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C R Freed

Publications and source records attributed to C R Freed.

At least 91 records · Page 5Linked to original sources
PubMed1982

Normal rats trained to circle show asymmetric caudate dopamine release.

Caudate catecholamine release was monitored by bilateral in vivo electrochemical electrodes in male Sprague-Dawley rats trained to circle for sucrose/water reward. Baseline release of dopamine was equal from both sides of caudate. When reinforced circling began, 44 +/- 4 percent greater catechol release occurred from the caudate contralateral to the circling direction. As turning subsided, differential release returned to basal levels. Further evidence that the catecholamine metabolism was affected by turning was obtained by direct measurement of caudate dopamine and DOPAC at selected time points. Concentration data showed relative increases in dopamine and DOPAC in the contralateral caudate. These data provide evidence that dopamine is released asymmetrically from caudate in unlesioned rats during voluntary behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Extracorporeal pump assistance--novel treatment for acute lidocaine poisoning.

Accidental bolus administration of lidocaine ranging in dosages from 1000 mg to 2000 mg has caused death in humans. Because lidocaine clearance depends upon hepatic blood flow, drug clearance in a hypotensive overdosed patient is poor so that a drug overdose is likely to be irreversible. Traditional approaches to drug removal include hemodialysis and charcoal hemoperfusion. Neither treatment would be effective for lidocaine overdose because the drug is a myocardial depressant and because the clearance rates of these techniques are 100-200 ml/min. Hepatic clearance of lidocaine is 1000 ml/min in a human with normal cardiac output. We have tested a new concept for removal of high clearance drugs that are associated with myocardial depression. Cardiac bypass support was used in a dog experiment to demonstrate that restoration of cardiac output could restore high clearance of lidocaine. Sixteen anesthetized dogs were given 30 mg/kg boluses of lidocaine. In one group of eight dogs, toxicity was treated with antiarrhythmic drugs, pressor drugs and cardioversion. Six out of eight of these animals died within 30 min after lidocaine infusion. In the second group of eight dogs, an extracorporeal bypass pump was used for 90 min after the lidocaine injection. None of these assisted animals died. Drug clearance in dogs treated with the extracorporeal pump was compared to drug clearance in eight dogs that received non-toxic lidocaine doses of 3 mg/kg. Drug clearance was 39.75 +/- 4.16 ml/kg/min in the overdosed animals compared to 38.29 +/- 8.6 ml/kg/min in the non-toxic animals. Thus, drug clearance was normal in dogs treated with the extracorporeal pump. These experiments suggest that short-term support of the circulation with an extracorporeal pump could theoretically be effective in reducing patient mortality from acute massive lidocaine overdose.

Animals↗
PubMed1981

A rapid and simple microassay for lidocaine in human blood plasma using gas-liquid chromatography with nitrogen detection.

Lidocaine is widely used in antiarrhythmic therapy, and the need to monitor the drug concentration in the blood of patients receiving lidocaine is well established. We have developed a new assay for lidocaine designed for the routine clinical therapeutic drug monitoring laboratory. A 100-microliter aliquot of blood plasma is treated with 50 microliters of internal standard solution and the mixture alkalinized. The drug and internal standard are extracted with toluene and analyzed by nitrogen-detection gas-liquid chromatography. A single extraction is used, and no solvent evaporation is required, resulting in a simple and rapid procedure. Using the single-point standard, the within-day coefficient of variation (CV) was 6.4%, while the between-day CV was 7.4%. Monoethylglycinexylidide, the major plasma metabolite of lidocaine, and several drugs potentially present in patients receiving lidocaine were shown not to interfere. The procedure has significant advantages over previously published similar methods.

Chromatography, Gas↗
PubMed1980

Antihypertensive pharmacology.

Although drug treatment of hypertension is associated with improved survival and decreased vascular complications, drug compliance is a major problem in the control of hypertension. All antihypertensive medications are associated with side effects; thus, it is a physician's responsibility to explain to each patient the side effects of the drugs he prescribes to treat hypertension, and to instill in the patient a sense of necessity for the treatment of hypertension. The choice of antihypertensive drug should be made based on each patient's lifestyle, overall health and ability to tolerate the drug. Ideally, the antihypertensive regimen should be simple, effective, convenient to take and have very few side effects.

Adolescent↗
PubMed1979

Reversed-phase high-performance liquid chromatography of catecholamines and their congeners with simple acids as ion-pairing reagents.

We have investigated the value of various common acids as ion-pairing reagents for high-efficiency separations of catecholamines and their metabolites in reversed-phase high-performance liquid chromatography. The retention of norepinephrine, alpha-methylnorepinephrine, dopamine, alpha-methyldopamine, L-dopa, alpha-methyldopa, dihydroxybenzylamine, epinephrine, carbidopa and DOPAC was measured in mobile phases composed of nitric, sulfuric, acetic and trichloroacetic acids at pH 2-5 and anion concentrations ranging from 5-500 mM. The solute capacity ratios were dependent on the hydrophobicity and concentration of the ion-pairing reagent and the pH of the mobile phase. Good retention, peak symmetry and high efficiency (3000 theoretical plates for 300 mm) was found for mobile phases composed of the strong inorganic acids and trichloroacetic acid. Chromatography was compared to that seen using the detergent sodium octylsulfate. Trichloroacetic acid gave retention and efficiency similar to sodium octylsulfate. These experiments show that simple acids can replace alkylsulfates as ion-pairing reagents for the separation of the catecholamines and their metabolites.

Catecholamines↗
PubMed1979

Drug acetylation phenotype unrelated to development of spontaneous systemic lupus erythematosus.

To ascertain if a genetically determined slow drug acetylation rate is correlated with the development of spontaneous systemic lupus erythematosus (SLE), as it is in drug-induced SLE, acetylation phenotypes of 27 patients with spontaneous SLE were determined after administration of dapsone. Thirty-three percent were slow acetylators, 63% were rapid acetylators, and one was indeterminate, a distribution not significantly different from that expected in control subjects. Among 4 pairs of first-degree relatives, all of whom had spontaneous SLE, 7 of the 8 individuals were rapid acetylators. We conclude that people who are slow acetylators are at no greater risk for developing spontaneous SLE than are rapid acetylators and that the slow acetylation phenotype is not correlated with familial SLE.

Acetylation↗
PubMed1978

Mass spectrometric measurement of catecholamine turnover in rat hypothalamus after long-term L-dopa infusion.

To test the effect of L-dopa on norepinephrine turnover in rat hypothalamus, we gave steady-state, long-term (19-hour) infusions of L-dopa to conscious, restrained rats. After 19 hours, infusions were switched to identical doses of 2,5,6-trideutero-L-dopa (D3-L-dopa) and production of D3-dopamine and D3-norepinephrine was followed at intervals thereafter. Animals were sacrificed and their hypothalami were dissected and divided into left and right halves. Using gas chromatography-mass spectrometry, we measured isotopic enrichment with one side of the hypothalamus and, after the addition of deuterated internal standards, determined total concentration of dopamine and norepinephrine in the other half of the same hypothalamus. Maximal steady-state enrichment by a given dose of D3-L-dopa was determined by 19-hour infusions of D3-L-dopa alone. Results show that total dopamine production is proportional to dopa dose. Norepinephrine synthesis, on the other hand, proceeds at a constant rate that is independent of dopa dose or dopamine concentration and which is similar to the endogenous rate reported by others using tracer techniques.

Animals↗
PubMedDate not supplied

Trained and amphetamine-induced circling behavior in lesioned, transplanted rats.

Rats were trained to turn for water reinforcement and then were given unilateral 6-hydroxydopamine lesions. After lesion, rats showed deficits in trained turning both contra- and ipsilateral to the side of the lesion, with contralateral turning more severely impaired. The lesioned rats were then transplanted with fetal mesencephalic dopamine tissue into striatum. A control group of lesioned rats were sham transplanted. Four weeks after transplant, 1.5 mg/kg D-amphetamine challenge injections were used to test the functioning of the transplants. In the control rats, D-amphetamine induced ipsilateral turning; in transplanted rats, D-amphetamine slowed the rate of ipsilateral turning or reversed the direction of amphetamine-induced rotation. Only rats which reversed their amphetamine-induced turn direction after transplant were used for the rest of the experiment. Trained turning was assessed at 4, 8, 12 and 16 weeks post transplant. Transplants did not improve learned performance at any time post transplant. When D-amphetamine was administered in conjunction with the trained turning sessions, a low dose (0.12 mg/kg) enhanced contralateral trained turn rates, without affecting ipsilateral turn rates. Higher doses of amphetamine reduced ipsilateral turn rate in the transplanted animals. The results of this study suggest that transplants alone do not reinstate performance of conditioned rotation.

Animals↗
PubMedDate not supplied

Changes in brain alpha-adrenergic receptors after alpha-methyldopa administration to spontaneously hypertensive rats.

The hypotensive action of methyldopa has been linked to production of the metabolites methyldopamine and methylnorepinephrine in brain. We have studied the effect of long-term (72 hour) intravenous infusions of methyldopa to awake restrained spontaneously hypertensive rats and normotensive Wistar-Kyoto control animals to look for differences in hypotensive effect, differences in concentrations of natural and alpha-methylated catecholamines, and differences in alpha 1 and alpha 2-adrenergic receptor populations. Results described here indicate that hypertensive rats have a greater reduction in blood pressure and a larger increase in hypothalamic and brain stem methylnorepinephrine concentrations than do the normotensive animals. The methylnorepinephrine concentration reached a plateau value in hypothalamus in both strains while pons and medulla showed progressive, dose-related increases in concentration. These regional and strain differences in the metabolism of alpha-methyldopa suggest that the production of methylnorepinephrine in brain stem nuclei is most correlated with the hypotensive action of methyldopa. alpha 2 Agonist binding (p-amino-clonidine) declined in both hypothalamus and brain stem, and the fall was greater in hypertensive than in normotensive rats. alpha 1-Adrenergic receptor binding (prazosin) was increased, again more in hypertensive than in normotensive rats. The down regulation of alpha 2-adrenergic receptors and the up regulation of alpha 1-adrenergic receptors are compatible with increased alpha 2-adrenergic agonist presynaptic inhibition of catecholamine release with resultant postsynaptic alpha 1-adrenergic receptor supersensitivity. Spontaneously hypertensive rats showed greater methylnorepinephrine production, larger up regulation of alpha 1-adrenergic receptors, and greater down regulation of alpha 2-adrenergic receptors than did the normotensive animals; these changes may be physiological markers for the greater antisympathetic action of methyldopa in hypertensive animals.

Animals↗
PubMedDate not supplied

Immunological responses to injury and grafting in the central nervous system of nonhuman primates.

Allogeneic transplantation for the therapy of human Parkinson's disease is being considered as a viable approach at several clinical centers worldwide. As an attempt to understand the basic biology of central nervous system (CNS) transplantation, our laboratory has developed an experimental nonhuman primate model for human Parkinson's disease and carried out preliminary studies directed at evaluating the potential pathology at the graft site. In addition, studies have been conducted to examine whether such transplantation procedures lead to specific and/or nonspecific immunologic sensitization of the host or results in generalized immunosuppression. Groups of rhesus macaques (Macaca mulatta) were either controls operated (n = 6), autografted with adrenal medullary and peripheral nerve tissue (n = 3), or allografted with fetal mesencephalic tissue (n = 6). Immunohistological studies demonstrated the presence of mononuclear cell infiltrates as early as 1 wk and up to 1 yr postoperatively, although the frequency of the infiltrating cells declined with time. The infiltrates consisted of variable numbers of cells which express CD2+, CD3+, CD4+, CD8+, CD19+, CD22+, CD25+, and CD68+. There appeared to be no difference in the frequency, kinetics, or phenotype of the infiltrating cells in operative controls compared with recipients of auto- or allografts. Tissue sections obtained postoperatively showed low levels of major histocompatibility complex (MHC) Class I antigens and no detectable level of MHC-Class II antigens in neural tissue. A small aliquot of tissue from the operative site was placed in vitro with media containing interleukin-2 (IL-2), which led to the exudation and growth of mononuclear cells that were predominantly CD4+ cells. Phenotypic studies of peripheral blood mononuclear cells (PBMC) from operative controls, auto- and allograft recipient monkeys performed at varying time periods postoperatively failed to show differences in the frequencies of subsets of T-cells, B-cells, NK-cells, or monocytes. Studies on aliquots of the same PBMC failed to show major functional differences in NK-cells, LAK cells, or response to polyclonal mitogens. Finally, recipients of allogeneic mesencephalic grafts failed to show evidence of donor-specific humoral or cellular sensitization. These data indicate that transplantation of autograft adrenal or allograft fetal mesencephalic tissues in the CNS of nonhuman primate did not induce detectable donor-specific sensitization nor nonspecific immunosuppression.

Adrenal Medulla↗
PubMedDate not supplied

Neural transplantation of hNT neurons for Huntington's disease.

Fetal striatal tissue transplants have been shown to restore motor deficits in rat and monkey models of Huntington's disease (HD). In the present study, using rats with unilateral striatal lesions, we compared fetal striatal tissue transplants to transplants of human NT (hNT) neurons. hNT neurons are terminally differentiated cells derived from the human NTera-2 cell line. In vitro, we have found that purified hNT neurons have a biochemical phenotype similar to that of human fetal striatal tissue. Both hNT neurons and fetal striatal tissue express mRNAs for glutamic acid decarboxylase, choline acetyltransferase, and the D1 and D2 dopamine receptors. Grafts of either hNT neurons or fetal striatal tissue into unilateral quinolinic acid-lesioned rat striatum improved methamphetamine-induced circling behavior. Sham controls showed no changes in methamphetamine-induced circling behavior. In the staircase test for skilled forelimb use, both transplant groups showed partial recovery in skilled use of the paw contralateral to the side of lesion, whereas the control animals showed continued deficits. These findings suggest that transplantation of hNT neurons may be an alternative to transplantation of fetal striatal tissue in the treatment of HD.

Animals↗