Folic acid infections

Hydroxymethyl-6-methyluracil (1043) was prepared many years ago from 6-methyl-uracil and formaldehyde, or in other ways. Since 1956 it has received much attention in the USSR under the (transliterated) name pentoxyl or pentoxil. It is used in several anaemic and disease conditions. For example, a mixture of folic acid and pentoxyl quickly reduces the anaemia resulting from lead poisoning pentoxyl stimulates the supply of serum protein after massive blood loss it stimulates wound healing it stimulates the immune response in typhus infection and it potentiates the action of sulfonamides in pneumococcus infections (70MI21300). 

The classic example is that of Prontosil (Figure 2.12) in which the compound is active against bacterial infection in animals though inactive against the bacteria in pure culture. The toxicity in animals is the result of reduction to the sulfanilamide (4-aminobenzenesulfonamide) that competitively blocks the incorporation of 4-aminobenzoate into the vitamin folic acid. 

Methotrexate 7.S-20 mg once weekly Oral or IM 4-8 weeks N, D, hepatotoxicity, alopecia, new-onset cough or SOB, MYL CBC, creatinine, LFTs q 4-8 weeks Monitor for signs of infection Concomitant use of folic acid Avoid alcohol Use contraception if childbearing potential... 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

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. 

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. 

All of these compounds are inhibitors of dihydrofolate reductase in bacteria, plasmodia, and humans. Fortunately, they have a significantly high affinity for bacterial and protozoan dihydrofolate reductases. Pyrimethamine, for example, inhibits parasite dihydrofolate reductase at levels several hundred times lower than required to inhibit dihydrofolate reductase in humans. This is the basis of their selective toxicity. The selective toxicity can be increased upon supplying additional folic acid to the host organism, which the parasite cannot use. In fact, diaminopyrimidines (trimetoprim, pyrimethamine) were initially suggested as medicinal and preventative drugs against malarial infections. It was shown that all powerful inhibitors of dihydrofolate reductase can remove the malarial parasite with relatively minor consequences in the host. 

Inadequate response A blunted or impeded therapeutic response may be due to infection, uremia, bone marrow suppressant drugs, concurrent iron or folic acid deficiency, or misdiagnosis. 

Megaloblastic anemia is characterized by the appearance of large cells in the bone marrow and blood due to defective maturation of hematopoietic cells. Folic acid or vitamin B12 deficiency will result in this type of anemia. Malabsorption, impaired use, chronic infections, and drugs can lead to folic acid or vitamin B12 deficiency. 

Sulfonamides are used for controlling urinary tract infections, acute and chronic lung infections (norcadiosis), protozoan infections of the nervous system (i.e., toxoplasmosis), and a variety of infections in humans and livestock. Their mode of activity is by inhibiting the multiplication of bacteria by competitively inhibiting para-aminobenzioc acid (PABA) in the folic acid metabolism cycle (O Neil et al., 2001). More specifically, they block the synthesis of folic acid in bacteria as the drugs are structurally similar to PABA. Folic acid is essential to the synthesis of amino acids and nucleic acids. In bacteria, folic acid is synthesized from PABA... 

PABA) incorporation into folic acid (inhibition of folate synthesis). In large proportion of Mycobacterium leprae infections e.g. in lepromatous leprosy, resistance can develop, so combination of dapsone, rifampicin and clofazimine is used in initial therapy. 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Sulfa drugs have a close structural resemblance to PABA. When taken by a person suffering from a bacterial infection, a sulfa drug is transformed by the body to the compound sulfanilamide, which attaches to the bacterial receptor sites designed for PABA, as shown in Figure 14.7, thereby preventing the synthesis of folic acid. Without folic acid, the bacteria soon die. The patient, however, because he or she receives folic acid from the diet, lives on. 

In acute and chronic urinary tract infection, the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra) exerts a truly synergistic effect on bacteria. The sulfonamide inhibits the utilization of p-amino-benzoic acid in the synthesis of folic acid (Figure 2.3), whereas trimethoprim, by inhibiting dihydrofolic acid reductase, blocks the conversion of dihydrofolic acid to tetrahydrofolic acid, which is essential to bacteria in the denovo synthesis of purines, pyrimidines, and certain amino acids. Because mammalian organisms do not synthesize folic acid and therefore need it as a vitamin in their daily diets, trimethoprim-sulfamethoxazole does not interfere with the metabolism of mammalian cells. 

A metabolic pathway that has received considerable attention is the conversion of 2 -deoxyuridine 5 -monophosphate (dUMP, 6.60) to thymidine 5 -monophosphate (TMP, 6.61) (Scheme 6.13). Without an adequate supply of TMP, a cell or bacterium cannot create DNA for cell division. Therefore, blocking TMP synthesis is an attractive method for slowing the advancement of certain cancers and bacterial infections. Important molecules in the methylation of dUMP are the various folic acid derivatives folic acid (FA, 6.62), dihydrofolic acid (DHF, 6.63), tetrahydrofolic acid (THF, 6.64), and N5, A1 "-methylene tetrahydrofolic acid (MTHF, 6.65) (Figure 6.23). These structures... 

Animals are unable to synthesize folic acid (6.62) and must consume adequate quantities in their diets. Plants and bacteria, however, are able to make folic acid. The first step of this synthesis is catalyzed by dihydropteroate synthetase and reacts dihydroptero-ate diphosphate (6.69) and para-aminobenzoic acid (PABA, 6.70) (Figure 6.25). Because this pathway is not found in humans, inhibition of the reaction is a method to ultimately stop TMP synthesis in an invading bacterium while not impacting the infected host. The sulfonamides, often called sulfa drugs, are a class of antibiotic that exploits the folic acid pathway and inhibits dihydropteroate synthetase. Sulfa drugs bind in the same fashion as PABA and act as competitive inhibitors. The active form of the first sulfa drug is sulfanilamide (6.71). Sulfamethoxazole (6.72) is a sulfa drug that is widely prescribed today.26... 

Sulfanilamide cannot be used to make folic acid, but the bacterial enzymes cannot distinguish between sulfanilamide and p-aminobenzoic acid. The production of active folic acid is inhibited, and the organism stops growing. Sulfanilamide does not kill the bacteria, but it inhibits their growth and reproduction, allowing the body s own defense mechanisms to destroy the infection. 

Sickle cell patients are hyposplenic and receive prophylactic phenoxymethylpenicillin to help prevent pneumococcal infection. Folic acid is supplementation may be given as the high red cell turnover increases requirements - though many prescribers find this unnecessary as they consider the UK diet contains sufficient folic acid. 

Anaemia occurs when there is a decrease in haemoglobin below the appropriate level for the age and sex of the individual. The anaemia maybe due to several factors as lack of iron, vitamin Bi2 and folic acid all affect red cell production, resulting in anaemia. Bi2 deficiency may also cause neurological problems, such as numbness and weakness. Patients with Bi2 deficiency may also report mood swings and seem to suffer more infection and mild gastrointestinal problems than normal, so Maria s moodiness, stomach upsets and colds may be significant. 

Sulfonamides were the first group of chemotherapeutic agents used for the prevention or treatment of bacterial infections in humans. Sulfonamides (e.g., sulfisoxazole) act by inhibiting bacterial synthesis of folic acid, a chemical required for synthesis of nucleic acid and protein. These drugs competitively inhibit the first step in the synthesis of folic acid—the conversion of para-aminobenzoic acid into dihydrofolic acid. Because humans absorb preformed folic acid from food, sulfonamide inhibition has only a minimal effect on hiunan cells. 

Asymptomatic or uncomplicated primary infection requires no treatment. Severe courses of disease are treated with pyrimethamine (50 mg/day for approx. 2 weeks, followed by 25 mg/day for approx. 2 weeks) or sulphamethoxydiazine (50 mg for day 1, 25 mg as from day 2 or 3) -t pyrimethamine (100 mg/kg BW/day) or clindamycin -i- pyrimethamine. As an alternative approach (e.g. in the first trimester of pregnancy), spiramycin may be given. In order to reduce the myelotoxicity of pyrimethamine, the administration of folic acid (10-15 mg/day) is recommended. 

Severe adverse drug reactions with trimethoprim and co-trimoxazole are rare (12-14). This also applies to children (15). The adverse effects of co-trimoxazole correspond to those expected from a sulfonamide (16). In HIV-infected patients, adverse effects of co-trimox-azole are more frequent and more severe (17-19). Hematological disturbances due to co-trimoxazole include mild anemia, leukopenia, and thrombocytopenia, which may be due to folic acid antagonism. Serious metabolic disturbances that are associated with trimethoprim include hyperkalemia and metabolic acidosis. Trimethoprim can cause hypersensitivity reactions. However, with co-trimoxazole, the sulfonamide is generally believed to be more allergenic (12). Generalized skin reactions predominate. Other effects, such as anaphylactic shock, are extremely rare (20-22). Carcinogenicity due to trimethoprim or co-trimoxazole has not been reported. 

---