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Biomedical subjects

R M Cohen

Publications and source records attributed to R M Cohen.

At least 127 records · Page 7Linked to original sources
PubMed1988

Bicarbonate secretion modulates ammonium absorption in rat distal colon in vivo.

Although the mammalian colon is thought to absorb large quantities of total ammonia, principally in the form of NH3, quantitative support for this hypothesis is lacking. In rat distal colon, we observed that NH3 was approximately 400 times more permeant than NH+4. In addition, colonic HCO-3 secretion influenced total ammonia (NH3 plus NH+4) absorption; that is, alteration of HCO-3 secretion caused a parallel change in total ammonia absorption. Perfusion with total ammonia also caused net HCO-3 secretion to switch to net absorption, and, in the setting of preexisting HCO-3 absorption, perfusate containing total ammonia enhanced HCO-3 absorption. These events suggest that colonic HCO-3 secretion titrates luminal NH+4 to NH3, permitting NH3 to diffuse from the lumen, while HCO-3 is titrated to carbon dioxide and also diffuses from the lumen. In support of titration of NH+4 and HCO-3, the magnitude of induced HCO-3 absorption approximated total ammonia absorption. This titration relationship suggests that, in kinetic studies, total ammonia absorption will be limited by a fixed rate of HCO-3 secretion. A model was developed that simulated these events.

Algorithms↗
PubMed1988

A new scale for the assessment of depressed mood in demented patients.

Twenty-one subjects with clinically diagnosed dementia of the Alzheimer type were rated on the Dementia Mood Assessment Scale, a new instrument intended to measure the severity of depressed mood in cognitively impaired patients. Ratings were based on direct observation and a semistructured interview of the patient. Interrater reliability was established. There were highly significant correlations between patients' scores on the instrument's 17-item depression subscale and their scores on global measures of depression and sadness. The potential usefulness of this new scale in assessing the severity of depression in demented patients longitudinally or under drug treatment conditions is discussed.

Adult↗
PubMed1988

Tranylcypromine compared with L-deprenyl in Alzheimer's disease.

The authors have previously reported mild improvement of behavior and cognition in a group of 17 nondepressed patients with dementia of the Alzheimer type (DAT) treated with two doses of L-deprenyl (10 and 40 mg/day). Seven of these patients subsequently received double-blind, placebo-controlled treatment with tranylcypromine. The patients experienced significant side effects, particularly orthostatic hypotension without compensatory pulse increase, during tranylcypromine treatment. These effects were more severe than those occurring during L-deprenyl treatment, and they occurred at substantially lower doses (mean dose, 16 mg/day). These data support the role of the inhibition of monoamine oxidase type A in the development of orthostatic hypotension in patients treated with monoamine oxidase inhibitors. They also raise the question of whether the observed sensitivity to monoamine oxidase inhibition is a function of age or disease. In either case, the greater toxicity of tranylcypromine makes inferences difficult regarding the relative efficacies of these drugs in treating patients with dementia of the Alzheimer type and may limit the potential usefulness of tranylcypromine in ameliorating some symptoms of this disease.

Aged↗
PubMed1987

Dysfunction in a prefrontal substrate of sustained attention in schizophrenia.

Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.

Adult↗
PubMed1987

MPP+ (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-, norepinephrine- and serotonin-containing neurons.

1-Methyl-4-phenylpyridine (MPP+) is an oxidative metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). MPP+ produced local cell death when injected directly into substantia nigra compacta, locus coeruleus, or dorsal and median raphe nuclei of rats. Corresponding significant decreases in dopamine, serotonin and norepinephrine levels were observed in the terminal areas. These observations indicate that MPP+ is a non-selective neurotoxin which causes lesions not only in dopaminergic neurons but also in noradrenergic and serotonergic systems following intracranial administration. Selective lesioning of these monoaminergic systems could only be achieved by a stereotaxic injection of MPP+ into specific brain regions containing monoamine neurons.

1-Methyl-4-phenylpyridinium↗
PubMed1987

The effects of biosynthetic human proinsulin on carbohydrate metabolism in non-insulin-dependent diabetes mellitus.

We compared the glucose-lowering effect of proinsulin, the precursor molecule of insulin, with that of insulin itself. In patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom proinsulin (0.2 U per kilogram of body weight) was subcutaneously injected at 9 a.m., fasting glucose levels (247 +/- 22 mg per deciliter [+/- SEM]) became normal within six hours and elevated rates of hepatic glucose output were lowered. The response to regular insulin (0.2 U per kilogram) was of similar magnitude but faster. Glucose clearance was stimulated less by proinsulin, reflecting its preferential action in suppressing glucose output. Hypoglycemia occurred in five of nine insulin-treated patients, but in only one of nine proinsulin-treated patients. After proinsulin injection at bedtime (30.5 +/- 4 U), serum proinsulin concentrations reached a peak by five hours and declined gradually thereafter. Fasting hepatic glucose output became normal, and euglycemia was sustained without overnight hypoglycemia. Proinsulin reduced plasma glucose more effectively than an equal unit dosage of NPH insulin, but since higher doses of NPH insulin were not used, no conclusions could be drawn about the relative desirability of these preparations for clinical use. We conclude that subcutaneously injected proinsulin has prolonged pharmacokinetics in plasma and can normalize plasma glucose in NIDDM characterized by severe hyperglycemia; as compared with the hypoglycemic effects of regular insulin, those of proinsulin are mostly due to suppression of hepatic glucose output, with little stimulation of glucose disposal and less hypoglycemia; and proinsulin may have a role in the treatment of NIDDM.

Blood Glucose↗
PubMed1987

Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose-response study.

We compared the cognitive and behavioral responses to three intravenous doses of scopolamine (0.1, 0.25, and 0.5 mg) and placebo of ten patients with dementia of the Alzheimer type (DAT) and ten age- and sex-matched elderly control subjects. The patients with DAT showed significant behavioral and cognitive but not physiologic changes at a lower scopolamine dose (0.25 mg) than did the normal elderly controls. Cognitive tests of new learning and semantic knowledge revealed significant impairments at the 0.25-mg scopolamine dose in the patients with DAT, while the responses of the control population were essentially unchanged. Behaviorally, mild euphoria, motor incoordination, and hostility occurred in the patients with DAT but not the controls at the 0.25-mg dose. These differences were unrelated to peripheral physiologic changes produced by the different scopolamine doses. These results indicate that central nervous system functions such as cognition and certain elements of behavior are more sensitive to temporary cholinergic blockade in patients with DAT than in normal age-matched controls. We review implications concerning the status of central cholinergic function in patients with DAT in light of neuropathologically demonstrated cholinergic system lesions in DAT.

Age Factors↗
PubMed1987

L-deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition.

Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

Adult↗
PubMed1987

Cognitive effects of L-deprenyl in Alzheimer's disease.

Monoamine neurotransmitter systems, along with cholinergic systems, are known to play important roles in cognition, and are disrupted in at least some patients with dementia of the Alzheimer type (DAT). This suggests that monoamine-enhancing drugs might ameliorate cognitive symptoms in certain patients with DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor which may selectively inhibit MAO-B at low doses, while at high doses it nonselectively inhibits MAO-A as well as MAO-B. We studied its effects on several types of cognitive function in 17 patients with DAT. Two doses of L-deprenyl (10 mg/day and 40 mg/day) and placebo were compared in a double-blind, serial treatment design. Episodic learning and memory, knowledge memory, attention, recognition, and performance on a continuous performance task were assessed at baseline and under these drug and placebo conditions. Statistically significant improvement was noted in performance on an episodic memory and learning task requiring complex information processing and sustained conscious effort during treatment with L-deprenyl 10 mg/day. Knowledge memory, intrusions, and other cognitive functions relevant to DAT were not altered by L-deprenyl at either dose.

Adult↗
PubMed1987

Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease.

Deprenyl, a monoamine oxidase (MAO) inhibitor with selective effects on MAO type-B at low doses, was administered to 13 patients with dementia of the Alzheimer type (DAT), a disorder reported to be associated with increased brain MAO-B activity. Cerebrospinal fluid was obtained for measurement of three monoamine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), by high pressure liquid chromatography with electrochemical detection. Deprenyl treatment (10 mg/day) for 3-4 weeks was associated with small but statistically significant reductions in HVA (21%) and 5-HIAA (15%) compared to baseline values. Subsequent administration of deprenyl at the higher dose of 40 mg/day for 3-4 more weeks led to greater reductions in HVA (40%) and MHPG (43%) than 5-HIAA (20%). These dose-dependent reductions are consistent with in vitro biochemical and anatomical data from primate brain suggesting that at low doses of deprenyl, MAO-B inhibition might be expected to selectively affect dopamine and serotonin-containing neurons, while at higher doses (which lead to MAO-A as well as MAO-B inhibition), noradrenergic neurons may become relatively more affected by the drug.

Aging↗
PubMed1987

Long-term imipramine treatment enhances locomotor and food intake suppressant effects of m-chlorophenylpiperazine in rats.

1 Administration of the 5-HT1B receptor agonist m-chlorophenylpiperazine (m-CPP) to rats produces dose-dependent decreases in locomotor activity and food intake. 2 The locomotor suppressant effect of m-CPP was inhibited by the 5-hydroxytryptaminergic antagonist, metergoline, but not by phentolamine, propranolol, clonidine, or haloperidol. 3 The locomotor suppressant effects of m-CPP were enhanced following long-term (but not short-term) treatment with imipramine, possibly reflecting the postulated development of a functional supersensitivity of 5-HT1B receptors mediating locomotion during longer-term antidepressant drug treatment. 4 The food intake suppressant effects of m-CPP were enhanced following both short (3-5 days) and longer-term (21 days) treatment with imipramine. Rapidly developing 5-hydroxytryptamine uptake inhibition may be responsible for this change, or it may represent an earlier adaptive change in the 5-HT1B receptors mediating food intake compared to more complexly modulated motor responses.

Animals↗
PubMed1987

CSF somatostatin in patients with Alzheimer's disease, older depressed patients, and age-matched control subjects.

Somatostatin-like immunoreactivity was measured in the CSF of 12 patients with Alzheimer's disease, 15 age-matched control subjects, and 20 older depressed subjects. Patients with dementia or depression were found to have lower CSF somatostatin concentrations than control subjects despite markedly different clinical presentations. Severity of depression was clearly different in all three groups but showed no significant correlation with CSF concentration of somatostatin. There was a significant positive correlation between CSF somatostatin-like immunoreactivity and cognitive functioning in all 47 subjects, but this association was not statistically significant within individual diagnostic groups. These data raise interesting questions about possible biological links between Alzheimer's disease and depression in older patients.

Age Factors↗
PubMed1987

The effect of biosynthetic human proinsulin on the hepatic response to glucagon in insulin-deficient diabetes.

The relative tissue specificities of biosynthetic human proinsulin and porcine insulin were compared in eight insulin-deficient diabetic patients. Variable proinsulin and insulin infusions were administered iv for at least 18 h on separate occasions to achieve euglycemia. Once equivalence with respect to this end point was established, the paired infusions were made constant and compared with respect to their effect on plasma glucose, hepatic glucose output (Ra), glucose utilization, glucose clearance, and blood beta-hydroxybutyrate, alanine, and glycerol in response to a glucagon infusion (3 ng/kg X min). Basal Ra did not differ between euglycemia established using proinsulin vs. insulin [1.92 +/- 0.12 vs. 1.65 +/- 0.07 mg/kg X min] when data were analyzed by multivariate analysis of variance; likewise, the increment in Ra in response to glucagon infusion did not differ between the two treatments (1.26 +/- 0.22 vs. 1.17 +/- 0.24 mg/kg X min). Blood beta OHB, alanine, and glycerol also did not differ between the insulin and proinsulin treatments. Under these conditions of prolonged infusion in which the differences in clearance properties between proinsulin and insulin do not play a role and which maintain basal euglycemia, the two compounds equally limit the response to a stimulus to hepatic glucose production. Under nonsteady state conditions, when the differences in clearance rates are operative, proinsulin may have relatively greater effects on Ra than do doses of insulin that are biologically equivalent after prolonged infusions.

Adult↗