Effect Of Folinic Acid Research Articles

The effects of folinic acid and l-methylfolate supplementation on serum total homocysteine levels in healthy adults

Hyperhomocysteinemia is recognized as a risk factor for several diseases and conditions. The aim of this study was to investigate and compare the efficacy of two total homocysteine (tHcy)-lowering treatments including folinic acid or l-methylfolate in healthy Greek adults. Two hundred and seventy-two healthy Greek adults (143 men, 129 women; mean age±SD: 43.0±15.3 years), with serum tHcy levels ≥10μmol/L received randomized folinic acid ("Folinic acid Group") or l-methylfolate ("l-methylfolate Group") orally for three months. All subjects with serum cobalamin (Cbl) levels <300pg/mL additionally received 1mg hydroxycobalamine intramuscularly twice a week for the first month only. Serum folate, Cbl and tHcy levels were determined using immunoassays methods at the beginning and the end of the study period. The MTHFR C677T and MTHFR A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. At the end of the 3-month intervention period, the levels of serum folate and Cbl increased significantly, whereas the levels of serum tHcy decreased significantly in the two groups. The individuals with MTHFR 677TT genotype had a significantly higher reduction in serum tHcy levels than the individuals with the MTHFR 677CC or MTHFR 677CT genotypes. Although the "Folinic acid Group" had a considerably higher increase in their serum folate levels (but not Cbl) than the "l-methylfolate Group", the reduction of serum tHcy levels between the two groups was not substantially different. The individuals with MTHFR 677CT genotype had a statistically significant higher reduction in serum tHcy levels when supplemented with folinic acid rather than l-methylfolate. The administration of folinic acid compared to l-methylfolate caused a higher increase of serum folate levels but no difference in the reduction of serum tHcy levels. The reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not MTHFR A1298C gene polymorphisms. The individuals with MTHFR 677CT genotype appear to benefit more by folinic acid than l-methylfolate supplementation.

Effect of folinic acid on serum homocysteine, TNFα, IL-10, and HMGB1 gene expression in head injury model

BackgroundHead injury or traumatic brain injury is the leading cause of mortality and morbidity. Many modalities of neuroprotection had been developed in brain injury but there was no much information regarding folinic acid's effect on neuroinflammation associated with homocysteine, TNFα, IL-10, and HMGB1. ObjectiveThis study aimed to investigate whether folinic acid has improving effect on head injury model. MethodThis study was done in the rat's head injury model using modified Marmarou weight drop model. Fifteen rats were randomized and grouped into 3 groups: Group A: Folinic acid (+), head injury (−); Group B: Folinic acid (−), head injury (+); Group C: Folinic acid (+), head injury (+). Folinic acid was administered intraperitoneally with a dose of 60 mg/m2. Blood samples were taken immediately after head injury (H0), 12 h (H12), and 24 h (H24) after head injury from the lateral vein of tail. Serum level of homocysteine, TNFα, and IL-10 were measured using ELISA, and HMGB1 gene expression was measured with Real-Time RT-PCR. ResultsThis study found serum level of homocysteine, TNFα, IL-10 and HMGB1 gene expression were markedly increased at all time points after head injury. Significantly lower level of serum homocysteine, TNFα, IL-10 and HMGB1 gene expression were found after 24 h treatment with folinic acid in group C compared to those in group B. ConclusionFolinic acid may have anti-inflammatory properties in traumatic brain injury by inhibition of serum level of homocysteine, TNFα, IL-10 and HMGB1 gene expression.

The Effect of Folinic Acid (FA) Rescue Following MTX Gvhd Prophylaxis on Regimen Related Toxicity and Transplantation Outcome: A Double Blind Randomized Controlled Study

<h3>Background</h3> The use of MTX for GVHD prophylaxis is associated with increased rates of oral mucositis (OM), delayed engraftment, hepatotoxicity and nephrotoxicity. Based on limited data, the EBMT and ELN working group recommend the use of FA-rescue to reduce MTX toxicity after alloHCT. We aimed to determine whether FA-rescue reduces the rate of MTX-induced toxicity in patients who receive post-transplant MTX for GVHD prophylaxis. <h3>Methods</h3> This is a double blind RCT conducted in 3 centers. We enrolled patients undergoing alloHCT from MSD or MUDs with a MAC regimen and PBSC grafts, and GVHD prophylaxis consisting CSA/MTX, plus ATG for MUDs. Patients were randomized to oral FA or placebo, stratified by center and conditioning intensity (standard <i>vs.</i> reduced toxicity MAC). FA administration started 24h after each MTX dose: 15 mg TID after MTX administration on day +1 and QID after MTX administration on days +3 and +6. The primary endpoint was the rate of grade 3-4 OM according to the WHO scale. A sample size of 58 subjects in each group was estimated to detect a difference in grade 3-4 OM of 50% <i>vs.</i> 25%. <h3>Results</h3> From 2/2016 through 7/2019, 52 patients with acute leukemia in CR (n = 45), MDS (n=6) or NHL in CR (n=1) were randomized to FA (n=28) or placebo (n=24). Patient characteristics were similar between groups (table). After enrolment of 52 patients, interim analysis revealed that the rate (46.6% <i>vs.</i> 45.8%, P=0.97) and duration (4 <i>vs.</i> 4 days) of grade 3-4 OM and the rate of OM of any severity (83.3% <i>vs.</i> 77.8%, P=0.65) were similar in both groups. Also, time to neutrophil and platelet engraftment, rates of febrile neutropenia and blood stream infections, VOD, need for opiates or TPN and time from HCT to discharge were not significantly different between groups. With a median follow-up of 9 months we did not observe any difference in rates of acute or chronic GVHD, DFS and OS. <h3>Conclusions</h3> The interim results, showing similar rates of grade 3-4 OM and secondary outcomes, do not support continuation of the study. FA-rescue following MTX GVHD prophylaxis does not seem to decrease regimen related toxicity and affect transplant outcomes.

Folinic acid after MTX as prophylaxis for GVHD in pediatric bone marrow transplantation.

The effect of folinic acid (FA) on toxicity secondary to the use of methotrexate (MTX) for the prevention of graft-versus-host disease (GVHD) has not been determined. We retrospectively analyzed data from 111 patients who received allogeneic bone marrow transplantation (allo-BMT) in our institution. Fifty patients did not receive FA (non-FA), 37 received FA four times (low dose, LD-FA), and 24 received FA 25 times (high dose, HD-FA) in BMT. No significant differences were observed in the severity of stomatitis after allo-BMT among the three groups while the median of peak value of ALT in HD-FA was significantly lower (P = 0.031). The median time to neutrophil engraftment after allo-BMT in the HD-FA group was significantly shorter than that in the non-FA group (P = 0.034). No significant difference in the median time to neutrophil engraftment was observed between the LD-FA and non-FA groups (P = 0.44). Stepwise multiple regression analysis revealed that the determinants of the shorter duration of neutropenia were transfused total nucleated cell dose (P = 0.001) and the administration of HD-FA (P = 0.036). There was no significant difference in 3-year overall survival among the three groups. Frequent administration of FA may reduce the time to neutrophil engraftment after hematopoietic stem cell transplantation.

Novel effects of folinic acid and folate supplementation on locomotor development in embryonic Zebrafish, Danio rerio

Novel effects of folinic acid and folate supplementation on locomotor development in embryonic Zebrafish, Danio rerio

Effects of folinic acid and Vitamin B 12 on ethanol-induced developmental toxicity in mouse

The objective of this study was to assess whether combined supplementation of folinic acid (FA) and Vitamin B 12 (VB 12) could suppress ethanol-induced developmental toxicity better than FA alone in mouse embryos cultured in vitro. In this study, exposure to 4.0 mg/ml ethanol for 48 h yielded growth retardation and various malformations of the embryos. FA (10 −5, 10 −4 mol/l) or VB 12 (10 −6, 10 −5 mol/l) alone supplementation improved the growth parameters moderately, however combined supplementation of the two vitamins (10 −5 mol/l FA plus 10 −6 mol/l VB 12, 10 −5 mol/l FA plus 10 −5 mol/l VB 12, 10 −4 mol/l FA plus 10 −6 mol/l VB 12 and 10 −4 mol/l FA plus 10 −5 mol/l VB 12) showed better protective effects, including both the growth and development parameters of the embryos, than either vitamin alone at the same dosage. The present investigation indicated that combined supplementation of folic acid and VB 12 might be a better choice than folic acid alone in the prevention of ethanol-induced birth defects.

Effects of folinic acid on forearm blood flow in patients with end-stage renal disease

Abnormalities of endothelial function are likely to contribute to the accelerated atherosclerotic risk in subjects with end-stage renal disease (ESRD). While folates can improve endothelial function, their role in ESRD has not been fully studied. The objective was to determine the acute and 12 week-effect of folinic acid on endothelium-dependent vasodilation in subjects with ESRD. Forearm blood flow (FBF) was assessed by strain gauge plethysmography at baseline and after 12 weeks in 34 ESRD patients (57 +/- 14 years). Vascular function was assessed with acetylcholine (ACh), and sodium nitroprusside (SNP). Patients were randomized to receive folinic acid (50 mg i.v. once weekly) or a matching placebo. A subset of 25 subjects also received folinic acid (500 microg/min intra-arterially) or placebo to determine the acute effect on ACh and SNP mediated dilation at the time of the baseline vascular study. Folinic acid acutely improved the maximum change in ACh mediated FBF (10.0 +/- 2.4 to 12.8 +/- 2.2 ml/min/100 ml, P = 0.017), but did not change SNP responses. Chronic active therapy did not change ACh or SNP-mediated increases in FBF. Folinic acid resulted in a non-significant decrease in homocysteine (21 +/- 6 vs 28 +/- 18 micromol/l, P = 0.16) and diastolic blood pressure was significantly reduced (P = 0.05). The present study demonstrated that folinic acid acutely improved endothelium-dependent vasodilatation in patients with ESRD suggesting a direct vascular effect. Chronic treatment with folinic acid did not show benefit in endothelial function, but did lower diastolic blood pressure. Further work is required to determine the optimal regime to protect vascular health in subjects with ESRD.

Biomodulation of 5-Fu cytotoxicity by folinic acid and its stereoisomers: in vitro experiments with different cell lines of prostatic cancer.

The results of cytotoxic chemotherapy for advanced, hormone-escaped prostate cancer have been disappointing. Evaluation of the effect of new drugs or new combinations with already known ones is required. The antimetabolite 5-fluorouracil (5-FU) has been shown to be active in prostate cancer, acting via inhibition of thymidylate synthase, an essential enzyme in DNA de novo synthesis. Experiments with cell lines of different tumors have shown that 5-FU activity can be modulated by addition of the coenzyme tetrahydrofolic acid (folinic acid). We investigated the effect of folinic acid and its stereoisomers on 5-FU action in different cell lines of prostate cancer. It was found that addition of non-toxic folinic acid led to a two- to fourfold better antiproliferative effect of 5-FU. The unnatural 6R isomer, which is a compound of chemically synthesized folinic acid, inhibited the modulatory effect of the natural 6S isomer. Our results indicated that a combination of folinic acid and 5-FU may result in a better response of patients with hormone-resistant prostate cancer than of patients treated with 5-FU alone.

Folinic Acid Protection Against Hematopoietic Depression Induced by Nitrous Oxide in Rats

We studied the degree of hematopoietic depression and spontaneous recovery of depressed hematopoietic cells with 50% nitrous oxide-oxygen inhalation for 6 or 12 h in 120 Sprague-Dawley rats. Bone marrow and blood were sampled serially immediately after, 1 day, 3 days, and 1 wk following nitrous oxide inhalation. After 1 wk of culturing of hematopoietic stem cells, the number of the colony-forming units of granulocytes and monocytes and the colony-forming units of T lymphocytes grown from bone marrow and blood were counted. There was no change in the number of colonies immediately after inhalation compared with the control group, but there was a significant decrease in the number of colonies 1 and 3 days after inhalation (P < 0.001), and 1 wk after inhalation, there was spontaneous recovery without any treatment. Nitrous oxide may depress the early phase of differentiation of hematopoietic stem cells such as granulocytes, monocytes, and lymphocytes as well as erythrocytes. Also, the degree of suppression was more intense after 12 h than after 6 h of inhalation. That is, the length of inhalation time corresponds to the intensity and rapidity of suppression. To evaluate the protective effect of folinic acid against hematopoietic depression, folinic acid (0.1 mg/0.3 mL) was injected intraperitoneally before or after nitrous oxide inhalation. The groups injected with folinic acid showed significant increase in the number of colonies, especially in the group receiving folinic acid 12 h and 1 h before nitrous oxide inhalation (P < 0.001). Pretreatment with folinic acid may prevent the hematopoietic depression caused by the prolonged and repeated use of nitrous oxide.

Effects of folinic acid on 5-fluorouracil induced cell lethality with or without cisplatin against head and neck laryngeal squamous carcinoma multicellular tumor spheroids.

We evaluated the efficacy of folinic acid (Leucovorin, LV) on cell lethality induced by 5-fluorouracil (FU) alone or in combination with cisplatin (DDP) by using the HEp-2 laryngeal squamous carcinoma multicellular tumor spheroids (MTS) system. For LV, non-toxic concentration of 10(-5) M was used. For cells in the monolayer, 6 and 24 h exposure to LV increased FU-induced cell lethality approximately 7- and 2-fold, respectively, whereas LV did not influence the effect of FU for MTS. LV's lack of effect on cells in MTS may be interpreted to mean that LV cannot penetrate the MTS. For the monolayer, simultaneous exposure to 3 drugs, DDP, FU and LV, produced synergistic interaction. However, sequential exposures were marginally synergistic or antagonistic, irrespective of sequence of DDP first or last. In contrast, DDP followed by FU plus LV was most synergistic for MTS. Simultaneous exposure was also synergistic, however, FU plus LV followed by DDP was antagonistic. These results suggest that LV is unable to penetrate into the MTS core to potentiate FU activity. DDP appears to have enhanced LV penetration into the MTS core. The exploration of means to overcome limited penetration of LV appears important for successful treatment of head and neck carcinoma.

Effect of folinic acid on the capacity of trimethoprim-sulfamethoxazole to prevent and treat Pneumocystis carinii pneumonia in rats.

Daily administration of 1 mg of folinic acid to immunosuppressed rats with incipient or established Pneumocystis carinii pneumonia did not impair the capacity of trimethoprim-sulfamethoxazole to either prevent or treat this disease. These observations constitute the first experimental support for the use of folinic acid to prevent or control cytopenias that occur in patients with Pneumocystis carinii pneumonia who are under trimethoprim-sulfamethoxazole treatment.

Comparative Bioautography of Folic and Folinic Acids of Erythrocytes and Livers of Normal Ducks and Ducks Infected with Malarial Parasites

Since the erythrocytes of ducks infected with P. lophurae contain much more folic and folinic acid than those of uninfected ducks, the Rf values of these growth factors in infected and uninfected red blood cells were compared. Paper chromatography followed by bioautography was used to determine the number of components supporting growth of L. casei and P. cerevisiae. Both normal and infected erythrocytes gave identical bioautographs having two components: (1) with Rf 0.5 active only for L. casei and (2) with Rf 0.7 active both for L. casei and P. cerevisiae. This finding fits the hypothesis that the increased levels of folic and folinic acids result from an altered metabolism of the host red cell rather than from synthesis by the parasites. Livers of infected ducks had less L. casei-active material than those of normal ones, but both showed identical bioautographs. The importance of folic acid and related compounds in the metabolism of malarial parasites is indicated by several facts: (1) the favorable effect of folinic acid on Plasmodium lophurae maintained extracellularly in vitro (Trager, 1958), (2) the favoring effect of para-aminobenzoic acid (Geiman, Anfinsen, McKee, Ormsbee, and Ball, 1946) and folic acid (Glenn and Manwell, 1956) on the development of malarial parasites growing intracellularly in suspensions of intact erythrocytes in vitro, and (3) the powerful antimalarial effect of substances such as pyrimethamine, which seems to act by interfering with the formation of folinic acid (Rollo, 1955; Trager, 1961). Trager (1959) found 20to 50-fold increase in folic acid and 5to 20-fold increase in folinic acid in erythrocytes of 2-month-old ducks infected with P. lophurae. He further found that only one-fifth to one-third of the increased amounts of the two growth factors were within the parasites; the remainder presumably was in the cytoplasm of the infected erythrocytes. It therefore seemed possible that the increased folic and folinic acid were formed Received for publication 10 July 1964. * Supported by Public Health Service Grant 5-T1AI-192. by the host red cells rather than by the parasites themselves. It was of interest to compare the Rf values of these two growth factors from erythrocytes and livers of normal ducks with those from the corresponding tissues of ducks infected with P. lophurae. MATERIALS AND METHODS Two-week-old ducklings were inoculated with P. lophurae in such a way as to give severe and highly synchronous infections (Trager, 1958). On the 5th day of infection blood was taken from infected birds and from corresponding uninfected ones. The red cells were washed, hemolyzed, and incubated 90 min in a diluted buffer with ascorbic acid (Toennies, Bueding, and Phillips, 1956). The hemolysates were deproteinized by autoclaving 1.5 min at 121 C, followed by centrifugation. Extracts from livers of infected and control animals were produced by grinding weighed portions in the buffer-ascorbic acid solutions and were then treated in the same way as hemolysates. The folic and folinic acid contents were determined by microbial assay with L. casei and P. cerevisiae, respectively (Toennies, Frank, and Gallant, 1953). Bioautographic assay Paper chromatography followed by bioautographic visualization of active compounds was used to determine the Rf of the components in liver and red cells which would support the growth of L. casei and P. cerevisiae. The methods used were essentially those of Colon and Moulder (1958) and Sirotnak and co-workers (1963).

The hematologic effect of folinic acid (citrovorum factor) in persons with pernicious anemia.

The hematologic effect of folinic acid (citrovorum factor) in persons with pernicious anemia.