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Biomedical subjects

J A Cramer

Publications and source records attributed to J A Cramer.

At least 91 records · Page 5Linked to original sources
PubMed1984

Human serum teratogenicity studied by rat embryo culture: epilepsy, anticonvulsant drugs, and nutrition.

Epileptic women have a greater risk for spontaneous abortions and children with birth defects than do nonepileptics. In a unique approach to identifying causes of these problems, we have cultured whole rat embryos for 48 h on blood sera from epileptics. In the first part of the study, three embryos were cultured on each serum sample from 128 different epileptics being treated with either single anticonvulsants or no drug to compare the teratogenicity of these drugs. Sera from subjects receiving either phenobarbital or no drug had comparable frequencies of cultured embryo abnormalities, which were lower than those from subjects taking phenytoin, valproic acid, or carbamazepine. In the second phase of the study, attempts to identify causes for serum teratogenicity led to the finding that the abnormalities and reduced embryo growth produced by many serum samples could be completely overcome by adding vitamins and/or amino acids to the serum. Of 53 samples tested, 32 (60%) were corrected by supplementation (17 of 23 phenytoin, seven of nine phenobarbital, six of 12 carbamazepine, none of six valproic acid, and two of three no drug). Although the results of this study provided a general assessment of drug teratogenicity that agreed with other studies and emphasized the role of nutrition in fetal defects, the importance of individual differences in causes of teratogenicity was also noted.

Amino Acids↗
PubMed1984

Treatment of seizures with medroxyprogesterone acetate: preliminary report.

Medroxyprogesterone acetate (MPA), a synthetic progesterone, was added to the antiepileptic drug regimen of 14 women who had uncontrolled seizures. Of the 11 women who developed amenorrhea, 7 reported fewer seizures during MPA therapy. Overall reductions in seizure frequency averaged 30% (n = 11), declining from a baseline 8.3 +/- 5.8 seizures per month to 5.1 +/- 4.1 seizures per month (p = 0.02). No serious side effects were encountered, but spotting was common. These preliminary data suggest further evaluation of MPA for catamenial seizures.

Epilepsy↗
PubMed1983

A design for the prospective evaluation of the efficacy and toxicity of antiepileptic drugs in adults.

The design for the comparative evaluation of the efficacy and toxicity of phenobarbital, phenytoin, primidone, and carbamazepine is outlined. A double-blind prospective study of a sufficient number of patients can determine the optimum drug to use initially for partial and generalized tonic-clonic seizures in adults. The rationale for methods defines the major parameters that should be addressed in order to determine optimum drug for longterm seizure therapy. Major problems in the function of such a project include aspects of sample size attainment, screening/recruitment, non-drug-related losses, and adjustments to the ongoing protocol. The design, with modifications, can be used to study other antiepileptic drugs and other types of seizures.

Adult↗
PubMed1982

Interaction between valproic acid and carbamazepine: an in vitro study of protein binding.

Valproic acid (VPA) is highly bound to plasma protein (92-96%) and is likely to compete with carbamazepine (CBZ), another drug that is bound extensively (75%). CBZ protein binding was evaluated in vitro by ultrafiltration at concentrations within the therapeutic range (6, 8, and 12 micrograms/ml), while also varying VPA concentrations (0, 50, and 100 micrograms/ml). Using ultrafiltration, we found a significant elevation (p less than 0.01) in free and percent-free CBZ for every CBZ concentration tested as the total VPA concentration increased. Maximal effect was evident at 12 micrograms/ml CBZ. The free fraction increased from 23.5% free CBZ controls (2.85% micrograms/ml free) to 29.5% free CBZ (3.56% micrograms/ml free), with 100 micrograms/ml VPA a 25% increase in free CBZ. This in vitro study demonstrates that VPA competes with CBZ for plasma protein binding sites, resulting in a significant increase in free CBZ that may be clinically important.

Blood Proteins↗
PubMed1980

Reversible trifluoroacetic acid-induced conformational changes in glycophorin A as detected by proton nuclear magnetic resonance spectroscopy.

High-field (270 MHz) 1H-NMR has been employed to study the solution conformation of glycophorin A, a sialoglycoprotein which spans the human erythrocyte membrane. Glycophorin A is one of the most fully characterized integral membrane proteins known, making it an excellent model for the study of membrane-bound proteins. This protein consists of three distinct domains: a glycosylated extracellular N-terminus, a hydrophobic intramembranous segment, and a polar cytoplasmic C-terminus. These domains contain aromatic residues which serve as convenient 1H-NMR conformational probes. The aromatic region of the NMR spectrum of glycophorin A in 2H2O shows single, well-resolved His and Tyr resonances. No resonances are observed, however, for the Phe residues which are located in or near the hydrophobic domain. These observations suggest that considerable heterogeneity with respect to segmental motions exists within the protein. This is consistent with circular dichroism data showing the intramembranous segment to be completely helical with the extremities of the protein being predominantly random coils. The helix of the hydrophrobic domain is remarkably resistant to conventional denaturing conditions including variations in pH, and temperature, and treatment with guanidine hydrochloride. However, in trifluoroacetic acid, which strongly solvates peptide backbones, there is extensive reversible unfolding of the helical structure as evidenced by the appearance of Phe resonances. Solvent titration experiments indicate that approximately a 1 : 1 volume ratio of trifluoroacetic acid to 2H2O is required to initiate unfolding of the helix.

Fluoroacetates↗
PubMed1980

Valproic acid and ethosuximide interaction.

The addition of valproic acid to ethosuximide in treatment to prevent seizures caused increased serum concentration of ethosuximide in four of five patients observed. Ethosuximide levels increased from 73 to 112 microgram/ml (53% higher), with concomitant toxicity. Both were reversed by reduction of the ethosuximide dose from 27.4 to 20.4 mg/kg. Serum concentrations of these two drugs should be monitored closely when they are given together.

Adolescent↗
PubMed1980

Regional pressure differences in the left ventricle.

Theoretically, if blood is to have directional flow and different magnitudes of velocity, pressure should be distributed in the left ventricle (LV) as a function of both space and time. Thus, regional pressure differences (RPD) were examined in the LV of 20 open-chested dogs. High-fidelity transducers were implanted through stab wounds at three positions in the LV: the base (B), equator (EQ), and apex (APX). Simultaneous, high-fidelity LV pressures were compared in each region under rest conditions and during graded infusions of isoproterenol and propranolol. In the baseline condition, there were slight but significant differences between the APX and B in end-diastolic pressure (EDP), peak systolic pressure (PSP), peak dp/dt and Vmax. At rest, the largest RPD between the APX and B in PSP was 9 mm Hg (mean +/- 1 SE = 2.1 +/- 0.5), and the largest during diastole was 5.1 mm Hg (mean +/- 1 SE = 1.2 +/- 0.4); the largest difference in Vmax was 30.5% (mean +/- 1 SE = 10.8 +/- 2.4). During isoproterenol infusion the RPD in PSP were accentuated; the largest seen was 84 mm Hg between APX and B (mean +/- 1 SE = 15.7 +/- 4.5). The largest difference in Vmax between B and APX was 188% (mean +/- 1 SE = 48.5 +/- 9.4). Propranolol obliterated these RPD. These results indicate that there are significant RPD in the LV cavity; during systole the highest pressures decrease sequentially from the apex to the equator and to the base; during diastole these RPD are of lesser magnitude. These RPD affect all derived pressure indices, and these changes can be increaed or decreased by drug intervention. These results are important for two reasons: 1) the position of catheters in the LV cavity is important when pressure-dependent LV parameters are compared in different conditions; and 2) in any force balance analysis of the left ventricle it is important to note that force generation by the left ventricle is an active process that transmits regional pressure differences to the LV cavity.

Animals↗
PubMed1979

Nuclear magnetic resonance determinations of permeation coefficients for maleic acid in phospholipid vesicles.

Lipid bilayer permeation coefficients for the neutral maleic acid molecule and the maleate monoanion have been determined by proton magnetic resonance techniques. Phosphatiydylcholine-cholesterol (2:1) unilamellar vesicles were prepared having an initial maleate anion concentration gradient stabilized by coupling to an impermeant potassium counterion. The coupling was released by addition of valinomycin, and the time evolution of external pH, internal pH, and maleate concentration followed using nuclear magnetic resonance areas and chemical shifts. Transport rate equations were numerically integrated to fit the date, yielding best fit permeation coefficients of 4 X 10(-9) and 4 X 10(-5) cm/s for maleate monoanion and maleic acid, respectively.

Cholesterol↗
PubMed1979

Valproic acid: in vitro plasma protein binding and interaction with phenytoin.

Because valproic acid (VPA) is highly bound to plasma protein, several variables affecting binding will significantly alter the quantity of free drug which is pharmacologically active. Therefore, total VPA plasma concentrations do not reflect the therapeutic strength of the drug in tissue. We have performed equilibrium dialysis and ultrafiltration studies of VPA binding to plasma protein. The converging data in these in vitro studies indicate a clinically significant alteration in the percent of free VPA when total drug concentration exceeds 80 micrograms/ml. Saturation of drug binding sites probably occurs in this range. At 20--60 micrograms/ml VPA there is 5% free drug, with a significant increase to 8% free at 80 micrograms/ml; free drug increases to over 20% at 145 micrograms/ml total VPA. Human plasma, which is low in albumin, has twice the quantity of free VPA as normal plasma (10 versus 5% free). The clinical evidence of interaction between VPA and phenytoin is confirmed in vitro by the increase in the free fraction of both drugs. VPA binding decreases by 3--6%, while phenytoin binding decreases 5--6% as both drugs reach high plasma concentrations. When appropriate, laboratory reports should be available defining concentration of free drug in plasma for optimal interpretation of drug concetrations relative to clinical effects.

Blood Proteins↗