Ann Hepatol. 2021 Oct 12:100561. doi: 10.1016/j.aohep.2021.100561. Online ahead of print.

ABSTRACT

INTRODUCTION AND OBJECTIVES: Immune Checkpoint Inhibitors (ICI) have shifted the paradigm of cancer therapy treatment. Despite their efficacy, ICIs may induce immune-related adverse events (irAE), which can affect various organs, namely the liver. This study intends to perform a comprehensive clinical description of the hepatic irAEs associated with ICI in a Portuguese population of a tertiary hospital centre.

MATERIALS AND METHODS: retrospective analysis of patients who developed immune mediated liver injury (IMLI), among a cohort of patients treated with ICIs between March 15th of 2015 and December 15th of 2019 in a tertiary hospital. We used both Common Terminology Criteria for Adverse Events (CTCAE) and Drug-Induced Liver Injury Network (DILIN) criteria to define liver injury.

RESULTS: Among 151 patients, eight (5,3%) patients developed liver injury grade ≥3, of which 5 had hepatic metastasis. As such, only 3 cases were classified as IMLI. All IMLI presented with cholestasis pattern; the median duration from ICI initiation to IMLI was 84 days and/or 4 ICI cycles; one patient registered IMLI one month after nivolumab suspension; all were treated with steroids and one was successfully submitted to ICI re-challenge; a favourable outcome was seen in all patients; the median time to hepatic biochemistries normalization was 150 days. Among 10 patients with previous hepatic conditions, only one developed liver injury grade 2.

CONCLUSIONS: Clinically significant ICI-related hepatotoxicity was uncommon; Immune-mediated liver injury may present a cholestatic pattern predominance. There was a low rate of liver injury of any kind in patients with previous hepatic disease while on ICI.

PMID:34653687 | DOI:10.1016/j.aohep.2021.100561

Eur J Hosp Pharm. 2021 Oct 14:ejhpharm-2021-002896. doi: 10.1136/ejhpharm-2021-002896. Online ahead of print.

ABSTRACT

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) are currently available for HIV patients.

OBJECTIVES: This study evaluated modifications in the renal safety profile in a large real-world cohort of patients who had received EVG/c/FTC/TAF or DTG/ABC/3TC.

METHODS: A retrospective observational study of HIV-infected patients who received EVG/c/FTC/TAF or DTG/ABC/3TC between March 2015 and June 2019 at a reference hospital in north-western Spain was conducted. Epidemiological, clinical, immunovirological data and information regarding antiretroviral therapy were recorded. The statistical differences between treatments were calculated.

RESULTS: A total of 457 patients were evaluated, 266 using EVG/c/FTC/TAF and 191 using DTG/ABC/3TC. Up to week 120, serum creatinine improved in both study groups among experienced patients (EVG/c/FTC/TAF 1.01±0.24 vs 0.91±0.19, p<0.001; DTG/ABC/3TC 1.08±0.24 vs 1.02±0.31, p<0.001), while in naïve patients serum creatinine remained stable compared with baseline. Statistically significant differences were found in serum creatinine when comparing both treatments at week 48 in experienced (0.94±0.21 vs 1.09±0.28, p<0.001) and naïve patients (0.89±0.16 vs 1.06±0.20, p=0.001), and among experienced patients at week 120 (0.91±0.19 vs 1.02±0.31, p=0.015) for the EVG/c/FTC/TAF and DTG/ABC/3TC groups, respectively. During the follow-up, 39 patients in EVG/c/FTC/TAF and 33 in DTG/ABC/3TC (p=0.449) discontinued treatment. The main reason for stopping treatment was adverse events, which were similar in both groups.

CONCLUSIONS: During the follow-up, patients experienced changes that were not clinically relevant in both treatment groups. Differences in renal events were not found.

PMID:34649965 | DOI:10.1136/ejhpharm-2021-002896

Eur J Hosp Pharm. 2021 Oct 14:ejhpharm-2021-002877. doi: 10.1136/ejhpharm-2021-002877. Online ahead of print.

ABSTRACT

BACKGROUND: Antithrombotic prophylaxis in hospitalised patients with SARS-CoV-2 acute infection has increased. Currently, most of the evidence relates to patients in intensive care units; however, there is little information on patients admitted to hospital wards and there is no consensus protocol on thromboprophylaxis during admission and after discharge.

OBJECTIVE: To assess the effectiveness of antithrombotic prophylaxis in patients admitted with COVID-19 and 30 days after discharge.

METHOD: A prospective observational study was conducted of patients admitted with COVID-19 in which the hospital thromboprophylaxis protocol was applied, classifying the patients as having a standard or high risk of thrombosis. Pharmacists performed a daily follow-up and actively intervened during admission and at discharge. The main outcome measure was the global incidence of symptomatic venous thromboembolism (VTE) related to hospitalisation.

RESULTS: A total of 113 patients were included, 98.23% of whom were admitted to a hospital ward. The incidence of hospital-acquired VTE was 1.77%. In 75.22% of the subjects, thromboprophylaxis was adjusted to the protocol during admission. A total of 23 pharmaceutical interventions were conducted, with an adherence of 52.17%. At discharge, 94.28% of the patients who had no haemorrhage and ≥4 points on the Padua Prediction Score required thromboprophylaxis, aligning with the protocol. The global incidence of haemorrhagic events during the follow-up period was 0.88%.

CONCLUSION: The incidence of hospital-acquired VTE was lower than that described in the literature. Although it cannot be certain that it is directly related to the instituted protocol, the data can show that the management of prevention of VTE is being optimally performed at the hospital. Long-term studies are needed to evaluate the incidence after discharge, as well as to agree on a specific protocol in the COVID-19 population for the prevention of these events during hospitalisation and post-discharge.

PMID:34649964 | DOI:10.1136/ejhpharm-2021-002877

Klin Mikrobiol Infekc Lek. 2020 Dec;26(4):138-139.

ABSTRACT

Antibiotics are considered to be one of the most important discoveries of medicine, which has significantly affected the mortality due to infectious diseases. Given their increasing use, certain problems arise over time, resulting from non-indicated and inadequate - administration of antibiotics. This results in increasing antibiotic resistance as well as a higher risk of side/adverse effects. Recently, these side effects of drugs have been used for indications other than those originally intended and approved. Such a process is called drug repositioning. Due to the recent increase in the cost of developing novel drugs and the high risk of failure in clinical trials, the pharmaceutical industry is trying to find new indications for existing drugs.

PMID:34648651

Aerosp Med Hum Perform. 2021 Sep 1;92(9):698-701. doi: 10.3357/AMHP.5882.2021.

ABSTRACT

INTRODUCTION: On December 2020 the U.S. Food and Drug Administration (FDA) authorized the emergency use of Pfizer-BioNTech COVID-19 vaccine. This new vaccine has several side effects that can potentially impair function, which warrants special attention regarding aircrews fitness to fly following vaccination.METHODS: A survey was conducted in the Israeli Air Force (IAF) Aeromedical Center in order to characterize the side effects and their duration following Pfizer-BioNTech COVID-19 vaccine administration to aviators.RESULTS: The most common side effect was injection site pain. Headache, chills, myalgia, fatigue, and weakness were more common following the second dose administration. The difference is statistically significant. Following the second vaccine, duration of side effects was longer compared to the first vaccine (P-value 0.002).CONCLUSION: The IAF Aeromedical center policy for Pfizer-BioNTech COVID-19 vaccine recipients among aircrew members, based on side effects duration and severity, is to temporarily ground from flight duties for 24 and 48 h following the first and the second dose, respectively.Gabbai D, Ekshtein A, Tehori O, Ben-Ari O, Shapira S. COVID-19 vaccine and fitness to fly. Aerosp Med Hum Perform. 2021; 92(9):698701.

PMID:34645549 | DOI:10.3357/AMHP.5882.2021

Kaku Igaku. 2021;58(1):91-101. doi: 10.18893/kakuigaku.oa.2105.

ABSTRACT

OBJECTIVE: To perform an exploratory analysis on the safety and effectiveness of radium-223 (Ra-223) by patient baseline age, using the results of a post-marketing surveillance study of Ra-223 in castration-resistant prostate cancer patients with bone metastasis in Japan.

METHOD: The safety analysis population of 296 patients was stratified into two groups based on age (<75 and ≥ 75 years-old [yo]), and their characteristics, drugrelated treatment-emergent adverse events (TEAEs), and clinical laboratory values were evaluated. Additionally, these endpoints were evaluated in patients aged ≥ 80 yo.

RESULTS: There were 148 patients in each of the <75-yo and ≥ 75-yo age groups, and 69 patients in the ≥ 80-yo age group. The characteristics of patients in the <75-yo group were suggestive of more aggressive disease at diagnosis of prostate cancer and a greater proportion of patients had prior chemotherapy compared with patients in the ≥ 75-yo age group. The incidences of overall drugrelated TEAEs and drug-related hematological TEAEs were slightly higher in the <75-yo age group; however, there was little difference in the incidences of drug-related TEAEs leading to drug discontinuation (1.4-4.1%) between patient groups. Changes in total alkaline phosphatase and prostate-specific antigen values were similar in all groups.

CONCLUSIONS: Ra-223 therapy seemed tolerable regardless of age in real-world practice in Japan. Especially, there were no new safety concerns of Ra-223 in elderly patients.

PMID:34645727 | DOI:10.18893/kakuigaku.oa.2105

Int J Mol Sci. 2021 Oct 1;22(19):10672. doi: 10.3390/ijms221910672.

ABSTRACT

The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients' quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.

PMID:34639014 | PMC:PMC8509363 | DOI:10.3390/ijms221910672

Cad Saude Publica. 2021 Oct 8;37(10):e00304420. doi: 10.1590/0102-311X00304420. eCollection 2021.

ABSTRACT

Since 1963, the World Health Organization has acknowledged pharmacovigilance as a priority area in global public health, guaranteeing permanent monitoring of drug safety. This study aimed to characterize the reports of adverse drug reactions received by the Porto Pharmacovigilance Centre (UFPorto), Portugal, in the unit's two decades of work. The analysis included all reports of suspected adverse drug reactions received from January 2001 to December 2019. We calculated the annual reporting rates and distribution by origin, type of notifier and place of work, severity, prior knowledge, and causality of the reported adverse drug reactions. During the study period, UFPorto received 9,711 notifications of suspected adverse drug reactions. Hospital institutions reported the most suspected adverse drug reactions (n = 6,003; 64%), as did physicians among healthcare workers (n = 5,284; 54.4%). The most frequently reported adverse events were severe (n = 6,275; 72%) and are described in the respective Summary of Product Characteristics (n = 6,978; 72%). Most of the reports received by UFPorto were evaluated as having "probable" causality (n = 7,473; 77%), independently of the type of notifier. The results are consistent with other data previously reported in the international medical literature and official national reports. However, the underreporting rates are still higher than expected. In approximately 20 years, UFPorto has experienced an increase in its activity in various areas of drug safety.

PMID:34644762 | DOI:10.1590/0102-311X00304420

BMC Pharmacol Toxicol. 2021 Oct 12;22(1):58. doi: 10.1186/s40360-021-00528-4.

ABSTRACT

INTRODUCTION: Coronavirus Disease (COVID-19) caused by Novel Coronavirus named as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was declared Pandemic by The World Health Organization (WHO) and a Public Health Emergency of International Concern (PHEIC) on January 30, 2020. Many COVID-19 vaccines have been developed, including CoronaVac vaccines by Sinovac. Health care workers, along with medical clerkship students are the priority to receive the vaccine. However, the Adverse Events Following Immunization (AEFI) of the CoronaVac remains unclear. This study aims to describe and analyze the adverse events following immunization (AEFI) of COVID-19 vaccination in medical students in clerkship programs.

METHOD: We conducted a cross-sectional study using a questionnaire to assess AEFI after CoronaVac vaccination among medical clerkship students. A Chi-Square test with 95 % of CI was used to determine whether gender correlated with symptoms of AEFI.

RESULT: We identified 144 medical clerkship students. The most common AEFI of SARS-CoV-2 vaccinations was localized pain in the injection site during the first dose with 25 (45 %) reports and the booster dose with 34 (67 %) reports. Then followed by malaise, the first dose with 20 (36 %) reports and the booster dose with 21 (41 %) reports. Other symptoms like headache, fever, shivering, sleepiness, nausea, dysphagia, and cold were also reported.

CONCLUSIONS: CoronaVac SARS-COV-2 vaccine has several mild symptoms of AEFI and not correlated with gender. Nevertheless, follow-up after vaccination is needed to prevent immunologic responses that may occur in some patients.

PMID:34641944 | PMC:PMC8508468 | DOI:10.1186/s40360-021-00528-4

Muscle Nerve. 2021 Oct 12. doi: 10.1002/mus.27436. Online ahead of print.

ABSTRACT

INTRODUCTION/AIMS: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates PPARδ to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. Objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.

METHODS: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo; study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.

RESULTS: A total of 64 (single dose cohort) and 37 (multiple dose cohort) participants were included. Following single doses of 1-120 mg, ASP0367 was rapidly absorbed with median time to maximum plasma concentration (tmax ) of 1.50-2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, tmax was delayed 1.7 hours. Following multiple once-daily doses, mean half-life of ASP0367 10-75 mg ranged from 14.1-17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed following repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild-to-moderate in severity; none were deemed drug-related. No clinically significant changes were observed on laboratory or electrocardiography evaluations. Treatment- and dose-dependent upregulation of six PPARδ target genes were observed with single and multiple doses of ASP0367.

DISCUSSION: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.

PMID:34642949 | DOI:10.1002/mus.27436

Drug Ther Bull. 2021 Oct 12:dtb-2021-000057. doi: 10.1136/dtb.2021.000057. Online ahead of print.

ABSTRACT

Overview of: Dinh A, Ropers J, Duran C, et al Discontinuing β-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial. Lancet 2021;397:1195-203.

PMID:34642244 | DOI:10.1136/dtb.2021.000057

J Clin Med. 2021 Oct 4;10(19):4584. doi: 10.3390/jcm10194584.

ABSTRACT

The launch of novel chemotherapeutic agents-in particular, proteasome inhibitors and immunomodulatory drugs-dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory factors and the development of PN in MM patients with particular emphasis on the application of VTD (bortezomib, thalidomide, dexamethasone) regimen. Our analysis identified increased concentrations of CCL2, IL-1β, and IFN-γ in plasma of MM patients during treatment, both with and without symptoms of PN, compared with untreated neuropathy-free MM patients. At the same time, the plasma concentration of IL-1β in patients with neuropathy was significantly increased compared with patients without PN before and during treatment. Moreover, the results were enhanced at the transcript level by performing global mRNA expression analysis using microarray technology. The most significant changes were observed in the expression of genes responsible for regulating immunological and apoptotic processes. An in-depth understanding of the mechanisms responsible for the development of DiPN might in the future reduce the incidence of PN and accelerate diagnosis, allowing the choice of neuropathy-free treatment strategies for MM.

PMID:34640602 | DOI:10.3390/jcm10194584

Zhonghua Gan Zang Bing Za Zhi. 2021 Sep 20;29(9):830-836. doi: 10.3760/cma.j.cn501113-20200117-00020.

ABSTRACT

Objective: To mine the signals of adverse drug reaction (ADR) of entecavir and tenofovir by using the US FDA Adverse Event Reporting System (FAERS) database, so as to provide reference for the safe clinical use of these two drugs. Methods: Reporting odds ratio (ROR) and proportion of report ratio (PRR) method were used to conduct data mining on the 26 quarterly reports of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database between the fourth quarter of 2012 to the first quarter of 2019. The ADR descriptive terminology in the report were standardized by using the World Health Organization Adverse Reaction Terminology (System-Organ Class). ROR and PRR methods common signals were screened. Results: 104 and 187 signals of ADR of entecavir and tenofovir dipivoxil were obtained by ROR and PRR methods. The main screened system-organ classes affected by signals of ADR of entecavir were systemic damage, hepatobiliary system damage, and urinary system damage. The main screened system-organ classes affected by signals of ADR of tenofovir were urinary system damage, skeletal and musculoskeletal system damage, and metabolic and nutritional disorders. Conclusion: The mining signals of adverse drug reaction of entecavir and tenofovir dipivoxil indicate that these two drugs can cause female reproductive system damage, fetal abnormalities, neonatal and infant abnormalities, and male reproductive system damage. However, in addition to the above-mentioned ADR, the ADR instruction manual excludes entecavir and tenofovir dipivoxil primarily for respiratory and visual system damage, and the tenofovir disoproxil primarily for skin and appendage damage, and hearing and vestibular function damage. Therefore, in clinical medication management, it is suggested to pay close attention to the choice of drugs for special population infected with HBV, monitor possible ADR during medication course, and provide pharmacological monitoring to achieve personalized medication.

PMID:34638200 | DOI:10.3760/cma.j.cn501113-20200117-00020

Afr J Prim Health Care Fam Med. 2021 Sep 29;13(1):e1-e8. doi: 10.4102/phcfm.v13i1.2880.

ABSTRACT

BACKGROUND: The high incidence of adverse drug reactions (ADRs) in children is of global concern. Enhancing the reporting of ADRs could contribute to making safer medicines available to children.

AIM: To assess parents' awareness of reporting ADRs and their knowledge on the reporting procedures in South Africa.

SETTING: South African parents with online access.

METHOD: A quantitative descriptive study was conducted based on an anonymous voluntarily web-based self-administered questionnaire that was distributed through Facebook® and LinkedIn™ to parents in South Africa.

RESULTS: The questionnaire was completed voluntarily by 206 respondents. The majority of participants (70.9%) were aware of the term ADR. Significant associations between not being aware of the term ADR and single marital status, lower education level, not having private medical aid and accessing public clinics for medical services were found. The majority (66.5%) of participants did report an ADR to a healthcare professional whilst only 15% reported it to a product manufacturer. More than half of the participants (58.7%) knew how to report ADRs whilst 72.8% knew what type of ADRs to report. Almost a third (32.5%) did not know where more information on ADR reporting could be found or how ADRs could be reported (31.5%).

CONCLUSION: The majority of the respondents were aware of the term ADR, indicative of a good knowledge basis on which ADRs to report and the importance of reporting ADRs. However, gaps in the respondents' knowledge were identified which highlighted specific groups of individuals to be targeted to increase ADR awareness and improve the knowledge on the reporting process.

PMID:34636609 | DOI:10.4102/phcfm.v13i1.2880

BMJ Open. 2021 Oct 11;11(10):e045778. doi: 10.1136/bmjopen-2020-045778.

ABSTRACT

OBJECTIVES: Computerised physician order entry (CPOE) systems facilitate the review of medication orders by pharmacists. Reports have emerged that show conception flaws or the misuse of CPOE systems generate prescribing errors. We aimed to characterise pharmacist interventions (PIs) triggered by prescribing errors identified as system-related errors (PISREs) in French hospitals.

DESIGN: This was a cross-sectional observational study based on PIs prospectively documented in the Act-IP observatory database from January 2014 to December 2018.

SETTING: PISREs from 319 French computerised healthcare facilities were analysed.

PARTICIPANTS: Among the 319 French hospitals, 232 (72.7%) performed SRE interventions, involving 652 (51%) pharmacists.

RESULTS: Among the 331 678 PIs recorded, 27 058 were qualified as due to SREs (8.2%). The main drug-related problems associated with PISREs were supratherapeutic (27.5%) and subtherapeutic dosage (17.2%), non-conformity with guidelines/contraindications (22.4%) and improper administration (17.9%). The PI prescriber acceptation rate was 78.9% for SREs vs 67.6% for other types of errors. The PISRE ratio was estimated relative to the total number of PIs. Concerning the certification status of CPOE systems, the PISRE ratio was 9.4% for non-certified systems vs 5.5% for certified systems (p<0.001). The PISRE ratio for senior pharmacists was 9.2% and that for pharmacy residents 5.4% (p<0.001). Concerning prescriptions made by graduate prescribers and those made by residents, the PISRE ratio was 8.4% and 7.8%, respectively (p<0.001).

CONCLUSION: Computer-related prescribing errors are common. The PI acceptance rate by prescribers was higher than that observed for PIs that were not CPOE related. This suggests that physicians consider the potential clinical consequences of SREs for patients to be more frequently serious than interventions unrelated to CPOE. CPOE medication review requires continual pharmacist diligence to catch these errors. The significantly lower PISRE ratio for certified software should prompt patient safety agencies to undertake studies to identify the safest software and discard software that is potentially dangerous.

PMID:34635512 | DOI:10.1136/bmjopen-2020-045778

Nucleic Acids Res. 2021 Oct 11:gkab897. doi: 10.1093/nar/gkab897. Online ahead of print.

ABSTRACT

Drug response to many diseases varies dramatically due to the complex genomics and functional features and contexts. Cellular diversity of human tissues, especially tumors, is one of the major contributing factors to the different drug response in different samples. With the accumulation of single-cell RNA sequencing (scRNA-seq) data, it is now possible to study the drug response to different treatments at the single cell resolution. Here, we present CeDR Atlas (available at https://ngdc.cncb.ac.cn/cedr), a knowledgebase reporting computational inference of cellular drug response for hundreds of cell types from various tissues. We took advantage of the high-throughput profiling of drug-induced gene expression available through the Connectivity Map resource (CMap) as well as hundreds of scRNA-seq data covering cells from a wide variety of organs/tissues, diseases, and conditions. Currently, CeDR maintains the results for more than 582 single cell data objects for human, mouse and cell lines, including about 140 phenotypes and 1250 tissue-cell combination types. All the results can be explored and searched by keywords for drugs, cell types, tissues, diseases, and signature genes. Overall, CeDR fine maps drug response at cellular resolution and sheds lights on the design of combinatorial treatments, drug resistance and even drug side effects.

PMID:34634794 | DOI:10.1093/nar/gkab897

J Dig Dis. 2021 Oct 11. doi: 10.1111/1751-2980.13058. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Functional constipation is a functional gastrointestinal disorders prevalent around the world. Lubiprostone is the first locally acting type-2 chloride channel activator in the treatment of constipation. The current study aimed to determine the efficacy and safety of lubiprostone in Chinese functional constipation adult patients .

METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. Functional constipation patients were randomized to receive treatment of lubiprostone (48 mcg/ day) or placebo for 4 weeks. The primary endpoint was the frequency of spontaneous bowel movements (SBMs) during the first week of treatment. The secondary endpoints included the median time of the first SBM, SBMs frequency at weeks 2, 3 and 4, weekly response rate of SBMs, the stool consistency score and average number of complete spontaneous bowel movements (CSBMs) per week.

RESULTS: In total, 259 patients were randomized with 130 in lubiprostone group and 129 in placebo group. SBM frequency was higher in lubiprostone group (4.88±4.09 per week) than that in the placebo group (3.22±2.01 per week) at week 1 (p<0.0001). SBM frequency was also higher in lubiprostone group at week 2, 3 and 4. The average number of CSBMs and the stool consistency score in lubiprostone group were significantly higher than that in placebo group at each week. No drug-related serious adverse events (AEs) occurred. The most commonly reported AEs was nausea.

CONCLUSIONS: Lubiprostone was superior to placebo in treating Chinese functional constipation patients with good safety profile. This article is protected by copyright. All rights reserved.

PMID:34633753 | DOI:10.1111/1751-2980.13058

Clin Pharmacol Drug Dev. 2021 Oct 11. doi: 10.1002/cpdd.1021. Online ahead of print.

ABSTRACT

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600-mg ziritaxestat labeled with a carbon-14 tracer (14 C-ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100-μg microdose, labeled with a microtracer amount of 14 C radiation, was administered in a separate part of the study, following an unlabeled 600-mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug-related product. There were 7 treatment-emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

PMID:34633152 | DOI:10.1002/cpdd.1021

Diagn Interv Imaging. 2021 Oct 7:S2211-5684(21)00218-7. doi: 10.1016/j.diii.2021.09.005. Online ahead of print.

NO ABSTRACT

PMID:34629324 | DOI:10.1016/j.diii.2021.09.005

Clin Lymphoma Myeloma Leuk. 2021 Sep 15:S2152-2650(21)02040-1. doi: 10.1016/j.clml.2021.09.010. Online ahead of print.

ABSTRACT

INTRODUCTION/BACKGROUND: The emergence of novel agents targeting the B-cell receptor pathway and BCL-2 has significantly changed the therapeutic landscape of CLL. We evaluated the safety and efficacy of single-agent ibrutinib in relapsed/refractory CLL in real-world settings.

PATIENTS/METHODS: A total of 200 relapsed/refractory CLL patients with a median age of 68 were included in this retrospective, multicenter, non-interventional study. Data of the study were captured from the patient charts of the participating centers.

RESULTS: The median for lines of previous chemotherapy was 2 (1-6); 62 (31.8%) patients had del17p and/or p53 mutations (del17p+/p53mut). Of the study group, 146 (75%) patients achieved at least PR, while 16 (8.7%) patients discontinued ibrutinib due to TEA. The most common drug-related adverse events were neutropenia (n: 31; 17.4%) and thrombocytopenia (n: 40; 22.3%), which were ≥ grade 3 in 9 (5%) and 5 (3.9%) patients, respectively. Pneumonia (n: 42; 23.7%) was the most common nonhematologic TEA. Atrial fibrillation (n: 5; 2.8%) and bleeding (n: 11; 6.3%) were relatively rare during the study period. Within a median follow-up period of 17 (1-74) months, 42 (21%) patients died. The estimated median OS of the study cohort was 52 months. Only the response to ibrutinib (CR/PR vs. SD/PD) was significantly associated with OS.

CONCLUSION: Our results indicate good safety and efficacy for single-agent ibrutinib in R/R CLL in daily practice.

PMID:34629286 | DOI:10.1016/j.clml.2021.09.010