Anti-PCSK9 treatment: Is ultra-low LDL always good?

Cardiovasc Res. 2018 Jun 20;:

Authors: Noto D, Giammanco A, Barbagallo CM, Cefalù AB, Averna MR

Abstract
Anti-pcsk9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-pcsk9 Mab inhibit the targeted LDL-receptor degradation induced by pcsk9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy.Though these drugs proved to be very safe in the short term, little is known about the possible long term effects, due to the short period of their marketing. The genetic low-cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a valuable opportunity to predict the long term effects of these drugs. By looking at the clinical features of such models we could be able to foresee possible drug-induced side effects. In the present review the correspondences and discordances between the side effects of anti-pcsk9 therapy and the corresponding LCS models will be examined in the attempt to forecast possible long term consequences of these novel lipid lowering agents.

PMID: 29931148 [PubMed - as supplied by publisher]

The safety, tolerability, and pharmacokinetic profile of GSK2838232, a novel 2nd generation HIV maturation inhibitor, as assessed in healthy subjects.

Pharmacol Res Perspect. 2018 Jul;6(4):e00408

Authors: Johnson M, Jewell RC, Peppercorn A, Gould E, Xu J, Lou Y, Davies M, Baldwin S, Tenorio AR, Burke M, Jeffrey J, Johns BA

Abstract
This work aimed to assess the safety, tolerability, pharmacokinetics (PK), and relative bioavailability of GSK2838232, an investigational HIV maturation inhibitor. GSK2838232 was administered over four dose-escalation studies in healthy subjects which assessed single oral doses (5-250 mg) and repeat doses (up to 200 mg once or twice daily) ±100 mg ritonavir (RTV) once daily. GSK2838232 administration (up to 250 mg) to 124 subjects across four studies resulted in few mild adverse events (AEs) with similar frequencies to placebo. There were no clearly identified drug-related AEs. GSK2838232 tested fasted was quickly absorbed with a tmax of 2-3 hours. With food, the absorption was delayed and more variable, with ~60% increase in AUC and Cmax. Overall, following single doses GSK2838232 AUC and Cmax generally exhibited proportional PK from 50 to 100 mg dose without RTV and from 50 to 250 mg with RTV and following repeated doses of 20-200 mg with RTV. In relative bioavailability studies, a micronized formulation was found to be suitable for development. At steady state, RTV increased GSK2838232 AUC and Cmax by 10- and 3-fold, respectively. Half-life was prolonged from ~17 hours nonboosted to ~34 hours with RTV. This boosting effect was also seen in repeat-dose GSK2838232 studies, which achieved the targeted plasma exposure with GSK2838232 as a once-daily regimen of up to 200 mg with RTV. The results of these studies demonstrated a favorable safety and PK profile for GSK2838232 and support its investigation for the treatment of HIV infection.

PMID: 29930812 [PubMed - in process]

Stevens-Johnsons syndrome or drug-induced lupus - a clinical dilemma: A case report and review of the literature.

Biomed Rep. 2018 Jul;9(1):37-41

Authors: Bojinca VC, Bojinca M, Gheorghe M, Birceanu A, Iosif CI, Balanescu SM, Balanescu AR

Abstract
Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.

PMID: 29930803 [PubMed]

Management of Subfoveal Perfluorocarbon Liquid: A Review.

Ophthalmologica. 2018;240(1):1-7

Authors: Liu W, Gao M, Liang X

Abstract
Perfluorocarbon liquid (PFCL) has been widely used in vitreoretinal surgeries, especially in retinal detachment treatment. A prominent complication of intraoperative PFCL application is inadvertent subretinal PFCL retention. Subfoveal PFCL, even in small amounts, receives much attention due to its potential side effect on the macular structure and function. Whether to observe with follow-up or to deal with surgery is often an intractable problem in the management of subfoveal PFCL. Safety and necessity are the 2 key issues in considering surgical treatment, that is, can we avoid surgically induced macular injury and will surgery be beneficial for the recovery of vision? Herein, the authors review sub-foveal PFCL retention with its risk factors, morphological manifestations, pathological studies, clinical natural consequences, and different surgical methods with their outcomes. Analysis of the existing literature shows that visual acuity improved significantly after subfoveal PFCL removal or displacement and was positively correlated with visual acuity before the operation.

PMID: 29669355 [PubMed - indexed for MEDLINE]

A hierarchical anatomical classification schema for prediction of phenotypic side effects.

PLoS One. 2018;13(3):e0193959

Authors: Wadhwa S, Gupta A, Dokania S, Kanji R, Bagler G

Abstract
Prediction of adverse drug reactions is an important problem in drug discovery endeavors which can be addressed with data-driven strategies. SIDER is one of the most reliable and frequently used datasets for identification of key features as well as building machine learning models for side effects prediction. The inherently unbalanced nature of this data presents with a difficult multi-label multi-class problem towards prediction of drug side effects. We highlight the intrinsic issue with SIDER data and methodological flaws in relying on performance measures such as AUC while attempting to predict side effects.We argue for the use of metrics that are robust to class imbalance for evaluation of classifiers. Importantly, we present a 'hierarchical anatomical classification schema' which aggregates side effects into organs, sub-systems, and systems. With the help of a weighted performance measure, using 5-fold cross-validation we show that this strategy facilitates biologically meaningful side effects prediction at different levels of anatomical hierarchy. By implementing various machine learning classifiers we show that Random Forest model yields best classification accuracy at each level of coarse-graining. The manually curated, hierarchical schema for side effects can also serve as the basis of future studies towards prediction of adverse reactions and identification of key features linked to specific organ systems. Our study provides a strategy for hierarchical classification of side effects rooted in the anatomy and can pave the way for calibrated expert systems for multi-level prediction of side effects.

PMID: 29494708 [PubMed - indexed for MEDLINE]

Sofosbuvir Adverse Events Profile in a Subset of Pakistani Population.

J Coll Physicians Surg Pak. 2018 Feb;28(2):146-149

Authors: Iqbal S, Yousuf MH, Raza A, Yousaf MI

Abstract
OBJECTIVE: To determine frequency and pattern of adverse events reporting in a subset of Pakistani population being treated for chronic hepatitis C with sofosbuvir combination therapy.
STUDY DESIGN: Descriptive study.
PLACE AND DURATION OF STUDY: Department of Medicine, Gastroenterology Division, Shalamar Hospital, Lahore, from September 2015 to May 2016.
METHODOLOGY: Patients who were offered sofosbuvir therapy for treatment of chronic hepatitis C were randomly enrolled. The study subset included both treatment nave as well as retreatment groups. Patients were screened for subjective as well as objective evidence of adverse events at regular intervals. Frequency was determined.
RESULTS: Among 196 patients with chronic hepatitis C, 192 patients received dual therapy consisting of ribavirin and sofosbuvir. The most frequent complaints in these subjects were fatigue, fever, myalgias and nausea accounting for 55%, 42%, 44.2% and 50%, respectively. Twenty-seven percent of patients reported with drop in hemoglobin of >2g/dl, while absolute neutropenia and moderate to severe thrombocytopenia was observed in 3% and 5% of patients, respectively. One patient died as a result of severe pancytopenia. Later derangements were all observed in patients with decompensated disease.
CONCLUSION: Sofosbuvir showed less severe adverse effects in terms of symptomatology and less frequent neutropenia and thrombocytopenia as compared to previous regimens. Careful monitoring is required, especially in those with decompensated liver disease.

PMID: 29394975 [PubMed - indexed for MEDLINE]

[Role of Pharmacy in the Promotion of Drug Safety in Pharmacotherapy].

Yakugaku Zasshi. 2018;138(2):149-150

Authors: Satoh M

PMID: 29386428 [PubMed - indexed for MEDLINE]

Documentation of penicillin adverse drug reactions in electronic health records: inconsistent use of allergy and intolerance labels.

Intern Med J. 2017 Nov;47(11):1292-1297

Authors: Inglis JM, Caughey GE, Smith W, Shakib S

Abstract
BACKGROUND: The majority of patients with penicillin allergy labels tolerate penicillins. Inappropriate avoidance of penicillin is associated with increased hospitalisation, infections and healthcare costs.
AIMS: To examine the documentation of penicillin adverse drug reactions (ADR) in a large-scale hospital-based electronic health record.
METHODS: Penicillin ADR were extracted from 96 708 patient records in the Enterprise Patient Administration System in South Australia. Expert criteria were used to determine consistency of ADR entry and suitability for further evaluation.
RESULTS: Of 43 011 unique ADR reports, there were 5023 ADR to penicillins with most being entered as allergy (n = 4773, 95.0%) rather than intolerance (n = 250, 5.0%). A significant proportion did not include a reaction description (n = 1052, 20.9%). Using pre-set criteria, 10.1% of reports entered as allergy had a reaction description that was consistent with intolerance and 31.0% of the entered intolerances had descriptions consistent with allergy. Virtually all ADR (n = 4979, 99.1%) were appropriate for further evaluation by history taking or immunological testing and half (50.7%, n = 2549) had documented reactions suggesting low-risk of penicillin allergy.
CONCLUSION: The frequency of penicillin allergy label in this data set is consistent with the known overdiagnosis of penicillin allergy in the hospital population. ADR documentation was poor with incomplete entries and inconsistent categorisation. The concepts of allergy and intolerance for ADR classification, whilst mechanistically valid, may not be useful at the point of ADR entry by generalist clinicians. Systematic evaluation of reported ADR is needed to improve the quality of information for future prescribers.

PMID: 28742226 [PubMed - indexed for MEDLINE]

[Adverse events related to medication in hospitals from the Valencian Community. EPIDEA Study 2005-2013].

Rev Esp Quimioter. 2017 Oct;30(5):319-326

Authors: Mollar-Maseres JB, Aranaz-Andrés JM, Martin-Moreno JM, Miralles-Bueno JJ, Requena-Puche J, Martínez-Morel HR, Luján-Tolosa MM

Abstract
OBJECTIVE: To determine the prevalence of Adverse Events related to Medication (AEM) in hospitals of the Valencian Community in the 2005-2013 study period, and to describe the associated risk factors and their impact.
METHODS: This study is based on data and methodology of the Study of Prevalence of Adverse Events in hospitals (EPIDEA), since its inception in 2005 until 2013. AEM produced in each year were analyzed.
RESULTS: We identified 344 AEM that occurred in 337 patients, among 35,103 patients studied, giving a prevalence of patients with AEM of 0.96% (IC95% 0.89-1.07). The most prevalent intrinsic risk factors for AEM were hypertension, diabetes and cancer. The most prevalent extrinsic risk factors were peripheral venous catheter, urinary catheter and central venous catheter. Therapeutic groups most frequently involved were systemic antibiotics, cardiovascular drugs and antineoplastics. The 61.17% of AEM was classified as moderate, followed by 27.18% as mild and 11.65% as severe. The 33.99% of EAM caused increase of the patient's stay and 39.90% of EAM caused the re-entry of patient. The 58.5% of AEM were avoidable. Mild AEM were avoidable in 46.3%, moderate AEM were avoidable in 60.3% and severe AEM were in 75% (p = 0.013).
CONCLUSIONS: The prevalence of patients with AEM in hospitals of the Community of Valencia for the period 2005- 2013 was 0.96%. More than half of AEM were preventable, and preventability increases significantly with the severity of the event.

PMID: 28722391 [PubMed - indexed for MEDLINE]

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

Pharm Stat. 2017 Nov;16(6):396-413

Authors: Yeung WY, Reigner B, Beyer U, Diack C, Sabanés Bové D, Palermo G, Jaki T

Abstract
The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

PMID: 28691311 [PubMed - indexed for MEDLINE]

Effect of food on the pharmacokinetic characteristics of a single oral dose of LCB01-0371, a novel oxazolidinone antibiotic.

Drug Des Devel Ther. 2018;12:1707-1714

Authors: Sunwoo J, Kim YK, Choi Y, Yu KS, Nam H, Cho YL, Yoon S, Chung JY

Abstract
Background: LCB01-0371 is a novel oxazolidinone antibiotic that blocks protein production by binding to bacterial 23S ribosomes. This antibiotic is active against Gram-positive bacteria. This study aimed to evaluate the effect of food on the pharmacokinetics (PKs) of LCB01-0371 and evaluate its safety profile.
Subjects and methods: A randomized, open-label, two-way crossover study was performed in 18 healthy Korean male subjects. All subjects received a single oral 800 mg dose of LCB01-0371 in each period under fed or fasting condition with a 7-day washout in between. The fed condition was defined as consumption of a meal of 800-1,000 kcal containinĝ50% of fat content. Serial blood samples were collected over 24 h after dosing, and the PK parameters were calculated by noncompartment analysis. All available data of the subjects who received LCB01-0371 at least once were included in the safety data summaries.
Results: In the fed condition, both the maximum plasma concentration (Cmax) and the total systemic exposure (area under the plasma concentration-time curve from time zero to the last observed time point [AUClast]) decreased by ~33% and 10%, respectively. The time to reach Cmax was delayed by ~1.25 h in the fed condition, whereas the mean elimination half-life remained similar in both conditions. In the fed/fasting condition, the geometric mean ratios and 90% CI of the Cmax and AUClast were 0.666 (0.470-0.945) and 0.897 (0.761-1.057), respectively. There were no drug-related adverse events (AEs) or serious AEs.
Conclusion: Although the Tmax after a single oral 800 mg dose of LCB01-0371 was slightly delayed under the fed condition compared to the fasting condition, the total systemic exposure was similar under both conditions. Therefore, LCB01-0371 could be administered regardless of food intake.

PMID: 29928114 [PubMed - in process]

Ipragliflozin Add-on Therapy to a GLP-1 Receptor Agonist in Japanese Patients with Type 2 Diabetes (AGATE): A 52-Week Open-Label Study.

Diabetes Ther. 2018 Jun 20;:

Authors: Ishihara H, Yamaguchi S, Nakao I, Sakatani T

Abstract
INTRODUCTION: Few data are available regarding ipragliflozin treatment in combination with glucagon-like peptide-1 (GLP-1) receptor agonists. The aim of this study was to evaluate the efficacy and safety of ipragliflozin in combination with GLP-1 receptor agonists in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM).
METHODS: This multicenter study (consisting of three periods: a 4-week washout period, a 6-week observation period, and a 52-week open-label treatment period) included patients aged ≥ 20 years who received a stable dose/regimen of a GLP-1 receptor agonist either solely or in combination therapy with a sulfonylurea for ≥ 6 weeks, with glycosylated hemoglobin (HbA1c) of ≥ 7.5% and a fasting plasma glucose (FPG) of ≥ 126 mg/dL. Ipragliflozin treatment was given at a fixed dose of 50 mg/day for 20 weeks, followed by 50 or 100 mg/day for 32 weeks. Changes from baseline in glycemic control and other parameters were examined; safety was also assessed.
RESULTS: The mean changes in HbA1c and body weight from baseline to end of treatment were - 0.92% and - 2.69 kg, respectively, in all ipragliflozin-treated patients (n = 103). Overall, sustained reductions from baseline were observed for HbA1c, FPG, self-monitored blood glucose, and body weight during the 52-week treatment. The dose increase of ipragliflozin to 100 mg/day resulted in better glycemic control and weight reduction for patients in whom the 50-mg dose was insufficient. Overall, 46.6% (48/103) of patients experienced drug-related adverse events. The most common drug-related treatment-emergent adverse events were pollakiuria (9.7%), hypoglycemia (8.7%), constipation (6.8%), and thirst (5.8%).
CONCLUSION: Combined therapy with ipragliflozin and GLP-1 receptor agonists/sulfonylureas was significantly efficacious in reducing glycemic parameters in patients with T2DM with inadequate glycemic control, and no major safety concerns were identified. The results from this study suggest that ipragliflozin can be recommended as a well-tolerated and effective add-on therapy to a GLP-1 receptor agonist for the treatment of T2DM.
TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT02291874).
FUNDING: Astellas Pharma Inc., Tokyo, Japan.

PMID: 29926400 [PubMed - as supplied by publisher]

Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial.

Lancet HIV. 2018 Jun 15;:

Authors: Daar ES, DeJesus E, Ruane P, Crofoot G, Oguchi G, Creticos C, Rockstroh JK, Molina JM, Koenig E, Liu YP, Custodio J, Andreatta K, Graham H, Cheng A, Martin H, Quirk E

Abstract
BACKGROUND: Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch.
METHODS: In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries. Eligible participants were aged 18 years or older, had an estimated glomerular filtration rate of 50 mL per min or higher, had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 6 months or more before screening, and were on a regimen consisting of boosted atazanavir or darunavir plus either emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated once-daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg), herein known as the bictegravir group, or to remain on their baseline boosted protease inhibitor regimen, herein known as the boosted protease inhibitor group, for 48 weeks. Randomisation was stratified by use of tenofovir disoproxil fumarate or abacavir at screening. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (by US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 4%. Efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting patients and is registered with ClinicalTrials.gov, number NCT02603107.
FINDINGS: Between Dec 2, 2015, and July 15, 2016, 578 participants were randomly assigned and 577 were treated (290 in the bictegravir group and 287 in the boosted protease inhibitor group). At week 48, five participants (2%) in the bictegravir group and five (2%) in the boosted protease inhibitor group had plasma HIV-1 RNA of 50 copies per mL or higher (difference 0·0%, 95·002% CI -2·5 to 2·5), thus switching to the bictegravir regimen was non-inferior to continued boosted protease inhibitor therapy. The overall incidence and severity of adverse events was similar between groups, although headache occurred more frequently in the bictegravir group than in the boosted protease inhibitor group. 233 (80%) participants in the bictegravir group and 226 (79%) in the boosted protease inhibitor group had an adverse event. Only two (1%) participants in the bictegravir group and one (<1%) in the boosted protease inhibitor group discontinued treatment because of adverse events. 54 participants (19%) in the bictegravir group had drug-related adverse events compared with six (2%) in the protease inhibitor group.
INTERPRETATION: Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection.
FUNDING: Gilead Sciences.

PMID: 29925490 [PubMed - as supplied by publisher]

Risk factors predisposing to the development of hypogammaglobulinemia and infections post-Rituximab.

Int Rev Immunol. 2017 Nov 02;36(6):352-359

Authors: Christou EAA, Giardino G, Worth A, Ladomenou F

Abstract
Rituximab (RTX) is a monoclonal antibody against CD20, commonly used in the treatment of hematological malignancies and autoimmune diseases. The use of RTX is related to the development of hypogammaglobulinemia and infections. Aim of this review is to summarize the evidence supporting the association of specific risk factors with the development of hypogammaglobulinemia and infections post-RTX. Immunological complications are more common in patients with malignant diseases as compared to non-malignant diseases. Moreover, the use of more than one dose of RTX, maintenance regimens, low pre-treatment basal immunoglobulin levels and the association with Mycophenolate and purine analogues represent risk factors for the development of hypogammaglobulinemia. The number of RTX courses, the evidence of low IgG levels for more than 6 months, the use of G-CSF, the occurrence of chronic lung disease, cardiac insufficiency, extra-articular involvement in patients with rheumatoid arthritis, low levels of IgG and older age have been correlated with a higher risk of infections. Even though the heterogeneity of the studies in terms of study population age and underlying disease, RTX schedules as well as differences in pre-treatment or concomitant therapy doesn't allow drawing definitive conclusions, the study of the literature highlight the association of specific risk factors with the occurrence of hypogammaglobulinemia and/or infections. A long term randomized controlled clinical trial could be useful to define a personalized evidence-based risk management plan for patients treated with RTX.

PMID: 28800262 [PubMed - indexed for MEDLINE]

An Economic Analysis of a Peanut Oral Immunotherapy Study in Children.

J Allergy Clin Immunol Pract. 2017 Nov - Dec;5(6):1707-1716

Authors: Shaker MS

Abstract
BACKGROUND: Peanut oral immunotherapy (POIT) decreases the probability of accidental recurrent systemic reactions but reactions from the therapy itself are frequent.
OBJECTIVE: The purpose of this economic analysis was to characterize the potential cost-effectiveness of POIT.
METHODS: Cohort simulations were used to evaluate the effect of POIT for children with peanut allergy. A POIT with probiotic was used in the base-case simulation and long-term survival was modeled using age-adjusted mortality together with the risk of food allergy-associated mortality.
RESULTS: The incremental POIT cost-effectiveness ratio was $2142 per quality-adjusted life-year. A mean number of 12.3 (95% CI, 12.0-12.5) and 2.0 (95% CI, 1.9-2.1) allergic reactions occurred in the POIT and avoidance groups over 20 years of simulation, with 2.3 (95% CI, 2.2-2.3) episodes of anaphylaxis treated with intramuscular epinephrine per subject in the POIT group and 1.1 (95% CI, 1.0-1.2) episodes per subject in the avoidance group. In sensitivity analyses, POIT was associated with lower rates of anaphylaxis than strict avoidance when the annual rate of accidental allergic reactions in the peanut avoidance group exceeded 25%, the annual rate of anaphylaxis in the POIT group dropped below 6%, or the probability of sustained unresponsiveness after 4 years of POIT was 68% or greater.
CONCLUSIONS: POIT may be cost-effective in a long-term economic model. However, treated patients may experience a greater rate of peanut-associated allergic reactions and anaphylaxis. The analysis was sensitive to rates of accidental allergic reactions, therapy-associated adverse events, and likelihood of therapy-induced tolerance.

PMID: 28606784 [PubMed - indexed for MEDLINE]

"Treating Through" Decision and Follow-up in Antibiotic Therapy-Associated Exanthemas.

J Allergy Clin Immunol Pract. 2017 Nov - Dec;5(6):1650-1656

Authors: Trautmann A, Benoit S, Goebeler M, Stoevesandt J

Abstract
BACKGROUND: Immediate discontinuation or replacement of suspected drugs is considered standard medical care in acute exanthematous skin reactions. In the treatment of bacterial infections, structurally different alternative antibiotics, however, are commonly second choice options due to a suboptimal antimicrobial activity or an unfavorable side effect profile. Nonetheless, "treating through," the continuation of antibiotic treatment despite an objective exanthema, is practiced only rarely.
OBJECTIVE: We aimed to assess whether "treating through" is an option for patients with severe bacterial soft tissue infections (severe cellulitis) who experience maculopapular exanthema (MPE) during antibiotic therapy.
METHODS: We retrospectively reviewed clinical data from 18 patients who developed MPE within a few days after initiation of intravenous antibiotic treatment. A decision to "treat through" was made when the suspected antibiotics (β-lactams, clindamycin, ciprofloxacin) were clinically effective and the benefits of continued treatment outweighed potential risks. Clinical and laboratory findings were closely monitored in an inpatient setting.
RESULTS: In 2 patients, a modification of antibiotic therapy was deemed necessary due to a significant increase of liver enzymes within 4 days after the initial decision to "treat through." Because of a progression of MPE under ongoing treatment with cefuroxime and clindamycin, clindamycin was discontinued in 1 patient. In another 3 patients, antibiotic treatment was modified because of insufficient improvement of the soft tissue infection. In the remaining 12 "treated through" cases, the skin symptoms improved despite unchanged continued antibiotic treatment, and relevant laboratory parameters remained within the normal range.
CONCLUSIONS: Careful risk-benefit assessment may enable the continuation of antibiotic therapy despite MPE, provided that patients are under close medical observation.

PMID: 28499779 [PubMed - indexed for MEDLINE]

Adverse Effects of Domperidone: Prolonged QuesT for Knowledge?

Dig Dis Sci. 2016 12;61(12):3384-3386

Authors: Bashashati M, Sarosiek I, Siddiqui T, McCallum RW

PMID: 27714509 [PubMed - indexed for MEDLINE]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/06/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2018/06/21

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Generalizability of clinical trials of advanced melanoma in the real-world, population-based setting.

Med Oncol. 2018 Jun 18;35(7):110

Authors: Sam D, Gresham G, Abdel-Rahman O, Cheung WY

Abstract
Results from novel therapeutics trials are not always generalizable to real-world patients. We aimed to determine the pattern in which trial findings are applied in a population-based setting of melanoma patients and consequent treatment outcomes. Patients with unresectable disease during 2011-2014 and referred to cancer centers in a large Canadian province were retrospectively reviewed. Based on eligibility criteria as described in registration trials of vemurafenib (Vem) and ipilimumab (Ipi), we classified patients into trial-eligible and ineligible and those treated and untreated with these agents. We identified 290 patients with known BRAF status for the Vem analysis and 212 patients previously treated with first-line agents for the Ipi analysis. For the Vem cohort, a total of 49 patients were considered trial-eligible, of whom 36 (73%) received treatment. For the Ipi cohort, there were 119 trial-eligible cases of whom 43 (36%) received therapy. Factors other than eligibility criteria most frequently associated with non-treatment in these cohorts included concerns regarding treatment harm and patient preferences. In multivariable analysis, overall survival was improved in Vem cohort patients considered trial-eligible and treated compared to those who were ineligible. Within the Ipi cohort, survival was improved in trial-eligible patients regardless of whether they received Ipi compared to ineligible patients. Real-world uptake of new melanoma treatments was suboptimal, and non-use in trial-eligible patients was frequent. Future clinical trials that are more pragmatically designed to include participants who better reflect the real-world population may facilitate increased uptake of novel therapeutics into routine clinical practice.

PMID: 29915956 [PubMed - in process]