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Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced 'PANIC' attack.
Frohman, EM, Villemarette-Pittman, NR, Cruz, RA, Longmuir, R, Rowe, V, Rowe, ES, Varkey, TC, Steinman, L, Zamvil, SS, Frohman, TC
Journal of the neurological sciences. 2020;:116935
Abstract
Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.
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Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
Burda, P, Kuster, A, Hjalmarson, O, Suormala, T, Bürer, C, Lutz, S, Roussey, G, Christa, L, Asin-Cayuela, J, Kollberg, G, et al
Journal of inherited metabolic disease. 2015;(5):863-72
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Abstract
In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
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Neonatal vitamin-responsive epileptic encephalopathies.
Gospe, SM
Chang Gung medical journal. 2010;(1):1-12
Abstract
The treatment of neonatal seizures generally relies on the use of one or more anticonvulsant medications along with evaluation and management of any underlying etiology. In some circumstances, neonatal seizures are refractory to therapy and result in poor outcomes, including death. Certain rare vitamin- responsive inborn errors of metabolism may present as neonatal encephalopathy with anticonvulsant-resistant seizures. Therefore, it is vital for the clinicians of caring for seizing encephalopathic newborns to consider these particular disorders early in the hospital course. Pyridoxine-dependent seizures are due to deficiency of alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) which is encoded by ALDH7A1. Seizures in infants who are pyridoxine-dependent must be treated using pharmacologic doses of pyridoxine (vitamin B(6)), and life-long therapy is required. Despite medical therapy, developmental handicaps, particularly in expressive language, are common. Folinic acidresponsive seizures are treated with supplements of folinic acid (5-formyltetrahydrofolate). Recently, patients with this condition were also demonstrated to be antiquitin deficient. Pyridoxal phosphate-dependent seizures result from a deficiency of pyridox(am)ine 5'-phosphate oxidase which is encoded by PNPO. Patients with this cause of seizures respond to pyridoxal phosphate but not to pyridoxine. This review discusses our current understanding of these three neonatal vitamin-responsive epileptic encephalopathies and a diagnostic and treatment protocol is proposed.
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FOLFOX versus FOLFIRI: a comparison of regimens in the treatment of colorectal cancer metastases.
Pasetto, LM, Jirillo, A, Iadicicco, G, Rossi, E, Paris, MK, Monfardini, S
Anticancer research. 2005;(1B):563-76
Abstract
Colorectal adenocarcinoma ranks second as a cause of death due to cancer in the Western world. Already at the time of the primary tumor, 15-25% of the patients present with liver metastases while another 20% will develop metastasis following treatment of the colorectal primary. Without any treatment the median survival after the detection of metastases is approximately 9 months, depending on the extent of the disease at the time of diagnosis. Clinical trials with the "FOLFOX and FOLFIRI families" of drugs, designed for the treatment of metastatic colorectal cancer, their results and the costs of each therapy are examined. For each drug, the cost/mg, the cost/mg/m2 and the cost/therapy (according to its duration) are evaluated according to the prices reported in the Italian Directory of Medicines and Manufacturers, 63rd Edition, November 2003.
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Phase II study of leucovorin, 5-fluorouracil and gemcitabine for locally advanced and metastatic pancreatic cancer (FOLFUGEM 2).
André, T, Noirclerc, M, Hammel, P, Meckenstock, R, Landi, B, Cattan, S, Selle, F, Codoul, JF, Guerrier-Parmentier, B, Mokhtar, R, et al
Gastroenterologie clinique et biologique. 2004;(8-9):645-50
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Abstract
AIM: FOLFUGEM 1 (leucovorin 400 mg/m2 combined with 5-flurorouracil (FU) bolus 400 mg/m2 then 5-FU 2-3 g/m2/46 hours and gemcitabine 1000 mg/m2 in 30 min) in patients with locally-advanced and metastatic pancreatic adenocarcinoma appeared to be toxic (neutropenia and alopecia). The aims of this phase II multicentric study were to evaluate the response rate, clinical benefit and tolerance of a new scheme of combined leucovorin, 5-FU and gemcitabine (FOLFUGEM 2). PATIENTS AND METHODS FOLFUGEM 2 associated leucovorin 400 mg/m2 in 2 hours followed by 5-FU 1000 mg/m2 in 22 hours, then gemcitabine 800 mg/m2 (10 mg/m2/min) with cycles every 14 days. Gemcitabine dose could be increased (1000 then 1250 mg/m2) when NCI/CTC toxicity was < or = grade 2. RESULTS Fifty-eight patients were included (locally-advanced tumor: N = 13 and metastatic: N = 45). Among the 39 patients with measurable disease, 11 had partial response (28.2%, 95% confidence interval: 14-42%) and 11 had stable disease (28.2%). On an intent-to-treat analysis, the objective response rate was 19% (95% confidence interval: 9-29%). Clinical benefit rate was 46%. Median progression-free survival and median overall survival were 3.1 and 7.2 months, respectively. There were 13% grade 3-4 neutropenia and 36% complete alopecia. CONCLUSION FOLFUGEM 2 schema has an antitumoral effect in advanced pancreatic cancer and has an acceptable toxicity which appears to be less than that of FOLFUGEM 1.
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UFT plus oral leucovorin calcium (Orzel) and radiation in combined modality therapy: a comprehensive review.
Minsky, BD
International journal of cancer. 2001;(1):1-10
Abstract
5-fluorouracil (5-FU) has become the most commonly used drug in combination with radiation therapy. The recent availability of oral formulations of 5-FU in conjunction with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. UFT (uracil:tegafur) plus oral leucovorin (Orzel) is the first oral DPD-inhibitory fluoropyrimidine. With daily administration, Orzel achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper summarizes the therapeutic rationale for Orzel and reviews the clinical experience with UFT and UFT/LV in combined modality therapy regimens.
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Second-line therapy in colorectal cancer.
Berlin, J
Oncology (Williston Park, N.Y.). 2000;(12 Suppl 11):21-6
Abstract
Second-line therapy is a relatively new concept for gastrointestinal oncologists. Although retreatment with fluorouracil (5-FU) is common, offering colorectal cancer patients a different chemotherapeutic agent as second-line therapy is a fairly recent strategy. The focus of this article is on the use and efficacy of oxaliplatin (Eloxatin) as second-line therapy for colorectal cancer. As such, this article will present very limited data on the toxicity of oxaliplatin regimens.