Overcoming Obstacles in Lipid-lowering Therapy in Patients with HIV - A Systematic Review of Current Evidence.

AIDS Rev. 2018;20(4):205-219

Authors: Dekkers CC, Westerink J, Hoepelman AIM, Arends JE

Abstract
Cardiovascular risk management in human immunodeficiency virus (HIV)-infected individuals is gaining increased attention due to the rising incidence and prevalence of cardiovascular disease in this population. Despite the availability of efficacious treatment strategies, implementation of guideline advocated preventive therapy, such as lipid-lowering therapy with statins, is hampered by perceived, expected, and real side effects as well as by expected interactions with combination antiretroviral therapy. These obstacles to optimal treatment have resulted in a large gap between the number of patients in whom lipid-lowering therapy is indicated and those actually taking lipid-lowering medication. In the past few years, research has shown that the majority of patient-reported side effects is not causally related to statin therapy but is attributable to the nocebo effect. Furthermore, excessive caution due to expected drug interactions between statins and antiretroviral therapy is often unnecessary, especially with novel classes of antiretroviral therapy. The main aim of this review is to discuss the causes and consequences of this lipid-lowering treatment gap in HIV-infected patients together with a practical guide on how to overcome these obstacles. In addition, new treatment options on the optimal cardiovascular management focusing primarily on novel classes of antiretroviral therapy and lipid-lowering medication will be discussed.

PMID: 30548018 [PubMed - indexed for MEDLINE]

Low Doses of Azathioprine are Effective in Combination With Infliximab in Inflammatory Bowel Disease but May not be During Induction Therapy.

J Crohns Colitis. 2018 Apr 27;12(5):628

Authors: Roblin X, Flourié B, Paul S

PMID: 29360962 [PubMed - indexed for MEDLINE]

Long-term efficacy and safety of bexarotene for Japanese patients with cutaneous T-cell lymphoma: The results of a phase 2 study (B-1201).

J Dermatol. 2019 May 15;:

Authors: Hamada T, Tokura Y, Sugaya M, Ohtsuka M, Tsuboi R, Nagatani T, Kiyohara E, Tani M, Setoyama M, Matsushita S, Kawai K, Yonekura K, Saida T, Iwatsuki K

Abstract
The present study (B-1201 clinical trial) was conducted as a multicenter, open-label, single-arm phase II study to evaluate the long-term safety, tolerability and efficacy of bexarotene. This study enrolled 10 Japanese adults aged more than 20 years with cutaneous T-cell lymphoma (CTCL) who completed the 24-week study period of the B-1101 trial. The objective response rate (ORR) was 53.8% (95% confidence interval, 25.1-80.8). In the early stage (IB), the ORR was 60% (3/5 cases). In the advanced stage (IIB and IIIA), the ORR was 57.1% (4/7 cases). The median time to response was 58 days (range, 27-168). The median treatment duration was 380 days (range, 33-1674). The median duration of response (DOR) could not be reached during the study period. The longest DOR reached 1618 days at the end of the B-1201 trial. Nine patients (56.3%) in the full analysis set (FAS) population experienced dose reduction of bexarotene. Common drug-related adverse events in the FAS population included hypothyroidism (93.8%), hypertriglyceridemia (81.3%), hypercholesterolemia (81.3%), leukopenia (68.8%) and neutropenia (56.3%). Dose-limiting toxicity (DLT) was present in five (38.5%) of the 13 patients in the 300 mg/m2 cohort. Of the five patients, four developed grade 3 neutropenia and one developed grade 4 hypertriglyceridemia. All DLT cases recovered after the discontinuation of bexarotene. None of the five patients discontinued this trial because of DLT. The B-1201 trial shows the long-term safety of oral bexarotene for Japanese patients with CTCL, despite frequent dose reduction.

PMID: 31090237 [PubMed - as supplied by publisher]

Sitagliptin and Liraglutide Modulate L-dopa Effect and Attenuate Dyskinetic Movements in Rotenone-Lesioned Rats.

Neurotox Res. 2019 Apr;35(3):635-653

Authors: Badawi GA, Abd El Fattah MA, Zaki HF, El Sayed MI

Abstract
L-dopa is still considered as the gold standard therapy for Parkinson's disease (PD); however, L-dopa-induced dyskinesia (LID) is a serious complication of long-term L-dopa treatment. The present study investigated the therapeutic potential of sitagliptin and liraglutide in comparisons with L-dopa against PD. In addition, their capacity to modulate L-dopa dose and/or side effects was investigated, too. Rats were injected with rotenone (3 mg/kg/day, s.c.) for 10 consecutive days to induce the experimental PD. The rotenone-treated rats were administered sitagliptin (30 mg/kg/day, p.o.) and liraglutide (50 μg/kg, s.c.) for 16 days either alone or together with L-dopa/carbidopa (50/25 mg/kg/day, i.p.). Scoring of LID was done on days 2, 4, 8, 12, and 16 in all L-dopa-treated groups. Twenty-four hours after the last administered dose of tested drugs, the behavior of rats in each group was screened by using the open-field test. Sitagliptin and liraglutide revealed marked attenuation of LID scores; in addition, they markedly increased animals' motor performance. Moreover, they preserved substantia nigra pars compacta (SNpc) tyrosine hydroxylase (TH) and vesicular monoamine transporter 2-positive (VMAT2) cells with prominent increase of the striatal dopamine (DA) content. On the other hand, they significantly decreased nigral neuromelanin (NM)-positive cells, activated microglia, gliosis, and other pathological changes. In conclusion, sitagliptin and liraglutide could be a promising therapeutic challenger in PD, modifying L-dopa effect and/or allowing the use of L-dopa with fewer side effects.

PMID: 30673988 [PubMed - indexed for MEDLINE]

Medicines under additional monitoring in the European Union.

Farm Hosp. 2019 01 01;43(1):19-23

Authors: Manso G, Neira F, Ortega S, Martín Arias LH, Sainz M, Salgueiro E

Abstract
OBJECTIVE: The objective of this study was to analyse the characteristics of  medicines subject to additional monitoring. We assessed the following aspects:  the criteria applied to approve a medicine as being subject to additional  monitoring; the authorized dispensing conditions; the pharmacological groups to which they belong; and their post-authorisation safety.
METHOD: We analysed the list published by the European Medicines Agency in  January 2017 (EMA/245297/2013 Rev.41). Information for the analysis was  obtained from the web sites of the European Medicines Agency and the Spanish  Agency of Medicines and Medical Devices.
RESULTS: We assessed 316 medicines subject to additional monitoring. The most  common criterion used to assign a medicine as being subject to additional  monitoring was it being a new active substance (n = 197 [62.3%]). Other  common criteria were requiring a post-authorisation safety study (n = 52  [16.5%]) and being a biologic medicine but not a new active substance (n = 49  [15.5%]). Regarding dispensing conditions, nearly 66% of these medicines were authorized under restricted conditions. Until January 2017, the Spanish Agency  of Medicines and Medical Device published 14 safety reports related to medicines subject to additional monitoring.
CONCLUSIONS: The group of medicines subject to additional monitoring mainly  includes new active substances. The most common pharmacological group is antineoplastic and immunomodulating agents. The postauthorisation safety  study has already produced information published by the Spanish Agency of  Medicines and Medical Devices.

PMID: 30624169 [PubMed - indexed for MEDLINE]

Preventable Adverse Drug Events Among Inpatients: A Systematic Review.

Pediatrics. 2018 09;142(3):

Authors: Gates PJ, Meyerson SA, Baysari MT, Lehmann CU, Westbrook JI

Abstract
: media-1vid110.1542/5799876436001PEDS-VA_2018-0805Video Abstract CONTEXT: Patient harm resulting from medication errors drives prevention efforts, yet harm associated with medication errors in children has not been systematically reviewed.
OBJECTIVE: To review the incidence and severity of preventable adverse drug events (pADEs) resulting from medication errors in pediatric inpatient settings.
DATA SOURCES: Data sources included Cumulative Index of Nursing and Allied Health Literature, Medline, Scopus, the Cochrane Library, and Embase.
STUDY SELECTION: Selected studies were published between January 2000 and December 2017, written in the English language, and measured pADEs among pediatric hospital inpatients by chart review or direct observation.
DATA EXTRACTION: Data extracted were medication error and harm definitions, pADE incidence and severity rates, items required for quality assessment, and sample details.
RESULTS: Twenty-two studies were included. For children in general pediatric wards, incidence was at 0 to 17 pADEs per 1000 patient days or 1.3% of medication errors (of any type) compared with 0 to 29 pADEs per 1000 patient days or 1.5% of medication errors in ICUs. Hospital-wide studies contained reports of up to 74 pADEs per 1000 patient days or 2.6% of medication errors. The severity of pADEs was mainly minor.
LIMITATIONS: Limited literature on the severity of pADEs is available. Additional study will better illuminate differences among hospital wards and among those with or without health information technology.
CONCLUSIONS: Medication errors in pediatric settings seldom result in patient harm, and if they do, harm is predominantly of minor severity. Implementing health information technologies was associated with reduced incidence of harm.

PMID: 30097525 [PubMed - indexed for MEDLINE]

Transcriptomic profiles of tissues from rats treated with anticancer drug combinations.

Sci Data. 2019 01 08;6:180306

Authors: Davis M, Knight E, Eldridge SR, Li J, Bushel PR

Abstract
To achieve therapeutic goals, many cancer chemotherapeutics are used at doses close to their maximally tolerated doses. Thus, it may be expected that when therapies are combined at therapeutic doses, toxicity profiles may change. In many ways, prediction of synergistic toxicities for drug combinations is similar to predicting synergistic efficacy, and is dependent upon building hypotheses from molecular mechanisms of drug toxicity. The key objective of this initiative was to generate and make publicly available key high-content data sets for mechanistic hypothesis generation as it pertains to a unique toxicity profile of a drug pair for several anticancer drug combinations. The expectation is that tissue-based genomic information that are derived from target tissues will also facilitate the generation and testing of mechanistic hypotheses. The view is that availability of these data sets for bioinformaticians and other scientists will contribute to analysis of these data and evaluation of the approach.

PMID: 30620345 [PubMed - indexed for MEDLINE]

Surface marker profiles on lung lymphocytes may predict the mechanism of immune-mediated pneumonitis triggered by tumor-infiltrating lymphocytes in lung cancer patients treated with pembrolizumab.

Lung Cancer. 2018 04;118:171-172

Authors: Oda K, Kato K, Nakamura M, Jotatsu T, Noguchi S, Kawanami T, Kido T, Yatera K

PMID: 29496324 [PubMed - indexed for MEDLINE]

Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update.

Clin Pharmacol Ther. 2018 04;103(4):574-581

Authors: Phillips EJ, Sukasem C, Whirl-Carrillo M, Müller DJ, Dunnenberger HM, Chantratita W, Goldspiel B, Chen YT, Carleton BC, George AL, Mushiroda T, Klein T, Gammal RS, Pirmohamed M

Abstract
The variant allele HLA-B*15:02 is strongly associated with greater risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine. The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.

PMID: 29392710 [PubMed - indexed for MEDLINE]

What to expect and when: benznidazole toxicity in chronic Chagas' disease treatment.

J Antimicrob Chemother. 2018 04 01;73(4):1060-1067

Authors: Aldasoro E, Posada E, Requena-Méndez A, Calvo-Cano A, Serret N, Casellas A, Sanz S, Soy D, Pinazo MJ, Gascon J

Abstract
Background: Benznidazole is one of the two most effective antiparasitic drugs for Chagas' disease treatment. However, knowledge about its toxicity profile is mostly based on post-marketing observational studies.
Objectives: Our study combines data from two prospective clinical trials designed to assess the safety of the drug newly produced by ELEA Laboratories (Abarax®).
Methods: Eligible participants were selected using a consecutive sampling strategy in the CINEBENZ and BIOMARCHA studies between 2013 and 2016 (EUDRACT 2011-002900-34 and 2012-002645-38, respectively, and clinicaltrials.gov NCT01755403 and NCT01755377, respectively). Enrolled subjects received treatment with 5 mg/kg/day benznidazole orally in two divided doses for 8 weeks and were followed up fortnightly.
Results: We observed 305 adverse reactions in 85 of 99 participants (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild and the median duration was 12 days. Most adverse reactions appeared in the first month of treatment except arthritis and peripheral neuropathy. Twenty-six patients did not complete treatment: 2 were withdrawn, 1 for ectopic pregnancy and 1 for epilepsy relapse due to cysticercosis; 2 were lost to follow-up; and 22 were owing to adverse reactions, two of them severe. We observed some unexpected adverse reactions that have not been described previously, such as psychiatric symptoms, erectile dysfunction, menstrual cycle alterations and lung infiltration.
Conclusions: There is a very high frequency of adverse reactions to benznidazole. Most adverse reactions are mild, but the treatment burden is significant and unexpected reactions are not rare. Severe reactions are uncommon, but they can be life-threatening. Further studies are necessary to optimize treatment.

PMID: 29351667 [PubMed - indexed for MEDLINE]

Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection.

J Antimicrob Chemother. 2018 04 01;73(4):1104-1106

Authors: Shaw E, Rombauts A, Tubau F, Padullés A, Càmara J, Lozano T, Cobo-Sacristán S, Sabe N, Grau I, Rigo-Bonnin R, Dominguez MA, Carratalà J

PMID: 29272413 [PubMed - indexed for MEDLINE]

Atazanavir and darunavir in pregnant women with HIV: evaluation of laboratory and clinical outcomes from an observational national study.

J Antimicrob Chemother. 2018 04 01;73(4):1025-1030

Authors: Floridia M, Masuelli G, Ravizza M, Tassis B, Cetin I, Sansone M, Degli Antoni A, Simonazzi G, Maccabruni A, Francisci D, Frisina V, Liuzzi G, Dalzero S, Tamburrini E, Italian Group on Surveillance of Antiretroviral Treatment in Pregnancy

Abstract
Background: Atazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparative data in pregnant women are limited. We assessed the safety and activity profile of these two drugs in pregnancy using data from a national observational study.
Methods: Women with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measures and main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatal gestational age-adjusted birthweight Z-score).
Results: Final analysis included 500 pregnancies with either atazanavir (n = 409) or darunavir (n = 91) exposure. No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA, haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the two groups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides (median 235.5 versus 179 mg/dL; P = 0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03 versus 3.27; P = 0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54 versus 0.32 mg/dL; P < 0.001).
Conclusions: In this observational study, the two main HIV PIs currently recommended by perinatal guidelines showed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in terms of main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug in some particular situations where the different impacts of treatment on lipid profile and bilirubin may have clinical relevance.

PMID: 29244115 [PubMed - indexed for MEDLINE]

Designing In and Around Tolerability Considerations for Immunotherapy Combinations.

Clin Pharmacol Ther. 2018 04;103(4):558-561

Authors: Stroh M

Abstract
Over a century ago, paths diverged in the treatment of cancer: the well-traveled path employed cytotoxic chemotherapy drugs, while one of the roads less traveled included immunotherapies. Cancer immunotherapy is now a path to durable responses, however not all patients benefit. Immunotherapy combinations promise responses for a larger proportion of patients, but tolerability can prove to be a barrier. Providing deep, durable responses to more patients requires us to successfully navigate emerging combination tolerability issues.

PMID: 29226337 [PubMed - indexed for MEDLINE]

The Evolution and Future of CAR T Cells for B-Cell Acute Lymphoblastic Leukemia.

Clin Pharmacol Ther. 2018 04;103(4):591-598

Authors: Annesley CE, Summers C, Ceppi F, Gardner RA

Abstract
Several CAR T designs with CD19 specificity have been associated with consistent responses in clinical trials with complete remission (CR) rates ranging from 70-90%. Relevant challenges remain to be addressed, such as production time, early loss of CAR T cells, relapse due to loss of the target antigen, and prevention of severe cytokine release syndrome and neurotoxicity. This review describes constructs, clinical trial results, side effects, and future direction of CAR T-cell therapy in B-ALL.

PMID: 29171004 [PubMed - indexed for MEDLINE]

Immune Checkpoint Inhibitor-Associated Colits and Hepatitis.

Clin Transl Gastroenterol. 2018 09 19;9(9):180

Authors: Reddy HG, Schneider BJ, Tai AW

Abstract
Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand PD-L1. ICPIs are now approved for the treatment of a wide array of malignancies, with rates of durable responses in the metastatic setting far exceeding what would be expected from conventional chemotherapy. ICPIs have also been associated with rare but serious immune-related adverse events due to over-activation of the immune system that can affect any organ, including the gastrointestinal tract and liver. As the use of ICPIs in oncology continues to increase, ICPI-associated colitis and hepatitis will be encountered frequently by gastroenterologists and hepatologists. This review will focus on the diagnosis and management of ICPI-associated colitis and hepatitis. We will also compare these ICPI-related toxicities with sporadic inflammatory bowel disease and autoimmune liver disease.

PMID: 30228268 [PubMed - indexed for MEDLINE]

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, January-March 2017.

Am J Health Syst Pharm. 2017 Jun 01;74(11):e292-e294

Authors: Office of Health and Constituent Affairs, U.S. Food and Drug Administration

PMID: 28546306 [PubMed - indexed for MEDLINE]

The Trade-off Between Speed and Safety in Drug Approvals.

JAMA Oncol. 2017 11 01;3(11):1465-1466

Authors: Jena AB, Zhang J, Lakdawalla DN

PMID: 27684643 [PubMed - indexed for MEDLINE]

Safety and tolerability of ranibizumab in uni/bilateral neovascular age-related macular degeneration: 12-month TWEYEs study.

Br J Ophthalmol. 2019 May 11;:

Authors: Bandello F, Staurenghi G, Ricci F, Midena E, Viola F, Lupieri Sinibaldi T, Colombo L, Peruzzi E, Bassanini S

Abstract
BACKGROUND: To evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)<2/10 and/or second eye affected, regardless of BCVA.
METHODS: In this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity.
RESULTS: Of the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5.
CONCLUSIONS: The low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.

PMID: 31079057 [PubMed - as supplied by publisher]

15 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")

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14 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 2019/05/11

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.