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Biomedical subjects

G F Carl

Publications and source records attributed to G F Carl.

At least 37 records · Page 2Linked to original sources
PubMed1988

Chronic primidone treatment in the rat: an animal model of primidone therapy.

A continuously protective, nontoxic, oral model of chronic treatment with primidone was developed in the rat. Rats were treated with primidone (100 mg/kg) by gastric gavage twice daily for up to 8 weeks. This treatment was continuously protective as measured by seizures induced by hexafluorodiethyl ether and minimally toxic as measured by weight gain. Plasma primidone concentration reached a peak (13 micrograms/ml) 2 hours after gavage and was almost undetectable by 12 hours. Plasma phenobarbital concentration peaked (52 micrograms/ml) at 6 hours postgavage after reaching a minimum (19 micrograms/ml) at one hour postgavage. Phenobarbital concentrations measured in plasma, brain and liver after 8 weeks of chronic treatment correlated significantly between each tissue and plasma.

Administration, Oral↗
PubMed1987

Effect of chronic primidone treatment on folate-dependent one-carbon metabolism in the rat.

Rats were treated chronically with primidone (100 mg/kg/12 hr, p.o.) for up to 8 weeks. The effects of this treatment on one-carbon metabolism were determined in brain and liver. Serine hydroxymethyltransferase activity increased in both brain (44%) and liver (50%). Methylenetetrahydrofolate reductase activity increased in liver (26%) with a significant correlation to the length of treatment, but in brain it was unchanged. Methyltetrahydrofolate:homocysteine methyltransferase activity increased in brain (43%) with a significant correlation to length of treatment, but in liver no effect was observed. Methionine adenosyltransferase activity in brain was significantly lower than control at only one point after 8 weeks of chronic treatment. S-Adenosylmethionine concentration in liver increased gradually (23%) during treatment. S-Adenosylhomocysteine concentrations decreased in brain (33%) and increased in liver (23%) with chronic primidone treatment. These data support the hypothesis that chronic primidone treatment leads to folate depletion through interference with folate metabolism.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1987

Chronic treatment of rats with primidone causes depletion of pteroylpentaglutamates in liver.

Anticonvulsants have been shown to cause folacin deficiency in chronically treated epileptic patients. However, a mechanism for this depletion has not been established. In the present study, the effects of chronic primidone treatment on folates in the rat were investigated. Using a continuously protective relatively nontoxic regimen of oral administration, it was found that primidone (100 mg/kg, twice per day) caused a decrease of pteroylpentaglutamates in the liver to less than half the control value within 1 wk. Total liver folacin concentration decreased by 30% in the first week followed by a slow gradual further decline with continuing treatment. Plasma folacin exhibited essentially the same pattern but no effect was observed on brain folacin concentration. Primidone was not detectable in plasma 12 h after gavage but phenobarbital was detectable. These data are consistent with the hypothesis that the anticonvulsant primidone (and/or phenobarbital) cause folate depletion via interaction with folate metabolism.

Animals↗
PubMed1986

Effect of chronic valproate treatment on folate-dependent methyl biosynthesis in the rat.

Folate deficiency has been associated with chronic anticonvulsant therapy. Characterization of the effects of individual anticonvulsants has been undertaken. Chronic treatment of rats with sodium valproate caused a decrease in liver folate concentration with concomitant increases in brain and plasma folate concentrations. After several weeks, these trends were reversed and folate concentrations tended to normalize. Chronic valproate treatment affected the activities of folate-dependent one-carbon enzymes: Serine hydroxymethyltransferase activity in liver was increased; methylenetetrahydrofolate reductase activity in both brain and liver was decreased; and methyltetrahydrofolate:homocysteine methyltransferase activity in both brain and liver decreased initially but returned toward normal with continued treatment. Methionine adenosyltransferase activity in brain declined after several weeks of treatment but the concentration of S-adenosylmethionine in liver increased with chronic valproate treatment. These data are consistent with the hypothesis that the effects of anticonvulsants on folates are a consequence of the mechanism of action of the anticonvulsant.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1986

Association of low blood manganese concentrations with epilepsy.

A comparison of hospitalized epileptic patients with matched normals showed that the mean whole blood manganese (Mn) concentration of the epileptic population was significantly lower than the mean of the normal population. The whole blood Mn concentration in the epileptics did not correlate either with seizure frequency or with anticonvulsant therapy. It was observed, however, that patients whose epilepsy was a result of trauma had significantly higher blood Mn concentrations than patients whose history was negative for trauma.

Adolescent↗
PubMed1985

Valproate metabolite concentrations in brain increase with chronic administration of sodium valproate.

Rats were treated chronically with sodium valproate for varying periods of time up to eight weeks. A statistically significant negative correlation between plasma concentrations of valproate-derived substances (VDS) and length of treatment was observed while a statistically significant positive correlation was found between brain VDS concentration and length of treatment. Liver VDS concentrations showed a tendency to decrease with time but this trend was not statistically significant. A new procedure was developed to measure the tissue levels of VDS.

Animals↗
PubMed1984

Effect of chronic phenobarbital treatment on folates and one-carbon enzymes in the rat.

Chronic oral phenobarbital treatment (50 mg/kg every 12 hr for 8 weeks), which was nontoxic and continuously protective against seizures in rats, significantly decreased folate concentration in liver (29%) but not in brain or plasma. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) in liver decreased with initiation of treatment but then increased with a significant correlation to the length of treatment. Phenobarbital also stimulated the activity of this enzyme slightly in vitro. Methionine adenosyltransferase (MAT) activity was inhibited by high concentrations of phenobarbital in vitro but was not affected in vivo. No significant effects of phenobarbital on the activities of serine hydroxymethyltransferase (SHMT) or 5-methyltetrahydrofolate:homocysteine methyltransferase (MHMT) were observed either in vivo or in vitro.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1983

The effect of chronic phenytoin treatment on tissue folate concentrations and on the activities of the methyl synthetic enzymes in the rat.

The folacin-depleting effect of phenytoin has been known clinically for many years, but a systematic investigation of this effect in animals has never been undertaken. In this study we found that chronic oral phenytoin treatment (100 mg/kg every 12 hours for 8 weeks) in rats significantly affected concentrations of folates in both liver and brain. Concentration of liver folates dropped to one-third the normal level even though concentration of plasma folates was not affected. Concentration of brain folates increased over the first 2 weeks of treatment and then declined to a level approximately three-fourths the normal concentration. The apparent activity of 5,10-methylenetetrahydrofolate reductase (MTR) increased as a function of the length of treatment in both brain and liver, but when phenytoin was added to the MTR assay in vitro, the activity was inhibited. No significant effects of phenytoin on the activities of serine hydroxymethyltransferase (SHMT), 5-methyltetrahydrofolate:homocysteine methyltransferase (MHMT) or methionine adenosyltransferase (MAT) were observed either in vivo or in vitro. These data are consistent with the hypothesis that phenytoin interacts with the metabolism of folates at the enzymatic level.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1983

Interaction of phenytoin and folate in the rat.

The interactions between folate and phenytoin were studied in the rat using a model in which constant, nontoxic, and continuously protective levels of phenytoin were maintained. After 10 days of treatment with phenytoin, liver folate concentration was decreased while brain, plasma, and adrenal folate concentrations remained unaffected. Oral folate supplementation (20 mg/kg) increased folate concentrations in all tissues examined in phenytoin-treated animals, but had no effect on phenytoin levels. Folate supplementation did, however, increase the recovery time after maximal electroshock seizures in phenytoin-treated rats, but did not influence phenytoin's ability to protect against tonic hindlimb extension. Oral folate supplementation in animals not treated with phenytoin also significantly increased folate concentrations in all tissues examined except brain.

Animals↗
PubMed1982

Fluorescent immunoassay for determining antiepileptic drug concentrations: clinical usefulness.

The need for rapid and accurate antiepileptic drug measurement in blood is well established. A substrate-labeled fluorescent immunoassay (FIA) has been developed that can measure phenobarbital, phenytoin, primidone, and carbamazepine in serum. To our knowledge, the primidone and carbamazepine assays have not previously been tested in a field trial. We compared FIA and the well-established antiepileptic drug immunoassay technique EMIT for the quantitation of both carbamazepine and primidone. In our hands, the FIA method compared favorably with the EMIT method for accuracy and reliability but is somewhat more time consuming. This method has the advantage of being more sensitive, however, and requires only a finger-stick blood sample. Because of this and the simplicity of the equipment required, the FIA system should also be relatively inexpensive to set up and to operate.

Anticonvulsants↗
PubMed1982

Comparison of fluorescent immunoassay (FIA) and enzyme-multiplied immunoassay technique (EMIT) for measurement of serum carbamazepine concentration.

The recently developed fluorescent immunoassay (FIA) for measuring serum carbamazepine concentration is compared to the established enzyme-multiplied-immunoassay-technique (EMIT). The Accuracy, precision and simplicity of these methods are comparable. The sensitivity of FIA is approximately eight times greater than the EMIT but the assay time required for FIA is longer. Potential improvements of the FIA technique are discussed.

Carbamazepine↗
PubMed1982

Comparison of fluorescent immunoassay and EMIT for assay of serum primidone concentration.

A fluorescent immunoassay procedure (FIA) for the assay of serum of plasma primidone concentrations that was developed by Ames Laboratories is compared to the established enzyme-multiplied immunoassay technique (EMIT) developed by Syva. The FIA compares favorably with the established EMIT system for accuracy, and the FIA is eight times more sensitive but requires a greater turnover time.

Fluorescent Antibody Technique↗
PubMed1982

Interactions between folates and carbamazepine or valproate in the rat.

Carbamazepine and valproate each afforded protection against seizures induced by electroshock or by inhalation of hexafluorodiethyl ether (HFDE). After injections of either anticonvulsant for 10 days, plasma folate concentration decreased, but brain folate concentration did not change. Folinic acid administration had no effect on the concentration of either anticonvulsant in plasma or brain. These findings are in contrast with the demonstrated effects of other anticonvulsants on folate biochemistry.

Animals↗
PubMed1980

Hyperformaldehydism: a unifying hypothesis for the major biochemical theories of schizophrenia.

A biochemical hypothesis concerning the etiology of schizophrenia is presented. This hypothesis postulates the presence of a genetically determined lesion in the disposition of one-carbon units leading to elevated levels of formaldehyde, i.e hyperformaldehydism. The relationships between this hypothesis and the existing major biochemical hypotheses of schizophrenia regarding dopamine and transmethylation are discussed.

Carbolines↗
PubMed1978

Association of Thy-1 differentiation alloantigen with synaptic complexes isolated from mouse brain.

Conventional fractionation procedures were used in an effort to define the subcellular distribution of the Thy-1 alloantigen in whole mouse brain. After discontinuous sucrose density gradient centrifugation of isotonic postnuclear particulate fractions, the bulk of Thy-1 was recovered in regions of the gradients containing synaptosomes. The synaptosome fraction that banded at 1.2 M sucrose yielded a specific activity for Thy-1 significantly greater than the synaptosomes separating at 1.4 M sucrose. Osmotic lysis of both synaptosome fractions resulted in further enrichment in Thy-1 activity, with no concomitant decrease in yields. The synaptosomal membranes obtained in this way were subsequently treated with Triton X-100 and subjected to further density gradient centrifugation. Although the detergent treatment resulted in some loss of antigenic activity, the gradient fractions that contained Thy-1 also were found by electron microscopy to be richest in synaptic junctional complexes. These findings suggest that Thy-1 is associated with synaptosomes and synaptic junctional complexes and therefore may be involved in the formation and/or maintenance of synaptic connections.

Animals↗
PubMed1978

Effect of methionine-loading on methyl group synthesis and activation in rat brain and liver.

Much greater increases in S-adenosylmethionine concentrations are observed in the liver in response to methionine-loading than in the brain due to differences in the methionine adenosyltransferase activities in these tissues. Liver methione adenosyltransferase exhibits a bimodal saturation curve with a nonlinear Line-weaver-Burk plot, indicating that high methionine concentrations are required for saturation. In the brain the methionine adenosyltransferase is saturated in vitro at a methionine concentration less than the normal physiological concentration. The increased S-adenosylmethionine concentrations in the livers of methionine-treated rats also account for the observed inhibition of N5,N10-methylenetetrahydrofolate reductase activity in this tissue. No inhibition of this enzyme is observed in the brain of methionine treated animals. Nor are S-adenosylmethionine concentrations increased significantly in brain. Serine hydroxymethyltransferase activity responds to methionine-loading by decreasing in brain and increasing in liver.

Animals↗