Abnormal Hepatic Function Research Articles

Association of Clopidogrel with Interstitial Lung Disease: Gaining Insight Through the Japanese Pharmacovigilance Database.

The P2Y12 receptor inhibitors clopidogrel and prasugrel are widely used. Clopidogrel and prasugrel have different metabolic pathways, but whether their adverse event (AE) profiles differ significantly is unclear. This study aimed to compare the possible AEs induced by clopidogrel and prasugrel and to assess the rank-order of their AEs submitted to a spontaneous reporting database. Data were extracted from the Japanese Adverse Drug Event Report database (JADER). Reports of AEs associated with clopidogrel and prasugrel were analyzed to calculate the reporting odds ratios (RORs) and 95% confidence intervals (CIs). Based on 5869 reports for clopidogrel (69.6%, men) and 513 reports for prasugrel (74.1%, men), 703 and 135 different AEs were identified, respectively. Bleeding complications including hemorrhage were commonly reported for both clopidogrel and prasugrel. As for AEs related to clopidogrel, unexpected AEs such as interstitial lung disease (227 reports; ROR, 1.77; 95% CI, 1.49-2.10), abnormal hepatic function (137 reports; ROR, 1.27; 95% CI, 1.07-1.51), and hepatocellular injury (96 reports; ROR, 120.0; 95% CI, 94.9-151.8) ranked at relatively high positions based on the number of occurrences, unlike prasugrel. This analysis of the national pharmacovigilance database highlights distinct AE profiles for clopidogrel and prasugrel. Unexpected AEs associated with clopidogrel were identified, providing valuable insights for clinical monitoring and patient safety.

Dietary curcumin supplementation attenuates hepatic damage and function abnormality in a chronic corticosterone-induced stress model in broilers

Chronic stress refers to the activation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated blood contents of ACTH and corticosterone (CORT), exhibiting significant adverse effects on health outcomes. Currently, natural polyphenol compounds are increasingly being explored as potential therapeutic agents and have been considered as a treatment option for a variety of stress-induced diseases. Curcumin (CUR) is the main substance in Curcuma longa (Zingiberacea) rhizome that has strong health-beneficial properties. The study aimed to assess the potential protective effects of CUR on hepatic oxidative stress damage and abnormal lipid deposition in a chronic CORT-induced stress (CCIS) model in broilers. One hundred and twenty experimental broilers were randomly divided into 1) control group (CON), 2) CUR group (200 mg/kg feed), 3) CORT group (4 mg/kg BW CORT) and 4) CORT+CUR group (200 mg/kg feed plus 4 mg/kg BW CORT). The liver histology, glycolipid metabolism and oxidative stress were determined. In addition, qPCR was performed to identify shifts in genes expression. Compared with CON group, broilers under CCIS showed a decreased body weight, body weight gain and average daily gain, while dietary CUR significantly reversed these adverse effects. Furthermore, the plasma contents of TCH, TG, HDL-C, LDL-C, TP, GLB and AST were all significantly increased in CCIS broilers, while dietary CUR obviously alleviated the increase of TCH, HDL-C, LDL-C and AST, and relieved the hepatic lipid deposition disorder and liver injury. Moreover, CCIS significantly increased the contents of MDA in both liver and plasma, and decreased the content of plasma SOD, while CUR obviously reversed these changes, showing reduced oxidative stress damage. Finally, the mRNA expressions of FAS, ACC, SCD and the protein level of PPAR-γ were significantly increased, meanwhile the mRNA expression of lipolytic genes ACOX1, ATGL and CPT as well as two major intracellular antioxidant enzymes SOD1 and GPX1 were obviously decreased, while CUR effectively reversed these effects. These results showed that dietary CUR effectively alleviated CCIS-induced body weight loss, hepatic oxidative damage and lipid deposition disorder, suggesting the possible therapeutic effectiveness of CUR against hepatic damage and function abnormality caused by CCIS.

Long-term safety of lanthanum carbonate in the real word: a 19-year disproportionality analysis from the FDA Adverse Event Reporting System

Background Lanthanum carbonate is widely used to manage serum phosphate and calcium levels in end-stage kidney disease (ESKD) patients, yet comprehensive long-term safety data are lacking. This study leverages the FDA Adverse Event Reporting System (FAERS) to assess the extended safety profile of lanthanum carbonate. Research design and methods We analyzed FAERS data (2004-2022) to study the association between lanthanum carbonate and adverse events (AEs). Using MedDRA v25.0, we identified risk signals through System Organ Classes (SOCs) and Preferred Terms (PTs). Disproportionality analyses quantified lanthanum carbonate-associated AE signals. Results Among 3,284 reports, 2,466 were primary suspected AEs linked to lanthanum carbonate. Males reported AEs more frequently than females. Patients aged over 64 represented the majority. Median onset time for lanthanum carbonate-related AEs was 146 days. Gastrointestinal disorders were prevalent. We identified 16 new signals, including stress, abnormal hepatic function, cholelithiasis, bile duct stone, gastric cancer, and adenocarcinoma gastric. Stress was notable, particularly in male patients over 65 and those with lower weight. Conclusions This study affirms lanthanum carbonate’s long-term safety for reducing elevated blood phosphorus levels. While gastrointestinal disorders were common, attention must focus on emerging AEs, particularly stress, especially in elderly patients.

Efficacy and safety of apatinib combined with nab-paclitaxel for second-line treatment of metastatic triple negative breast cancer (TNBC): An open-label phase II trial.

e13127 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Preclinical studies have demonstrated that apatinib can enhance the anti-tumor effect of taxanes in TNBC via promoting apoptosis and suppressing migration and invasion of tumor cells. Previous studies have also shown the role of apatinib in combination with chemotherapy for treating TNBC. However, combinational treatment of apatinib and nab-paclitaxel for metastatic TNBC has not been reported. Therefore, the objective of this study was to evaluate the safety and efficacy of apatinib in combination with nab-paclitaxel as a second-line treatment for TNBC. Methods: This is a single-center, single-arm, and open-label prospective study. The patients enrolled in this study had metastatic TNBC, ECOG PS 0-2, at least one measurable lesion, and had previously received one systemic therapy except apatinib and nab-paclitaxel. They were treated with apatinib (250mg, PO, QD) plus nab-paclitaxel (125mg/m2, IV, day 1, 8 and 15) every 3 weeks as second-line treatment until disease progression, unacceptable toxicity, or consent withdrawal. The study utilized RECIST v1.1 to assess efficacy and NCI-CTCAE 5.0 to report adverse events. The study's primary endpoints were tolerability and progressive free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Twenty patients were enrolled by the cut-off date of December 1st, 2023. The median age was 55 years (range 31-76) and all had an ECOG PS of 0-1. Ninety percent of the sample had a Ki67 of 30% or higher, while 85% tested negative for PD-L1. All patients had distant metastases, with 35.0% having visceral metastasis and 35% having metastatic sites of 3 or more. 70% of patients had undergone surgery on the primary tumor. All patients received apatinib plus nab-paclitaxel treatment, with a median of 9 cycles (range 2-25), were included in the safety dataset. All patients experienced grade 1-2 treatment-related adverse events (TRAEs). Haematological toxicity of grade 3-4 with neutropenia occurred in 25.0% of patients. In addition, non-haematological toxicities were observed in 10% of patients, including abnormal hepatic function (5.0%) and hypertension (5.0%). No treatment-emergent adverse event (TEAE) resulted in death during the study. Out of the 20 evaluated patients, the median progression-free survival (PFS) was 6.7 months (95% CI: 6.0-NR). The objective response rate (ORR) was 65.0% (13/20), and the disease control rate (DCR) was 90.0% (18/20), according to RECIST v1.1. The median overall survival (OS) has not yet been reached. Conclusions: The combination of apatinib and nab-paclitaxel showed promising antitumor activity in patients with metastatic TNBC as a second-line treatment, with a manageable safety profile. Clinical trial information: NCT05019690 .

Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

A case report on Kyrle’s disease in patient with diabetes mellitus

Kyrles disease classified under acquired perforating dermatosis, is a rare skin condition predominantly affecting 30-50-year-old females. Characterized by pruritic hyperkeratotic and ulcerated nodules, the disease involves the transepidermal clearance of aberrant endogenous components, leading to inflammatory reactions and expulsion of keratin and cellular material. The etiology though not fully understood, suggests changes in dermal connective tissue may play a role. In case report, a 56-year-old male with type II diabetes mellitus presented knee pain and 3 mm papules on lower limbs. Laboratory findings revealed hematological and metabolic abnormalities, and a skin biopsy confirmed Kyrle’s disease features. Laboratory reports indicated abnormalities in hematology, blood glucose, lipid profile, hepatic and renal function. Biopsy results confirmed acanthosis, hyperkeratosis, dysplsia and granulomatous inflammation. The association of Kyrle’s disease and metabolic abnormalities, emphasizing diabetes and chronic renal failure. Potential pathways involve oxidative damage, endoplasmic stress, and vasculopathy. Treatment options include keratolytics, emollients, antihistamines. Kyrle’s disease often linked to diabetes and chronic renal failure, is a chronic condition with variable remission periods. Early detection and appropriate management are crucial for improving patients’ quality of life. Understanding the association with metabolic abnormalities guides effective therapeutic approaches for this rare dermatological condition.

Protective mechanism and clinical application of SGLT2 inhibitors in patients with type 2 diabetes mellitus complicated with abnormal liver function

Type 2 diabetes (T2DM) patients with abnormal liver function will further aggravate the complexity of the disease and affect the quality of life of patients. Sodium-glucose cotransporter protein 2 (SGLT2) inhibitors are novel hypoglycemic agents that may produce hepatoprotective effects in patients with T2DM combined with hepatic function abnormalities by improving hyperglycemic toxicity, regulating lipid metabolism, decreasing visceral adiposity, anti-inflammatory, antioxidant and other possible mechanisms. However, the exact mechanism has not been clarified and further studies are still needed. In this article, we reviewed the possible mechanisms of hepatoprotective effects of SGLT2i on patients with T2DM combined with abnormal liver function and the progress of clinical application, in order to providing reference for the rational application of SGLT2i.

Updated efficacy and safety of larotrectinib (laro) in patients (pts) with TRK fusion gastrointestinal (GI) cancer.

109 Background: NTRK gene fusions are oncogenic drivers in various tumors. Laro, a highly selective, central nervous system-active TRK inhibitor, is approved for tumor-agnostic use in pts with TRK fusion cancer, based on a rapid, robust, and durable objective response rate (ORR) in various cancers. We report data on a subset of pts with TRK fusion GI cancer treated with laro with longer follow-up. Methods: Pts with TRK fusion GI cancer in the phase II clinical trial NAVIGATE (NCT02576431) were included. Responses were independent review committee (IRC)-assessed (RECIST v1.1). Results: As of July 2022, 42 pts were enrolled. Median age was 67.0 years (range 32–90). Tumor types included colorectal (CRC; n=24), pancreatic (n=7), cholangiocarcinoma (n=4), gastric (n=3), and one each of appendiceal, duodenal, esophageal squamous cell carcinoma, and hepatocarcinoma. Among the pts with CRC, 14 were microsatellite-instability-high (MSI-H), eight were not MSI-H (which includes microsatellite stable), and two had unknown microsatellite status. Five (12%), 11 (26%), 15 (36%) and 11 (26%) patients had received 0, 1, 2, or ≥3 prior lines of systemic therapy, respectively. Four pts with CRC (three MSI-H) received prior immune-oncology (IO) therapy; best response to IO therapy was partial response (PR) in one pt, progressive disease (PD) in two pts, and not evaluable in one pt. Among 34 IRC-eligible pts, ORR was 29% (95% CI 15–47): two complete responses (CR; 6%), eight PR (24%), 17 stable disease (SD; 50%), two PD (6%), and five not evaluable (15%). Median time to response was 1.8 months (mo). Median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 27.3 mo (95% CI 5.6–not estimable [NE]), 7.2 mo (95% CI 3.5–12.3), and 14.1 mo (95% CI 6.1–36.5). In the 19 IRC-eligible pts with CRC, ORR was 47% (95% CI 24–71): two CR (11%), seven PR (37%), nine SD (47%), and one not evaluable (5%); five of nine responders were MSI-H. Median DoR, PFS, and OS for all IRC-eligible pts with CRC were 27.3 mo (95% CI 5.6–NE), 29.4 mo (95% CI 5.4–NE), and 29.4 mo (95% CI 6.1–NE). Treatment duration ranged from 0.3 to 44+ mo. At data cutoff, 23 pts were alive. Treatment-related adverse events (TRAEs) were mostly Grade 1/2. Grade 3/4 TRAEs were reported in seven (17%) pts (two each increased alanine aminotransferase and aspartate aminotransferase; one each abnormal hepatic function, hyperesthesia, nausea, anemia, decreased neutrophils, decreased white blood cells, and decreased platelets). No pts discontinued treatment due to TRAEs. Results from the most recent cutoff date, July 2023, will be presented at the congress. Conclusions: Laro continued to demonstrate long-lasting responses, extended survival, and a favorable safety profile in pts with TRK fusion GI cancer, including those with MSI-H CRC. This supports the wider adoption of next-generation sequencing testing for NTRK gene fusions in pts with GI cancer. Clinical trial information: NCT02576431 .

Efficacy and safety of camrelizumab combined with TACE for hepatocellular carcinoma: a systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) represents a highly lethal and recurrent neoplasm, with limited effective treatment regimens available. Camrelizumab, as a novel PD1 inhibitor combined with transcatheter arterial chemoembolization (TACE), has been widely used in the treatment of HCC. However, there remains a contentious debate regarding the clinical value of the TACE and camrelizumab combination. This study seeks to investigate the efficacy and safety of this combination treatment regimen in patients with HCC. The related studies were retrieved from four online databases, including Pubmed, Cochrane Library, EMBASE, and Web of Science, up to June 1, 2023. The selection of studies was based on screening of titles, abstracts, and full-texts. The primary efficacy outcomes included complete response (CR), objective response rate (ORR), and disease control rate (DCR), while safety outcomes evaluated all treatment-related adverse events (AEs). Additionally, secondary outcomes such as overall (OS) and progression-free survival (PFS) were extracted for further survival analysis. The quality of the included trials was assessed using the MINORS tool. Publication bias was evaluated through funnel plot and Egger's test. A total of 17 publications involving 1,377 cases were included. The pooled CR rate, ORR, and DCR of the patients treated with TACE plus camrelizumab had a pooled CR rate of 8% (95% CI: 0.01-0.15, p=0.03), ORR of 47% (95% CI: 0.42-0.52, p<0.00001) and DCR of 82% (95% CI: 0.77-0.88, p<0.00001), respectively. Compared with a control group that did not receive TACE or camrelizumab, the pooled RR of CR rate, ORR, and DCR were 1.61 (95% CI: 1.27-2.04, p<0.0001), 1.56 (95% CI: 1.19-2.05, p=0.001) and 1.55 (95% CI: 1.19-2.03, p=0.001), respectively. Besides, the combination regimen can prolong the OS (HR=2.60, 95% CI: 2.25-3.02, p<0.00001) and PFS (HR=4.90, 95% CI: 1.94-12.38, p=0.0008). However, the incidence of treatment-related AEs was relatively high (77%), with 29% for grade 3 AEs. The most common AEs observed were pain (47%), fever (46%), hepatic function abnormalities (44%), hypoalbuminemia (39%), and hypertension (37%). The combination treatment did not increase the incidence of AEs compared to the control group, except for the hand-foot skin reaction (RR=0.85, 0.74-0.97, p=0.01), hepatic encephalopathy (RR=4.29, 2.51-7.35, p<0.00001) and nausea (RR=1.35, 1.13-1.61, p=0.001). Combination therapy of TACE plus camrelizumab has shown notable clinical benefits, improved survival, and a manageable safety profile in patients with HCC, but it is essential to monitor and manage the specific toxicities, especially for the camrelizumab-related AEs.

A prospective phase II single-arm study and predictive factor analysis of irinotecan as third-line treatment in patients with metastatic gastric cancer.

Currently, there is no recommended standard third-line chemotherapy for metastatic gastric cancer. In this study, we aimed to evaluate irinotecan's efficacy and safety in treating metastatic gastric cancer after the failure of first- and second-line chemotherapy. Prospective single-arm, two-center, phase II trial. Patients were aged 18-70 years, with histologically confirmed gastric adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0-1, progressed during or within 3 months following the last administration of second-line chemotherapy and had no other severe hematologic, cardiac, pulmonary, hepatic, or renal functional abnormalities or immunodeficiency diseases. Eligible patients received 28-day cycles of irinotecan (180 mg/m2 intravenously, days 1 and 15) and were assessed according to the RECIST 1.1 criteria every two cycles. Patients who discontinued treatment for any reason were followed up every 2 months until death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity. A total of 98 eligible patients were enrolled in this study. In the intention-to-treat population, the median OS was 7.17 months, the median PFS was 3.47 months, and the ORR and DCR were 4.08% and 47.96%, respectively. In the per-protocol population, the median OS was 7.77 months, the median PFS was 3.47 months, and the ORR and DCR were 4.82% and 50.60%, respectively. The incidence of grade 3 or 4 hematological and non-hematological toxicities was 19.4%, and none of the patients died owing to adverse events. Cox regression analysis revealed neutropenia and baseline thrombocyte levels were independently correlated with PFS and OS. Irinotecan monotherapy is an efficient, well-tolerated, and economical third-line treatment for patients with metastatic gastric cancer as a third-line treatment. ClinicalTrials.gov identifier: NCT02662959.

GS-441524 and molnupiravir are similarly effective for the treatment of cats with feline infectious peritonitis.

Although not registered for feline infectious peritonitis (FIP) in Japan, nucleoside analogs have shown efficacy and we have been offering them to owners of cats with FIP at our clinic since January 2020. The aim of this study was to investigate outcomes in cats with FIP who received GS-441524 or molnupiravir. Diagnosis of FIP was based on clinical signs, laboratory test results, and the presence of feline coronavirus RNA in blood or effusion aspirate. After providing verbal and written information, owners of cats with a presumptive diagnosis of FIP with a were offered antiviral treatment with commercially sourced GS-441524 from June 2020, and either GS-441524 or compounded molnupiravir from January 2022. Dosing was 12.5-25 mg/kg/day for GS-441524 and 20-40 mg/kg/day for molnupiravir, depending on the presence of effusion and neurological and/or ocular signs, and continued for 84 days. Overall, 118 cats with FIP (effusive in 76) received treatment, 59 with GS-4421524 and 59 with molnupiravir. Twenty cats died, 12/59 (20.3%) in the GS-441524 group and 8/59 (13.6%) in the molnupiravir group (p = 0.326), with most deaths within the first 10 days of starting treatment. Among survivors, neurological and ocular signs resolved in all but one cat, who had persistent seizures. Of the cats completing treatment, 48/48 in the GS-441524 group and 51/52 in the molnupiravir group achieved remission. Laboratory parameters normalized within 6 to 7 weeks of starting drug administration. Adverse events, such as primarily hepatic function abnormalities, were transient and resolved without specific intervention. Our data indicate that GS-441524 and molnupiravir show similar effects and safety in cats with FIP.

Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial

Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, safety, and tolerability of ARCT-154-a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant-with the BNT162b2 (Comirnaty; Pfizer-BioNTech) mRNA vaccine when administered as a fourth-dose booster. This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 [Spikevax; Moderna]) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18-64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded -10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing. Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321-7363]) were non-inferior to those in the BNT162b2 group (3934 [2993-5169]) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26-1·63). Seroresponse rates were 65·2% (95% CI 60·2-69·9) in the ARCT-154 group versus 51·6% (46·4-56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8-20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1·30 (1·07-1·58)-with seroresponse rates of 69·9% (65·0-74·4) and 58·0% (52·8-63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination. In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants. Japanese Ministry of Health, Labour, and Welfare. For the Japanese translation of the abstract see Supplementary Materials section.

Long‐term safety of oral edaravone in Japanese patients with amyotrophic lateral sclerosis: Sub‐analysis of a global, open‐label, phase 3 study

AbstractIntroduction/AimsPatients with amyotrophic lateral sclerosis (ALS) experience a slower rate of physical function decline when treated with intravenous edaravone. The oral suspension formulation of edaravone (105 mg) has a similar pharmacokinetic profile to intravenous edaravone (60 mg/60 min). The long‐term safety of oral edaravone in Japanese patients with ALS has not been reported. Therefore, a sub‐analysis of Japanese patients in a global phase 3 study (NCT04165824) was conducted to evaluate the safety and tolerability of oral edaravone in Japanese patients with ALS.MethodsThis study was a global, open‐label, phase 3 study to evaluate the long‐term safety and tolerability of oral edaravone in patients with ALS. Patients with ALS received oral edaravone (105 mg/day) for 48 weeks. Adverse events in Japanese patients were assessed at week 48.ResultsAmong the 185 patients enrolled globally, 65 patients were enrolled in Japan (mean age, 59.3 years; mean disease duration, 1.5 years). Most patients experienced treatment‐emergent adverse events (TEAEs) (84.6%), and the most common TEAEs by week 48 were constipation (15.4%), insomnia (12.3%), and back pain (10.8%). Two serious TEAEs were reported: atrial fibrillation and pleural effusion (both n = 1). Three adverse drug reactions (ADRs) were reported: diarrhea, abnormal hepatic function, and fatigue (all n = 1). There were no serious ADRs or TEAEs/ADRs that led to study drug discontinuation.DiscussionOral edaravone had a similar safety profile to intravenous edaravone in Japanese patients, and good tolerability over 48 weeks. No new safety concerns were observed in this population.

Efficacy, safety, and tissue penetration of solithromycin in Japanese patients with otorhinolaryngological infections

ObjectiveTo assess the efficacy, safety, and tissue penetration of solithromycin for the treatment of otorhinolaryngological infections, we conducted three studies: a tissue penetration study with patients scheduled to undergo otorhinolaryngological tissue removal, an open-label study comprising patients with otitis media, pharyngitis, laryngitis, and tonsillitis, and a non-inferiority study compared with high-dose cefcapene-pivoxil (CFPN-PI). MethodsTissue penetration study; 17 patients with chronic rhinosinusitis, chronic otitis media, chronic tonsillitis, or palatine tonsillar hypertrophy, who required resection or removal of their tissue, were enrolled. Solithromycin was administered orally, and otorhinolaryngological tissues were collected 3.5–6 h after drug administration; blood was collected within 15 min before and after drug administration. The collected tissues and blood concentrations were measured at a central laboratory. Open-label study; 55 patients who were diagnosed with acute otitis media, laryngopharyngitis, or tonsillitis were enrolled. Solithromycin was administered orally 800 mg on Day 1, while on days 2–7, 400 mg of the drug was administered once daily. The primary endpoint is the clinical response at Test-of-Cure (TOC: 5–10 days after completion) Non-inferiority study; 283 patients with acute rhinosinusitis or acute exacerbation of chronic rhinosinusitis were randomized into either the solithromycin group or CFPN-PI group. Solithromycin was administered 800 mg once daily on Day 1 and 400 mg once daily while on Days 2–7 in solithromycin group, and CFPN-PI was administered 150 mg three times a day while on Days 1–7 in CFPN-PI group. The primary endpoint is the clinical response at TOC. ResultsIn the tissue penetration study, the tissue concentration ratios (tissue concentration/plasma concentration) of solithromycin were 4.19 in the sinonasal mucosa, 1.33 in the middle ear mucosa, and 6.12 in the palatine tonsil tissue. In the open-label study, the efficacy rates at the TOC were 97.0 % for acute otitis media, 100 % for laryngopharyngitis, and 81.8 % for tonsillitis. In the non-inferiority study comprising patients with rhinosinusitis, the efficacy rate at the TOC was 87.7 % for solithromycin and 89.7 % for CFPN-PI. The difference in the efficacy rate (95 % confidence interval) was -2.0 % (-9.4 % to 5.4 %), verifying the non-inferiority of solithromycin to CFPN-PI. The most common adverse events in patients administered solithromycin were diarrhea (20.7 %), nausea and nasopharyngitis (3.6 %,), pharyngitis and elevated hepatic function test results (3.1 %), and abnormal hepatic function (2.1 %). ConclusionBased on the findings, it is suggested that solithromycin is useful for the treatment of otorhinolaryngological infections.

Impact of Age on Hemostasis of Patients with Immune Thrombocytopenia

Introduction Incidence of primary immune thrombocytopenia (ITP) has two peaks: one in children and young adult and one in the elderly. Management of older patients represents a challenge, because older age is associated with increased frailty, comorbidities, polypharmacy, and worse outcome. Moreover, we cannot rule out the effect of old age on hemostasis of individuals without ITP. Objectives We aimed to compare characteristics of hemostasis in healthy controls and in patients with ITP stratified according to their age in ≤65 years old (yo) and &amp;gt;65 yo, in order to determine if old age modifies hemostasis and if there is an increased risk of bleeding in older patients with ITP. Methods This is a prospective project that was approved by the Ethics Committee from Hospital Universitario La Paz. Informed consent was signed before sampling. ITP patients (n=100≤65 yo and n=68&amp;gt;65 yo) and healthy controls (n=100≤65 yo and n=28&amp;gt;65 yo) were recruited. Patients with ITP and participants with uncontrolled hypertension, artery disease, abnormal hepatic or renal function tests, a diagnosis of a bleeding disorder or thrombopathy, treatment with drugs that could affect hemostasis or a history of thrombotic episodes were excluded. We evaluated platelet activation markers (TRAP and ADP-induced activation of fibrinogen receptor determined through PAC1-binding, and TRAP-induced P-selectin exposure with anti-P-selectin antibody); active caspase-3, -7, -8 and -9; surface loss of sialic acid determined by the binding of Ricinus Communis Agglutinin I (RCA) to galactose residues; and presence of GlcNAc residues on platelet's surface determined by the binding of Wheat Germ Agglutinin (WGA). Neuraminidase 1 (NEU1) associated to membrane of quiescent platelets were tested with anti-NEU1-Alexa 546 antibody. All samples were analyzed by flow cytometry. Thrombin generation was measured in platelet-poor plasma by Calibrated automated thrombogram (CAT) and coagulation was triggered by proper recalcification and the addition (final concentrations) of 1 pmol/l of recombinant human tissue factor and 4 µmol/l of phospholipid mixture (PPP-Reagent LOW). The following parameters were measured: Lagtime (= time when 10 nmol/l thrombin is formed); peak height (PH = maximum thrombin concentration reached); and endogenous thrombin potential (ETP = area under the thrombin-concentration-vs-time curve) were calculated with the Thrombinoscope software package (Thrombinoscope BV). Statistical analyses were performed with GraphPrism 6.0. Comparisons between controls vs ITP patients with similar range of age; controls ≤65 vs &amp;gt;65 yo; and ITP patients ≤65 vs &amp;gt;65 yo were performed with 2 way ANOVA and p&amp;lt;0.05 were considered as significant. Results Table 1 shows results obtained. There was no difference in age between controls and ITP groups with the same age range. Platelets from patients with ITP had a low ability to be activated when compared to their corresponding control group, and impairment in activation of fibrinogen receptor was even more evident for the older group of ITP patients.This fact was not due to a reduction in the number of fibrinogen receptors. Caspases 3, 8 and 9 were higher in ITP patients than their age-matched controls. Moreover, caspase 3 was higher in older ITP than in patients ≤65 yo. Regarding analyses of glycoside residues, platelets from patients with ITP had less sialic acid and more GlcNAc residues on their surface when compared with the corresponding controls. Surprisingly, sialic content in platelets from controls &amp;gt; 65yo was higher than in the controls ≤65 yo, and this fact is in accordance to the lowest content of NEU1 associated to their membrane. Plasma from ITP patients had a higher capacity to generate thrombin when compared with their age-matched control group. Nevertheless, both groups (control and ITP)&amp;gt; 65 yo generated less thrombin than the groups ≤65 yo. No differences were observed in other CAT parameters. Conclusion Platelets from patients with ITP are less functional than those from control groups. This impairment seemed to be more pronounced in platelets from patients &amp;gt;65 yo, putting forward the possibility of an increased risk of bleeding in older patients with ITP. This study also demonstrates that old age might modify hemostasis even in individuals without ITP. Work supported by Instituto de Salud Carlos III (ISCIII) (PI19/00772, PI22/01489), co-funded by the European Union.

Predictive factors for severe outcomes in substance abuse-related emergency visits: A 5-year retrospective analysis at a medical center in Taiwan.

Substance abuse is a considerable medical issue worldwide, yet current surveillance systems in Taiwan offer limited insights into the clinical characteristics and outcomes of substance abuse patients. This study aimed to delineate the epidemiology of emergency department visits related to substance abuse at a hospital in Taiwan and to identify factors predictive of severe complications or mortality. A retrospective analysis was conducted on substance abuse-related emergency department visits at a medical center in Taiwan between 2009 and 2013. Eligible participants were individuals aged 20 or older who had confirmed substance abuse through urinalysis. Variables such as patient demographics, substances abused, clinical characteristics, and outcomes were collected. Severe outcomes were defined as admission to the intensive care unit, requirement for endotracheal intubation, or in-hospital death. Logistic regression models were employed to identify factors contributing to severe outcomes. The cohort consisted of 623 patients, of whom 64.0% were female and 67.1% were aged between 20 and 49 years. Benzodiazepines were detected in 75.3% of patients, while z-drugs (specifically zopiclone, zolpidem, or zaleplon) were found in 27.8%. Depressants, stimulants, and hallucinogens were present in 14.9%, 10.6%, and 0.6% of the cases, respectively. Of the patient, 121 (19.4%) experienced severe outcomes, including 116 (18.6%) intensive care unit admissions, 73 (11.7%) intubations, and 11 (1.8%) in-hospital deaths. Multivariable logistic regression analysis revealed multiple predictors of severe outcomes, such as emergency department triage level, aspiration pneumonia, leukocytosis, abnormal hepatic function, abnormal renal function, hypernatremia, and hypocalcemia. In Taiwan, benzodiazepines emerged as the most prevalent substance of abuse among emergency department visitors, and a significant proportion of these patients experienced severe outcomes. Continuous monitoring of severe outcome predictors is essential for enhanced understanding and management.

Endovascular treatment of postoperative hemorrhage after pancreatectomy: a retrospective study

BackgroundRuptured aneurysm is a serious complication of distal pancreatectomy (DP) or pancreatoduodenectomy (PD) that can be life-threatening if not treated promptly. This study aimed to examine the efficacy of a Viabahn stent graft for stopping bleeding after pancreatectomy.MethodsBetween April 2016 and June 2022, we performed 245 pancreatectomies in our institution. Six patients experienced postoperative bleeding and underwent endovascular treatment.ResultsAll six cases of bleeding occurred post-PD (3.7%). The bleeding was from gastroduodenal artery (GDA) pseudoaneurysms in three patients, and Viabahn stent grafts were inserted. All three patients did not show liver function abnormalities or hepatic blood flow disorders. One patient with a Viabahn stent graft experienced rebleeding, which required further management to obtain hemostasis. Of the six cases in which there was hemorrhage, one case of bleeding from the native hepatic artery could not be managed.ConclusionsUsing the Viabahn stent graft is an effective treatment option for postoperative bleeding from GDA pseudoaneurysms following PD. In most cases, using this device resulted in successful hemostasis, without observed abnormalities in hepatic function or blood flow.

The Real-World Outcomes of Ponatinib in 724 Patients with CML and Ph + ALL : A Post-Marketing Surveillance Study with a Special Interest in Arterial Occlusive Events in Japan

Introduction Ponatinib inhibits the BCR::ABL1 kinase, including a variant with threonine-to-isoleucine at position 315 (T315I) (Cortes et al. N Eng J Med. 2013; 369:1783-96); however, it has been reported that ponatinib is associated with a higher risk of major arterial events than other TKIs among patients with CML, those with a resistance/intolerance (r/i) to prior TKIs, and with patients with relapsed/refractory (r/r) Ph + ALL. ( Leuk Lymphoma. 2016; 57(6):1300-10.) Owing to the low prevalence of this disease (Ning et al. Exp Hematol Oncol 2020; 9 (29)), SEER Cancer Statistics Review 1975-2018. National Cancer Institute 2021, Ching-Hong et al. N Engl J Med 2004; 350:1535-48), the amount of data concerning patients treated with ponatinib is limited, indicating that the safety and efficacy of ponatinib require further evaluation. Therefore, we conducted a post-marketing surveillance (PMS) study to assess the safety and efficacy of ponatinib, focusing on arterial occlusive events (AOEs), to optimize its use in clinical practice in Japan. Methods This PMS study investigated the safety and efficacy of ponatinib (ICLUSIG ®, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) in patients with r/i CML who have been treated with TKIs and patients with r/r Ph + ALL. We collected clinical data from all patients in Japan who started ponatinib administration between November 21, 2016, and June 30, 2018. The observation period was two years (or until the end of ponatinib administration). AEs and ADRs were classified using the Medical Dictionary of Regulatory Affairs (MedDRA) version 25.0. Surveillance was conducted in accordance with the Japanese Ministerial Ordinance on Good Post-Marketing Study Practice for Drugs. Results A total of 807 patients were enrolled from 334 facilities. Safety analysis was conducted for all 724 patients; 421 (58.1%) participants were males with a sample median age of 62.0 years. The median (range) follow-up duration was 258.0 (1-1,436) days for the overall population, 729.5 (7-1,436) days for patients with CML-CP, and 168.0 (1-1,254) days for patients with Ph + ALL. As for safety data, adverse reactions (ADRs) were observed in 58.29% (422/724) of participants. The most common ADRs included platelet count decreases (8.15% - 59/724), hypertension (7.73% - 56/724), rash (5.56% - 41/724), decreased neutrophil count (4.83% - 35/724), and abnormal hepatic function (4.28% - 31/724). The most common serious ADR was a 2.49% (18/724) decrease in the platelet count. The incidence of AOEs was 6.49% (47/724) among the overall population, 6.22% (12/193) among patients with CML-CP, and 5.90% (23/390) among patients with Ph + ALL. The incidence of AOEs per 100 person-year was 6.8 events in total, 4.5 events in CML-CP, and 7.1 events in Ph + ALL. The incidence of cerebrovascular events was higher than that of cardiovascular events and peripheral vascular events in patients with CML-CP; there were no deaths related to AOEs in patients with CML-CP during the follow-up duration of PMS. Univariate logistic regression analysis revealed significant associations between AOEs and age (OR 1.039, 95% CI 1.017-1.062), hypertension (OR 2.137, 95% CI 1.169-3.907), and diabetes (OR 1.950, 95% CI 1.026-3.707). Regarding efficacy data, among the 89 patients with CML-CP who had not achieved MMR (MMR; BCR-ABL1transcripts [IS] ≤ 0.1%) before treatment with ponatinib, the cumulative MMR rates at weeks 12, 24, 52, and 104 were 22.8%, 36.9%, 58.8%, and 67.2%, respectively. Among the 19 patients with the BCR::ABL1 T315I mutation, the cumulative MMR rates at 12, 24, 52, and 104 weeks were 42.1%, 47.4%, 75.3%, and 75.3%, respectively. In patients with Ph + ALL, the CCyR rates at weeks 0, 12, 24, 52, and 104 were 35.4% (51/144), 77.1% (108/140), 73.6% (53/72), 83.6% (46/55), and 80.0% (36/45), respectively. Conclusions This two-year post-marketing surveillance of patients with r/i CML and r/r Ph+ ALL has demonstrated the general favorable safety and efficacy of ponatinib to patients in Japan. The main adverse reactions were those events reported in the clinical trials up until the time of approval. Furthermore, regarding AOE, no expression levels exceeding the results of the clinical trial were confirmed. However, patients with advanced age and who have predisposing factors for AOEs should be closely monitored for possible adverse vascular events.

Efficacy and safety of utidelone plus capecitabine in advanced first-line therapy for metastatic breast cancer: A multicenter real-world study

BackgroundThe purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic breast cancer patients who had previously received anthracycline and taxane. At the same time, we compared the efficacy of utidelone plus capecitabine and vinorelbine plus cisplatin in advanced first-line treatment of metastatic breast cancer. Patients and methodsA retrospective cohort of 11 patients with metastatic breast cancer previously treated with anthracycline and taxane (including neoadjuvant and adjuvant therapies) for advanced first-line with utidelone plus capecitabine, 32 patients treated with second-line or above, and 60 patients with vinorelbine plus cisplatin between October 2011 and August 2022 was collected. The first and second groups were treated with utidelone plus capecitabine, and the third group was treated with vinorelbine plus cisplatin. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), objective response rate (ORR), and treatment safety. ResultsBy 03/31/2023, median PFS reached 11.70 months (95 % CI 0.093–0.141) in utidelone plus capecitabine group in the advanced first-line therapy, compared to 5.60 months (95 % CI 0.025–0.079) in the second-line or above therapy [HR 0.42, (95 % CI 0.226–0.787), P = 0.0077]. In utidelone plus capecitabine, the median OS was not reached in the advanced first-line therapy, with a mean overall survival of 23.16 months (95 % CI 0.198–0.265); whereas the median OS in the second-line or above therapy was 19.50 months (95 % CI 0.083–0.307), with a mean overall survival of 16.89 months (95 % CI 0.136–0.202) [HR 0.26, (95 % CI 0.098–0.678), P = 0.0495]. The ORR for advanced first-line therapy was 27.27 % (95%CI 0.060, 0.610) compared with 15.63 % (95%CI 0.053, 0.328) for second-line or above. In advanced first-line therapy, utidelone plus capecitabine was superior to vinorelbine plus cisplatin with a median PFS of 6.12 months (95 % CI 0.051–0.072) [HR 0.49, (95 % CI 0.286–0.839), P = 0.0291]. Compared with utidelone plus capecitabine, the median OS in vinorelbine plus cisplatin advanced first-line therapy group was 35.37 months (95 % CI 0.258–0.449), and the mean overall survival was 40.79 months (95 % CI 0.315–0.501) [HR 0.54, (95 % CI 0.188–1.568), P = 0.2587]. The ORR for vinorelbine plus cisplatin was 18.33 % (95 % CI 0.095, 0.304). The most common adverse events in our study were neurological toxicity, hand-foot syndrome, hematological toxicity, gastrointestinal toxicity, and hepatic and renal function abnormalities. There were no deaths due to adverse effects during the utidelone plus capecitabine treatment period. ConclusionsIn MBC, advanced first-line therapy with utidelone plus capecitabine resulted in more favorable PFS, OS, and ORR than second-line or above therapy. In advanced first-line therapy, utidelone plus capecitabine had superior PFS, and ORR compared with vinorelbine plus cisplatin. This study concludes that utidelone plus capecitabine is a more valuable chemotherapy option in advanced first-line MBC.

Hepatobiliary Adverse Reactions during Treatment with Cladribine: Analysis of Data from the European Spontaneous Reporting System.

Cladribine belongs to the group of disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS). According to the highlights of a meeting held by the Pharmacovigilance Risk Assessment Committee (PRAC) on 14 January 2022, cladribine may be associated with the occurrence of liver injury, and thus liver function monitoring is recommended. Using data from the European spontaneous reporting database (EudraVigilance-EV), we aimed to describe the main characteristics of Individual Case Safety Reports (ICSRs) reporting cases of hepatobiliary disorders related to cladribine. The reporting odds ratio (ROR) was calculated to provide the probability of reporting hepatobiliary ICSRs among DMTs used to treat MS. Overall, 118 ICSRs described the occurrence of cladribine-induced hepatobiliary ADRs. The majority of the ICSRs reported ADRs that were classified as serious (93%), and the outcome was mostly reported as "unknown" (50.8%). The most reported hepatobiliary disorders were drug-induced liver injury, abnormal hepatic function, ALT increases, liver disorders, hepatic failure, jaundice, lymphocyte count decreases, hepatotoxicity and hypertransaminasemia. The majority of cladribine-induced hepatic ADRs occurred in female patients belonging to the age group of 18-65 years. Considering the seriousness of cladribine-induced hepatic ADRs, a close monitoring of patients receiving this drug is highly recommended. In this context, further pharmacovigilance studies evaluating the hepatic safety profile of cladribine are strongly needed.