Interactions Between Therapeutic Proteins and Small Molecules: The Shared Role of Perpetrators and Victims.

Clin Pharmacol Ther. 2017 Oct;102(4):649-661

Authors: Cavaco M, Goncalves J

Abstract
Therapeutic proteins (TPs) are becoming increasingly important as therapeutic agents. A consequence of expanding their clinical indications is coadministration with well-established small-molecule drugs (sMDs), which could lead to unpredictable effects. According to the existing regulatory guidance, the development of an sMD includes the evaluation of potential drug-drug interactions (DDIs). For TPs, only a few drug interaction studies have been published. Limited clinically relevant models, long half-lives, and complex elimination pathways are among the associated difficulties.

PMID: 28002637 [PubMed - indexed for MEDLINE]

Comparative Assessment of Off-label and Unlicensed Drug Prescriptions in Children: FDA Versus ANSM Guidelines.

Clin Ther. 2016 Aug;38(8):1833-44

Authors: Berdkan S, Rabbaa L, Hajj A, Eid B, Jabbour H, Osta NE, Karam L, Khabbaz LR

Abstract
PURPOSE: The main objectives of this study were to assess the incidence of off-label (OL) and/or unlicensed (UL) prescriptions in a sample of pediatric Lebanese patients by using US Food and Drug Administration (FDA) and the French Medical Regulatory Authority (ANSM) regulations. The goal was to analyze the divergences between regulations and to identify those drugs most commonly involved in OL-UL utilization.
METHODS: This study was a retrospective analysis (500 pediatric files) conducted in a Lebanese University hospital in 3 pediatric wards (chronic diseases, acute diseases, and the pediatric intensive care unit).
FINDINGS: The frequency of OL-UL drug use was significantly different between pediatric wards (P < 0.001), with the highest incidence occurring in the intensive care unit. The most frequent OL-UL prescriptions occurred with cancer (oncology) admissions. Age was significantly related to OL-UL frequency (highest incidence in children aged between 0 and 1 year). The number of drugs prescribed per patient ranged between 1 and 20 (mean [SD], 4.13 [2.6]). The incidence of OL-UL prescriptions was significantly higher in patients treated with a greater number of medicines (P < 0.001). Overall, 58.9% of drug prescriptions were authorized according to ANSM and 50.7% according to FDA regulations; 11.1% (ANSM) and 15.8% (FDA) were UL, and 30.2% (ANSM) and 33.5% (FDA), respectively, were OL use (where OL for the indication were the most common). The highest percentage of OL-UL prescriptions was seen with the following groups: blood and blood-forming organs, genitourinary system, and sex hormones. Divergence between FDA and ANSM was mainly observed for OL medicines. UL prescriptions assessed according to both regulations showed similar results.
IMPLICATIONS: This study highlights the need for prescribers to continuously examine updates to official regulations to avoid using an OL-UL drug whenever possible. It also calls for better harmonization between worldwide official guidelines concerning drugs used in children to reduce risk factors for adverse drug reactions.

PMID: 27392716 [PubMed - indexed for MEDLINE]

Loss of confidence in vaccines following media reports of infant deaths after hepatitis B vaccination in China.

Int J Epidemiol. 2016 Apr;45(2):441-9

Authors: Yu W, Liu D, Zheng J, Liu Y, An Z, Rodewald L, Zhang G, Su Q, Li K, Xu D, Wang F, Yuan P, Xia W, Ning G, Zheng H, Chu Y, Cui J, Duan M, Hao L, Zhou Y, Wu Z, Zhang X, Cui F, Li L, Wang H

Abstract
BACKGROUND: China reduced hepatitis B virus (HBV) infection by 90% among children under 5 years old with safe and effective hepatitis B vaccines (HepB). In December 2013, this success was threatened by widespread media reports of infant deaths following HepB administration. Seventeen deaths and one case of anaphylactic shock following HBV vaccination had been reported.
METHODS: We conducted a telephone survey to measure parental confidence in HepB in eleven provinces at four points in time; reviewed maternal HBV status and use of HepB for newborns in birth hospitals in eight provinces before and after the event; and monitored coverage with hepatitis B vaccine and other programme vaccines in ten provinces.
RESULTS: HepB from the implicated company was suspended during the investigation, which showed that the deaths were not caused by HepB vaccination. Before the event, 85% respondents regarded domestic vaccines as safe, decreasing to 26.7% during the event. During the height of the crisis, 30% of parents reported being hesitant to vaccinate and 18.4% reported they would refuse HepB. Use of HepB in the monitored provinces decreased by 18.6%, from 53 653 doses the week before the event to 43 688 doses during the week that Biokangtai HepB was suspended. Use of HepB within the first day of life decreased by 10% among infants born to HBsAg-negative mothers, and by 6% among infants born to HBsAg-positive mothers. Vaccine refusal and HepB birth dose rates returned to baseline within 2 months; confidence increased, but remained below baseline.
CONCLUSIONS: The HBV vaccine event resulted in the suspension of a safe vaccine, which was associated with a decline of parental confidence, and refusal of vaccination. Suspension of a vaccine can lead to loss of confidence that is difficult to recover. Timely and credible investigation, accompanied by proactive outreach to stakeholders and the media, may help mitigate negative impact of future coincidental adverse events following immunization.

PMID: 27174834 [PubMed - indexed for MEDLINE]

A model for measuring the health burden of classic congenital adrenal hyperplasia in adults.

Clin Endocrinol (Oxf). 2016 Sep;85(3):361-98

Authors: Hummel SR, Sadler S, Whitaker MJ, Ara RM, Dixon S, Ross RJ

Abstract
AIM: Patients with classic congenital adrenal hyperplasia (CAH) have poor health outcomes. In the absence of a comprehensive observational study, this manuscript provides a model to estimate the lifetime disease burden of adults with classic CAH.
METHODS: The model, built in Excel, comprises subdomains addressing the health consequences of CAH and synthesises evidence from clinical and epidemiological studies on health outcomes.
RESULTS: The model estimates that adults with classic CAH will implement 'sick day rules' (doubling or tripling glucocorticoid and/or use of parenteral therapy) 171 times over their lifetime and attend hospital for adrenal crisis on 11 occasions. In a population of 1000, over 200 will die of a condition complicated by adrenal crisis resulting, on average, in a loss of 7 years of life. Patients with CAH may also suffer from excess CVD events. Treatment with glucocorticoids almost doubles the risk of bone fractures in patients with CAH compared to the general population, leading on average to an additional 0·8 fractures per patient with CAH over their lifetime.
CONCLUSIONS: The disease burden model highlights gaps in evidence, particularly regarding intensity of care and adrenal crisis, and the relationship between control of CAH and risks of CVD, osteoporosis, diabetes and infertility. The model can be used for research on the impact of new clinical pathways and therapeutic interventions in terms of clinical events and cost.

PMID: 26991412 [PubMed - indexed for MEDLINE]

Pediatric lung transplantation.

J Thorac Dis. 2017 Aug;9(8):2675-2683

Authors: Benden C

Abstract
Pediatric lung transplantation has been undertaken since the 1980s, and it is today considered an accepted therapy option in carefully selected children with end-stage pulmonary diseases, providing carefully selected children a net survival benefit and improved health-related quality of life. Nowadays, >100 pediatric lung transplants are done worldwide every year. Here, specific pediatric aspects of lung transplantation are reviewed such as the surgical challenge, effects of immunosuppression on the developing pediatric immune system, and typical infections of childhood, as it is vital to comprehend that children undergoing lung transplants present a real challenge as children are not 'just small adults'. Further, an update on the management of the pediatric lung transplant patient is provided in this review, and future challenges outlined. Indications for lung transplantation in children are different compared to adults, the most common being cystic fibrosis (CF). However, the primary diagnoses leading to pediatric lung transplantation vary considerably by age group. Furthermore, there are regional differences regarding the primary indication for lung transplantation in children. Overall, early referral, careful patient selection and appropriate timing of listing are crucial to achieve real survival benefit. Although allograft function is to be preserved, immunosuppressant-related side effects are common in children post-transplantation. Strategies need to be put into practice to reduce drug-related side effects through careful therapeutic drug monitoring and lowering of target levels of immunosuppression, to avoid acute-reversible and chronic-irreversible renal damage. Instead of a "one fits all approach", tailored immunosuppression and a personalized therapy is to be advocated, particularly in children. Further, infectious complications are a common in children of all ages, accounting for almost 50% of death in the first year post-transplantation. However, chronic lung allograft dysfunction (CLAD) remains the major obstacle for improved long-term survival.

PMID: 28932575 [PubMed]

Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled Analysis of Long-Term Clinical Trial Safety Data in Rheumatoid Arthritis.

Arthritis Rheumatol. 2017 Sep;69(9):1751-1761

Authors: Genovese MC, Kremer JM, van Vollenhoven RF, Alten R, Scali JJ, Kelman A, Dimonaco S, Brockwell L

Abstract
OBJECTIVE: To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long-term tocilizumab treatment for rheumatoid arthritis in clinical trials.
METHODS: Data were pooled from patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease-modifying antirheumatic drugs [DMARDs]) in phase III or IV clinical trials, long-term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient-years of tocilizumab exposure for this pooled analysis.
RESULTS: Overall, 16,204.8 patient-years of tocilizumab exposure (mean ± SD duration of exposure 3.9 ± 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1-3× ULN in 59%/55% of patients, >3-5× ULN in 8.9%/3.3% of patients, and >5× ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3× ULN occurred in 7.7%/3.6% of patients, and ≥2 consecutive elevations >3× ULN occurred in 1.9%/0.4% of patients. Elevations >3× ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient-years [95% confidence interval 0.02-0.09]) occurred in the tocilizumab studies.
CONCLUSION: Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.

PMID: 28597609 [PubMed - indexed for MEDLINE]

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12 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 2017/09/20

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Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: subgroup analysis of a randomized clinical trial.

J Diabetes Investig. 2017 Sep 16;:

Authors: Ma RC, Del Prato S, Gallwitz B, Shivane VK, Lewis-D'Agostino D, Bailes Z, Patel S, Lee J, von Eynatten M, Di Domenico M, Ross SA

Abstract
AIMS/INTRODUCTION: Type 2 diabetes mellitus (T2DM) is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enrol predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed T2DM patients in Asia with marked hyperglycemia.
MATERIALS AND METHODS: This was a post-hoc subgroup analysis of a multinational, parallel-group clinical trial in which 316 newly diagnosed T2DM patients with glycated hemoglobin A1c (HbA1c) 8.5-12.0% were randomized to double-blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary endpoint was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries.
RESULTS: After 24 weeks, mean ± SE reduction from baseline in HbA1c (mean 10.0%) was -2.99 ± 0.18% with linagliptin/metformin and -1.84 ± 0.18% with linagliptin; a treatment difference of -1.15% (95% CI -1.65 to -0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. Mean body weight change after 24 weeks was -0.45 ± 0.41 kg and 1.33 ± 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference: -1.78 kg [95% CI -2.99, -0.57, P = 0.0043]). Drug-related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations.
CONCLUSIONS: In people from Asia with newly diagnosed T2DM and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy may be a viable treatment for such individuals. This article is protected by copyright. All rights reserved.

PMID: 28921919 [PubMed - as supplied by publisher]

Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis.

Int J Cardiol. 2017 Sep 01;:

Authors: Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P

Abstract
BACKGROUND: Atrial fibrillation occurs frequently after open-heart surgery. It is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare costs. Prophylactic administration of colchicine may mitigate post-operative atrial fibrillation (POAF).
METHODS: We searched PubMed, ClinicalTrials.gov and CENTRAL databases to identify randomized controlled trials (RCTs) that; (1) compared prophylactic use of colchicine to placebo, or usual care, in patients with sinus rhythm who underwent elective open-heart surgery and (2) reported POAF-incidence. We excluded trials focused on incidence of atrial fibrillation after percutaneous interventions or colchicine treatment of diagnosed pericarditis or post-pericardiotomy-syndrome. A random-effects model was used to pool data for POAF-incidence as the primary outcome and for drug-related adverse effects, major adverse events (death and stroke), and hospital length-of-stay as secondary outcomes.
RESULTS: We included five RCTs (1412 patients). Colchicine treatment reduced POAF-events by 30% versus placebo or usual care (18% vs. 27%, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.84, p=0.0002). Adverse drug-related effects, especially gastrointestinal intolerance, increased with colchicine; (21% vs. 8.2%, RR 2.52, 95% CI 1.62 to 3.93, p<0.0001). However, major adverse events were unchanged (3.2% vs. 3.2%, RR 0.96, 95% CI 0.48 to 1.95, p=0.92). Length-of-stay decreased by 1.2days with colchicine (95% CI -1.89 to -0.44, p=0.002).
CONCLUSION: Colchicine demonstrated superior efficacy versus usual care for prevention of atrial fibrillation after cardiac surgery. Moreover, colchicine treatment was associated with shorter hospital stays. These benefits outweigh increased risk of adverse drug-related effects; although further work is needed to minimize gastrointestinal effects.

PMID: 28918897 [PubMed - as supplied by publisher]

Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial.

Lancet HIV. 2017 Sep 11;:

Authors: Cahn P, Kaplan R, Sax PE, Squires K, Molina JM, Avihingsanon A, Ratanasuwan W, Rojas E, Rassool M, Bloch M, Vandekerckhove L, Ruane P, Yazdanpanah Y, Katlama C, Xu X, Rodgers A, East L, Wenning L, Rawlins S, Homony B, Sklar P, Nguyen BY, Leavitt R, Teppler H, ONCEMRK Study Group

Abstract
BACKGROUND: Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation.
METHODS: In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than -10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233.
FINDINGS: Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI -4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported.
INTERPRETATION: A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy.
FUNDING: Merck & Co, Inc.

PMID: 28918877 [PubMed - as supplied by publisher]

Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data.

Int J Cancer. 2017 Sep 01;141(5):1018-1028

Authors: Wang W, Lie P, Guo M, He J

Abstract
Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events with the use of immune checkpoint inhibitors (ICPIs), overall risks have yet to be reported. Therefore, we assessed the risk of hepatotoxicity associated with inhibitors of the immune checkpoint. We examined data from the Pubmed, Medline and Google Scholar databases. We also examined original studies and review articles for crossreferences Eligible studies included randomized Phase II to Phase III trials of cancer patients treated with nivolumab, pembrolizumab, ipilimumab, tremelimumab. The authors extracted relevant information on participants' characteristics, all-grade and high-grade hepatotoxicity and information on the methodology of the studies. In total, 17 trials were considered eligible for the meta-analysis. The odds ratio for all-grade hepatotoxicity for CTLA-4 inhibitors (Ipilimumab and tremelimumab) was 1.24 (95% confidence interval 0.75, 2.05; p = 0.39) and for high-grade hepatotoxicity was 1.93 (95% confidence interval 0.84, 4.44; p =0.12). Moreover, the odds ratio for all-grade hepatotoxicity for PD-1 inhibitors was 1.52 (95% confidence interval 1.24, 1.86; p < 0.0001) and for high-grade hepatotoxicity was 0.48 (95% confidence interval 0.29, 0.80; p =0.005). The analysis of data showed that CTLA-4 inhibitors seem to be associated with a higher risk of all- and high-grade hepatotoxicity compared with control regimens, whereas PD-1 inhibitors seem to be associated with a lower risk of all- and high-grade hepatotoxicity compared with control regimens.

PMID: 28263392 [PubMed - indexed for MEDLINE]

Italian intersociety consensus on DOAC use in internal medicine.

Intern Emerg Med. 2017 Apr;12(3):387-406

Authors: Prisco D, Ageno W, Becattini C, D'Angelo A, Davì G, De Cristofaro R, Dentali F, Di Minno G, Falanga A, Gussoni G, Masotti L, Palareti G, Pignatelli P, Santi RM, Santilli F, Silingardi M, Tufano A, Violi F, SIMI (Italian Society of Internal Medicine), FADOI (Federation of Associations of Hospital Doctors on Internal Medicine), SISET (Italian Society for the Study of Haemostasis and Thrombosis)

Abstract
The direct oral anticoagulants (DOACs) are drugs used in clinical practice since 2009 for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation, and for the treatment and secondary prevention of venous thromboembolism. The four DOACs, including the three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and one direct thrombin inhibitor (dabigatran) provide oral anticoagulation therapy alternatives to Vitamin K antagonists (VKAs). Despite their clear advantages, the DOACs require on the part of the internist a thorough knowledge of their pharmacokinetic and pharmacodynamic characteristics to ensure their correct use, laboratory monitoring and the appropriate management of adverse events. This document represents a consensus paper on the use of DOACs by representatives of three Italian scientific societies: the Italian Society of Internal Medicine (SIMI), the Federation of the Associations of Hospital Managers (FADOI), and the Society for the Study of Haemostasis and Thrombosis (SISET). This document formulates expert opinion guidance for pragmatic managing, monitoring and reversing the anticoagulant effect of DOACs in both chronic and emergency settings. This practical guidance may help the internist to create adequate protocols for patients hospitalized ion internal medicine wards, where patients are often elderly subjects affected by poly-morbidities and renal insufficiency, and, thus, require particular attention to drug-drug interactions and peri-procedural protocols.

PMID: 28191610 [PubMed - indexed for MEDLINE]

Serious Adverse Reactions From Anti-tuberculosis Drugs Among 599 Children Hospitalized for Tuberculosis.

Pediatr Infect Dis J. 2017 Aug;36(8):720-725

Authors: Li Y, Zhu Y, Zhong Q, Zhang X, Shu M, Wan C

Abstract
BACKGROUND: The purpose of the study was to summarize the clinical characteristics of serious adverse reactions (ARs) related to anti-tuberculosis (TB) drugs in children hospitalized for TB. A comprehensive understanding of these drug-related ARs may serve to improve patient prognosis.
METHODS: Inpatients diagnosed with TB from 2008 to 2013 were enrolled retrospectively. The patients' demographics, diagnosis and ARs were recorded and analyzed for comprehensive evaluation.
RESULTS: Of the 599 enrolled patients, 3.51% (21 of 599) developed serious ARs related to anti-TB drugs. Hepatotoxicity was the most common reaction (1.84%, 11 of 599). The incidence of rash with or without fever was 1% (6 of 599), and that of auditory impairments and renal injury was 0.33% (2 of 599) and 0.17% (1 of 599), respectively. One patient experienced hepatotoxicity, rash and fever. Hospital stay of inpatients with serious ARs was significantly longer (median: 24 days; range: 8-62 days) than that of those without reactions (median: 11 days; range: 1-83 days), though no distinctions were observed between the 2 groups with regard to average age, gender or involved organs. Hepatotoxicity occurred 6-30 days after the start of anti-TB treatment (median: 6 days) and 75% of the inpatients remained asymptomatic. Hepatotoxicity was traced to the drugs isoniazid, rifampin and pyrazinamide, while fever was mainly linked to pyrazinamide. In addition, streptomycin and amikacin led to auditory impairments and renal injury, respectively. Serious ARs of all inpatients were controlled and managed successfully.
CONCLUSIONS: The incidence of serious ARs from anti-TB drugs among children inpatients was 3.5% and mainly consisted of hepatotoxicity. Inpatients with serious ARs tended to have longer hospital stays.

PMID: 28060046 [PubMed - indexed for MEDLINE]

Association of nutritional status-related indices and chemotherapy-induced adverse events in gastric cancer patients.

BMC Cancer. 2016 Nov 18;16(1):900

Authors: Seo SH, Kim SE, Kang YK, Ryoo BY, Ryu MH, Jeong JH, Kang SS, Yang M, Lee JE, Sung MK

Abstract
BACKGROUND: Malnutrition in gastrectomized patients receiving chemotherapy is associated with the susceptibility to chemotherapy-related adverse events. This study evaluated pre-operative nutritional status-related indices associated with adverse events in post-operation gastric cancer patients receiving chemotherapy.
METHODS: Medical records of 234 gastrectomized patients under adjuvant tegafur/gimeracil/oteracil chemotherapy with extended lymph node dissection were analyzed. Nutritional status assessment included Patient-Generated Subjective Global Assessment (PG-SGA), body weight, body mass index, serum albumin concentration, and Nutrition Risk Index (NRI). Chemotherapy-originated adverse events were determined using Common Terminology Criteria for Adverse Events.
RESULTS: PG-SGA indicated 59% of the patients were malnourished, and 27.8% of the patients revealed serious malnutrition with PG-SGA score of ≥9. Fifteen % of patients lost ≥10% of the initial body weight, 14.5% of the patients had hypoalbuminemia (<3.5 g/dL), and 66.2% had NRI score less than 97.5 indicating moderate to severe malnutrition. Hematological adverse events were present in 94% (≥grade 1) and 16.2% (≥grade 3). Non-hematological adverse events occurred in 95.7% (≥grade1) and 16.7% (≥grade 3) of the patients. PG-SGA and NRI score was not associated with treatment-induced adverse events. Multivariate analyses indicated that female, low body mass index, and hypoalbuminemia were independent risk factors for grade 3/4 hematological adverse events. Age was an independent risk factor for grade 3/4 non-hematological adverse events. Neutropenia was the most frequently occurring adverse event, and associated risk factors were female, total gastrectomy, and hypoalbuminemia.
CONCLUSIONS: Hypoalbuminemia, not PG-SGA or NRI may predict chemotherapy-induced adverse events in gastrectomized cancer patients.

PMID: 27863481 [PubMed - indexed for MEDLINE]

Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century.

J Physiol. 2016 Dec 01;594(23):6893-6908

Authors: Hill AP, Perry MD, Abi-Gerges N, Couderc JP, Fermini B, Hancox JC, Knollmann BC, Mirams GR, Skinner J, Zareba W, Vandenberg JI

Abstract
Risk stratification in the context of sudden cardiac death has been acknowledged as one of the major challenges facing cardiology for the past four decades. In recent years, the advent of high performance computing has facilitated organ-level simulation of the heart, meaning we can now examine the causes, mechanisms and impact of cardiac dysfunction in silico. As a result, computational cardiology, largely driven by the Physiome project, now stands at the threshold of clinical utility in regards to risk stratification and treatment of patients at risk of sudden cardiac death. In this white paper, we outline a roadmap of what needs to be done to make this translational step, using the relatively well-developed case of acquired or drug-induced long QT syndrome as an exemplar case.

PMID: 27060987 [PubMed - indexed for MEDLINE]

Comparison of Unintentional Exposures to Codeine and Hydrocodone Reported to Texas Poison Centers.

J Emerg Med. 2016 May;50(5):744-52

Authors: Day L, Kleinschmidt K, Forrester MB, Feng SY

Abstract
BACKGROUND: Hydrocodone has recently been reclassified as a Schedule II drug by the United States Drug Enforcement Administration and Food and Drug Administration in order to curtail prescription drug abuse. There is concern that analgesic substitutes, such as codeine, will not be as safe or effective.
OBJECTIVE: The purpose of this study is to compare the demographics, adverse events, and medical outcomes of patients who had unintentional hydrocodone or codeine exposures through the use of a state's poison center database.
METHODS: The Texas Poison Center Network's database was utilized to find all reported unintentional ingestions or adverse reactions of products containing codeine or hydrocodone. Comparisons were made between the two medications by calculating the rate ratios (RR) and 95% confidence intervals (CI).
RESULTS: Children aged 5 years or younger were more exposed to codeine (51.6%). Hydrocodone exposures had more serious outcomes (11% vs. 9%; RR = 0.82; 95% CI 0.73-0.91) and had more nausea (7.1% vs. 2.8%; RR = 0.4; 95% CI 0.32-0.48) and vomiting (6.5% vs. 3.3%; RR = 0.51; 95% CI 0.43-0.62). Hydrocodone had a higher rate of intravenous fluids administration (2.4% vs. 1.7%; RR = 0.71; 95% CI 0.54-0.92) and antiemetics (0.4% vs. 0.1%; RR = 0.23; 95% CI 0.08-0.64). Codeine was more closely associated with dermal reactions and patients were given antihistamines (2.5% vs. 1.3%; RR = 1.88; 95% CI 1.46-2.41) more frequently. Cardiovascular side effects, ataxia, and headache occurred equally between the groups.
CONCLUSIONS: Both drugs had a wide array of reported side effects, but the overall incidence of serious outcomes was low.

PMID: 26899518 [PubMed - indexed for MEDLINE]

Predicting drug-induced QT prolongation and torsades de pointes.

J Physiol. 2016 May 01;594(9):2459-68

Authors: Roden DM

Abstract
Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia ('torsades de pointes'). This syndrome of drug-induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, which has driven both clinical care and drug regulation, holds that cardiac repolarization represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (IKr ) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarizations thought to trigger torsades de pointes. This review describes the evidence in support of this construct, and describes the way in which clinical and whole heart experiments have informed molecular mechanisms and vice versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.

PMID: 26660066 [PubMed - indexed for MEDLINE]

Bacterial Pneumonia in Older Adults.

Infect Dis Clin North Am. 2017 Sep 12;:

Authors: Henig O, Kaye KS

Abstract
The incidence of pneumonia increases with age, and is particularly high in patients who reside in long-term care facilities (LTCFs). Mortality rates for pneumonia in older adults are high and have not decreased in the last decade. Atypical symptoms and exacerbation of underlying illnesses should trigger clinical suspicion of pneumonia. Risk factors for multidrug-resistant organisms are more common in older adults, particularly among LTCF residents, and should be considered when making empiric treatment decisions. Monitoring of clinical stability and underlying comorbid conditions, potential drug-drug interactions, and drug-related adverse events are important factors in managing elderly patients with pneumonia.

PMID: 28916385 [PubMed - as supplied by publisher]

Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients.

Best Pract Res Clin Endocrinol Metab. 2017 Jun;31(3):349-361

Authors: Resteghini C, Cavalieri S, Galbiati D, Granata R, Alfieri S, Bergamini C, Bossi P, Licitra L, Locati LD

Abstract
Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.

PMID: 28911730 [PubMed - in process]