Fatal Adverse Events of Dabigatran Combined With Aspirin in Elderly Patients: An Analysis Using Data From VigiBase

Introduction: The elderly are vulnerable to cardiovascular diseases and the incidence of atrial fibrillation (AF) and venous thromboembolism (VTE) increases significantly with age. Dabigatran is a commonly used new oral anticoagulant approved by the FDA for stroke prevention in patients with non-valvular AF and VTE treatment and prevention. Aspirin is commonly used as a preventive drug for cardiovascular diseases. AF and coronary heart disease share many risk factors, so these two diseases often coexist and thus dabigatran and aspirin are often combined in those people. The aim of this study was to analyze the clinical characteristics of fatal adverse events of dabigatran combined with aspirin in elderly patients, and to provide references for clinical rational use of drugs.Materials and Methods: Fatal adverse events related to the combined use of dabigatran and aspirin in elderly patients aged over 75 were extracted from the WHO global database of individual case safety reports (VigiBase). Well-documented reports, vigiGrade completeness score ≥0.80, or with an informative narrative, were analyzed with a focus on the clinical features of the cases.Results: From 1968 up to January 19, 2020, there were 112 eligible reports in VigiBase from 13 countries, of which 33 were identified as well-documented. Of these 33, 19 were male (58%) and 14 were female (42%), the average age of the patients was 84 (75–95 years), with five cases of extreme weights (>100 kg in one case, <50 kg in four cases). There were 31 cases of death by internal bleeding (mainly 15 of gastrointestinal hemorrhage and 12 of intracranial hemorrhage) and two cases of the sudden death of unknown cause. Medication errors existed in 15 patients. The times to onset (TTO) was provided in 24 cases, ranging from 2 days to 4 years, and in 12 patients occurred within a month. Of the 31 patients with fatal bleeding events, 29 were associated with other factors that increase the risk of bleeding, such as diseases (hypertension, renal impairment, stroke, gastrointestinal related diseases, hypothyroidism, and cancer), drugs (antiplatelets, anticoagulants, thrombolytics, P glycoprotein substrates, non-steroidal anti-inflammatory drugs, hormones, selective serotonin reuptake inhibitors, and acetaminophen) and other factors (low body weights and alcohol consumption), and 21 of these contained two or more risk factors.Conclusion: The fatal adverse events associated with the combined use of dabigatran and aspirin in elderly patients were mainly serious bleeding events, which often occurred within 1 month. Most of these cases had medication errors and most of the patients had multiple diseases, medications, or other conditions at the same time that increase the risk of bleeding. It is suggested that prescription of dabigatran and aspirin in elderly patients should go along with alertness for medication errors, care for correct dose or control of other bleeding risk factors, and the combined medication time should be as short as possible to minimise serious adverse events.

No Increase in Short-Term Mortality Following COVID-19 Vaccination Among Nursing Home Residents

Reports of fatal adverse events following mRNA-based vaccination for COVID-19 in Norwegian nursing home (NH) residents have raised concern regarding vaccine safety in very old and frail persons. A limitation of these reports, however, is the absence of contemporaneous control groups, particularly given the high baseline mortality in this population. Using electronic health records’ data on resident deaths, hospital transfer, vaccination, and daily census from Genesis Healthcare, a large NH provider spanning 24 U.S. states, we compared 7-day mortality and hospitalization rates for vaccinated versus unvaccinated NH residents. Between December 18, 2020 and December 31, 2020, 7006 residents across 118 NHs were vaccinated with the first dose. Mortality and hospital transfer rates within 7 days of vaccination were compared to rates for: (1) unvaccinated residents in the same facility within 7 days of the vaccine clinic (n=4414), and (2) residents in 166 yet-to-be-vaccinated facilities between December 25, 2020 and January 1, 2021 (n=17,076). We excluded residents with a positive SARS-CoV-2 diagnostic test within 20 days prior to their 7-day observation window. Mortality rates per 100,000 residents were lower among vaccinated (587, 95%CI: 431, 798) versus unvaccinated residents within the same facilities (984, 95%CI: 705, 1382), and compared to residents in not-yet-vaccinated facilities (912, 95%CI: 770-1080), with overlapping 95% CIs. Hospital transfers were lower among vaccinated residents than in either comparison group, but with overlapping CIs. Our findings suggest that short term mortality rates appear unrelated to vaccination for COVID-19 in NH residents, and should dispel concerns raised by previous reports.

Anti-Angiogenesis Maintenance Therapy in Newly Diagnosed and Relapsed Ovarian Cancer: A Meta-analysis of Phase III Randomized Controlled Trials

Aim: Anti-angiogenesis agents have been added as maintenance therapy in ovarian cancer over the past decade. The aim of this meta-analysis was to analyze the efficacy of anti-angiogenesis therapy in newly diagnosed and relapsed ovarian cancer.Methods: PubMed, Embase, and Cochrane databases were searched for all phase III randomized controlled trials (RCTs) that assessed the efficacy and toxicity of anti-angiogenesis agents in ovarian cancer. Overall survival (OS) and progression-free survival (PFS) were used to evaluate the effectiveness of anti-angiogenesis therapy in ovarian cancer.Results: A total of 6097 patients with newly diagnosed ovarian cancer from 5 phase III RCTs and 2943 patients with relapsed ovarian cancer from 6 phase III RCTs were included in this meta-analysis. The pooled results showed that anti-angiogenesis maintenance therapy significantly improved PFS (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.76–0.93; p = 0.001), but not OS (HR, 0.98; 95% CI, 0.91–1.05; p = 0.49) compared with placebo in patients with newly diagnosed ovarian cancer. In patients with relapsed ovarian cancer, the pooled results showed a significant improvement on OS (HR, 0.89; 95% CI, 0.82–0.98; p = 0.02) and PFS (HR, 0.61; 95% CI, 0.52–0.72; p < 0.001). The pooled results also showed that the anti-angiogenesis agents were associated with an increase in the occurrence of severe hypertension, neutropenia, diarrhea, thrombocytopenia, headache, and bleeding in ovarian cancer. However, infrequent fatal adverse events occurred in the anti-angiogenesis groups.Conclusions: Study results suggest that anti-angiogenesis agents were an effective therapy for newly diagnosed and relapsed ovarian cancer, especially for relapsed ovarian cancer. Anti-angiogenesis agents may be associated with some severe but not fatal adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021283647

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma

Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.

Chemotherapy with the Use of TKIs Based on MRD Has the Potential to Avoid Hematopoietic Stem Cell Transplantation in Treatment for Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study ALL-Ph13

Aims: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients generally have a poor prognosis when treated with chemotherapy alone. In adults, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is still the standard strategy for Ph+ALL. However, in children, HSCT should be avoided as much as possible to eliminate late complications. There are some reports showing that the combination of tyrosine kinase inhibitors (TKIs) with chemotherapy may avoid HSCT in childhood Ph+ALL. Thus, we planned this clinical trial (JPLSG ALL-Ph13) with the aim of improving outcomes with as few HSCT by chemotherapy with TKIs based on Ig/TCR minimal residual disease (MRD). Methods: Patients aged 1 to 19 with Ph+ALL were enrolled in JPLSG ALL-Ph13 Study. The diagnosis of Ph+ALL was performed using reverse-transcription PCR for BCR-ABL1. Chemotherapy follows the BFM ALL high-risk regimen (IA, IB, HR3, HR2, HR1, III, IM, III, IM, III, and maintenance). Imatinib was started on day 15 of induction therapy and continued until the final day of maintenance therapy (Ima group). If Ig/TCR MRD was positive (≥10 -4) at the end of IB, imatinib was changed to dasatinib and chemotherapy was continued (Dasa group). If MRD was positive at the end of the HR blocks, HSCT was performed (HSCT group). Results: During the period 2013-17, 43 patients were registered in this study, and 2 patients were excluded by not meeting inclusion criteria. Thirty-three, 7, and 1 patient were stratified into Ima, Dasa, and HSCT groups, respectively. Induction rate was 52.6% at the end of IA and 89.2% at the end of IB. MRD-negative rate was 61.3% at the end of IB and 87% at the end of HR. Although 51.2% of patients eventually received HSCT, only 13.9% received HSCT at the first complete remission. In all patients, the 3-year event-free survival (EFS) rate was 65.1%, and the 3-year overall survival (OS) rate was 85.1%. Four patients died of serious infections during treatment (2 in IA, 2 in 1st III). Interpretation: In our previous study for children with Ph+ALL (the JPLSG Ph+ALL04 study), all patients underwent HSCT, with the 3-year EFS rate of 57% and the OS rate of 80%. In this ALL-Ph13 study, the EFS and OS are almost the same as those in the Ph+ALL04. These are also almost the same as those in the EsPhALL2010 study, which aimed at avoiding HSCT. However, as in the EsPhALL2010 study, the comparatively high incidence of fatal adverse events was a problem with this study. Conclusion: Chemotherapy with the use of TKIs based on MRD has the potential to avoid HSCT in treatment for children with Ph+ALL. Reducing the occurrence of fatal adverse events is a future challenge to overcome. Disclosures No relevant conflicts of interest to declare.

Crizotinib in Sarcomatous Malignancies Harboring ALK Fusion With a Definitive Partner(s): Response and Efficacy

Sarcoma or sarcomatoid malignancies are a set of mesenchymal-origin malignancies with vast heterogeneity in clinical and molecular characteristics. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase oncoprotein expressed by several tumors, including sarcomas. Crizotinib is an effective ALK inhibitor. In this review paper, we summarized findings from the literature regarding the use of crizotinib for the treatment of sarcoma and sarcomatoid malignancies harboring ALK fusions with definitive partners (with the given gene(s) name) from the years 2010 to 2021.One hundred and four articles were retrieved and after exclusion, 28 studies containing 33 patients were finally selected. All 33 patients were treated with crizotinib. Among the 33 cases, 19 were adult patients, 11 were pediatric patients, and 3 cases did not have data on age and/or gender. Most cases had a primary abdominal lesion (16/30), followed by thoracic (10/30), trunk (3/30), retroperitoneal (1/30), and one case of right medial thigh (case 7). Stage IV disease was reported in 76.7% (23/30) of patients. The objective response rate and disease control rate was 86.7% (26/30) and 96.7% (29/30), respectively, which were assessed on average of 8 weeks after crizotinib initiation. Rapid improvement of symptoms was observed within one to two weeks in some cases including patients with extensive diseases or poor performance. There was no difference in crizotinib response between pediatrics and adult cases. Crizotinib is effective; however, surgery remains the mainstay of therapy, with newer evidence showing concurrent crizotinib with surgery conferring long-term overall survival. However, we should still be cognizant of the heterogeneous landscape of crizotinib efficacy and its associated fatal adverse events.

An open-label, exploratory documentation of proving-symptoms of CVN01 (Coronavirus nosode from the clinical sample) in healthy volunteers

INTRODUCTION Homeopathic Pathogenetic Trials (Proving) are human studies to examine the pathogenetic effects of investigational drugs in high dilution on healthy volunteers. As a part of the new coronavirus nosode development process for prophylactic use, the phase 1 study was conducted. The documentation of proving symptoms for a fast-track nosode development for a pandemic condition was the objectives of this study. MATERIALS AND METHODS An open-label trial to evaluate the safety and proving symptoms of Coronavirus nosode given orally to 10 volunteers (18-65 years age and of both the genders). Volunteers were administered 6 doses of nosode as 6 pills twice daily for 3 consecutive days. Pre and post examinations (physical), vital signs, and laboratory investigations, were done at day 0, 17, 34. Symptoms experienced by the volunteers were recorded. RESULTS Symptoms reported by volunteers were analyzed. The symptoms reported were mild to severe but reversible and matching with the symptoms produced by the viral infection. There were no serious/fatal adverse events during the study. The basic biochemistry and Liver Function tests were not affected by the Nosode. CONCLUSION New nosode developed during a pandemic condition produced certain symptoms in the homeopathic pathogenetic trial as a part of the Phase 1 study.

EVALUATION OF ANTIOXIDANT POTENTIAL AND REDUCING POWER OF CALLUS INDUCED FROM LEAVES OF ASYSTASIA GANGETICA (L.) T.ANDERSON

Objective: Neuropathic pain arises from demage, or pathological changes in the peripheral or central nervous system. The pain is difficult to treat as standard treatment with conventional analgesics doesn`t typically provide effective relief of pain. Methods: It was a one year study of utilization and analysis of prescriptions for PNDs (Painful neuropathic disorders). The parameters evaluated were demographic profile of the patient (age and gender), type and etiology of PNDs, drug data (name of the group of drugs with individual drugs, mono or polytherapy, number of drugs per prescription, formulation) and associated adverse drug reactions (ADR) with the prescribed drug. Results: Maximum number of patients of PNDs resides in the age group of 18 – 35 y (41.2%) & more common in females. The most common PND encountered was painful diabetic neuropathy (43.9%) followed by cervical and lumbar radiculopathy, postherpetic neuralgia. 2942 drugs were prescribed in 1020 prescriptions, out of which 96.8% were oral and 3.2% were topical formulations. Most frequently prescribed group of the drug was tricyclic antidepressants (27.3%) followed by anticonvulsants (25.3%). Polypharmacy was seen 89.7% as compared to monotherapy (10.3%). Only 132 ADRs of various types were seen. The most common organ system affected was central nervous system followed by gastrointestinal systems. The most common drugs implicated for ADRs were TCAs (24.4%), anticonvulsants (16.6%), and Pregabeline (9.8%). There were no fatal adverse events. Mild to moderate ADRs included constipation, nausea, vomiting, drowsiness, dryness of mouth. Conclusion: The choice of drug depends on etiology of neuropathic pain, drug efficacy and availability and also on ADR profile.

PATTERNS OF PRESCRIPTION AND ADR MONITORING OF DRUGS IN THE MANAGEMENT OF NEUROPATHIC PAIN IN A TERTIARY CARE TEACHING HOSPITAL

Objective: Neuropathic pain arises from damage or pathological changes in the peripheral or central nervous system. The pain is difficult to treat as standard treatment with conventional analgesics doesn`t typically provide effective relief of pain. Methods: It was a one-year study of utilization and analysis of prescriptions for PNDs (Painful neuropathic disorders). The parameters evaluated were demographic profile of the patient (age and gender), type and etiology of PNDs, drug data (name of the group of drugs with individual drugs, mono or polytherapy, number of drugs per prescription, formulation) and associated adverse drug reactions (ADR) with the prescribed drug. Results: Maximum number of patients of PNDs resides in the age group of 18 – 35 yrs (41.2%) & more common in females. The most common PND encountered was painful diabetic neuropathy (43.9%) followed by cervical and lumbar radiculopathy, postherpetic neuralgia. 2942 drugs were prescribed in 1020 prescriptions out of which 96.8% were oral and 3.2% were topical formulations. Most frequently prescribed group of the drug was tricyclic antidepressants (27.3%) followed by anticonvulsants (25.3%). Polypharmacy was seen 89.7% as compared to monotherapy (10.3%). Only 132 ADRs of various types were seen. The most common organ system affected was the central nervous system followed by gastro intestinal systems. The most common drugs implicated for ADRs were TCAs (24.4%), anticonvulsants (16.6%), and Pregabeline (9.8%). There were no fatal adverse events. Mild to moderate ADRs included constipation, nausea, vomiting, drowsiness, dryness of mouth. Conclusions: The choice of drug depends on etiology of neuropathic pain, drug efficacy and availability and also on ADR profile.

The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma

ABSTRACTSurvival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. These findings are important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity—often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.