Uridine Triacetate Research Articles

Economic Model of Uridine Triacetate Versus Supportive Care for the Treatment of Patients with Life-Threatening Early-Onset Severe Toxicity.

Early-onset severe toxicity following the administration of 5-fluorouracil (5-FU) or capecitabine occurs in approximately 10-30% of patients receiving fluoropyrimidine therapy in the USA and is fatal to at least 0.5% of patients treated. Supportive care measures used to manage symptoms of toxicity are associated with extended hospital length of stay, high cost of care, and poor survival. Uridine triacetate is indicated as an emergency treatment for patients who exhibit early-onset, severe or life-threatening toxicity, and has been shown to significantly improve clinical outcomes. Despite its life-saving capability to reverse early-onset severe toxicity, uridine triacetate may be underutilized. This study aims to evaluate the economic impact of uridine triacetate as a rescue therapy for adult patients from the US hospital payer perspective for early-onset severe toxicity, who are expected to die without treatment. A decision tree model was developed to compare inpatient survival, hospital length of stay, and inpatient healthcare resource utilization for patients treated with and without uridine triacetate. Costs associated with hospitalization, including supportive care measures and monitoring were evaluated, considering medications and procedures commonly used to manage various severe toxicities experienced (e.g., gastrointestinal, hematological, etc.). The model compared the hypothetical current practice, in which approximately half of patients expected to die from early-onset severe toxicity receive uridine triacetate in addition to supportive care, with the proposed future practice in which all eligible patients receive uridine triacetate during their hospital stay. Hypothetical practical scenarios for US institutions were also considered. For each adult patient hospitalized for early-onset severe or life-threatening toxicity who would be expected to die without treatment, adoption of uridine triacetate as a rescue treatment was associated with clinical benefits, including increased inpatient survival (48.5%) and a 7.3-day reduction in total hospital length of stay per patient. Treatment of each additional patient with uridine triacetate was associated with an incremental cost of US$25,247 per patient. Seventy percent of the drug cost was offset by reduction in inpatient healthcare resources utilization. This cost offset is likely underestimated as it does not include additional savings from potential reimbursements associated with changes in hospital length of stay, readmissions and discounting. Hypothetical scenarios demonstrated that model outputs were most sensitive to changes in length of stay and hospitalization costs. Optimal treatment with uridine triacetate for all hospitalized patients in the USA expected to die from early-onset severe toxicity has the potential to improve inpatient survival at a minimal inpatient budget increase. The majority of the drug cost is offset by a reduction in the length of hospital stay and associated costs.

Abstract 4134417: Cardiotoxicity Conundrum: Distinguishing Immune Checkpoint Inhibitor Myocarditis from Fluorouracil Cardiotoxicity in Concurrent Therapy

Case Description: The patient is a 37-year-old male with metastatic gastroesophageal junction adenocarcinoma presenting with chest pain and dyspnea two days after initiation of leucovorin, fluorouracil, oxaliplatin (FOLFOX), and nivolumab therapy. He was tachycardic and hypotensive with elevated cardiac biomarkers and globally reduced left ventricular systolic function. Suspecting immune checkpoint inhibitor (ICI) myocarditis versus fluorouracil (5-FU) cardiotoxicity, he was treated simultaneously for both. After starting high-dose steroids and before uridine triacetate, he had improved symptoms, cardiac function, biomarkers, and invasive hemodynamics. Though his endomyocardial biopsy did not show inflammatory cell infiltrates, his CMR demonstrated increased T1 and T2 relaxation times consistent with myocarditis. Testing revealed normal dihydropyrimidine dehydrogenase (DPD) activity. He completed uridine triacetate and was discharged on a steroid taper. At follow-up, he remained clinically stable, tolerating oxaliplatin and docetaxel (FLOT) initiation and nivolumab rechallenge without 5-FU. Discussion: This case is challenging as the presentation does not conclusively identify a causative agent. The patient’s symptom severity suggests ICI myocarditis, while the early onset points to 5-FU cardiotoxicity. His quick recovery of cardiac function after medication cessation suggests 5-FU-associated Takotsubo cardiomyopathy. His improvement after steroids raises concern for an adverse immunologic response as in ICI myocarditis or idiosyncratic reactions to oxaliplatin with 5-FU. This patient received ICI therapy and chemotherapy, increasing his risk for cardiac immune-related adverse events. His protracted 5-FU infusion increased his risk for 5-FU cardiotoxicity, but his normal DPD activity mitigates this risk. Although his biopsy was negative, it cannot exclude ICI myocarditis. By the IC-OS 2021 consensus, he meets the criteria for ICI myocarditis presenting 48 hours after nivolumab exposure with cardiogenic shock, elevated cardiac biomarkers, decline in cardiac function, and CMR with elevated T1 and T2 relaxation times. Yet, his biomarkers remained normal with nivolumab rechallenge, arguing against ICI myocarditis and suggesting 5-FU as the culprit. Early recognition and differentiation of the culprit in concurrent therapies impact management and future treatment options. Rechallenge carries risk and requires interdisciplinary collaboration to ensure patient safety.

Review of the fluoropyrimidine antidote uridine triacetate.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

Uridine triacetate: the saviour in waiting, finally arrives

Cancer of the gastrointestinal tract is one of the very common solid cancers. Colorectal cancer is one of the types in which the anticancer drug 5-fluorouracil (5-FU) or its prodrug capecitabine is used. Toxicity to 5-FU or capecitabine is a common occurrence in patients receiving it. In such conditions, dose reduction or drug discontinuation for some time was the only way out apart from some supportive measures. An exhaustive search was always on to find a suitable antidote for the toxicity. The molecule uridine triacetate was studied for a long to be used in this condition. A systematic search of the existing literature about uridine triacetate was done with available sources like PubMed, Google Scholar, etc. Information about uridine triacetate was assembled and processed from these sources. Uridine triacetate was given orphan drug status for this indication a few years back. After a clinical trial, the drug was finally approved by the US FDA on December 11, 2015, for use in case of toxicity to 5- 5-FU or capecitabine. Well, stat Therapeutics has been marketing the drug under the trade name of Vistogard. Uridine triacetate works by preventing the toxic metabolite of 5-FU from entering and establishing itself in the RNA framework, by competing with the toxic metabolites. It is a relatively safe drug with minimal side effects. This article discusses the molecule uridine triacetate, its structure, metabolism, and kinetics in the body, the why and how of its action, and finally the results and findings of the clinical trial done with it.

Abstract 14751: A Rare Presentation of 5-Fluorouracil-Induced Cardiotoxicity

Background: 5-fluorouracil (5-FU) is associated with numerous cardiotoxic effects, most commonly chest pain and acute coronary syndrome. Less common effects include arrhythmias, myocarditis, pericarditis, and heart failure. We present a rare case of 5-FU causing cardiogenic shock. Case: A 54-year-old man with metastatic esophageal adenocarcinoma presented at 3:50 with chest pain that began the day before at 16:00, shortly after starting a 5-FU pump. Electrocardiogram (EKG) showed normal sinus rhythm with no ST or T wave changes. High sensitivity troponin T was 18 ng/L, followed by 24 ng/L at 1 hour and 81 ng/L at 6 hours. Computed tomography angiography (CTA) ruled out pulmonary embolism. Transthoracic echocardiogram (TTE) showed a globally reduced left ventricular ejection fraction (LVEF) of 35-40%. The patient received metoprolol and was scheduled for coronary CTA to investigate for coronary disease. Over the next few hours, he continued to report chest pain. Repeat troponin at 18:12 was 235 ng/L. Repeat EKG showed new anterior ST depressions. Posterior EKG did not show ST elevations. Repeat TTE revealed LVEF of 15%. The patient underwent left and right heart catheterization at 21:14, which showed normal coronary arteries, pulmonary artery pressure 50/31 mmHg (mean 38 mmHg), pulmonary capillary wedge pressure 36 mmHg, and cardiac index 1.1 L/min/m 2 . An Impella device was placed for circulatory support. He was treated with vasopressors and milrinone. Given concern for 5-FU toxicity, he received the antidote uridine triacetate 10 g IV every 6 hours for 5 days. LVEF improved to 70%. He was treated with nifedipine for possible coronary vasospasm. He was discharged 8 days later with heart failure medications. Conclusion: 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. Management includes stopping the offending agent and starting anti-anginal drugs and uridine triacetate. Uridine triacetate is deacetylated to uridine, which prevents cell damage and death via competitive inhibition of 5-FU.

Using real-world evidence (RWE) in regulatory decision making: A study of 6 oncology approvals with RWE included in the product label.

6611 Background: The 21st Century Cures Act in 2016 enhanced the FDA’s ability to include the use of real-world data (RWD) and consideration of RWE in the development and approval of new medical products. Currently, limited assessments of the use of RWE in FDA approved oncology product reviews exist in the literature. This study was conducted to determine how RWE was used in FDA decisions for oncology drug approvals between 2015 and 2022. Methods: A systematic review of FDA submission documents and product labels available on the FDA website from 2020 to 2022, in addition to an exhaustive manual search of grey literature and the results of a targeted literature search from 2015 to 2019 were used to identify RWE that were included in FDA submission documents and in approved product labels. Results: In total, 124 oncology product evaluations were reviewed in the 2020 to 2022 literature search. Twenty-nine oncology product NDAs and BLAs included RWE to support efficacy, safety, or indication, of which the majority (n=26) ultimately had RWE accepted as evidence by the FDA for the submission. In these cases, RWE was used to add context (n=16), to support the indication or safety (n=7), to provide substantial basis for indication or safety (n=2), as a statistical comparison (n=2), or for informational purposes only (n=1). Feedback from the FDA reviewers for reasons RWE studies were not considered during product approval reviews included methodology issues, sample size concerns, and omission of patient level data. 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. RWE was used to support the initial indication for the majority of products (n=5) and also supported label expansion (n=1). RWE was incorporated in the product label postmarketing experience section (n=3), the clinical studies section (n=2), and the warnings/precautions section (n=1). Conclusions: 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. These examples show consistent use of RWE since the approval of the 21st Century Cares Act and provide evidence of a promising new direction with the creation of the FDA guideline/program for RWE.

Oral Capecitabine Exposures and Use of Uridine Triacetate: A 20-Year Retrospective Analysis.

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 96h of exposure. This study seeks to characterize accidental and intentional capecitabine exposures and uridine triacetate use, about which little has been published. 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. In total, 81 of 128 reviewed cases were included, with a median age of 63years. 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. 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.

A Detailed Review on Dihydropyrimidine Dehydrogenase Enzyme Deficiency-Autosomal Recessive Condition

Abstract: Dihydropyrimidine dehydrogenase deficiency (DPD) is an autosomal recessive condition. The DPD enzyme is in charge of the 5-fluorouracil drug’s metabolism. Patients having DPD deficiency, when get administered with 5-fluorouracil drug, leads to drug toxicity due to increased concentration of drug in the body. Determining the DPYD (gene encoding DPD) genotyping and DPYD phenotyping will provide the best strategy to know the DPD deficiency in patients. Tegafur and Capecitabine are available prodrugs for the 5-fluorouracil medication. Genomic techniques appear to be a superior indirect evaluation for screening DPD deficiency in the clinical environment. Other than this there are several diagnostic tests such as Uracil oral loading dose, Uracil Breath test, Rapid UPLC-UV (Ultra performance liquid chromatography-Ultravoilet) method, and DPD activity in mononuclear cells from the peripheral circulation. An antidote Uridine Triacetate is available for treating the toxicity produced by 5-FU (5-Fluorouracil) in DPD deficient patient. Hence, this review explains briefly about the DPD enzyme, its deficiency, its diagnosis, and how to manage the DPD deficient patient undergoing chemotherapy. Keywords: DPD, 5-Fluorouracil, Capecitabine, Tegafur, Uracil Breath test, Uridine triacetate.

Case report: Uridine triacetate in the management of delayed onset 5-fluorouracil toxicity: A case report and review of literature

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.

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 (3CLpro) 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 3CLpro 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 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro 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.

HEREDITARY OROTIC ACIDURIA WITH UNUSUAL PRESENTATION- A RARE CASE REPORT

Hereditary orotic aciduria (HOA) is an extremely rare inborn error of pyrimidine metabolism. It results from a defect in the uridine-5-monophosphate synthase (UMPS) gene. It can result in megaloblastic anemia, developmental delay and crystalluria. Molecular genetics is the conrm diagnostic modality. Uridine triacetate is the only established treatment. We thus report a case of 13 month male child having developmental delay with regression, dysmorphic facies, nystagmus, skeletal abnormalities and massive hepatosplenomegaly with past history of repeated LRTI. After clinical evaluation, an impression of storage disorder was presumed. Bicytopenia was also obtained in CBC with high MCV. After detailed evaluation with haematological, bone marrow, TMS and GCMS of urine, a diagnosis of hereditary orotic aciduria was established. Although extremely rare, hereditary orotic aciduria should be suspected in any child with megaloblastic bone marrow, immunodeciency or when developmental delay and anemia coexist

Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine.

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. 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. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G > A, c.1679T > G, c.2846A > T, c.1236G > A and c.557A > G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: 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.

5-FU Cardiotoxicity: Vasospasm, Myocarditis, and Sudden Death.

5-fluorouracil (5-FU) is one of the most common causes of cardiotoxicity associated with chemotherapy. The manifestations of 5-FU cardiotoxicity are diverse, and there are no established clinical guidelines addressing the diagnosis and management of this condition. Here we summarize the mechanistic and clinical data available to guide clinicians in caring for patients with suspected 5-FU cardiotoxicity. The decision to resume 5-FU treatment in patients with suspected cardiovascular toxicity remains challenging. Testing for predisposing genetic variants may be helpful, particularly in patients with other signs of 5-FU toxicity. 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.

Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling

Predicting Drug Interactions with Human Equilibrative Nucleoside Transporters 1 and 2 Using Functional Knockout Cell Lines and Bayesian Modeling

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation

Uridine triacetate - an antidote in the treatment of 5-fluorouracil or capecitabine poisoning

ABSTRACTIntroduction: In 2015, vistogard was approved both the US FDA and the European Medicines Agency (EMA) as an antidote in the treatment of 5-FU poisoning following an overdose of 5-FU or capecitabine or in patients exhibiting early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g. gastrointestinal toxicity and/or neutropenia) within 96 h following the end of 5-FU or capecitabine administration.Areas covered: This paper reviews the history of the development of vistogard (uridine triacetate) to its current status in clinical practice. Vistogard is an orally active prodrug of uridine, which has made a more effective uridine administration technique possible to improve the tolerability of intravenous and oral fluoropyrimidines, including capecitabine. In addition to preclinical data, we also reviewed the data on all the published patients who received vistogard secondary to overdosed 5-FU or capecitabine, or exhibited early onset of severe toxicities.Expert opinion: Vistogard is the first and the only antidote to overdose and early-onset, severe, or life-threatening toxicities from 5-Fluorouracil or capecitabine.

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study.

Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers. The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri-acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri-acyl ester derivatives and l-α-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) - as a mammalian cell membrane model - have been performed by differential scanning calorimetry (DSC). The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri-acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri-myristoyl uridine and tri-stearoyl uridine are different. We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model.

5-Fluorouracil and Capecitabine: Assessment and Treatment of Uncommon Early-Onset Severe Toxicities Associated With Administration.

Uncommon early-onset severe toxicities from 5-fluorouracil (5-FU) and capecitabine can be fatal if early warning signs are not recognized and treated promptly. This article delineates the differences between expected side effects and uncommon early-onset severe toxicities from 5-FU and capecitabine. It also provides background for understanding the reasons patients may develop these toxicities and reviews the efficacy of standard supportive care against a novel therapy (uridine triacetate). A panel of nurses convened to review the literature about toxicities associated with 5-FU and capecitabine administration and determined methods to educate nurses about toxicities and treatment. Standard supportive care for 5-FU and capecitabine toxicities is associated with high fatality rates. Uridine triacetate treatment within 96 hours of administration is associated with survival.

Prompt treatment with uridine triacetate improves survival and reduces toxicity due to fluorouracil and capecitabine overdose or dihydropyrimidine dehydrogenase deficiency

Prompt treatment with uridine triacetate improves survival and reduces toxicity due to fluorouracil and capecitabine overdose or dihydropyrimidine dehydrogenase deficiency

Fluoropyrimidine-induced cardiotoxicity.

Fluoropyrimidine-induced cardiotoxicity.