is the of choice for the treatment of RA and is the anchor drug for most combination therapies; it is also the benchmark for the efficacy and safety of new disease-modyfing therapies. At the dosages used for the treatment or has been shown to stimulate adenosine release from cells, producing an anti-inflammatory effect.
is an antimetabolite belonging to the class of folic acid analogs . Folic acid is an essential dietary factor that is converted by enzymatic reduction to a series of tetrahydrofolate (FH4) cofactors that provide methyl groups for the synthesis of precursors of (thymidylate and purines) and (purines). Interference with metabolism reduces the cellular capacity for one-carbon transfer and the necessary methylation reactions in the synthesis of purine ribonucleotides and thymidine monophosphate (TMP), thereby inhibiting replication.
Mechanism of action. The primary target of is the enzyme To function as a cofactor in 1-carbon transfer reactions, folate must be reduced by to Inhibitors such as with high affinity for (Ki 0.01-0.2 nM), cause partial depletion of the cofactors (5-10 methylene tetrahydrofolic acid and N-10 formyl tetrahydrofolic acid) required for the synthesis of thymidylate and purines. In addiction, like cellular folates, undergoes convertion to a series of polyglutamates ( -PGs) in both normal and tumor cells. This -PGs constitute an intracellular storage form of folates and folate analogs and dramatically increase inhibitory potency of the analog for additional sites, including Thymidylate Synthase (TS) and 2 early enzymes in the purine biosynthetic pathway. The dihydrofolic acid polyglutamates that accumulate in cells behind the blocked reaction also act as inhibitors of TS and other enzymes.
Dr. Frank acknowledged the body’s capacity for synthesizing nucleic acids “de novo,” but rejected the presupposition that dietary (or exogenous) nucleic acids are not essential because the body can or will fulfill all of its own requirements. If this were the case, according to Frank, then one would not expect the often remarkable effects of dietary nucleic acid supplementation, both for aged or debilitated individuals, and for athletes or generally healthy persons. In both types of individuals, he describes nucleic acid supplementation as “unequivocal” in its effects (117).
Folate coenzymes are responsible for the following important metabolic functions: 1) Formation of purines and pyrimidines which, in turn, are needed for synthesis of the nucleic acids DNA and RNA. 2) Formation of heme, the iron-containing protein in hemoglobin, 3) Interconversion of the 3-carbon amino acid serine from the 2-carbon amino acid glycine, 4) Formation of the amino acids tyrosine from phenylalanine and glutamic acid from histidine, 5) Formation of the amino acid methionine from homocysteine (Vitamin B12 as methylcobalamin also is needed for this conversion). Elevated levels of homocysteine have been implicated in a wide range of health disorders. In the reconversion of homocysteine to methionine the body uses the methionine to make the important amino acid s-adenosylmethionine (SAMe) which is known to be helpful in cases of depression, 6) Synthesis of choline from ethanolamine, 7) Formation and maturation of red and white blood cells, and 8) Conversion of nicotinamide to N'-methylnicotinamide.
Folinic acid, also known as 5-formyl tetrahydrofolate, is one active form in a group of vitamins known as folates. In contrast to folic acid, a synthetic form of folate, folinic acid is one of the forms of folate found naturally in foods. Folate deficiency is believed to be the most common vitamin deficiency in the world due to food processing, food selection, and intestinal disorders. In the body folinic acid may be converted into any of the other active forms of folate.
Antimicrobial pyrimethamine, a folic acid antagonist which inhibits the dihydrofolate reductase (DHFR), is a major enzyme in the purine pathway in organism (). Pyrimethamine is effective against tachyzoites in acute toxoplasmosis but has no effect on cysts in chronic stage of disease. In addition it has cytotoxity effects as shown in vitro (, ) and in animal studies ().
Dr. Frank explained the biochemical relation of vitamins and nucleic acids, and specifically used the example of the B-complex vitamins. In metabolizing Vitamin B3 (niacin or niacinamide), for example, the body requires energy for conversions that properly break down the vitamin into its usable components. Thus, cells convert niacin to coenzyme nicotinamide adenine dinucleotide (NAD), which may then be converted to NADP via a phosphate transfer from ATP. The initial reaction involves nicotinic acid with 5-phosphoribosyl 1-pyrophosphate to produce nicotinic mononucleotide (NMN).
He notes that phosphoribosyl pyrophosphate also is the basic compound for purine synthesis (and is formed from ribose-5-phosphate plus ATP). This indicates that the energy of level of a cell plays an essential role in the synthesis of NMN (the precursor of NAD), and therefore that the greater the rate of ATP synthesis, the greater the rate of synthesis of NMN. The next step in the metabolism of niacin involves NMN reacting with ATP to create desamido-NAD, where ATP acts both as a source of energy and a component of the NAD coenzyme.
Ultimately ATP is crucial to the formation of the NAD coenzyme (an important coenzyme in cellular energy metabolism). Thus, Dr. Frank states that higher Krebs cycle activity and oxygen-energy metabolism favors synthesis of NAD, given the availability of niacin (or niacinamide). Moreover, a higher level of niacin (or niacinamide) likewise would favor its own conversion into the active NAD coenzyme. Dr. Frank points to the evident relation of energy metabolism and NAD synthesis, wherein increased nucleic acid and nucleotide intake produces increased energy metabolism and ATP production, which in turn enables both more effective metabolism of niacin and further increases in cellular NAD. He therefore finds a very evident relationship between dietary nucleic acids and NAD with respect to energy production and related metabolism (151).
Dr. Frank relates similar processes for other vitamins (e.g., riboflavin and pantothenic acid) that he finds representative of the B-complex. From his own clinical experience, he relates his observation of definite increases in energy among subjects receiving high-dosage B-complex vitamins (e.g., 50–200 mg of thiamin daily plus other balanced B factors) given with high nucleic acid intake. His clinical observations correspond with his technical analysis of the synergistic biochemical relations between dietary nucleic acids and B vitamins in energy production.
Dr. Frank also discusses other vitamins in his books (e.g., Vitamin A). He concludes: “It is apparent that nucleic acid and nucleotide intake are most importantly related to vitamin usage and function and that the greater the nucleic acid intake, within limits not yet determined, the greater the synthesis and usage of many and perhaps most coenzymes” (153).
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The biological importance of ribose relates to the fact that it is the rate-limiting compound that regulates the activity of the purine nucleotide pathway of adenine nucleotide metabolism. As such, ribose plays a central role in the synthesis of ATP, coenzyme-A, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), DNA, RNA, and other important cellular constituents. Ribose is the only known compound the body can use for performing this critical metabolic function.
Specifically, ribose administration bypasses the slow and rate-limited pentose phosphate pathway to stimulate adenine nucleotide synthesis and salvage in vivo. In addition, it has been shown that de novo adenine nucleotide synthesis in skeletal muscle is rate limited by the availability of ribose.
Ribose derivatives play a significant role in the body. Important ribose derivatives encompass those having phosphate groups attached at the 5 position, including mono-, di-, and triphosphate forms, and 3-5 cyclic monophosphates. Diphosphate dimers, known as coenzymes, form an essential class of compounds with ribose. When such purine and pyrimidine derivatives are coupled with ribose, they are known as nucleosides (bases attached to ribose). Phosphorylated nucleosides are known as nucleotides. When adenine (a purine derivative) is coupled to ribose it is known as adenosine. ATP is the 5’-triphosphate derivative of adenosine. (The adenine portion of ATP consists of ribose and adenine. The triphosphate portion of ATP consists of three phosphate molecules.)
Given the importance of ribose as an essential part of nucleic acids, nucleotides, nucleosides, its role in the production of energy (as ATP), and its ability to increase synthesis and salvage of nucleotides in the body, the inclusion of ribose in a formula designed to provide high levels of nucleic acids appears especially appropriate.
Anti-Toxoplasma activity of sulfonamides is by inhibiting dihydrofolate-synthetase enzyme essential in the purine pathway in Toxoplasma, while have minor cytotoxicty and side effects (,). is commonly prescribed while other sulfonamides, sulfapyrazine, sulfamerazine and sulfadimidine are also effective and can be used as trisulfapyrimidine combination (sulfadimidine, sulfamerazine and sulfadiazine).
Alternatively pyrimethamine plus sulfadiazine and leucovorin is given to pregnant women in the late second and third trimesters to treat positive infected fetus by means of PCR for amniotic fluid or suspected with abnormal ultrasound after the 18 week of pregnancy following written consent and under close supervision (, ). Pyrimethamine plus sulfadiazine passes placental barrier and is recommended for women with acquired acute infection after 18 weeks of gestation. Due to the increased risk of maternal-fetal transmission of the organisms in late pregnancy indicated (). Pyrimethamine 50 mg/day and sulfadiazine 3g/day is administered until delivery with hematological monitoring. Pyrimethamine plus sulfadiazine significantly reduce the rate of Toxoplasma isolation from the placenta and antibody synthesis of specific IgM and IgG titers in the neonate. Side effects include fetal injury. Trimethoprim plus sulfamethoxazole has been recommended as an alternative to treat congenital toxoplasmosis during pregnancy ().