A method for quantitation of normetanephrine in human cerebrospinal fluid is described. An amine-specific reagent, sulfosuccinimidyl propionate, is used to obtain the lipid soluble N-propionyl ...derivative of normetanephrine, which can be separated and quantitated in presence of other biogenic amines by liquid chromatography with electrochemical detection. The method is reproducible, linear, and precise at the relatively low concentrations of unconjugated normetanephrine occurring in human cerebrospinal fluid. Hospitalized, drug-free, alcoholic patients were found to have cerebrospinal fluid unconjugated normetanephrine concentrations in the 0.5-1.5 nanomolar range. The practical limit of sensitivity for the method is about 0.025 pmole per ml of CSF.
CGP 6085 A 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl, a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent ...with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.
Large doses (960 to 3200 mg/day) of propranolol were taken by eight patients with chronic schizophrenia in a double‐blind therapeutic trial. To investigate the effects of such treatment on central ...monoaminergic processes, samples of cerebrospinal fluid (CSF) were drawn before starting the study and after 31 to 63 days (X̄=49 days) on propranolol. Concentrations in CSF of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), 5‐hydroxyindoleacetic acid (5‐HIAA), and homovanillic acid (HVA), the principal metabolites of norepinephrine, serotonin, and dopamine, were determined by HPLC with electrochemical detection. The level of HVA did not change. CSF 5‐HIAA levels decreased an average of 34%, which indicates reduced turnover of serotonin in the central nervous system (CNS). There was a strong correlation between duration of treatment with propranolol and change in CSF 5‐HIAA levels. The concentration of MHPG in CSF increased an average of 39%; this could have resulted from increased turnover of CNS norepinephrine as a consequence of the blockade of central β‐adrenoceptors or of altered metabolism and clearance of peripheral MHPG. Psychotic symptoms of the patients, as indicated by the 3‐day average score on the Bunney‐Hamburg scale, were not affected by treatment.
Clinical Pharmacology and Therapeutics (1984) 36, 33–39; doi:10.1038/clpt.1984.135
Nineteen children (mean +/- SD age, 14.5 +/- 2.3 years) with severe, primary obsessive-compulsive disorder completed a ten-week, double-blind, controlled trial of clomipramine hydrochloride (mean ...dosage, 141 mg/day) or placebo, each of which was administered for five weeks. Half of the subjects had not responded to previous treatment with other tricyclic antidepressants. There was a significant improvement in observed and self-reported obsessions and compulsions that was independent of the presence of depressive symptoms at baseline. Improvement in obsessive-compulsive symptoms did not correlate significantly with plasma concentrations of the drug or its metabolites. Clomipramine appears to be effective in the treatment of children with obsessive-compulsive disorder and the treatment seems to be independent of an antidepressant effect.
Ethanol, a highly lipid-soluble compound, appears to exert its effects through interactions with the cell membrane. Cell membrane alterations indirectly affect the functioning of membrane-associated ...proteins, which function as channels, carriers, enzymes and receptors. For example, studies suggest that ethanol exerts an effect upon the gamma-aminobutyric acid (GABA)-benzodiazepine-chloride ionophore receptor complex, thereby accounting for the biochemical and clinical similarities between ethanol, benzodiazepines and barbiturates. The patient with acute ethanol poisoning may present with symptoms ranging from slurred speech, ataxia and incoordination to coma, potentially resulting in respiratory depression and death. At blood alcohol concentrations of greater than 250 mg% (250 mg% = 250 mg/dl = 2.5 g/L = 0.250%), the patient is usually at risk of coma. Children and alcohol-naive adults may experience severe toxicity at blood alcohol concentrations less than 100 mg%, whereas alcoholics may demonstrate significant impairment only at concentrations greater than 300 mg%. Upon presentation of a patient suspected of acute ethanol poisoning, cardiovascular and respiratory stabilisation should be assured. Thiamine (vitamin B1) and then dextrose should be administered, and the blood alcohol concentration measured. Subsequent to stabilisation, alternative aetiologies for the signs and symptoms observed should be considered. There are presently no agents available for clinical use that will reverse the acute effects of ethanol. Treatment consists of supportive care and close observation until the blood alcohol concentration decreases to a non-toxic level. In the non-dependent adult, ethanol is metabolised at the rate of approximately 15 mg%/hour. Haemodialysis may be considered in cases of a severely ill child or comatose adult. Follow-up may include referral for counselling for alcohol abuse, suicide attempts, or parental neglect (in children). The ethanol withdrawal syndrome may be observed in the ethanol-dependent patient within 8 hours of the last drink, with blood alcohol concentrations in excess of 200 mg%. Symptoms consist of tremor, nausea and vomiting, increased blood pressure and heart rate, paroxysmal sweats, depression, and anxiety. Alterations in the GABA-benzodiazepine-chloride receptor complex, noradrenergic overactivity, and hypothalamic-pituitary-adrenal axis stimulation are suggested explanations for withdrawal symptomatology.
Twelve healthy men between 22 and 27 years of age participated in an experiment on interactions between zimelidine and ethanol. Zimelidine, 200 mg/24 hours, was administered for 10 days and ethanol, ...0.5 and 1.0 g/kg of body weight, or placebo drinks were administered either with placebo capsules or on the last 3 days of zimelidine treatment. A battery of tests measuring skilled performance was used. The higher dose of ethanol increased plasma zimelidine and norzimelidine concentrations. Ethanol impaired standing steadiness, tracking, and one aspect of verbal information processing. Zimelidine improved tracking. No significant pharmacodynamic ethanol-zimelidine interactions were observed.
Serious suicidal behavior, affective disorders, and a variety of other psychopathologic behaviors and syndromes have been found to correlate with measures of the serotonin system. Clinical studies ...have employed a range of serotonin indexes, including the cerebrospinal fluid level of 5-hydroxyindoleacetic acid, the prolactin response to serotonin agonists, such as fenfluramine hydrochloride, and platelet serotonin-related proteins or serotonin content. Many of these indexes are correlated with suicidal behavior, but the interrelationship of these biologic measures has been uncertain. We studied the relationship of a series of serotonin indexes in patients in whom these measures were correlated with suicidal behavior. A positive correlation was found between cerebrospinal fluid 5-hydroxyindoleacetic acid and the maximal prolactin response to fenfluramine but not with platelet serotonin2 receptor indexes. The fenfluramine-stimulated maximal prolactin response correlated with platelet serotonin2 receptor number, particularly in older patients. We conclude that cerebrospinal fluid 5-hydroxyindoleacetic acid measurements cannot be replaced but can be complemented by less invasive procedures, such as a fenfluramine challenge test or platelet serotonin2 measures, in the study of the relationship of the serotonin system to psychiatric disorders.
The plasma norepinephrine (NE) level was measured in 45 depressed patients and in 41 normal control subjects. Patients who met DSM-III criteria for a major depressive episode with melancholia ...(MDE-MEL; N = 16), and those with MDE but with melancholia in a previous episode (MDE-PMEL; N = 8), had significantly higher levels of plasma NE than normal control subjects while lying and standing and a greater change in the levels; whereas, patients with MDE alone (N = 10) and patients with dysthymic disorder (N = 11) had levels of NE comparable with control levels. Bipolar patients (N = 7), all with current melancholia or a history of it, had significantly lower levels of NE while lying down or standing than depressed unipolar patients with similar histories of melancholia. Among unipolar patients with melancholia, nonsuppressors on the dexamethasone suppression test had significantly higher lying-down NE values than did suppressors, suggesting that dysregulation of both the hypothalamic-pituitary-adrenal axis and the peripheral sympathetic nervous system occur together in this subgroup of depressed patients.
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