Biomedical subjects
Publications and source records attributed to R M Cohen.
A chronically depressed patient who had not responded to treatment with several tricyclic antidepressants and monoamine oxidase inhibitors alone, responded within hours following the addition of lithium to ongoing tranylcypromine treatment in a double-blind medication trial. The findings are discussed in the context of reports of lithium augmentation of other antidepressants.
Twenty-four patients presenting with cough and/or nonwheezing dyspnea were evaluated with methacholine inhalation challenge (MC), distilled water inhalation challenge (DC), intracutaneous tests to varying concentrations of methacholine, total eosinophil counts (TEC), sinus and chest x-rays. We found a statistically significant difference (P less than .005) in the mean TEC in those patients with a positive MC test and those with a negative test. Hyperreactivity of the airways to methacholine in asthmatics is not found in the skin. Distilled water inhalation did not serve to substitute for MC as a test of hyperreactive airways. The TEC is an excellent screening test as a predictor of patients with cough or dyspnea who have hyperreactive airways.
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Long-term administration of the tricyclic antidepressant desipramine did not change the rate of self-stimulation responding in the A10 (ventral tegmental) area but significantly attenuated the suppressive effect of the selective alpha 2-adrenergic agonist clonidine on this behavior. These findings demonstrate an involvement of noradrenergic mechanisms in the regulation of ventral tegmental self-stimulation and further suggest that adaptive changes in inhibitory presynaptic noradrenergic receptors may be involved in desipramine's antidepressant effects.
Treatment of rat cerebral cortical membranes with phospholipase A2 affects, in a parallel fashion, beta-, alpha 1- and alpha 2-adrenergic receptor binding, but not the affinity of these receptors for their respective ligands. Pretreatment of membranes with 0.1 percent glutaraldehyde blocks the effects of phospholipase A2 on adrenergic receptor binding. The results support the hypothesis that desensitization or "masking" of adrenergic receptors may involve changes in membrane lipid composition. Furthermore, glutaraldehyde may prove a useful tool in the investigation of the dynamic roles of lipids in receptor function and more specifically, their regulation and coupling to physiological events.
Deprenyl has previously been reported to be a selective monoamine oxidase (MAO) type B inhibitor, which is associated with little or no enhancement of the pressor effects of tyramine. Employing an intravenous steady-state tyramine infusion technique, the effects of different doses of deprenyl and, for comparison, the mixed inhibitor tranylcypromine on the pressor response to tyramine were studied in 11 depressed patients. After 3 weeks of treatment, deprenyl produced dose-proportionate increases in tyramine sensitivity at all three doses (10, 30, and 60 mg/day) when compared to placebo baseline tyramine responses. While only a modest (3.7-fold) increase in tyramine sensitivity was found with the 10 mg/day deprenyl dose, the increase in tyramine sensitivity at the 60 mg/day dose of deprenyl (22-fold) approached that found with tranylcypromine. Reductions in plasma 3-methoxy,4-hydroxyphenylglycol (MHPG), used as a possible index of in vivo MAO-A inhibition, were highly correlated with increases in tyramine pressor sensitivity (r = 0.82). The data suggest that deprenyl acts as a relatively selective MAO-B inhibitor at low doses, but that this selectivity is lost at higher doses, resulting in a significant "crossover" inhibition of MAO-A and increased tyramine pressor sensitivity.
A challenge paradigm was designed to test the functional sensitivity to anticholinergic agents in Alzheimer's disease. Ten patients with dementia of the Alzheimer type were serially administered three different intravenous doses of the centrally active anticholinergic drug scopolamine and placebo. Testing was carried out in a placebo-controlled, double-blind fashion to measure cognitive, physiologic and behavioral changes. Alzheimer patients showed a marked, dose-related behavioral and cognitive sensitivity to temporary cholinergic blockade. Scopolamine testing may serve as an index of the status of central cholinergic functional integrity, and ultimately may prove useful as a diagnostic or staging test in the evaluation of the cholinergic system in dementia. Research is currently under way with elderly age-matched controls and populations with other neuropsychiatric disorders to explore this hypothesis further.
The effects of 6-hydroxydopamine (6-OHDA) lesions on brain adrenergic receptor adaptation to 21 days of treatment with the selective monoamine oxidase type A (MAO-A) inhibitor clorgyline were studied in rats. 6-OHDA pretreatment effectively blocked the decrease in alpha 1-, alpha 2- and beta-adrenergic receptor densities observed in response to clorgyline treatment. In saline-treated rats, 6-OHDA reduced norepinephrine (NE) to 8% of control levels, modestly reduced dopamine (DA) to 67% of controls, but did not affect serotonin (5HT) levels in the cortex, Clorgyline administration to shams increased NE and 5HT to 239% and 160% of their respective control levels, but did not effect DA levels. 6-OHDA lesions attenuated clorgyline's effect on cortical NE levels but not 5HT. The results suggest that beta-adrenergic receptor adaptation to MAOI's as with tricyclic antidepressants is a response to an increase in catecholamine receptor occupancy, and that a similar molecular mechanism is responsible for the observed clorgyline induced changes in alpha-adrenergic receptors.
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The effects of monoamine oxidase inhibiting antidepressant drugs on behavioral and biochemical measures of dopamine receptor status were measured in the rat. Male Wistar rats received clorgyline (1 mg/kg/day for 21-28 days), pargyline (1 mg/kg/day for 21-28 days) or a combination of these regimens. They were then either tested for stereotypy induced by 1 mg/kg SC injection of apomorphine or were sacrificed and their striata used to measure specific [3H]spiroperidol binding. All three chronic treatment regimens produced statistically significant increases in apomorphine induced stereotypy: there was, however, no significant difference between the three drug regimens. None of the antidepressant drug treatments significantly affected [3H]spiroperidol binding in the corpus striatum. This study demonstrates that behavioral and biochemical measures of dopamine function may not always be closely correlated. It is proposed that the behavioral changes may be related to alterations in other monoaminergic systems, which are known to have fibres running into the nigrostriatal pathway.
Utilizing a double-blind crossover design, the hormonal effects of high dose, 2 mg/kg, were compared to low dose, 0.4 mg (approx. 5 micrograms/kg), naloxone administration in physically healthy humans. A significant naloxone dose effect on plasma cortisol levels was found (p less than 0.001), but no significant effect on plasma or serum levels of prolactin, follicle stimulating hormone, luteinizing hormone, norepinephrine or epinephrine. These results confirm involvement of the endogenous opioid system (EOS) in the tonic regulation of the hypothalamicpituitary-adrenal axis, but fail to find evidence of EOS involvement in the regulation of adrenal medullary function or the gonadotrophic axis in man. The results are however consistent with a continuing action of naloxone as an EOS antagonist even at high doses in man.
Dementia of the Alzheimer type (DAT) is known to be a heterogeneous syndrome with many clinical manifestations, including depression. In the present study, the thyrotropin-releasing hormone (TRH) stimulation test, previously used as a possible biological marker of depression, was administered to 15 DAT patients and 10 elderly controls. Seven out of 15 (47%) of the patients but none of the controls showed a blunted response with maximal changes of thyroid-stimulating hormone (TSH) from baseline of less than or equal to 7 microIU/ml following injection of 500 micrograms of TRH. The degree of blunting did not correlate with concurrent depression ratings.
Positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose was performed in nine chronic schizophrenic patients both when medication-free and when medicated with neuroleptics. Total brain cortex, temporal cortex, and basal ganglia glucose use was significantly increased with medication; however, there was no change in anterior/posterior metabolic gradients.
Since a complete map of insulin-related peptides in humans requires consideration of proinsulin, Arg32/Glu33-split proinsulin, Arg65/Gly66-split proinsulin, des-Arg31,Arg32-proinsulin, des-Lys64, Arg65-proinsulin, and insulin, we applied high performance liquid chromatography coupled with radioimmunoassay to investigate the formation of proinsulin conversion intermediates in vitro and in vivo. Kinetic analysis of proinsulin processing by a mixture of trypsin and carboxypeptidase B (to stimulate in vivo processes) revealed (a) a rapid decline in proinsulin concommitant with formation of conversion intermediates, (b) formation of des-Arg31, Arg32-proinsulin and des-Lys64,Arg65-proinsulin in the ratio 3.3:1 at steady state, and (c) complete conversion of the precursor to insulin during extended incubation. Studies on normal human pancreas identified a similar ratio of des-Arg31,Arg32-proinsulin to des-Lys64,Arg65-proinsulin (approximately 3:1), whereas two insulinomas contained sizable amounts of des-Arg31,Arg32-proinsulin, but barely detectable amounts of des-Lys64,Arg65-proinsulin. None of the tissues contained measurable quantities of Arg32/Glu33- or Arg65/Gly66-split proinsulin. Analysis of plasma from three diabetic subjects managed by the intravenous infusion of human proinsulin revealed less than 1% processing of the circulating precursor to conversion intermediates and no processing of the precursor to human insulin. Nevertheless, analysis of plasma from the same subjects managed by the subcutaneous infusion of proinsulin revealed 4-11% processing of the precursor to intermediates that had the properties of des-Arg31,Arg32-proinsulin and Arg65/Gly66-split proinsulin. We conclude that (a) processing of proinsulin to insulin in vivo as in vitro likely occurs by preferential cleavage at the Arg32-Glu33 peptide bond in proinsulin, (b) proinsulin is inefficiently processed in the vascular compartment, and (c) subcutaneous administration of the precursor can result in the formation of conversion intermediates with the potential for contributing to biological activity.
A radioimmunoassay for human proinsulin (hPl) has been developed using biosynthetic hPl prepared by recombinant DNA technology as immunogen, standard, and tracer. The antiserum was raised in a guinea pig and then adsorbed against insulin and C-peptide conjugated to Sepharose to improve its specificity. After adsorption of the antiserum, the cross-reactivities to insulin and C-peptide were each less than 0.2%. Competition studies using in vitro enzymatically split forms of proinsulin demonstrated that the major antigenic determinant recognized was the junctional region between the B-chain of insulin and the C-peptide. The range of the assay extended from 10 to 150 fmol/tube, with a 50% displacement of 45-55 fmol/tube. This sensitivity proved suitable for measurements of serum hPl concentrations during infusion of biosynthetic hPl into normal subjects and type I diabetic subjects. Eighty-five of 89 serum samples from the normal subjects and each of 20 samples from diabetic subjects diluted in parallel with the hPl standard. Since the direct assay sensitivity was not sufficient for measurement of endogenous hPl levels, a simple procedure for quantitative extraction of proinsulin-like material (PLM) from up to 40 ml of plasma on insulin antibody-Sepharose columns was developed. Logit-log slopes were calculated for dilutions of extracts of samples collected in the fasting state and 60 min after 75 g or oral glucose from eight healthy subjects. The slopes of 15 of the 16 samples did not differ significantly from the slope of the hPl standard.(ABSTRACT TRUNCATED AT 250 WORDS)
Cortical function during insulin-induced hypoglycemia was studied in 14 normal controls and 12 type I diabetic patients by measuring the reaction time to a visual stimulus. Each subject was studied on two occasions, during insulin-induced hypoglycemia and under euglycemic conditions. The mean reaction time during euglycemic conditions was 260 +/- 6 ms in the controls and 309 +/- 11 ms in the diabetic subjects (P less than 0.001) and did not change significantly over a 2-h period. Intravenous (i.v.) insulin administration to both groups of subjects resulted in similar reductions in glucose concentrations, which were maintained below 50 mg/dl for at least 30 min. Under these conditions, the reaction time increased significantly (mean increase 104 +/- 37 ms [P less than 0.02] in the controls and 75 +/- 28 ms [P less than 0.02] in the diabetic subjects). However, significant variability in responsiveness was observed in individual subjects. Three of the 14 controls and 4 of the 12 diabetic subjects showed no significant change in reaction time during hypoglycemia, while the remainder demonstrated significant increases. Individual differences were not correlated with severity or duration of hypoglycemia or counterregulatory hormone responses. The maximum increase in reaction time occurred as long as 60 min after the nadir glucose and returned to baseline 10-40 min after normalization (greater than 60 mg/dl) of the plasma glucose level. Subjective awareness of hypoglycemia was unrelated to the change in reaction time.(ABSTRACT TRUNCATED AT 250 WORDS)
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