Folic acid treatment

Nitrofurantoin prodnces oxidant stress and cellnlar damage by different mechanisms (43). It can distnrb folate metabolism, leading to a megaloblastic component in pre-existing (mostly hemolytic) anemia, which responds to folic acid treatment. 

B. Leucovorin (N -formyl THF, folinic acid) is used as an antidote for cells that have decreased levels of folic acid. Treatment of leukemia patients with methotrexate kills the tumor cells but also other normal rapidly dividing cells. N -formyl THF is normally administered 24 hours following treatment with methotrexate it can be converted to THF by these normal cells by bypassing the block caused by methotrexate. Therefore, these normal cells can synthesize deoxythymidine and carry out DNA synthesis. 

Zhao, Q., Behringer, R.R., Decrombrugghe, B. 1996. Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cartl homeobox gene. Nat. Genet. 13, 275-283. 

Catalytic reduction of folic acid to 5,6,7,8-tetrahydrofolic acid (225) proceeds fast in trifluoroacetic acid (66HCA875), but a modified method using chemical reductants leads with sodium dithionite to 7,8-dihydrofolic acid (224). Further treatment with sodium borohydride gives (225) which has been converted into 5-formyl-(6i ,S)-5,6,7,8-tetrahydro-L-folic acid (leucovorin) (226) by reaction with methyl formate (equation 70) (80HCA2554). 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

Bile acid sequestrants may interfere with die digestion of fats and prevent die absorption of die fat-soluble vitamins (vitamins A, D, E, and K) and folic acid. When die bile acid sequestrants are used for long-term therapy, vitamins A and D may be given in a water-soluble form or administered parenterally. If bleedingtendencies occur as die result of vitamin K deficiency, parenteral vitamin K is administered for immediate treatment, and oral vitamin K is given for prevention of a deficiency in the futum... 

The anemias discussed in this chapter include iron deficiency anemia, anemia in patients witii chronic renal disease pernicious anemia, and anemia resulting from a folic acid deficiency. Table 45-1 defines these anemias. Drugp used in treatment of anemia are summarized in die Summary Drug Table Drugp Used in die Treatment of Anemia. 

The underlying cause of anemia (e.g., blood loss iron, folic acid, or vitamin B12 deficiency or chronic disease) must be determined and used to guide therapy. As discussed previously, patients should be evaluated initially based on laboratory parameters to determine the etiology of the anemia (see Fig. 63-3). Subsequently, the appropriate pharmacologic treatment should be initiated based on the cause of anemia. 

Pemetrexed Pemetrexed 500 mg/m2 (day 1), vitamin B12 1 mg IM 1-2 weeks before treatment initiation and every 9 weeks thereafter, folic acid 1 mg daily beginning 3 weeks before treatment initiation 21 days 5-6%... 

Folic acid and its metabolites called folates are essential to the cell s functions. They act as coenzymes in many biochemical processes. Folate-dependent enzymes are vital to rapidly dividing cell populations, such as the neoplastic or normal-stem cells. Therefore, they are a target for anti-folates in anti-cancer treatment. 

Some effects of irradiation on vitamins have been mentioned earlier. It appears that irradiation and heat treatment affect vitamins differendy. Apparendy, vitamins Br B6, B12 and folic acid decompose less under as high a radiation dose as 60 kGy than under autoclaving at 120°Cfor 20 minutes. On the other hand, vitamin C is much more sensitive to irradiation. Generally, the radiosensitive vitamins are also sensitive to light, heat, and oxygen. In fresh foods, the vitamins that are most susceptible to irradiation are A and E. There is also some decomposition of vitamins B, and C. Other vitamins are fairly stable under irradiation. However, for the most part, the vitamins are more susecptible to heat treatment than to irradiation. 

After the milling process, any gaseous treatments are applied, any powder treatments, e.g. ascorbic acid, are added, as well as any fortifying ingredients such as calcium sulfate. Different countries have various policies on fortifying flour. In the UK, white flour is fortified with calcium to make up for the calcium lost by not making a wholemeal flour. In the USA, bread is fortified with folic acid. It is possible for an untreated flour to be mixed with a flour improver containing the powder treatments. 

Patients sustain convulsions and neurological deterioration. The urine contains low levels of the metabolites of serotonin, norepinephrine and dopamine. The reductase also plays a role in the maintenance of tetrahydrofolate levels in brain, and some patients have had low folate levels in the serum and CNS. Treatment has been attempted with tryptophan and carbidopa to improve serotonin homeostasis and with folinic acid to replete diminished stores of reduced folic acid. This therapy is sometimes effective. Diagnosis involves assay of DHPR in skin fibroblasts or amniotic cells. Phenylalanine hydroxylase activity is normal. 

Prognosis is more favorable in the pyridoxine-respon-sive patients. Patients who respond to large doses of vitamin B6 (250-500 mg/day for several weeks) have the best prognosis. Efficacy of treatment usually is reflected in a reduction of blood homocystine and methionine to normal or near-normal levels. Since supplementation with pyridoxine can cause a deficiency of folic acid, the latter should be given (2-5 mg daily) at the same time. Any patient receiving pyridoxine should be monitored carefully for any signs of hepatotoxicity and for a peripheral neuropathy (see Ch. 36). 

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

The chemistry, metabolism, and clinical importance of folic acid have been the subject of many excellent reviews (A7, Gil, H14, H20, Rl). Folic acid deficiency leads to a macrocytic anemia and leucopenia. These symptoms are due to inadequate synthesis of nucleic acid. The synthesis of purine bases and of thymine, required for nucleic acid synthesis, is impaired in folic acid deficiency. Detection of folic acid activity in biologic fluids and tissues is of the utmost importance it distinguishes between the various anemias, e.g., those due to vitamin Bi2 or folic acid deficiency. Because morphology of the abnormal red cell does not help in diagnosing vitamin deficiency, one must rely on assay methods for differential diagnosis. Treatment of pernicious anemia with folic acid has led to subacute combined degeneration of the spinal cord despite... 

Nutrient supplementation during alcohol detoxification includes thiamine, magnesium sulfate, folic acid, and a multivitamin. During the rehabilitation and continuing care stages of treatment for alcohol dependence, nutrient supplementation includes thiamine and a multivitamin. 

The healthy small intestine contains only a small bacterial population, unlike the colon. However, an acute infection of the mucosa by a virus, bacterium or other parasite can reduce its motility, allowing a huge proliferation of the resident bacteria. Absorption of both macro- and micronutrients is impaired, resulting in the disorder known as sprue. Folic acid is particularly poorly absorbed, causing reduced rates of repair of mucosal cells. Hence, the damage persists and worsens to create a vicious circle. Treatment involves administration of an antibiotic to kill the bacteria and folic acid to allow damaged tissue to recover. The clinical presentation includes bulky stools, steatorrhoea (fatty faeces) and weight loss. 

Johnson and colleagues made a provocative observation in the course of exploratory preclinical toxicological studies of vincristine, namely, that folinic acid (Leucovorin citrovorum factor 5-formyl-5,6,7,8-tetrahy-drofolic acid) was able to protect mice from the toxicity of high doses of vincristine lb). Vincristine, at a dose of 2.5 mg/kg administered intravenously, resulted in a mortality of 90% over a period of 30 days, but treatment with folinic acid lowered the mortality to 25%. The protection against vincristine toxicity did not occur when folic acid was substituted for folinic acid. A report has appeared (45) indicating that there is no specific protective effect of folinic acid against vincristine toxicity in mice and that the protection can be observed by comparable treatment with isotonic saline solution. As discussed in Section Vll, there is not conclusive evidence that folinic acid is able to ameliorate vincristine toxicity in humans (46). 

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. 

Currently, the most widely used are sulfisoxazole, sulfamethoxazole, sulfadiazine, sul-famethizole, and trisulfapyrimidine (a mixture of sulfamerazine, sulfamethazine, and sulfadiazine). The first two drugs mentioned are the most widely used. The long-lasting sulfonamide (sulfadioxin) is used only in combination with pyrimethamine (an antagonist of folic acid) for prevention and treatment of tropical fever. 

Megaloblastic anem/a.- Treatment of megaloblastic anemias due to a deficiency of folic acid as seen in tropical or nontropical sprue, anemias of nutritional origin, pregnancy, infancy, or childhood. 

Parenteral Treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. 

Folic acid antagonist overdosage In the treatment of accidental overdosages of folic acid antagonists, administer leucovorin as promptly as possible. As the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin s effectiveness in counteracting toxicity decreases. 

HYDROXOCOBALAMIN, CRYSTALLINE Adm n ster IM only. The recommended dosage is 30 meg/day for 5 to 10 days, followed by 100 to 200 meg/month. Children may be given a total of 1 to 5 mg over 2 weeks or more in doses of 100 meg, then 30 to 50 meg every 4 weeks for maintenance. Institute concurrent folic acid therapy at the beginning of treatment if needed. 

Folic acid is used for the treatment of folate deficiency. Oral folic acid is usually the therapy of choice. For megaloblastic anemia doses of 5 mg daily for 4 months should be effective. Folinic acid is available in a parenteral formulation which may be indicated when oral therapy is not feasible and for rescue treatments following certain anti-cancer regimens. 

Pemetrexed is chemically similar to folic acid. It inhibits three enzymes used in purine and pyrimidine synthesis - thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA. In 2004 it was approved for treatment of malignant pleural mesothelioma and as a second-line agent for the treatment of non-small cell lung cancer. Adverse effects include gastrointestinal complaints, bone marrow suppression, alopecia, allergic and neurotoxic reactions. 

The suifones are structural analogues of PABA and are competitive inhibitors of folic acid synthesis. Suifones are bacteriostatic and are used only in the treatment of... 

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