uridine triacetate (PN 401) / Wellstat - LARVOL DELTA

PN401. Anesthetic Considerations in Thoracic and Thoracoabdominal Aortic Disease (ASA 2024) - "Learning Objective 2 Utilize mitigation strategies to minimize neurologic and renal complications resulting from thoracic aortic procedures. Learning Objective 3 Employ modern evidence-based medicine to treat acquired coagulopathy from open surgical approaches to the thoracic aorta"

Anesthesia • Cardiovascular • Hematological Disorders

Neutropenic Enterocolitis After Single Dose of CAPOX in Newly Diagnosed Colon Cancer (ACG 2024) - "He had received his first dose of adjuvant chemotherapy, CAPOX (capecitabine and oxaliplatin), four days after surgery...Oncology recommended Filgrastim and Uridine Triacetate, and gastroenterology advised bowel rest, an nasogastric tube, and Octreotide infusion...Early recognition and intervention are crucial to mitigate complications like septic shock. Further research is needed to reduce NE-associated morbidity and mortality."

Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Mucositis • Neutropenia • Oncology • Pain • Palliative care • Septic Shock • Solid Tumor • Stomatitis

Nucleo(s)tide metabolism as basis for drug development; the Anne Simmonds award lecture. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "This background was fundamental in our studies on how to optimize application of existing drugs (5-fluorouracil [5FU], thiopurines, antifolates such as methotrexate) but also to support development of novel drugs such as gemcitabine, novel antifolates, S-1, TAS-102 and fluorocyclopentenylcytosine. Knowledge of their metabolism helped to design rational combinations such as of gemcitabine with cisplatin, one of the most widely used drug combinations for various cancers. The combination of 5FU with uridine, led to the development of triacetyluridine registered for emergency treatment of patients with lethal 5FU toxicity...The latter actually led to the most interesting results. Investigation of (nucleoside/nucleotide) metabolism remains an exciting field of research."

Journal • Cardiovascular • Infectious Disease • Oncology • Pediatrics • Rheumatology

FLUOROPYRIMIDINE-ASSOCIATED SEVERE CARDIOTOXICITY TREATED WITH URIDINE TRIACETATE (ACC 2024) - "Background: 5-fluorouracil (5-FU) associated cardiotoxicity is infrequent and remains poorly defined...An ECG revealed lateral ST elevations, which normalized promptly after stopping 5-FU and nitroglycerin administration... It is crucial to monitor patients receiving 5-FU for any signs of cardiotoxicity, as early interventions can be critical. Uridine triacetate may play an essential role in life-threatening toxicities."

Cardiomyopathy • Cardiovascular • Colon Cancer • Colorectal Cancer • Congestive Heart Failure • Coronary Artery Disease • Gastrointestinal Cancer • Heart Failure • Myocardial Infarction • Oncology • Pain • Solid Tumor • DPYD

A CASE OF 5-FLUOROURACIL INDUCED ACUTE HEART FAILURE (ACC 2024) - "After undergoing radical appendectomy with diverting loop, patient received FOLFOX (folinic acid, fluorouracil, and oxaliplatin) therapy...Patient also received uridine triacetate for presumed 5-FU associated cardiomyopathy... 5-FU confer benefit to patients with solid tumors however with limited use due to cardiotoxicity. The above case demonstrates the need to further define cardio-protective strategies for patients receiving 5-FU."

Clinical • Appendix Cancer • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Critical care • Gastrointestinal Cancer • Heart Failure • Oncology • Peritoneal Cancer • Respiratory Diseases • Solid Tumor

HEREDITARY OROTIC ACIDURIA: AN UNCOMMON PRESENTATION IN A PEDIATRIC PATIENT (ASPHO 2024) - "The patient's orotic acid level was found to be 2,986 mmol (normal: 0.7 to 5.1 mmol) The patient started uridine triacetate... A thorough work up was completed for this patient with initial symptoms of neutropenia and normocytic anemia. After preliminary testing, a diagnosis of MDS was heavily considered with the potential for a bone marrow transplant. A definitive diagnosis was found after whole exome sequencing."

Clinical • Anemia • Aplastic Anemia • Bone Marrow Transplantation • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Metabolic Disorders • Myelodysplastic Syndrome • Neutropenia • Oncology • Pediatrics • Transplantation

Novel bi-allelic CAD variants cause epileptic encephalopathy responsive to triacetyluridine supplementation (SIMD 2024) - "At her first genetics evaluation, she had mild developmental delays and seizures were well controlled with levetiracetam. Triacetyluridine is 4- to 6-times more bioavailable than uridine alone and is FDA approved for treatment of hereditary orotic aciduria as well as for fluorouracil and capecitabine toxicities. The CAD-knockout cells used in functional studies demonstrate growth only with uridine supplementation, further supporting this in vivo treatment approach. This patient's case demonstrated improved efficacy of triacetyluridine compared to uridine monophosphate (UMP), though conceivably a higher dose of UMP"

CNS Disorders • Developmental Disorders • Epilepsy

A Rare Presentation of 5-Fluorouracil-Induced Cardiotoxicity (AHA 2023) - "He was treated with vasopressors and milrinone...He was treated with nifedipine for possible coronary vasospasm... The incidence of cardiotoxicity from 5-FU ranges from 1.2-18%. Mechanistic theories include coronary vasospasm and direct cellular injury. Symptoms usually present within 12 hours of initiation but may present up to 2 days later."

Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • CNS Disorders • Congestive Heart Failure • Depression • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Heart Failure • Oncology • Pain • Psychiatry • Pulmonary Embolism • Respiratory Diseases • Solid Tumor

PN401. Maladaptive mechanisms of chronic pain: from cells to circuits (ASA 2023) - "His research reveals the potential of targeting neural circuits for patients with chronic pain. Together, these talks will provide a new picture of the spinal, cortical, and brain-wide structure of specific cell-type networks underlying the transition from acute to chronic pain."

Pain

Two patients with fluoropyrimidine overdose successfully managed without uridine triacetate. (PubMed, J Oncol Pharm Pract) - "The rationale for abstaining from the use of uridine triacetate was the inadequacy of evidence backing its clinical and cost-effectiveness and the fact that uridine triacetate is not registered for the use in the European Union. Comparison of clinical outcomes of the already published open-label cohort with clinical outcomes of a comparable, well-described, best supportive care cohort is required before the added value of uridine triacetate can be determined. In addition, there is a need for a valid predictor of toxicity after fluoropyrimidine overdose."

Journal • Critical care • DPYD

Using real-world evidence (RWE) in regulatory decision making: A study of 6 oncology approvals with RWE included in the product label. (ASCO 2023) - "Ultimately, across the 2015 to 2019 targeted literature review and the 2020 to 2022 FDA submission document review, 6 oncology product labels incorporated RWE: palbociclib, uridine triacetate, lutetium Lu 177 DOTATATE, bevacizumab-adcd, naxitamab-gqgk, and decitabine/cedazuridine. These results suggest that RWE has become an important part of regulatory decision-making for oncology drug approval. Twenty-six of 29 RWE studies were accepted as evidence for the submission. For the 6 oncology products that include RWE in the product label, RWE was most frequently used to support the initial indication and was included in the postmarketing experience section."

Clinical • HEOR • Real-world • Real-world evidence • Oncology

Oral Capecitabine Exposures and Use of Uridine Triacetate: A 20-Year Retrospective Analysis. (PubMed, Clin Drug Investig) - "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."

Journal • Retrospective data

PN401. An Update on Uterotonics and Tranexamic Acid (ASA 2022) - "Appraise the impact of tranexamic acid in obstetric hemorrhage. Outline the downstream effects of altered oxytocin signaling in the peripartum period."

Hematological Disorders • Obstetrics • Postpartum Hemorrhage

"Oncologists must remember this or call the pharmD to save your ass (again) Chemo extravasation Anthracyclines = Dexrazoxane Cisplatin = Sodium thiosulfate Docetaxol = Hyaluronidase Mitoxantrone = DMSO Methotrexate = glucarpidase 5FU/capecitabine = uridine triacetate" (@AaronGoodman33)

Oncology

Reversible Toxic Encephalopathy Involving the Cerebellum and Subcortical White Matter Attributed to Capecitabine. (PubMed, Am J Med Sci) - "Capecitabine is an anticancer drug related to 5-fluorouracil (5-FU) that is used to treat multiple cancers. Whether uridine triacetate is a reasonable treatment choice for patients with life-threatening toxic encephalopathy depends on the availability of reliable clinical data. Prescreening for dihydropyrimidine dehydrogenase genotype variants and detection of 5-FU degradation rate prior to capecitabine treatment may become an effective way to avoid toxic reactions by regulating the therapeutic dose for each patient, which remains to be investigated and needs more clinical data to support."

Journal • Review • CNS Disorders • Oncology

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. (PubMed, Molecules) - "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. 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."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

PN401. Through the Looking Glass and Beyond the EEG: In Vivo Imaging of Neuronal Activity During Wakefulness and General Anesthesia (ASA 2021) - "Identify how neurons integrate synaptic responses in their dendrites, generate output signals, and collectively contribute to different brain states. Discuss opportunities to better understand state transitions accompanying loss and return of consciousness."

Preclinical • Anesthesia

"Oncologists must remember this or call the pharmD to save your ass (again) Chemo extravasation Anthracyclines = Dexrazoxane Cisplatin = Sodium thiosulfate Docetaxol = Hyaluronidase Mitoxantrone = DMSO Methotrexate = glucarpidase 5FU/capecitabine = uridine triacetate" (@AaronGoodman33)

Oncology

"Antidotes for Oncology Boards Chemo extravasation Anthracyclines = Dexrazoxane Cisplatin = Sodium thiosulfate Docetaxol = Hyaluronidase Mitoxantrone = DMSO Methotrexate = glucarpidase 5FU/capecitabine = uridine triacetate Ifosfamide neurotoxicity = methylene blue?" (@AaronGoodman33)

Oncology

[VIRTUAL] Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine. (ASCO 2021) - "At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years . A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA."

Clinical • Gastrointestinal Disorder • Gene Therapies • Oncology • DPYD

5-FU Cardiotoxicity: Vasospasm, Myocarditis, and Sudden Death. (PubMed, Curr Cardiol Rep) - "5-fluorouracil (5-FU) is one of the most common causes of cardiotoxicity associated with chemotherapy...Uridine triacetate is a recently approved antidote that can improve clinical outcomes in patients with life-threatening fluoropyrimidine cardiotoxicity. 5-FU cardiotoxicity remains poorly understood, with limited mechanistic or prospective clinical trial data available to define risk factors or effective management strategies. Risk stratification and therapeutic decisions should be individualized, based on the risk-benefit ratio of continuing 5-FU therapy for each patient."

Journal • Review • Cardiovascular

Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling. (PubMed, Mol Pharmacol) - "Twenty-one compounds inhibited uridine uptake and abacavir, nevirapine, ticagrelor, and uridine triacetate had different IC values for ENT1 and ENT2...Clofarabine and cladribine were ENT1 and ENT2 substrates, while nevirapine and lexibulin were ENT1 and ENT2 non-transported inhibitors...Novel CRISPR/Cas9 functional knockouts of ENT1 and ENT2 in HeLa S3 cells were generated and characterized. Determining drug interactions with these transporters can be useful in identifying and predicting compounds that are ENT1 and ENT2 substrates, and can circumvent the blood-testis barrier through this transepithelial transport pathway in Sertoli cells."

Journal

Alternative Treatment Options in Patients with Colorectal Cancer Who Encounter Fluoropyrimidine-Induced Cardiotoxicity. (PubMed, Onco Targets Ther) - "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."

Clinical • Journal • Review • Atrial Fibrillation • Breast Cancer • Cardiovascular • Colorectal Cancer • Congestive Heart Failure • Gastrointestinal Cancer • Gastrointestinal Disorder • Heart Failure • Hypotension • Myocardial Infarction • Oncology • Solid Tumor

[VIRTUAL] PN401. RV Failure in the Surgical Patient in Advanced Heart Failure (ASA 2020) - "Session Learning Objective 3 Identify pharmacological approaches for supporting a failing right ventricle. Session Learning Objective 4 Review mechanical approaches for supporting a failing right ventricle."

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure

Capecitabine-induced cerebellar toxicity and TYMS pharmacogenetics. (PubMed, Anticancer Drugs) - "No re-challenge was given to this patient but he was able to tolerate irinotecan, oxaliplatin, and bevacizumab without any toxicities. Patients on fluoropyrimidines, including capecitabine with new neurological symptoms must be investigated for a rare but real central neurotoxicity. Though the treatment of 5-FU neurotoxicity is supportive care but use of uridine triacetate may be indicated in few patients, especially with overdose."

Biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pain • Solid Tumor