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Palivizumab prophylaxis for respiratory syncytial virus in infants with cystic fibrosis: is there a need?

Eur J Clin Microbiol Infect Dis. 2018 Jun;37(6):1113-1118

Authors: Bjornson C, Chan P, Li A, Paes B, Lanctôt KL, Mitchell I

Abstract
Respiratory syncytial virus (RSV) infection in cystic fibrosis (CF) infants is associated with significant morbidities. This study's objective is to evaluate the effectiveness and adverse events related to palivizumab (PVZ) in CF infants. Data on respiratory-related illness (RIH) and RSV hospitalizations (RSVH) were collected retrospectively in CF infants aged < 2 years in Alberta, Canada, from 2000 to 2017. Logistic regression models were used to compare the odds of RSVH or RIH in PVZ infants from the Canadian registry of palivizumab (CARESS) versus untreated (UPVZ) infants from Alberta, after adjusting for potential confounders. Illness severity was compared between cohorts using χ2 and t tests. A total of 267 CF infants were included: 183 (PVZ) and 84 (UPVZ). A total of 53.3% were tested for RSV. Fifty-five infants experienced a RIH and 10 had a RSVH. The PVZ cohort experienced similar odds of RSVH but decreased odds of RIH versus UPVZ, adjusting for gestational age, birth weight, birth during RSV peak months, and presence of siblings (Exp(B) = 0.23 [0.11-0.49], p < 0.0005). In RSVH-related subjects, PVZ subjects experienced shorter length of overall stay (LOS; t = 2.39 [df = 7], p = 0.048). In those with a RIH, the PVZ group had shorter overall intensive care unit (t = 3.52 [df = 15], p = 0.003) and hospital LOS (t = 2.11 [df = 52], p = 0.04). No serious adverse events were related to PVZ. The odds of RSVH were similar between groups, but PVZ subjects had decreased odds of RIH. The low number of RSV tests performed may explain the similarity in RSVH rates. Significant differences in LOS may indicate decreased RSVH and RIH illness severity in the PVZ versus UPVZ groups.

PMID: 29557081 [PubMed - indexed for MEDLINE]

Changing Patterns in Oral Bisphosphonate Initiation in Women between 2004 and 2012.

J Am Geriatr Soc. 2017 03;65(3):656-658

Authors: Lee DR, Ettinger B, Chandra M, Hui RL, Lo JC

PMID: 28152162 [PubMed - indexed for MEDLINE]

Liver toxicity in the era of immune checkpoint inhibitors: A practical approach.

Crit Rev Oncol Hematol. 2018 Dec;132:125-129

Authors: Belli C, Zuin M, Mazzarella L, Trapani D, D'Amico P, Guerini-Rocco E, Achutti Duso B, Curigliano G

Abstract
Immune checkpoint inhibitors have revolutionized the cancer treatment with an approved efficacy in different solid tumors and hematologic malignancies. These agents are increasing the indication in cancer treatment, but can be associated with serious immune-related adverse effects (IRAEs). Dermatologic and gastrointestinal toxicities are the most common IRAE followed by endocrinopathies with a different time of occurrence. Rarely cases of gastrointestinal toxicities are observed almost 2 years after initiation of the therapy. In this review we focus on liver toxicity related to these immunotherapeutic agents for which the largest amount of safety data is available. The management of drug-induced liver toxicity is very complicated and in same cases may take a long period of time to be resolved. A prompt recognition of liver IRAEs and an appropriate management of this event, requiring close collaboration with other specialist figures, could improve its treatment with evident implication on the efficacy of the therapy.

PMID: 30447917 [PubMed - in process]

STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial.

J Immunother Cancer. 2018 Nov 16;6(1):119

Authors: Reilley MJ, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, Curran M, Liu Q, Zhou T, Schmidt J, Jo M, Lee SJ, Yamashita M, Hughes SG, Fayad L, Piha-Paul S, Nadella MVP, Xiao X, Hsu J, Revenko A, Monia BP, MacLeod AR, Hong DS

Abstract
BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL.
METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.
RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.
CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.
TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

PMID: 30446007 [PubMed - in process]

Safety profile of trifluridine/tipiracil monotherapy in clinical practice: results of the German compassionate-use program for patients with metastatic colorectal cancer.

BMC Cancer. 2018 Nov 16;18(1):1124

Authors: Kasper S, Kisro J, Fuchs M, Müller C, Schulz-Abelius A, Karthaus M, Rafiyan MR, Stein A

Abstract
BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016.
METHODS: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting.
RESULTS: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population.
CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.

PMID: 30445951 [PubMed - in process]

EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis.

Haematologica. 2018 Nov 15;:

Authors: Vannucchi AM, Te Boekhorst PAW, Harrison CN, He G, Caramella M, Niederwieser D, Boyer-Perrard F, Duan M, Francillard N, Molloy B, Wroclawska M, Gisslinger H

Abstract
EXPAND (phase 1b, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99x109/L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99x109/L) or stratum 2 (50-74x109/L), with the primary objective of determining the maximum safe starting dose; key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, N=44; stratum 2, N=25), 24.6% (17 of 69) of patients were still receiving treatment. The maximum safe starting dose was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia (grade 4 [stratum 1, N=1; stratum 2, N=2]) was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the maximum safe starting dose cohort (stratum 1, N=20; stratum 2, N=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the maximum safe starting dose. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the maximum safe starting dose of 10 mg twice daily (NCT01317875).  .

PMID: 30442723 [PubMed - as supplied by publisher]

Efficacy and safety of immunological adjuvants. Where is the cut-off?

Biomed Pharmacother. 2018 Sep;105:616-624

Authors: Batista-Duharte A, Martínez DT, Carlos IZ

Abstract
Research over the past several decades has provided insight into the mode of action of adjuvants. However, the main focus of attention has been the efficacy in the induction of protective immunogenicity, while less effort has been devoted to the study of toxicity mechanisms. Evidences suggest that several mechanisms that are responsible for the immunostimulating effects are, at the same time, responsible of the adverse effects. In this context, it is often very difficult to establish the boundaries between immunostimulation and immunotoxicity to reach the ideal balance of efficacy/safety. During decades, hundreds of adjuvants and adjuvant formulations have been proposed as immunostimulants for vaccines but very few have been used in human vaccines due to toxicity concerns. In this review, relevant aspects about immunotoxicology of adjuvants, based on clinical and experimental studies are discussed. Some effects are only observed under hyperstimulating regimens using non-approved adjuvants for human use, but these are nonetheless useful to understanding basic principles of adjuvant toxicity. The acute local and systemic reactions, during the first hours and those that can be observed after the third day of vaccination in the inoculation site and systemically are discussed.

PMID: 29894962 [PubMed - indexed for MEDLINE]

[Indirect and mixed mechanisms of action in toxic myopathies].

Ann Pharm Fr. 2018 Jul;76(4):273-285

Authors: Khelfi A, Azzouz M, Abtroun R, Reggabi M, Alamir B

Abstract
Toxic myopathies are a group of pathologies characterized by a structural and/or functional disturbance of muscles induced by an exogenous agent. The most frequent are those induced by drugs used in clinical practice. Illegal drugs, pesticides, solvents, metals and even physical and gaseous agents can cause this kind of disease and exert toxicity on muscle tissues. Some toxins from animals, plants or micro-organisms are potent myotoxic agents, which can lead to fatal complications. Respiratory arrest and rhabdomyolysis are often referred to as the ultimate complications of these pathologies. Several mechanisms of action can be triggered. Muscles may represent a direct target for exogenous agents by acting on the myocyte components or indirect target by inducing functional disorders. These disorders are triggered by neuromuscular interferences (organophosphates, antipsychotics, curares, etc.) and endocrine (glucocorticoids and ethyl alcohol), immune (d-penicillamine and statins) and hydroelectrolytic system dysfunctions (diuretics, laxatives and toluene). Direct and indirect effects can be induced by the same toxic agent, such as carbon monoxide, glucocorticoids, ethyl alcohol and some toxins from snake venoms.

PMID: 29803327 [PubMed - indexed for MEDLINE]

Efficacy and safety of tenofovir disoproxil fumarate versus low-dose stavudine over 96 weeks: a multi-country randomised, non-inferiority trial.

J Acquir Immune Defic Syndr. 2018 Nov 12;:

Authors: Venter WDF, Kambugu A, Chersich MF, Becker S, Hill A, Arulappan N, Moorhouse M, Majam M, Akpomiemie G, Sokhela S, Poongulali S, Feldman C, Duncombe C, Brown Ripin DH, Kumarasamy N

Abstract
BACKGROUND: Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF).
SETTING: HIV-1-infected treatment-naive adults in India, South Africa and Uganda METHODS: A phase-4, 96-week, randomized, double-blind, non-inferiority trial compared d4T 20mg BD and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/ml at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials·gov (NCT02670772).
RESULTS: Between 2012 and 2014, 536 participants were recruited per arm. At week-96, trial completion rates were 75.7% with d4T/3TC/EFV (n=406) and 82.1% with TDF/3TC/EFV (n=440, p=0.011). Non-completion was largely due to virological failure (6.2% [33] with d4T/3TC/EFV versus 5.4% [29] with TDF/3TC/EFV; p=0.60). For the primary endpoint, d4T/3TC/EFV was non-inferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference=-1.49%, 95%CI=-6.3,3.3; p<0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; p<0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; p<0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (p=0.03). Hip bone density measures, however, showed greater loss with TDF.
CONCLUSIONS: Low-dose d4T combined with 3TC/EFV demonstrated non-inferior virological efficacy compared to TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 30422900 [PubMed - as supplied by publisher]

Effect of a Pharmacist-Led Educational Intervention on Inappropriate Medication Prescriptions in Older Adults: The D-PRESCRIBE Randomized Clinical Trial.

JAMA. 2018 Nov 13;320(18):1889-1898

Authors: Martin P, Tamblyn R, Benedetti A, Ahmed S, Tannenbaum C

Abstract
Importance: High rates of inappropriate prescribing persist among older adults in many outpatient settings, increasing the risk of adverse drug events and drug-related hospitalizations.
Objective: To compare the effectiveness of a consumer-targeted, pharmacist-led educational intervention vs usual care on discontinuation of inappropriate medication among community-dwelling older adults.
Design, Setting, and Participants: A cluster randomized trial (D-PRESCRIBE [Developing Pharmacist-Led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly]) that recruited community pharmacies in Quebec, Canada, from February 2014 to September 2017, with follow-up until February 2018, and randomly allocated them to intervention or control groups. Patients included were adults aged 65 years and older who were prescribed 1 of 4 Beers Criteria medications (sedative-hypnotics, first-generation antihistamines, glyburide, or nonsteroidal anti-inflammatory drugs), recruited from 69 community pharmacies. Patients were screened and enrolled before randomization.
Interventions: Pharmacists in the intervention group were encouraged to send patients an educational deprescribing brochure in parallel to sending their physicians an evidence-based pharmaceutical opinion to recommend deprescribing. The pharmacists in the control group provided usual care. Randomization occurred at the pharmacy level, with 34 pharmacies randomized to the intervention group (248 patients) and 35 to the control group (241 patients). Patients, physicians, pharmacists, and evaluators were blinded to outcome assessment.
Main Outcomes and Measures: Discontinuation of prescriptions for inappropriate medication at 6 months, ascertained by pharmacy medication renewal profiles.
Results: Among 489 patients (mean age, 75 years; 66% women), 437 (89%) completed the trial (219 [88%] in the intervention group vs 218 [91%] in the control group). At 6 months, 106 of 248 patients (43%) in the intervention group no longer filled prescriptions for inappropriate medication compared with 29 of 241 (12%) in the control group (risk difference, 31% [95% CI, 23% to 38%]). In the intervention vs control group, discontinuation of inappropriate medication occurred among 63 of 146 sedative-hypnotic drug users (43.2%) vs 14 of 155 (9.0%), respectively (risk difference, 34% [95% CI, 25% to 43%]); 19 of 62 glyburide users (30.6%) vs 8 of 58 (13.8%), respectively (risk difference, 17% [95% CI, 2% to 31%]); and 19 of 33 nonsteroidal anti-inflammatory drug users (57.6%) vs 5 of 23 (21.7%), respectively (risk difference, 35% [95% CI, 10% to 55%]) (P for interaction = .09). Analysis of the antihistamine drug class was not possible because of the small sample size (n = 12). No adverse events requiring hospitalization were reported, although 29 of 77 patients (38%) who attempted to taper sedative-hypnotics reported withdrawal symptoms.
Conclusions and Relevance: Among older adults in Quebec, a pharmacist-led educational intervention compared with usual care resulted in greater discontinuation of prescriptions for inappropriate medication after 6 months. The generalizability of these findings to other settings requires further research.
Trial Registration: ClinicalTrials.gov Identifier: NCT02053194.

PMID: 30422193 [PubMed - in process]

The efficacy and safety of tazobactam/ceftolozane in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection.

J Infect Chemother. 2018 Nov 09;:

Authors: Arakawa S, Kawahara K, Kawahara M, Yasuda M, Fujimoto G, Sato A, Yokokawa R, Yoshinari T, Rhee EG, Aoyama N

Abstract
We report efficacy and safety results for a combination of a novel cephalosporin class antibiotic and a β-Lactamase inhibitor, tazobactam/ceftolozane (1:2) at a dose of 1.5 g intravenously every 8 h in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. This study design was a nonrandomized, multicenter, open-label trial, and the treatment period was 7 days. Of 115 patients enrolled in this study, 114 received tazobactam/ceftolozane, and 90 were included in the efficacy analyses. Ninety-nine isolates (bacterial count ≥105 CFU/mL) were identified by urine culture. The main baseline uropathogens were Escherichia coli (80 isolates), Klebsiella pneumoniae (8 isolates), and Proteus mirabilis (3 isolates). Of these, 13 isolates were ESBL-producers. The favorable per-patient microbiological response rate at 7 days after the final administration of tazobactam/ceftolozane was 80.7% (71/88). The response rate in uncomplicated pyelonephritis was 90.0% (36/40), complicated pyelonephritis 63.6% (14/22), and complicated cystitis 80.8% (21/26). The favorable clinical response rate was 96.6% (86/89), and composite response rate (based on microbiological and clinical response) was 80.7% (71/88). The eradication rate by uropathogen was 83.5% (66/79) in E. coli, 42.9% (3/7) in K. pneumoniae, and 100% (3/3) in P. mirabilis. The incidence of drug-related adverse events was 17.5% (20/114 patients). The most common drug-related adverse events were diarrhea and alanine aminotransferase increased in 5.3% (6/114 patients each). Drug-related serious adverse events and deaths were not observed. These results support the safety and efficacy of tazobactam/ceftolozane and suggest it will be a useful treatment for uncomplicated pyelonephritis and complicated urinary tract infection.

PMID: 30420153 [PubMed - as supplied by publisher]

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.

Lancet. 2018 Nov 09;:

Authors: Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, Hung CC, Rockstroh JK, Girard PM, Sievers J, Man C, Currie A, Underwood M, Tenorio AR, Pappa K, Wynne B, Fettiplace A, Gartland M, Aboud M, Smith K, GEMINI Study Team

Abstract
BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug region for the treatment of HIV-1 infection in ART-naive adults METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both regimen drugs were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively.
FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication.
INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection.
FUNDING: ViiV Healthcare.

PMID: 30420123 [PubMed - as supplied by publisher]

Change over time in the rates of adverse events in patients receiving systemic therapy for psoriasis: A cohort study.

J Am Acad Dermatol. 2018 04;78(4):798-800

Authors: Descalzo MA, Carretero G, Ferrándiz C, Rivera R, Daudén E, Gómez-García FJ, de la Cueva P, Herrera-Ceballos E, Belinchón I, López-Estebaranz JL, Alsina M, Sánchez-Carazo JL, Ferrán M, Baniandrés O, Carrascosa JM, Llamas-Velasco M, Ruiz-Genao D, Herrera-Acosta E, Muñoz-Santos C, García-Doval I, Biobadaderm Study Group

PMID: 29146129 [PubMed - indexed for MEDLINE]

Short-term reasons for withdrawal and adverse events associated with apremilast therapy for psoriasis in real-world practice compared with in clinical trials: A multicenter retrospective study.

J Am Acad Dermatol. 2018 04;78(4):801-803

Authors: Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J

PMID: 29017843 [PubMed - indexed for MEDLINE]

Generally Regarded As Safe.

Ocul Surf. 2017 01;15(1):152-155

Authors: Novack GD

PMID: 27871773 [PubMed - indexed for MEDLINE]

Safety and immunogenicity of HBAI20 Hepatitis B vaccine in healthy naïve and nonresponding adults.

J Viral Hepat. 2018 09;25(9):1048-1056

Authors: Koc ÖM, Savelkoul PHM, van Loo IHM, Peeters A, Oude Lashof AML

Abstract
Approximately 5% of the healthy adult population respond inadequately to the commercial recombinant hepatitis B vaccines. As the recombinant vaccines all have an aluminium-based adjuvant, we tried to enhance the immune response by adding a cytokine-based adjuvant. This new adjuvant AI20, containing 20 μg recombinant human IL-2 attached to 20 μg aluminium hydroxide, was added to HBVaxPro©-10 μg (HBAI20). In a double-blind randomized controlled trial (RCT), 24 naïve subjects were randomized to receive either HBAI20 or commercial HBVaxPro©-10 μg vaccine. In an open-label study, 10 nonresponders received HBAI20 vaccine. All participants received 3 vaccinations (0, 1 and 6 months). In the RCT, the occurrence of any adverse events or severe events was similar between the trial arms. At month 7, all naïve participants were seroprotected; moreover, 92% in the HBAI20 group had protective antibodies 10 days after the second vaccination vs 58% in the HBVaxPro©-10 μg group, P = .16. In the open-label study, no serious adverse events were noted. The HBAI20 vaccine was able to elicit protective anti-HBs titres in 90% of nonresponders, 1 month after the third vaccination. According to these results, the new HBAI20 vaccine seems safe, well-tolerated and may promote more rapid protection against hepatitis B infection.

PMID: 29660190 [PubMed - indexed for MEDLINE]

Dealing With the Nocebo Effect: Taking Physician-Patient Interaction Seriously.

Am J Bioeth. 2017 06;17(6):48-50

Authors: Widdershoven G, Meynen G, Metselaar S

PMID: 28537824 [PubMed - indexed for MEDLINE]

Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity.

Nat Protoc. 2018 Nov 09;:

Authors: Sharma A, McKeithan WL, Serrano R, Kitani T, Burridge PW, Del Álamo JC, Mercola M, Wu JC

Abstract
Cardiotoxicity has historically been a major cause of drug removal from the pharmaceutical market. Several chemotherapeutic compounds have been noted for their propensities to induce dangerous cardiac-specific side effects such as arrhythmias or cardiomyocyte apoptosis. However, improved preclinical screening methodologies have enabled cardiotoxic compounds to be identified earlier in the drug development pipeline. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to screen for drug-induced alterations in cardiac cellular contractility, electrophysiology, and viability. We previously established a novel 'cardiac safety index' (CSI) as a metric that can evaluate potential cardiotoxic drugs via high-throughput screening of hiPSC-CMs. This metric quantitatively examines drug-induced alterations in CM function, using several in vitro readouts, and normalizes the resulting toxicity values to the in vivo maximum drug blood plasma concentration seen in preclinical or clinical pharmacokinetic models. In this ~1-month-long protocol, we describe how to differentiate hiPSCs into hiPSC-CMs and subsequently implement contractility and cytotoxicity assays that can evaluate drug-induced cardiotoxicity in hiPSC-CMs. We also describe how to carry out the calculations needed to generate the CSI metric from these quantitative toxicity measurements.

PMID: 30413796 [PubMed - as supplied by publisher]

Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial.

Lancet Diabetes Endocrinol. 2018 Nov 06;:

Authors: de Zeeuw D, Renfurm RW, Bakris G, Rossing P, Perkovic V, Hou FF, Nangaku M, Sharma K, Heerspink HJL, Garcia-Hernandez A, Larsson TE

Abstract
BACKGROUND: Many patients with diabetic kidney disease have residual albuminuria and are at risk of disease progression. The ALBUM trial investigated the efficacy of a novel, orally active inhibitor of vascular adhesion protein-1, ASP8232, compared with placebo for reducing albuminuria in individuals with type 2 diabetes and chronic kidney disease.
METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial, we randomly assigned individuals (aged 18-85 years) from 64 clinical sites in nine European countries to receive ASP8232 40 mg or placebo orally once daily for 12 weeks using a web-based randomisation schedule (block size 4), stratified by country. Eligible patients had a urinary albumin-to-creatinine ratio (UACR) of 200-3000 mg/g, an estimated glomerular filtration rate of at least 25 mL/min per 1·73 m2 but lower than 75 mL/min per 1·73 m2, HbA1c less than 11·0% (97 mmol/mol), and stable treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic medication for 3 months or more. The primary endpoint was mean change from baseline to week 12 in log-transformed first morning void UACR, which was assessed in all patients who received at least one dose of study drug and had at least one post-baseline UACR measurement (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. Participants and investigators were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT02358096.
FINDINGS: 125 participants were randomly assigned to receive ASP8232 (n=64) or placebo (n=61), of whom 120 (60 in each group) were included in the full analysis set; all participants were assessed for safety endpoints. At 12 weeks, UACR decreased by 17·7% (95% CI 5·0 to 28·6) in the ASP8232 group and increased by 2·3% (-11·4 to 18·1) in the placebo group; the placebo-adjusted difference between groups was -19·5% (95% CI -34·0 to -1·8; p=0·033). 39 (61%) patients in the ASP8232 group and 34 (56%) patients in the placebo group had a treatment-emergent adverse event, of which 16 in the ASP8232 group and four in the placebo group were drug-related. The most frequently reported adverse events that were possibly drug-related in the ASP8232 group were renal impairment (five patients) and decreased eGFR (three patients); in the placebo group, no single drug-related treatment-emergent adverse event was reported by more than one participant.
INTERPRETATION: ASP8232 is effective in reducing albuminuria in patients with diabetic kidney disease and is safe and well tolerated. These findings warrant further research to ascertain the effect of ASP8232 on delaying progression of diabetic kidney disease.
FUNDING: Astellas.

PMID: 30413396 [PubMed - as supplied by publisher]