Preexposure Intradermal Rabies Vaccination: A Noninferiority Trial in Healthy Adults on Shortening the Vaccination Schedule From 28 to 7 Days.

Clin Infect Dis. 2019 02 01;68(4):607-614

Authors: Soentjens P, Andries P, Aerssens A, Tsoumanis A, Ravinetto R, Heuninckx W, van Loen H, Brochier B, Van Gucht S, Van Damme P, Van Herrewege Y, Bottieau E

Abstract
Background: The existing 4-week preexposure rabies vaccination schedule is costly and often not practicable. Shorter effective schedules would result in wider acceptance.
Methods: We conducted a noninferiority trial in 500 healthy adults comparing the safety and immunogenicity of a 2-visit (days 0 and 7) intradermal (ID) primary vaccination (2 doses of 0.1 mL ID of the human diploid cell culture rabies vaccine [HDCV] at days 0 and 7) vs a standard 3-visit schedule (single dose of 0.1 mL ID at days 0, 7, and 28). One year to 3 years after primary vaccination, a single booster dose of 0.1 mL ID of HDCV was given to evaluate the anamnestic rabies antibody response. The primary endpoint for immunogenicity was the percentage of subjects with an adequate antibody level >0.5 IU/mL 7 days after the booster injection. The safety endpoint was the proportion of participants developing adverse reactions following the primary vaccination and/or booster dose.
Results: All subjects in both study groups possessed a rabies antibody titer >0.5 IU/mL on day 7 following the booster dose. Following the booster dose, subjects exposed to the double-dose 2-visit ID schedule had a geometric mean titer of 37 IU/mL, compared with 25 IU/mL for the single-dose 3-visit schedule (P < .001). Local reactions at the injection site following primary vaccination were mild and transient.
Conclusions: In healthy adults, ID administration of a double dose of 0.1 mL of HDCV over 2 visits (days 0 and 7) was safe and not inferior to the single-dose 3-visit schedule.
Clinical Trials Registration: NCT01388985, EudraCT 2011-001612-62.

PMID: 29939243 [PubMed - indexed for MEDLINE]

Immediate Versus Deferred Switching From a Boosted Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen in Virologically Suppressed Patients With High Cardiovascular Risk or Age ≥50 Years: Final 96-Week Results of the NEAT022 Study.

Clin Infect Dis. 2019 02 01;68(4):597-606

Authors: Gatell JM, Assoumou L, Moyle G, Waters L, Johnson M, Domingo P, Fox J, Martinez E, Stellbrink HJ, Guaraldi G, Masia M, Gompels M, De Wit S, Florence E, Esser S, Raffi F, Stephan C, Rockstroh J, Giacomelli A, Vera J, Bernardino JI, Winston A, Saumoy M, Gras J, Katlama C, Pozniak AL, European Network for AIDS Treatment 022 (NEAT022) Study Group

Abstract
Background: Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to a dolutegravir (DTG)-based regimen may improve lipid profile.
Methods: European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)-infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs).
Results: Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, -.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata.
Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile.
Clinical Trials Registration: NCT02098837 and EudraCT: 2013-003704-39.

PMID: 29912307 [PubMed - indexed for MEDLINE]

13 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 2020/03/17

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13 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 2020/03/17

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.

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226.

Lung Cancer. 2020 Feb 28;143:1-11

Authors: Juergens RA, Hao D, Ellis PM, Tu D, Mates M, Kollmannsberger C, Bradbury PA, Tehfe M, Wheatley-Price P, Robinson A, Bebb G, Laskin J, Goffin J, Hilton J, Tomiak A, Hotte S, Goss GD, Brown-Walker P, Sun X, Tsao MS, Cabanero M, Gauthier I, Song X, Dennis PA, Seymour LK, Smoragiewicz M, Laurie SA

Abstract
This multicenter phase Ib study aimed to establish a recommended phase II dose for durvalumab (Du) ± tremelimumab (Tr) in combination with standard platinum-doublet chemotherapy. Eligible patients were enrolled into one of six dose levels (DL) of Du ± Tr which included concomitant treatment with standard platinum-doublet regimens; (pemetrexed, gemcitabine, etoposide, (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin)). Dose escalation was according to a Rolling Six type design. Both weight-based and fixed dosing of Du and Tr were explored. Du was continued until progression. Tr dosing was finite (up to 6 doses) with increasing dose and/or frequency by DL. 136 patients were enrolled. The majority of drug-related adverse events (AEs) were ≤ grade 2 and attributable to chemotherapy. AEs considered related to immunotherapy were mainly ≤ grade 2; the most frequent (occurring ≥10 %) were colitis/diarrhea, skin, and thyroid dysfunction. Seven patients had DLTs including pneumonitis, myocarditis, diarrhea, encephalitis, motor neuropathy, and enterocolitis. There were 2 treatment-related deaths. Tr and Du exposures did not appear affected by chemotherapy. Among the 73 non-small cell lung cancer (NSCLC) patients treated, the objective response rate was 51 % (95 %CI = 38.7-62.6 %) with a median progression-free and overall survival of 6.5 months (95 % CI = 5.5-9.4 months) and 19.8 months (95 % CI = 14.8 months - not yet reached) respectively. Anti-tumour activity was observed across PD-L1 subtypes. Du 1500 mg q3w and Tr 75 mg q3wx5 can be safely combined with platinum-doublet chemotherapy. Efficacy among NSCLC patients appears comparable to results from other immunotherapy and chemotherapy combination trials. NCT02537418.

PMID: 32169783 [PubMed - as supplied by publisher]

Spontaneous reports of hypersensitivity adverse drug reactions in Portugal: a retrospective analysis.

Expert Opin Drug Saf. 2020 Mar 13;:

Authors: Mendes D, Oliveira AR, Alves C, Batel Marques F

Abstract
Background: Hypersensitivity adverse drug reactions (ADRs) are usually serious, unpredictable and associated with high morbidity and mortality. This study describes cases of hypersensitivity ADRs spontaneously reported in Central Portugal.Methods: Spontaneous reports (SRs) of ADRs received between January 2010 and December 2017 were reviewed to identify cases of hypersensitivity reactions, using the Standardised MedDRA Query (SMQ) "Hypersensitivity". Cases were assessed for seriousness, expectedness and causality. Descriptive statistics were used to analyse data.Results: Among 2050 SRs, 598 (29.2%) contained hypersensitivity ADRs. A total of 657 (90.5%) cases were serious, 569 (78.4%) unexpected, and 469 (64.6%) certainly related to drug exposure. Among 726 hypersensitivity ADRs, anaphylactic reactions (n=93;12.8%), rash maculopapular (n=82;11.3%), rash (n= 67;9.2%) and DRESS (n=54;7.4%) were more common. Frequently implicated drug classes comprised antibiotics (n=150;23.0%), antineoplastic agents (n=124;19.0%), allopurinol (n=54;8.3%), and anti-inflammatories (n=44;6.8%). Top-causative drugs were allopurinol (n=54;8.3%), docetaxel (n=46;7.1%) and trimethoprim/sulfamethoxazole (n=26;4.0%).Conclusions: Most hypersensitivity ADRs were serious, unexpected and with strong causal relationship with suspected drugs. Allopurinol was the top-causative drug. In addition to antibiotics and anti-inflammatories, antineoplastic agents were frequently cited. The results of this study deserve further investigation to better characterize risk factors associated with hypersensitivity ADRs, particularly in those induced by allopurinol and antineoplastic agents.

PMID: 32167395 [PubMed - as supplied by publisher]

Management of dermatologic adverse events from cancer therapies: recommendations of an expert panel.

An Bras Dermatol. 2020 Feb 15;:

Authors: Cury-Martins J, Eris APM, Abdalla CMZ, Silva GB, Moura VPT, Sanches JA

Abstract
With the development of new cancer therapies, systemic toxicity profile and effects on survival achieved an important improvement. However, a constellation of toxicities has emerged, even more remarkably, cutaneous adverse events. This report, developed by a board of Brazilian experts in oncodermatology, aims to establish a guideline for the dermatological care of oncologic patients. When possible, evidence-based recommendations were made, but in many cases, when strong evidence was not available, a consensus was reached, based on some data supporting therapies combined with personal experiences.

PMID: 32165025 [PubMed - as supplied by publisher]

Safety and effectiveness of peficitinib (ASP015K) in patients with rheumatoid arthritis: interim data (22.7 months mean peficitinib treatment) from a long-term, open-label extension study in Japan, Korea, and Taiwan.

Arthritis Res Ther. 2020 Mar 12;22(1):47

Authors: Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Song YW, Chen YH, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Nakashima Y, Shiomi T, Yamada E

Abstract
BACKGROUND: Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52 weeks' duration. However, safety and effectiveness after long-term treatment have not been assessed.
METHODS: This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12 weeks) and phase 3 (RAJ3 and RAJ4; 52 weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n = 843) received oral peficitinib once daily (100 mg, or 50 mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150 mg) or reduced (to 50 mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP).
RESULTS: Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7 months and the maximum dose was 100 mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6 - 3.1), herpes zoster-related disease 6.8 (95% CI, 5.6 - 8.3), and malignancies 1.1 (95% CI, 0.7 - 1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively.
CONCLUSIONS: The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6 years was well tolerated in Asian patients with RA.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

PMID: 32164762 [PubMed - in process]

[Medicaments and oral healthcare. Adverse effects of medicaments: the 'Big Five' of bone healing].

Ned Tijdschr Tandheelkd. 2020 Jan;127(1):19-27

Authors: Beumer LJ, Witjes MJH

Abstract
the bone can still be present long after patients have stopped taking the medication. Patients are often able to report accurately what disorder(s) they have and certain disorders should cause dentists to be alert. Patients who can be defined as the Big Five users of bone-modulating medicaments are: 1. patients with osteoporosis, 2. patients who have been long-term users of glucocorticoids, 3. patients with solid tumours, 4. patients with multiple myeloma and 5. patients with congenital or hereditary bone disorders. These patient groups have an indication for bone-modulating medicaments. These are anti-resorptive medications (such as bisphosphonates and denosumab) or anti-angiogenic medications. By recognising the correct patient group, dentists can ask appropriate questions about the use of medicaments in the present or in the past. A dentist can recognise patients with a risk of medication-related osteonecrosis by using this method.

PMID: 32159525 [PubMed - indexed for MEDLINE]

Evaluation of clinical manifestations, health risks, and quality of life among women with polycystic ovary syndrome.

PLoS One. 2019;14(10):e0223329

Authors: Sidra S, Tariq MH, Farrukh MJ, Mohsin M

Abstract
This study aimed to evaluate the clinical manifestations and health risks associated with polycystic ovary syndrome (PCOS) and its impact on quality of life (QOL) in Pakistan. A detailed cross-sectional study was conducted on PCOS among women of reproductive age visiting the gynecology and obstetrics and endocrinology departments at primary and tertiary care hospitals located in Abbottabad, Kohat, and Islamabad. In total, 440 patients meeting the inclusion criteria were included. A checklist was specifically designed to identify symptoms and health risks, including adverse drug reactions, complications, irrational prescription or underprescription, and drug-drug interactions. The Short Form-12 questionnaire was used to evaluate the QOL of patients with PCOS. Data collected were analyzed for descriptive and inferential statistics using chi-square test, analysis of variance, and post hoc analysis. All patients exhibited the cardinal symptoms of PCOS, including obesity (n = 352, 80%), acne (n = 296, 67.3), hirsutism (n = 299, 68%), hyperglycemia (n = 278, 63.2%), and irregular menstruation (n = 316, 71.8%). Ultrasonography confirmed that 268 (61%) patients had multiple cysts of >10 mm in diameter. Patients with untreated PCOS exhibited a high prevalence of health risks including hypertension (n = 87, 19.8%), diabetes (n = 268, 60.9%), sleep apnea (n = 11, 2.5%), infertility (n = 146, 33.2%), increased endometrial thickness (n = 21, 4.8%), miscarriages (n = 68, 15.5%), high cholesterol level (n = 85, 19.3%), and hyperandrogenism (n = 342, 77.7%). Most patients exhibited low QOL scores (n = 374, 85%), with depression being the largest contributor to low QOL. Apart from novel results, this study found an association between depression and low QOL in patients with PCOS, suggesting the need for reviewing the management guidelines and psychological health assessment of women with PCOS.

PMID: 31603907 [PubMed - indexed for MEDLINE]

Development of medication-related counselling skills in senior medical students: a checklist-based approach.

BMC Med Educ. 2019 Sep 05;19(1):335

Authors: Gupta S, Shaw J

Abstract
BACKGROUND: Effective communication between healthcare providers and patients has been established as a vital element in medication compliance and patient safety. Medical curricula worldwide include medication-related counselling skill as a learning outcome for medical graduates. However, this aspect of health-care training is frequently informal and poorly structured in most medical schools. This paper provides an interesting view of students' experiences of using a checklist-based approach to develop and practice patient counselling in relation to prescribed medications.
METHODS: The authors describe introduction of a thirteen item "Patient Education Checklist" (PEC) as part of an optional checklist based exercise (CBE) in year 4 and 5 clinical blocks. Students consulted PEC to discuss relevant practical issues related to medication intake with their patients. Students were expected to submit reflective case summaries regarding their experience of using PEC to counsel patients over a two-week period. The textual data from student submissions was analysed using inductive content analysis.
RESULTS: We received 13 year4 and 17 year5 student submissions. A content analysis of student reflections identified four dominant themes 1.Enhancement in self-confidence in relation to patient education (86.7%), 2. PEC perceived useful for patient counselling (83.3%), 3. Recognising variation in health literacy levels of patients (50%), 4.Fear of overloading the patient with information (23.3%). Students realised the need to present the medication related knowledge in simple language and tailor the amount of information as per patients' understanding. Student reflections included interesting observations about the wide variation in health literacy of patients and insights into patients' concerns and frequent misconceptions about medicines.
CONCLUSION: Students perceived PEC as a useful tool in adding focus and structure to student patient interactions. They report that it substantially improved their confidence and added quality to patient encounters. Future research is required to assess the effect of CBE on medication compliance and therapeutic outcome. PEC might serve as a useful resource for pharmacy and nursing students.

PMID: 31488168 [PubMed - indexed for MEDLINE]

Medicines for Europe - 13th Pharmacovigilance Conference (January 29, 2020 - Amsterdam, the Netherlands).

Drugs Today (Barc). 2020 Feb;56(2):165-168

Authors: Hamaui Cuadrado S

Abstract
This year, following the European Medicines Agency (EMA) relocation due to the Brexit process, the 13th Pharmacovigilance Conference organized by Medicines for Europe took place in Amsterdam, the Netherlands. The pharmaceutical industry is usually associated with the development and launch of new drugs for the market, but it is also committed to finding new ways of making existing drugs and processes (e.g., pharmacovigilance [PV]) more efficient and better for patients. In relation to this, a variety of topics were on the agenda at the conference, including updates on the progress of the EudraVigilance (EV) system for monitoring and analyzing potential drug-related adverse events, as well as highlights on the E.U. Network Strategy to 2025 and the EMA multi-annual work program related to big data acceptability, electronic product information (ePI) Key Principles and Roadmap for implementation, and work-sharing ongoing projects for achieving harmonization of requirements and processes. Adrian van den Hoven (Director General, Medicines for Europe) opened the conference looking towards the future, emphasizing what the current PV system needs to do in order to adapt to new landscapes. With big data, robotization, automation or globalization, there are many opportunities to streamline and become smarter on the horizon.

PMID: 32163531 [PubMed - as supplied by publisher]

Bevacizumab in Combination with TAS-102 Improves Clinical Outcomes in Patients with Refractory Metastatic Colorectal Cancer: A Retrospective Study.

Oncologist. 2020 Mar;25(3):e469-e476

Authors: Fujii H, Matsuhashi N, Kitahora M, Takahashi T, Hirose C, Iihara H, Yamada Y, Watanabe D, Ishihara T, Suzuki A, Yoshida K

Abstract
OBJECTIVE: TAS-102 is effective for treating patients with metastatic colorectal cancer (mCRC). This study determined whether combining bevacizumab (Bmab) with TAS-102 improves clinical outcomes in refractory mCRC.
PATIENTS AND METHODS: We retrospectively analyzed data from Japanese patients with refractory mCRC who received TAS-102 (35 mg/m2 , twice a day) with (T-B group) or without Bmab (TAS-102 monotherapy; T group) between July 2014 and December 2018. The primary endpoint was median overall survival (OS), and secondary endpoints were median time to treatment failure, overall response rate, and the incidence of adverse events. Clinical outcomes were compared using propensity score matched analysis.
RESULTS: Data from 57 patients were analyzed (T-B group: 21 patients, T group: 36 patients). Median OS was significantly longer in the T-B group than the T group (14.4 months vs. 4.5 months, p < .001). Cox proportional hazard analysis showed that combination therapy with Bmab was significantly correlated with OS. Propensity score matched analysis confirmed that the median OS was significantly longer in the T-B group than the T group (14.4 months vs. 6.1 months, p = .006) and that there was a significant correlation between Bmab and OS. The incidence of hypertension (grade ≥2) as an adverse event was significantly higher in the T-B group than the T group (23.8% vs. 0.0%, p = .005), whereas other adverse events were comparable between the two groups.
CONCLUSION: Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC refractory to standard therapies.
IMPLICATIONS FOR PRACTICE: Combining bevacizumab (Bmab) with TAS-102 significantly improved overall survival and several prognostic indicators in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies, with manageable toxicities. Treatment with Bmab in combination with TAS-102 is significantly associated with improved clinical outcomes in patients with mCRC.

PMID: 32162797 [PubMed - in process]

Automated Decision Support for Drug-Induced Long QT.

S D Med. 2020 Mar;73(3):112-115

Authors: Lupu RA, Twedt H, Chavour S, Larson EA

Abstract
Advancements in clinical informatics and translational genomics are changing the way we practice medicine. Automated decision support currently helps providers adjust prescribing patterns to reduce the likelihood of QT prolongation based upon drug-drug interaction. A similar approach is being explored for drug-gene interaction. Like many adverse drug reactions, QT prolongation can be influenced by variability in genetic factors. However, drug-induced QT prolongation can occur in the absence of any known ion channel gene abnormalities. We therefore review differences between congenital long QT syndrome and drug-induced long QT syndrome, and we underscore the need for decision support that integrates EKG data.

PMID: 32142229 [PubMed - indexed for MEDLINE]

Comparison of effects of UGT1A1*6 and UGT1A1*28 on irinotecan-induced adverse reactions in the Japanese population: analysis of the Biobank Japan Project.

J Hum Genet. 2019 Dec;64(12):1195-1202

Authors: Hikino K, Ozeki T, Koido M, Terao C, Kamatani Y, Murakami Y, Kubo M, Mushiroda T

Abstract
It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.

PMID: 31586129 [PubMed - indexed for MEDLINE]

Real-world evaluation of the safety and tolerability of abacavir/dolutegravir/lamivudine in an incarcerated population.

Int J STD AIDS. 2019 10;30(12):1163-1168

Authors: Brizzi MB, Chiampas TD, Michienzi SM, Young JD, Patel MC, Badowski ME

PMID: 31558124 [PubMed - indexed for MEDLINE]

Predictive Value of Cellular Accumulation of Hydrophobic Bile Acids As a Marker of Cholestatic Drug Potential.

Toxicol Sci. 2019 04 01;168(2):474-485

Authors: Burban A, Sharanek A, Humbert L, Eguether T, Guguen-Guillouzo C, Rainteau D, Guillouzo A

Abstract
Drug-induced cholestasis is mostly intrahepatic and characterized by alterations of bile canaliculi dynamics and morphology as well as accumulation of bile acids (BAs) in hepatocytes. However, little information exists on first changes in BA content and profile induced by cholestatic drugs in human liver. In this study, we aimed to analyze the effects of a large set of cholestatic and noncholestatic drugs in presence of physiological serum concentrations and 60-fold higher levels of 9 main BAs on cellular accumulation of BAs using HepaRG hepatocytes. BAs were measured in cell layers (cells + bile canaliculi) and culture media using high-pressure liquid chromatography coupled with tandem mass spectrometry after 24 h-treatment. Comparable changes in total and individual BA levels were observed in cell layers and media from control and noncholestatic drug-treated cultures: unconjugated BAs were actively amidated and lithocholic acid (LCA) was entirely sulfated. In contrast, cellular accumulation of LCA and in addition, of the 2 other hydrophobic BAs, chenodeoxycholic acid and deoxycholic acid, was evidenced only with cholestatic compounds in presence of BA mixtures at normal and 60-fold serum levels, respectively, suggesting that LCA was the first BA to accumulate. Cellular accumulation of hydrophobic BAs was associated with inhibition of their amidation and for LCA, its sulfation. In conclusion, these results demonstrated that cellular accumulation of unconjugated hydrophobic BAs can be caused by various cholestatic drugs in human hepatocytes and suggest that their cellular detection, especially that of LCA, could represent a new strategy for evaluation of cholestatic potential of drugs and other chemicals.

PMID: 30629237 [PubMed - indexed for MEDLINE]

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 2020/03/12

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.

Efficacy and Safety of treatment with dupilumab for severe asthma.

Allergy. 2020 Mar 10;:

Authors: Agache I, Song Y, Rocha C, Beltran J, Posso M, Steiner C, Alonso-Coello P, Akdis C, Akdis M, Canonica GW, Casale T, Chivato T, Corren J, Del Giacco S, Eiwegger T, Firinu D, Gern JE, Hamelmann E, Hanania N, Mäkelä M, Martín IH, Nair P, O'Mahony L, Papadopoulos NG, Papi A, Park HS, Pérez de Llano L, Quirce S, Sastre J, Shamji M, Schwarze J, Canelo-Aybar C, Palomares O, Jutel M

Abstract
Dupilumab, a fully human monoclonal antibody against Interleukin-4 receptor α is approved as add-on maintenance treatment for inadequately controlled type 2 severe asthma. This systematic review evaluates the effectiveness, safety and economic impact of dupilumab compared to standard of care for uncontrolled severe asthma. Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important asthma-related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. Three RCTs including 2735 subjects > 12 years old and 24 to 52 weeks of follow-up were included. Dupilumab reduced with high certainty severe asthma exacerbations (RR 0.51; 95%CI 0.45 to 0.59) and oral corticosteroid use (mean difference (MD) -28.2 mg/day; 95% CI -40.7 to -15.7). Asthma control (ACQ-5), quality of life (AQLQ) and rescue medication use [puffs/day] improved, without reaching the minimal important clinical difference: ACQ-5 MD -0.28 (95%CI -0.39 to -0.17); AQLQ MD +0.28 (95% CI 0.20 - 0.37); rescue medication MD -0.35 (95%CI -0.73 to +0.02). FEV1 increases (MD +0.15; 95% CI +0.11 to +0.18) (moderate certainty). There is increased rate of dupilumab-related adverse events (AEs) (moderate certainty) and of drug-related serious AEs (low certainty). The incremental cost-effectiveness ratio versus standard therapy was 464,000 $/QALY (moderate certainty). More data on long term safety are needed both for children and adults, together with more efficacy data in the paediatric population.

PMID: 32154939 [PubMed - as supplied by publisher]

Evaluation of Renal Safety Between Imipenem/Relebactam and Colistin Plus Imipenem in Patients With Imipenem-Nonsusceptible Bacterial Infections in the Randomized, Phase 3 RESTORE-IMI 1 Study.

Open Forum Infect Dis. 2020 Mar;7(3):ofaa054

Authors: Brown ML, Motsch J, Kaye KS, File TM, Boucher HW, Vendetti N, Aggrey A, Joeng HK, Tipping RW, Du J, DePestel DD, Butterton JR, Paschke A

Abstract
Background: In the randomized controlled RESTORE-IMI 1 clinical trial (NCT02452047), imipenem/cilastatin (IMI) with relebactam (IMI/REL) was as effective as colistin plus IMI for the treatment of imipenem-nonsusceptible gram-negative infections. Differences in nephrotoxicity were observed between treatment arms. As there is no standard definition of nephrotoxicity used in clinical trials, we conducted analyses to further understand the renal safety profile of both treatments.
Methods: Nephrotoxicity was retrospectively evaluated using 2 acute kidney injury assessment criteria (Kidney Disease Improving Global Outcomes [KDIGO] and Risk, Injury, Failure, Loss, and End-stage Kidney Disease [RIFLE]). Additional outcomes included time to onset of protocol-defined nephrotoxicity and incidence of renal adverse events.
Results: Of 47 participants receiving treatment, 45 had sufficient data to assess nephrotoxicity (IMI/REL, n = 29; colistin plus IMI, n = 16). By KDIGO criteria, no participants in the IMI/REL but 31.3% in the colistin plus IMI group experienced stage 3 acute kidney injury. No IMI/REL-treated participants experienced renal failure by RIFLE criteria, vs 25.0% for colistin plus IMI. Overall, the time to onset of nephrotoxicity varied considerably (2-22 days). Fewer renal adverse events (12.9% vs 37.5%), including discontinuations due to drug-related renal adverse events (0% vs 12.5%), were observed in the IMI/REL group compared with the colistin plus IMI group, respectively.
Conclusions: Our analyses confirm the findings of a preplanned end point and provide further evidence that IMI/REL had a more favorable renal safety profile than colistin-based therapy in patients with serious, imipenem-nonsusceptible gram-negative bacterial infections.
ClinicalTrialsgov Identifier: NCT02452047.

PMID: 32154325 [PubMed]