Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

J Clin Pharmacol. 2020 01;60(1):125-139

Authors: Darpo B, Benson C, Brown R, Dota C, Ferber G, Ferry J, Jarugula V, Keirns J, Ortemann-Renon C, Pham T, Riley S, Sarapa N, Ticktin M, Zareba W, Couderc JP

Abstract
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

PMID: 31378962 [PubMed - indexed for MEDLINE]

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1.

HIV Res Clin Pract. 2021 Feb 02;:1-17

Authors: Huhn GD, Wilkin A, Mussini C, Spinner CD, Jezorwski J, El Ghazi M, Van Landuyt E, Lathouwers E, Brown K, Baugh B, AMBER and EMERALD study groups

Abstract
BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).
OBJECTIVE: To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent).
METHODS: Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials).
RESULTS: D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio.
CONCLUSIONS: D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.

PMID: 33528318 [PubMed - as supplied by publisher]

Differences in detected safety signals between benzodiazepines and non-benzodiazepine hypnotics: pharmacovigilance study using a spontaneous reporting system.

Int J Med Sci. 2021;18(5):1130-1136

Authors: Toyoshima M, Noguchi Y, Otsubo M, Tachi T, Teramachi H

Abstract
Introduction: In recent years, there has been an increasing number of people who feel sleep-deprived owing to sudden changes in the social environment. Patients prescribed benzodiazepine-based hypnotics (BZ drugs) also develop movement disorder action and memory disorders as adverse events (AEs), and they have further problems such as dependency and tolerance because of long-term use. Therefore, the use of non-benzodiazepine-based hypnotics (Z-drugs) is recommended for patients with insomnia. However, as AEs have also been reported for Z-drugs, it is important to identify these when switching hypnotics. Methods: To understand AEs to be noted when switching from BZ drugs to Z-drugs, we evaluated the differences in AEs developed by both these drugs using volcano plots and safety signals. For this, data registered in the Japanese Adverse Drug Event Report database were used. Results: The volcano plot and safety signals revealed six characteristic Z-drug-induced AEs. Parasomnias (ln odds ratio [OR]: 3.28, -log P: 4.34, proportional reporting ratio [PRR]: 23.47, χ 2: 309.27), Cortical dysfunction NEC (ln OR: 2.76, -log P: 4.34, PRR: 3.62, χ 2: 16.14), and Psychiatric symptoms NEC (ln OR: 2.66, -log P: 2.18, PRR: 2.51, χ 2: 6.63) were detected only in Z-drugs, and safety signals of Suicidal and self-injurious behaviour, Deliria, and Overdoses NEC were also detected with BZ drugs. However, the strength of safety signals was much higher with the Z-drugs. Conclusion: AEs related to falls and bone fractures are expected to be more strongly onset in BZ drugs than in Z-drugs, which are said to have less muscle relaxant action. However, there was no particularly significant difference in this parameter between the two drug classes. Understanding the difference between these AEs of Z-drugs and BZ drugs is important for the proper use of hypnotics.

PMID: 33526972 [PubMed - in process]

There are no "side" effects, just "core" effects of antipsychotic pharmacotherapy.

Acta Psychiatr Scand. 2021 02;143(2):99-100

Authors: Fornaro M

PMID: 33452692 [PubMed - indexed for MEDLINE]

Applying the Medications at Transitions and Clinical Handoffs Toolkit in a Rural Primary Care Clinic: Implications for Nursing, Patients, and Caregivers.

J Nurs Care Qual. 2020 Jul/Sep;35(3):233-239

Authors: Jarrett T, Cochran J, Baus A

Abstract
BACKGROUND: Adequate medication reconciliation is related to patients' safety. Rural populations are at increased risk of adverse drug events due to errors in medication reconciliation and often receiving medical care across multiple health care entities and across long distances with separate electronic medical records.
METHODS: This study examined the implementation of Medications at Transitions and Clinical Handoffs Toolkit (MATCH) in a rural primary care clinic and assessed the acceptability and feasibility of implementation.
INTERVENTION: MATCH was developed as a workflow process intervention to improve medication reconciliation.
RESULTS: Findings from MATCH implementation indicate that the process improved medication reconciliation workflow. A shared definition of current medications across providers and patients was essential.
CONCLUSIONS: Empowering patients and caregivers with tools and language to work with providers, particularly nurses, to conduct medication reconciliation during primary care clinic visits is key to improving patient medication reconciliation in rural settings.

PMID: 32433146 [PubMed - indexed for MEDLINE]

Association of DNA repair gene variants with colorectal cancer: risk, toxicity, and survival.

BMC Cancer. 2020 May 12;20(1):409

Authors: Salimzadeh H, Lindskog EB, Gustavsson B, Wettergren Y, Ljungman D

Abstract
BACKGROUND: Single nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615, ERCC2-rs238406, and ERCC2-rs13181 with colorectal cancer (CRC) risk, relapse-free survival (RFS), overall survival (OS), and toxicity during chemotherapy.
METHODS: SNPs were analysed in 590 CRC cases and 300 controls using TaqMan technology. The association of SNPs with CRC risk and toxicity during chemotherapy was analysed using Chi2 test. The Kaplan-Meier method and log-rank test was used to measure the effects of the SNPs on RFS and OS.
RESULTS: The CC genotype of ERCC2-rs238406 and the ERCC2-rs13181 C allele were associated with a significantly increased risk of CRC. The ERCC1-rs11615 genotype T/T was associated with stomatitis in adjuvant chemotherapy (p = 0.03). Also, more patients with the ERCC2-rs13181 C allele needed dose reduction compared to patients with the A/A genotype (p = 0.02). In first line chemotherapy, more patients with the ERCC1-rs11615 C allele suffered from nausea compared to those with the T/T genotype (p = 0.04) and eye reactions and thrombocytopenia were more common in patients with the ERCC2-rs13181 C allele compared to the A/A genotype (p = 0.006 and p = 0.004, respectively). ERCC2- rs238406 C/C was also associated with a higher frequency of thrombocytopenia (p = 0.03). A shorter 5-year OS was detected in stage I & II CRC patients with the ERCC2- rs238406 C allele (p = 0.02). However, there was no significant association between the SNPs and 5-year RFS.
CONCLUSIONS: Both SNPs in ERCC2 were associated with risk of CRC as well as toxicity during first line treatment. In addition, ERCC2- rs238406 was linked to OS in early stage CRC. The ERCC1-rs11615 variant was associated with toxicity during adjuvant chemotherapy. The results add support to previous findings that SNPs in ERCC1 and ERCC2 have a prognostic and predictive value in clinical management of CRC.

PMID: 32397974 [PubMed - indexed for MEDLINE]

Treatment and its side effects in ANCA-associated vasculitides - Study based on POLVAS registry data.

Adv Med Sci. 2020 Mar;65(1):156-162

Authors: Biedroń G, Włudarczyk A, Wawrzycka-Adamczyk K, Wójcik K, Sznajd J, Zdrojewski Z, Masiak A, Czuszyńska Z, Majdan M, Jeleniewicz R, Klinger M, Jakuszko K, Rowaiye OO, Brzosko M, Brzosko I, Dębska-Ślizień A, Storoniak H, Tłustochowicz W, Kur-Zalewska J, Wisłowska M, Madej M, Hawrot-Kawecka A, Głuszko P, Kucharz EJ, Musiał J, Szczeklik W

Abstract
PURPOSE: The aim of this study is to present the treatment modalities and associated side effects in a Polish nation-wide ANCA-associated vasculitides (AAV) patients' cohort.
MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with AAV between 1990 and 2016, included in the POLVAS registry was performed. Standard descriptive statistic methods were used with an emphasis on the treatment modalities.
RESULTS: There were 625 patients diagnosed with AAV included in this study: 417 cases of granulomatosis with polyangiitis (GPA; 66.7%), 106 cases of microscopic polyangiitis (MPA; 17.0%) and 102 cases of eosinophilic granulomatosis with polyangiitis (EGPA; 16.3%). The mean age at the date of diagnosis was 50.4 (±15.7) years and the median observational period amounted to 4.0 (2.0-8.0) years. Glucocorticosteroids (GCs) were the medicaments most frequently used for remission induction (593/622; 95.3%), followed by cyclophosphamide (487/622; 78.3%), rituximab (44/622; 7.1%), and methotrexate (39/622; 6.3%). GCs were also most frequently administered for maintenance therapy (499/592; 84.3%), followed by azathioprine (224/592; 37.8%), methotrexate (136/592; 23.0%) and mycophenolate mofetil (99/592; 16.7%). The median cumulative doses of cyclophosphamide and rituximab equalled 7.99 g (4.18-14.0) and 2000 mg (1500-2800), respectively. The most commonly observed adverse events included: infections - 214/551 cases (38.8%), which were associated with the time of observation (OR = 1.05; 95% CI 1.01-1.10), the use of GCs intravenous pulses (OR = 2.76; 95% CI 1.68-4.54) and need for haemodialysis (OR = 1.73; 95% CI 1.10-2.71).
CONCLUSIONS: Polish patients with AAV were predominantly treated according to appropriate guidelines. The most frequent adverse events were typical for usually administered immunosuppressive treatment.

PMID: 31958704 [PubMed - indexed for MEDLINE]

Safety, efficacy and cost of two direct-acting antiviral regimens: A comparative study in chronic hepatitis C Egyptian patients.

J Clin Pharm Ther. 2020 Jun;45(3):539-546

Authors: Ibrahim Mohammed Ebid AH, Ashraf Ahmed O, Hassan Agwa S, Mohamed Abdel-Motaleb S, Mohamed Elsawy A, Hagag RS

Abstract
WHAT IS KNOWN AND OBJECTIVE: Direct-acting antivirals (DAAs) have become the most widely used treatment of chronic hepatitis C infection. Comparative studies on DAAs regimens approved by the Egyptian Ministry of Health for easy-to-treat genotype 4 (G4) Egyptian patients are still deficient. In this prospective study, we compared the efficacy and cost of two DAA regimens that are used in the treatment of Egyptian chronic hepatitis C virus (HCV) G4. The cost-saving regimen is determined.
METHODS: Eligible patients were randomized into 2 groups. Group 1 (Gp 1) received sofosbuvir plus daclatasvir, and group 2 (Gp 2) received ombitasvir, paritaprevir and ritonavir plus ribavirin (RBV) for 12 weeks. Data were collected and evaluated at baseline and at weeks 4, 8 and 12. Sustained virologic response 12 weeks after the end of treatment (SVR12 ) was evaluated. Cost-minimization analysis (CMA) was performed.
RESULTS AND DISCUSSION: Eligibility was achieved in 107 patients, Gp1 included 57 patients, and Gp 2 included 50 patients. Two patients dropped out from Gp 2 due to non-compliance. All patients in the two groups showed negative HCV blood levels at the end of treatment. At the 24th week, 3 relapsers (5.2%) were detected in Gp1 and 2 relapsers (4.1%) were detected in Gp 2. SVR12 was 54/57 (94.7%) and 46/48 (95.8%) for Gp 1 and Gp 2, respectively. After the 12th week of treatment, a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and haemoglobin levels were observed in both groups. Albumin levels declined in Gp 2 only. CMA showed higher cost in Gp 2 than Gp 1, although similar efficacy and safety.
WHAT IS NEW AND CONCLUSION: The two DAA regimens showed high SVR12 and safety in Egyptian HCV G4 patients. Sofosbuvir plus daclatasvir is the cost-saving regimen.

PMID: 31889322 [PubMed - indexed for MEDLINE]

Assessment of factors associated with completeness of spontaneous adverse event reporting in the United States: A comparison between consumer reports and healthcare professional reports.

J Clin Pharm Ther. 2020 Jun;45(3):462-469

Authors: Toki T, Ono S

Abstract
WHAT IS KNOWN AND OBJECTIVE: The objectives of this study were to explore completeness of direct adverse event (AE) reports from consumers and healthcare professionals (HCPs), and to discuss the reasons completeness varied among reporters with different occupations.
METHODS: We used a total of 5475 direct AE reports to the United States (US) Food and Drug Administration (FDA) from the first and second quarters of 2016 and assessed completeness of basic information (eg, patient sex, age, weight) and information relevant to AEs (eg, suspect and concomitant drugs). Logistic regression analysis was conducted to evaluate the associations between report completeness and reporting backgrounds.
RESULTS AND DISCUSSION: The completeness of AE reports from consumers was generally greater than that of reports from HCPs. Completeness of specific items varied among different occupations, which may reflect accessibility to, and/or availability of, relevant information for each type of reporter. There was a clear association between the proportion of 'known' ADRs in a report and completeness, suggesting that consumers and HCPs are likely to consult labelling information when reporting AEs.
WHAT IS NEW AND CONCLUSION: The quality of AE reports seemed to depend on information costs accrued to potential reporters. Researchers should consider the impact of database heterogeneity and possible sample selection bias when using spontaneous AE reports as a sample of events in the United States.

PMID: 31765498 [PubMed - indexed for MEDLINE]

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JAMA. 2021 Feb 2;325(5):482-483. doi: 10.1001/jama.2020.17308.

NO ABSTRACT

PMID:33528524 | DOI:10.1001/jama.2020.17308

Sleep Med. 2021 Jan 5;79:145-151. doi: 10.1016/j.sleep.2021.01.005. Online ahead of print.

ABSTRACT

BACKGROUND: Under-diagnosis of obstructive sleep apnea (OSA) is common because of the demanding and time-consuming nature of polysomnography (PSG). Herein, we assessed the utility of a short daytime dexmedetomidine-induced PSG for diagnosis of OSA in adults.

METHODS: This was a single-center, prospective, diagnostic trial. We evaluated 86 patients using a full overnight PSG and a short diurnal drug-induced PSG (DIPSG). DIPSG was induced by continuous intravenous dexmedetomidine infusion. Sedation depth was monitored and maintained using the Narcotrend index (50-70). Diagnostic performance for DIPSG with different apnea-hypopnea index (AHI) cut-off values were calculated. Bland-Altman plots used for analysis. Sleep architecture and position were compared.

RESULTS: We studied 47 OSA patients and 39 healthy volunteers. Sensitivity and specificity for detection of OSA by DIPSG were 92% and 79%, respectively, for an AHI cut-off value of 5, 90% and 77%, respectively, for an AHI cut-off value of 15, and 95% and 85%, respectively, for an AHI cut-off value of 30. The DIPSG bias was -5 (-25; 15) for AHI and -3 (-13; 7) for minimal oxygen saturation. N2 sleep was increased (32.9% vs. 50.75%, respectively; p < 0.01) and REM sleep was decreased (21.35% vs. 1.24%, respectively; p < 0.01) during DIPSG. Twenty-eight (33%) participants had postural shifts during DIPSG. No significant adverse events were observed during DIPSG.

CONCLUSIONS: Dexmedetomidine-induced PSG had a good sensitivity and specificity, and can be used as a screening tool for diagnosis of OSA in adults.

CHINESE CLINICAL TRIAL REGISTRATION: ChiCTR1900024044.

PMID:33524840 | DOI:10.1016/j.sleep.2021.01.005

Endocrinol Diabetes Metab Case Rep. 2021 Jan 27;2021:20-0123. doi: 10.1530/EDM-20-0123. Online ahead of print.

ABSTRACT

SUMMARY: A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.

LEARNING POINTS: A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.

PMID:33522491 | PMC:PMC7849457 | DOI:10.1530/EDM-20-0123

Cureus. 2020 Dec 27;12(12):e12325. doi: 10.7759/cureus.12325.

ABSTRACT

Acute pancreatitis is an acute inflammatory process of the pancreas that is associated with multiple etiologies. The two most common causes are gallstones and acute alcohol intoxication. However, medications are often overlooked when determining the cause. Empagliflozin is a type of sodium-glucose transport protein 2 (SGLT-2) inhibitor used for the treatment of type 2 diabetes mellitus. Given that this medication is new, the adverse effects have not been fully reported in the literature. Currently, the most commonly reported side effects are genitourinary infections such as cystitis or yeast infection although acute pancreatitis as a result of empagliflozin is very rare. Here, we discuss a case of a 64-year-old female who presented with severe pancreatitis after recently initiating the use of empagliflozin. Based on the timing of her presentation and her hospital workup to rule out many of the common etiologies, it was concluded that empagliflozin was the likely cause of her acute pancreatitis. With SGLT-2 inhibitors such as empagliflozin, becoming popular as first-line in the management of diabetes, this case may hope to raise awareness of the possible adverse effects related to it. Additionally, this case also emphasizes the importance of identifying iatrogenic related pancreatitis.

PMID:33520523 | PMC:PMC7837635 | DOI:10.7759/cureus.12325

Yakugaku Zasshi. 2021;141(2):179-185. doi: 10.1248/yakushi.20-00196-4.

ABSTRACT

Industrial reforms utilizing artificial intelligence (AI) have advanced remarkably in recent years. The application of AI to big data analysis in the medical information field has also been advancing and is expected to be used to find drug adverse effects that cannot be predicted by conventional methods. We have developed an adverse drug reactions analysis system that uses machine learning and data from the Japanese Adverse Drug Event Report (JADER) database. The system was developed using the C# programming language and incorporates the open source machine learning library Accord.Net. Potential analytical capabilities of the system include discovering unknown drug adverse effects and evaluating drug-induced adverse events in pharmaceutical management. However, to apply the system to pharmaceutical management, it is important to examine the characteristics and suitability of the level of AI used in the system and to select statistical methods or machine learning when appropriate. If these points are addressed, there is potential for pharmaceutical management to be individualized and optimized in the clinical setting by using the developed system to analyze big data. The system also has the potential to allow individual healthcare facilities such as hospitals and pharmacies to contribute to drug repositioning, including the discovery of new efficacies, interactions, and drug adverse events.

PMID:33518637 | DOI:10.1248/yakushi.20-00196-4

J Pharm Pract. 2021 Feb 1:897190021989931. doi: 10.1177/0897190021989931. Online ahead of print.

ABSTRACT

Neurological toxicity is a relatively rare adverse reaction reported in elderly patients treated with cephalosporins. We present a case of ceftazidime-induced encephalopathy in the context of acute kidney injury in an 80-year-old female treated for a Pseudomonas aeruginosa prosthetic joint infection. During the course of treatment, the patient developed sudden confusion and disorientation. The patient's mental state progressively worsened, eventually leading to intubation and admission to the intensive care unit. As imaging and laboratory analyses revealed no alternative causes explaining the patient's symptoms, ceftazidime was stopped under the suspicion of drug-induced neurotoxicity. Shortly after ceftazidime discontinuation, the patient's condition drastically improved and returned to baseline within 5 days. This case reveals the potential severity of cephalosporin-induced neurotoxicity in elderly patients and highlights the importance of quickly detecting such adverse events in order to prevent dire outcomes.

PMID:33517818 | DOI:10.1177/0897190021989931

Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: a systematic review and meta-analysis.

Crit Rev Oncol Hematol. 2021 Jan 27;:103238

Authors: Pellegrini L, Novak U, Andres M, Suter T, Nagler M

Abstract
The use of ibrutinib is hampered by major bleeding events and atrial fibrillation. Speculating whether randomized controlled trials might underestimate the risk of adverse events in clinical practice, we conducted a systematic review and meta-analysis studying patients treated in any setting and indication. We systematically searched the literature using MEDLINE and EMBASE databases for case series, cohort studies, or randomized controlled trials and retrieved all data in parallel. Proportions of patients with adverse events were pooled in relevant subgroups using the binominal distribution and Freeman-Tukey double arcsine transformation. Among 2'537 records screened, 85 were finally included, comprising 7'317 patients. Methodological quality according to the Newcastle-Ottawa Scale was rated as moderate to poor with regard to bleeding events and atrial fibrillation; 106 studies were excluded because of missing data at all. Reported events varied substantially between 0% and 78% (any bleedings), 0% and 25% (major bleedings), and 0% and 38% (new-onset atrial fibrillation). Pooled estimates were 28% (95% confidence interval 22%, 34%), 3% (2%, 4%), and 8% respectively (7%, 10%). The risk of events was higher in studies with an older population, high ibrutinib dosage, thrombocytopenia, antithrombotic treatment, and retrospective studies. In conclusions, reporting of bleeding events and atrial fibrillation varied substantially among studies. These observations, in combination with the estimates obtained, suggest a relevant risk in clinical practice.

PMID: 33515702 [PubMed - as supplied by publisher]

A Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adding Omarigliptin to Insulin Therapy in Japanese Patients with Type 2 Diabetes and Inadequate Glycemic Control.

Diabetes Obes Metab. 2021 Jan 29;:

Authors: Kadowaki T, Seino Y, Kaku K, Okamoto T, Kameya M, Sato A, Hirano T, Oshima N, Gantz I, O'Neill EA, Engel SS, Omarigliptin Study 039 Group

Abstract
AIMS: To evaluate the efficacy and safety of adding the once-weekly oral DPP-4 inhibitor omarigliptin to treatment of Japanese patients with type 2 diabetes and inadequate glycemic control on insulin monotherapy.
MATERIALS AND METHODS: In a 52-week clinical trial, Japanese patients on insulin monotherapy were randomized to once-weekly omarigliptin 25 mg (N=123) or placebo (N=61) for a 16-week, double-blind, placebo-controlled period. After Week 16, patients continued or switched to omarigliptin for a 36-week open-label period.
RESULTS: From a mean baseline of approximately 8.8%, the Week 16 least squares mean changes in HbA1c were -0.61% (omarigliptin) and 0.29% (placebo); the between-group difference was -0.90%, p<0.001. At Week 52, the mean change from baseline in HbA1c was -0.57% in both the group on omarigliptin for 52 weeks and the group on omarigliptin for 36 weeks (switched from placebo at Week 16). During the first 16 weeks of treatment, the incidences of adverse events (AEs), serious AEs, drug-related AEs, and discontinuation from trial medication due to an AE were similar in both groups. A slight increase in incidence of symptomatic hypoglycaemia was observed in the omarigliptin group (n=13 [10.6%]) compared with placebo (n=4 [6.6%]). No severe hypoglycaemia was reported during the study. No new safety signals emerged with treatment beyond Week 16 through Week 52.
CONCLUSION: The addition of once-weekly omarigliptin to insulin therapy for up to 52 weeks was generally well tolerated and provided clinically meaningful improvement in glycemic control throughout the trial period. (ClinicalTrials.gov: NCT02906709). This article is protected by copyright. All rights reserved.

PMID: 33512755 [PubMed - as supplied by publisher]

A Phase 1 Study of KHK4083: A Single-Blind, Randomized, Placebo-Controlled Single-Ascending-Dose Study in Healthy Adults and an Open-Label Multiple-Dose Study in Patients With Ulcerative Colitis.

Clin Pharmacol Drug Dev. 2021 Jan 29;:

Authors: Furihata K, Ishiguro Y, Yoshimura N, Ito H, Katsushima S, Kaneko E, Shimabe M, Mukai M, Watanabe R, Morishige T

Abstract
OX40 plays an essential role in maintaining late T-cell proliferation and survival by suppressing apoptosis and by inducing T-cell memory formation. Here, we report the results of the phase 1 study of KHK4083, a fully human antimonoclonal antibody specific for OX40. In this study, we aimed to assess the safety and tolerability of a single intravenous or subcutaneous administration of KHK4083 compared with placebo in healthy Japanese and Caucasian subjects and determined the pharmacokinetics (PK) and immunogenicity. Also, we assessed the preliminary efficacy and pharmacodynamics of multiple intravenous doses in Japanese patients with moderate to severe ulcerative colitis (UC). Drug-related treatment emergent adverse events occurred in 21 healthy subjects (58.3%) and 5 patients with UC (62.5%) after administration of KHK4083. There were no serious adverse events. The PK profile of a single intravenous dose of 10 mg/kg KHK4083 was similar in healthy Japanese and Caucasian subjects. Of 8 UC patients, a clinical response was observed in 3 patients (37.5%) and clinical remission in 2 patients (25.0%) in week 6. Our study demonstrated the safety and tolerability of single and multiple administrations of KHK4083 in healthy Japanese and Caucasian subjects and Japanese patients with moderate to severe UC. It also indicated favorable pharmacological properties of the drug.

PMID: 33512065 [PubMed - as supplied by publisher]

Suspected cholestatic liver injury induced by favipiravir in a patient with COVID-19.

J Infect Chemother. 2021 Feb;27(2):390-392

Authors: Yamazaki S, Suzuki T, Sayama M, Nakada TA, Igari H, Ishii I

Abstract
Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon β-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.

PMID: 33402301 [PubMed - indexed for MEDLINE]