Folate adverse effects

Drug efficacy is directly related to its intracellular concentration level, so it is necessary to evaluate the MTX concentration in cells. In particular, MTX is a folate antagonist, thus it binds to dihydrofolate reductase in competition with folate [71-77]. A low intracellular level of MTX caused by high efflux and low uptake in resistant cells is also the main disadvantage of MTX medication [78,79]. This leads to a high dosage of MTX for cancer treatment, which is also directly associated with adverse effects. 

Folate play an important role in the biosynthesis of DNA bases and in amino acid metabolism. An adeguate intake of folate reduces the risk of abnormalities in early embryonic brain development, specifically the risk of malformations of the embryonic brain/spinal cord. Therefore a proper intake is strictly recommended for pregnant women. Megaloblastic anemia is the ultimate consequence of an inadequate folate intake. No adverse effects have been associated with the consumption of excess folate from foods [417]. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing hence, dietary supplementation with 1 mg/d folic acid is recommended. 

The difference between the outcome of the Swiss Heart Study and that of FACIT illustrates how difficult it is to explain the results in terms of the biological effects of vitamin therapy. The positive results of the Swiss Heart Study seem to confirm the classical homocysteine hypothesis, which holds that homocysteine is an important atherosclerotic determinant and that lowering of homocysteine with vitamin therapy might reduce the rates of cardiovascular events. However, it is more difficult to explain the results of FACIT by an adverse effect of low plasma homocysteine, and consequently, a less simplistic perspective on the methionine-homocysteine metabolism and the multiple effects of folate, B6, and B 2 is needed. 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

Vitamin Be-Responsive Inborn Errors of MetaboUsm Indices of Vitamin Bg Nutritional Status Reference Intakes of Vitamin Bg Adverse Effects of Hyperhomocysteinemia Indices of Folate and Vitamin B12 Nutritional Status... 

Adverse effects. Any sulphonamide-induced allergic reactions can be severe, e.g. erythema multiforme, Stevens-Johnson syndrome and foxic epidermal necrolysis. Because of its antifoT action the combination should not be used by pregnant women imless they take a folate supplement. 

Adverse effects include CNS symptoms (reversible blurring of vision, diplopia, dizziness and ataxia) and depression of cardiac AV conduction. Alimentary symptoms, skin rashes, blood disorders and liver and kidney dysfunction also occur. Osteomalacia by enhanced metabolism of vitamin D (enzyme induction) occurs over years so also does folate deficiency. Enzyme induction reduces the efficacy of combined and progestogen-only contraceptives. Carbamazepine impairs cognitive function less than phenytoin. 

Crossover studies have shown that mesalazine has about a 10-fold lower potential than sulfasalazine for inducing allergic reactions or causing intolerance. Adverse effects with all aminosalicylates include (generally more frequent with sulfasalazine) headache, nausea, abdominal pain, dyspepsia, fatigue, rash, fever, rarely exacerbation of the disease, pancreatitis, pericarditis, pneumonitis, liver disease, nephritis, and bone marrow depression. Watery diarrhea is an adverse effect unique to olsalazine, while anorexia, folate malabsorption, hemolysis, neutropenia, agranulocytosis, male infertility, and neuropathy are unique to sulfasalazine. 

There has been some discussion as to whether an adverse effect of folic acid on seizures represents a direct epileptogenic effect or results from interference with the effects of anticonvulsants. Initially, it was supposed that foUc acid provokes seizures, and the first report of an epileptic patient with megaloblastic anemia in whom folate therapy resulted in an exacerbation of seizures was published in 1960. Although several subsequent controlled studies failed to show any adverse effect on seizure frequency linked to folic acid supplementation, case reports and uncontrolled studies have documented worsening seizure frequency in some patients given folic acid, but the susceptibility factors at play have not been identified. 

Reduced folates are co-factors for the 5-fluorodeoxy-uridine monophosphate-thymidilate synthetase reaction. Leucovorin (calcium fohnate) therefore potentiates the toxicity of 5-fluorouracil, and fatal adverse effects have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. This has led some groups to recommend that initial dose levels of fluorouracil should be lowered by 20% and that therapy be stopped temporarily at the first sign of distal gastrointestinal adverse effects (SEDA-15, 414). 

In one study, 10 patients (of an original 29) were stiU taking methotrexate after a mean of 13 years and a mean cumulative dose of 9.7 g (4). The overall drug withdrawal rate was 48%, and the rate of adverse effects, particularly on the gut and central nervous system, fell with time (85% at basehne, 90% at 90 months, 62% at 160 months). It was felt that routine folate supplementation might have contributed to the observed reduction in toxicity, except for mouth ulcers or soreness. Very similar findings were found in another long-term (132 months) prospective study (5). 

Raised methotrexate serum concentrations (over 100 nmol/1 at 36-42 hours after ingestion) are expected to increase the likelihood of several adverse effects, that is, gastrointestinal and hematological effects, but similar adverse effects can be found even with low methotrexate serum concentrations. Reduced red cell folate concentrations during methotrexate treatment also related to adverse effects and rises in liver enzjmes, and red cell folate concentrations above 800 nmol/1 protected against common adverse effects and treatment withdrawal (6). Several investigators now advocate the concomitant use of folic acid (5-7 mg/week and up to 27.5 mg/week) to reduce some of methotrexate-associated adverse effects without reducing its efficacy (7). 

In a meta-analysis of 307 patients with rheumatoid arthritis from seven randomized clinical trials, of whom 147 took folate supplementation, hematological adverse effects were not significantly reduced in the folate group (8). However, there was a 79% reduction in mucosal and gastrointestinal adverse effects in patients taking folic acid and a non-significant trend toward a reduction (42%) in patients taking folinic acid. Disease activity was not modified by low doses of folate. Finally, the authors noted that folinic acid is more expensive. 

One of the biochemical adverse effects of nitric oxide is inactivation of vitamin B12, with subsequent potentiation of folate deficiency (19). This effect is mediated by irreversible oxidation of the cobalt residue in vitamin B12 to its Co++ and Co forms. This leads to a reduction in methionine synthetase activity, with downstream effects on DNA synthesis. Previous studies have identified five patients with unsuspected vitamin B12 deficiency who developed subacute combined degeneration of the spinal cord following inhalation anesthesia with nitrous oxide... 

Sulfonamides have adverse effects on all bone marrow-derived cell lines. The resulting disturbances include hemolytic anemia, folate deficiency anemia, neutropenia, thrombocytopenia, and pancytopenia. While adverse effects on erythrocytes are rare, the rates of leukopenia, neutropenia, and thrombocytopenia are highly variable. In a hospital drug monitoring program, leukopenia or neutropenia occurred in 0.4% of 1809 patients treated with co-trimox-azole (54), and thrombocytopenia of mild-to-moderate degree in 0.1% (54,55), similar to figures recorded in other studies (56,57). Pancytopenia is an extremely rare form of adverse reaction to sulfonamides (58). 

Most hematological adverse effects associated with trimethoprim have been reported with co-trimoxazole. These include macrocytic and megaloblastic anemia, aplastic anemia, neutropenia, hypersegmentation of leukocytes, thrombocytopenia, and pancytopenia (12,61-63,75-79). Sulfonamides alone have not been associated with folate deficiency, but in combination with trimethoprim they can deplete folate stores in patients with preexisting deficiency of folate or vitamin B12 (80). Treatment with co-trimoxazole can impair the function of mobilized autologous peripheral blood stem cells (81). 

Most patients who require dialysis have a normocytic normochronic anemia and a hypoproliferative bone marrow. As erythropoiesis decreases with advancing renal disease, iron shifts from circulating red cells to the reticuloendothelial system, leading to high serum ferritin levels. Repeated blood transfusion is also a common cause of iron overload and hyperferritinemia. Clearly the most important cause of the anemia of chronic renal failure is decreased erythropoietin production by the kidneys uremic patients have much lower plasma erythropoietin levels than comparably anemic patients with normal renal function (E8). Less important causes are shortened red cell survival, iron or folate deficiency, aluminum intoxication, and osteitis fibrosa cystica (E8). Uremic retention products such as methylguanidine (G10) and spermidine (R2) may also have an adverse effect on erythropoiesis. 

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