treatment, EPS should be systematically evaluated, especially when negative symptoms and disorganization or cognitive alteration are present. Monotherapy with a second-generation antipsychotic should be preferentially initiated for patients with these side effects.

PMID: 30695288 [PubMed - in process]

Biology of Heme: Drug Interactions and Adverse Drug Reactions with CYP450.

Curr Top Med Chem. 2019;18(23):2042-2055

Authors: Kumar N, Chugh H, Sood D, Singh S, Singh A, Awasthi AD, Tomar R, Tomar V, Chandra R

Abstract
Heme is central to functions of many biologically important enzymes (hemoproteins). It is an assembly of four porphyrin rings joined through methylene bridges with a central Fe (II). Heme is present in all cells, and its synthesis and degradation balance its amount in the cell. The deregulations of heme networks and incorporation in hemoproteins lead to pathogenic state. This article addresses the detailed structure, biosynthesis, degradation, and transportation associated afflictions to heme. The article is followed by its roles in various diseased conditions where it is produced mainly as the cause of increased hemolysis. It manifests the symptoms in diseases as it is a pro-oxidant, pro-inflammatory and pro-hemolytic agent. We have also discussed the genetic defects that tampered with the biosynthesis, degradation, and transportation of heme. In addition, a brief about the largest hemoprotein group of enzymes- Cytochrome P450 (CYP450) has been discussed with its roles in drug metabolism.

PMID: 30499388 [PubMed - indexed for MEDLINE]