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Biomedical subjects

Joseph E Baggott

Publications and source records attributed to Joseph E Baggott.

13 recordsLinked to original sources
PubMed2006

Medical foods: products for the management of chronic diseases.

Medical foods are a specific category of therapeutic agents created under the Orphan Drug Act of 1988, which separated medical foods from drugs for regulatory purposes. Products in this category share the requirements that they are intended for the nutritional management of a specific disease, are used under the guidance of a physician, and contain ingredients that are generally recognized as safe (GRAS). An example of medical foods are formulations intended to manage patients with inborn errors in amino acid metabolism. Newer medical foods are designed to manage hyperhomocysteinemia, pancreatic exocrine insufficiency, inflammatory conditions, cancer cachexia, and other diseases.

Chronic Disease↗
PubMed2004

The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis.

OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.

Adenosine↗
PubMed2004

Effect of methotrexate therapy on bone mineral density and body composition in rat adjuvant arthritis.

OBJECTIVE: To test whether methotrexate (MTX) therapy of rat adjuvant arthritis (AA) prevents loss of bone mineral density (BMD) and loss of adipose and lean body mass compared to pair-fed controls with untreated rat AA (positive controls) and rats without AA (negative controls). METHODS: AA was induced by a Mycobacterium butyricum injection at the base of the tail of 5-week-old female Lewis rats. The MTX-treated group was injected with adjuvant and then treated twice weekly with MTX (1.0 mg/kg/wk intraperitoneally). To control for the effects of AA on appetite and weight, food given to control animals and MTX-treated rats with AA was limited to that consumed by rats with untreated AA. At 42 days post-adjuvant injection, the animals were sacrificed and tibial BMD was measured. Body composition was analyzed for percentage fat, protein, ash, and water. RESULTS: There was no difference in ankle edema score or ankle width between the negative controls and MTX-treated group at necropsy. BMD was significantly higher in the negative controls versus positive controls and MTX-treated and in MTX-treated versus positive controls. There was significantly less body fat and protein and greater body water in the positive controls and MTX group compared to the negative controls. CONCLUSION: MTX prevents loss of BMD in the tibia in the rat AA model compared to positive controls. While MTX is effective in lowering inflammation in rat AA, there are still significant losses in BMD and body composition, which may have implications for rheumatoid arthritis.

Animals↗
PubMed2003

5,10-methenyltetrahydrofolate cyclohydrolase, rat liver and chemically catalysed formation of 5-formyltetrahydrofolate.

The 5,10-methenyltetrahydrofolate (5,10-CH=H4folate) synthetase catalyses the physiologically irreversible formation of 5,10-CH=H4folate from 5-formyltetrahydrofolate (5-HCO-H4folate) and ATP. It is not clear how (or if) 5-HCO-H4folate is formed in vivo. Using a spectrophotometric assay for 5-HCO-H4folate, human recombinant 5,10-CH=H4folate cyclohydrolase, which catalyses the hydrolysis of 5,10-CH=H4folate to 10-HCO-H4folate, was previously shown to catalyse inefficiently the formation of 5-HCO-H4folate at pH 7.3 [Pelletier and MacKenzie (1996) Bioorg. Chem. 24, 220-228]. In the present study, we report that (i) the human cyclohydrolase enzyme catalyses the conversion of 10-HCO-/5,10-CH=H4folate into 5-HCO-H4folate (it is also chemically formed) at pH 4.0-7.0; (ii) rat liver has a very low capacity to catalyse the formation of 5-HCO-H4folate when compared with the traditional activity of 5,10-CH=H4folate cyclohydrolase and the activity of the 5,10-CH=H4folate synthetase; and (iii) a substantial amount of 5-HCO-H4folate reported to be present in rat liver is chemically formed during analytical procedures. We conclude that (i) the cyclohydrolase represents some of the capacity of rat liver to catalyse the formation of 5-HCO-H4folate; (ii) the amount of 5-HCO-H4folate reported to be present in rat liver is overestimated (liver 5-HCO-H4folate content may be negligible); and (iii) there is little evidence that 5-HCO-H4folate inhibits one-carbon metabolism in mammals.

Aminohydrolases↗
PubMed2003

The energy cost of adjuvant-induced arthritis in rats.

OBJECTIVE: To test the hypothesis that rats with adjuvant-induced arthritis (AIA) need more metabolic energy to maintain body weight than healthy control rats or rats with AIA treated with methotrexate (MTX). METHODS: Rat AIA was induced by Mycobacterium butyricum injection at the base of the tail. The MTX-treated group was injected with MTX (1.0 mg/kg/week) in phosphate buffered saline. Negative controls (i.e., disease-free) and the MTX-treated group were pair-fed with positive controls (i.e., untreated AIA rats) to ensure equal mean body weights. RESULTS: An additional 0.85 gm of food per day per rat was needed by the positive control group and 0.54 gm per day by the MTX-treated group to maintain a body weight comparable with that of the negative control group during days 5-15 post-adjuvant injection. During days 15-34 post-adjuvant injection an additional 1.4 gm of food per day per rat was needed by the positive controls and 0.62 gm by the MTX-treated group. CONCLUSION: The results of this study indicate that adjuvant arthritis has a metabolic cost, which increases substantially as the disease becomes clinically apparent (days 15-34). MTX treatment does not completely eliminate the caloric cost of the disease. During days 5-15 post-adjuvant injection, an average of 6% of the total calories eaten by the positive controls was metabolized to support subclinical inflammation and other physiologic processes of this disease. During the active phase of the disease (i.e., clinical inflammation), this value increased to 18% of total calories.

Animals↗
PubMed2002

Oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate by complex IV of rat mitochondria.

We hypothesized that the unanticipated bioactivity of orally administered unnatural carbon-6 isomers, (6R)-5-formyltetrahydrofolate (5-HCO-THF) and (6S)-5,10-methenyltetrahydrofolate (5,10-CH-THF), in humans [Baggott, J. E., and Tamura, T. (1999) Biochim. Biophys. Acta 1472, 323-32] is explained by the rapid oxidation of (6S)-10-formyltetrahydrofolate (10-HCO-THF), which is produced by in vivo chemical processes from the above folates. An oxidation of 10-HCO-THF produces 10-formyldihydrofolate (10-HCO-DHF), which no longer has the asymmetric center at carbon-6 and is metabolized by aminoimidazole carboxamide ribotide (AICAR) transformylase forming bioactive dihydrofolate. Since cytochrome c (Fe(3+)) rapidly oxidizes both (6R)- and (6S)-10-HCO-THF [Baggott et al. (2001) Biochem. J. 354, 115-22], we investigated the metabolism of 10-HCO-THF by isolated rat liver mitochondria. We found that 10-HCO-THF supported the respiration of mitochondria without uncoupling ATP synthesis. The site of electron donation was identified as complex IV, which contains cytochrome c; the folate product was 10-HCO-DHF, and the reaction was saturable with respect to 10-HCO-THF. Both (6S)- (unnatural) and (6R)-10-HCO-THF supported the respiration of mitochondria, whereas (6S)-5-formyltetrahydrofolate (5-HCO-THF) was inactive. To our knowledge, this cytochrome c oxidation of 10-HCO-THF to 10-HCO-DHF in the mitochondrial intermembrane space represents a possible folate metabolic pathway previously unidentified and would explain the bioactivity of unnatural carbon-6 isomers, (6R)-5-HCO-THF and (6S)-5,10-CH-THF, in humans.

Animals↗
PubMed1997

The form of folate affects the mechanisms of methotrexate resistance in Enterococcus hirae [corrected].

Several mechanisms have been described to explain the resistance of cells to methotrexate (MTX); however, the basis for the heterogeneity of mechanisms has been obscure. It was hypothesized that the type of MTX resistance in a single species can be influenced by the form of extracellular folate supplied during the development of resistance. Two strains of MTX-resistant Enterococcus hirae [corrected] were developed by transferring the bacteria to media containing increasing concentrations of MTX in the presence of constant concentrations of either 5-formyl-5,6,7,8-tetrahydropteroylglutamic acid (5-HCO-H4PteGlu) or pteroylglutamic acid (PteGlu). These resistant strains were designated E. hirae/MTX/5-HCO-H4PteGlu and E. hirae/MTX/PteGlu, respectively [corrected]. The mechanisms of MTX resistance included: (1) increased folic acid reductase (FAR) activity in both resistant strains but increased dihydrofolate reductase (DHFR) activity only in E. hirae/MTX/PteGlu [corrected]; (2) decreased synthesis and intracellular retention of MTX containing two glutamyl residues; (3) decreased uptake of MTX accompanied by decreased uptake of folates; and (4) reduction of folate-binding capacity. Among these, the form of folate present in the media during the development of resistance affected DHFR and FAR activities and the transport of folates. These findings, together with data from other laboratories, suggest that it may be important to use a reduced form of folate, a more physiological form than oxidized PteGlu, in the media during the development of resistance for the study of the mechanisms of MTX resistance in cultured cells.

Biological Transport↗