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Hospital Pharmacy Apr 2016Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The...
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The April 2016 monograph topics are von Willebrand factor (recombinant), daratumumab, elotuzumab, uridine triacetate, and ixazomib. The MUE is on lesinurad.
PubMed: 27303081
DOI: 10.1310/hpj5104-328 -
Hospital Pharmacy Jun 2016Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The...
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The June 2016 monograph topics are elbasvir/grazoprevir, ixekizumab, brivaracetam, reslizumab, and sofosbuvir/velpatasvir. The Safety MUE is on reslizumab.
PubMed: 27354750
DOI: 10.1310/hpj5106-484 -
Clinical Drug Investigation May 2023Capecitabine is an oral prodrug of 5-fluorouracil. Toxicity can occur during therapy as well as acutely with overdose and particular genetic susceptibilities. Uridine...
BACKGROUND AND OBJECTIVES
Capecitabine is an oral prodrug of 5-fluorouracil. Toxicity can occur during therapy as well as acutely with overdose and particular genetic susceptibilities. Uridine triacetate is an effective antidote if given within 96 h of exposure. This study seeks to characterize accidental and intentional capecitabine exposures and uridine triacetate use, about which little has been published.
METHODS
A retrospective review of capecitabine exposures from 30 April 2001 to 31 December 2021 reported to a statewide poison control center was performed. All single-substance oral exposures were included.
RESULTS
In total, 81 of 128 reviewed cases were included, with a median age of 63 years. In total, 49 were acute-on-chronic exposures and 32 were acute exposures in capecitabine-naïve patients, 29 of which were accidental. Fifty-six (69%) were managed at home. Of these, none later recontacted the poison control center to report symptoms or were known to have later had healthcare facility evaluations. Of the 25 cases presenting for healthcare facility evaluation, 4 were acutely symptomatic. Thirteen were eligible for uridine triacetate, and six received it; no new or progressive toxicity was reported after. Three developed mild latent toxicity; otherwise, no morbidity or mortality was reported.
CONCLUSIONS
Accidental acute-on-chronic and acute ingestions of capecitabine appear to be well tolerated; most cases were managed at home. Unfortunately, little is known regarding the threshold at which toxicity may present following exposures. The threshold may vary individually given genetic susceptibilities. Management was heterogeneous, likely reflecting inadequate guidelines. Further research is needed to better delineate at-risk populations and treatment strategies.
Topics: Humans; Middle Aged; Capecitabine; Retrospective Studies; Antimetabolites, Antineoplastic; Genetic Predisposition to Disease
PubMed: 37072662
DOI: 10.1007/s40261-023-01268-5 -
Cancer Jan 2017Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase...
BACKGROUND
Increased susceptibility to 5-fluorouracil (5-FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Life-threatening 5-FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early-onset severe or life-threatening 5-FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5-FU metabolites.
METHODS
In 2 open-label clinical studies, patients who presented with a 5-FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5-FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care.
RESULTS
A total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate-treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5-FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%).
CONCLUSIONS
In these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5-FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345-356. © 2016 American Cancer Society.
Topics: Acetates; Antimetabolites, Antineoplastic; Capecitabine; Drug Overdose; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Uridine
PubMed: 27622829
DOI: 10.1002/cncr.30321 -
Frontiers in Pharmacology 20225-fluorouracil (5FU) and capecitabine are fluoropyrimidine anti-neoplastic drugs commonly used in the treatment of different types of cancer. Hereditary dihydropyrimdine...
5-fluorouracil (5FU) and capecitabine are fluoropyrimidine anti-neoplastic drugs commonly used in the treatment of different types of cancer. Hereditary dihydropyrimdine deaminase (DPD), thymidylate synthase mutations and drug overdose may lead to life-threatening toxicities. Uridine triacetate (UTA) is an emergency treatment for overdoses and early onset, severe or life-threatening toxicities from fluoropyrimidines. It is approved for use in adults and children within 96 h of last fluoropyrimidine administration. We present the case of a 64-year-old male treated with 5-FU and oxaliplatin as adjuvant systemic therapy for stage IIIA rectal cancer who developed delayed central nervous system toxicity 18 days after initiating chemotherapy. He had rapidly worsening encephalopathy and ataxia. Laboratory workups, MRI brain and EEG were negative. He was started on UTA with concerns of 5-FU toxicity due to the life-threatening nature of his condition even beyond the recommended 96-h time cut-off. He had rapid improvement in clinical status and resolution of encephalopathy. DPD deficiency testing later resulted as heterozygous for IVS14+1G>A allele indicating enzyme deficiency. This report demonstrates the importance of identifying delayed side effects with fluoropyrimidine therapy and potential treatment for reversing these effects. We also did an extensive literature review and obtained reports from the uridine triacetate clinical trials on patients receiving UTA after the 96-h cut-off. Based on our experience and previous published reports, a patient developing life-threatening delayed 5-FU toxicity should also be considered for UTA on a case-by-case basis.
PubMed: 36160401
DOI: 10.3389/fphar.2022.977734 -
OncoTargets and Therapy 20205-Fluorouracil (5-FU) remains to be the backbone of chemotherapy regimens approved for treatment of colorectal cancer and other gastrointestinal cancers and breast... (Review)
Review
5-Fluorouracil (5-FU) remains to be the backbone of chemotherapy regimens approved for treatment of colorectal cancer and other gastrointestinal cancers and breast cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5-18%. Previous studies also concluded that rechallenging a patient with previous 5-FU cardiotoxicity with either lower dose or another mode of administration could result in repeat of cardiac complication in up to 45% of patients. Nearly 13% of patients died upon re-exposure to 5-FU. Clinical manifestations of cardiac complications of fluoropyrimidines including angina, myocardial infarction, arrhythmias, hypotension, Tako-Tsubo syndrome, heart failure, cardiogenic shock, pericarditis, and even sudden death have been reported. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far. The author describes here treatment options for patients with metastatic colorectal cancer who have encountered fluoropyrimidine-induced cardiotoxicity, including switching to a different fluoropyrimidine, switching to a different schedule of intravenous 5-FU, or switching to a non-fluoropyrimidine-containing chemotherapy regimen if one exists. Switching to a non-fluoropyrimidine-containing chemotherapy regimen is usually the most feasible choice for patients with metastatic disease as data on adjuvant setting is usually a fluoropyrimidine or its combination with oxaliplatin at present.
PubMed: 33116601
DOI: 10.2147/OTT.S264156 -
JACC. CardioOncology Jun 2020
Review
PubMed: 34396241
DOI: 10.1016/j.jaccao.2020.04.005 -
Molecules (Basel, Switzerland) Dec 2021This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL) through molecular docking,...
Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment.
This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CL of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CL. The free energy of binding also demonstrates the stability of the PP-3CL complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.
Topics: Acetates; Antiviral Agents; Coronavirus 3C Proteases; Coronavirus Papain-Like Proteases; Cytidine Diphosphate Choline; Drug Evaluation, Preclinical; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protease Inhibitors; SARS-CoV-2; Uridine; COVID-19 Drug Treatment
PubMed: 34946540
DOI: 10.3390/molecules26247458