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Biomedical subjects

M L Rao

Publications and source records attributed to M L Rao.

At least 73 records · Page 4Linked to original sources
PubMed1994

Quantification of chlorprothixene, levomepromazine and promethazine in human serum using high-performance liquid chromatography with coulometric electrochemical detection.

Isocratic reversed-phase high-performance liquid chromatography with coulometric electrochemical detection was optimised to quantify the neuroleptic drugs chloroprothixene, levomepromazine, and promethazine in human serum. The method involves extraction of the neuroleptic drugs in n-heptane-isoamylalcohol from the alkalinized serum, followed by chromatographic separation on a Nucleosil CN column with acetonitrile-pyridine-sodium acetate buffer as the mobile phase. The extraction recovery was > 85% for each neuroleptic drug. The sensitivity and selectivity required for pharmacokinetic studies was obtained with a dual coulometric analytical cell operating in the oxidative screen mode. The lower limit of detection in human serum for chlorprothixene, levomepromazine, and promethazine, was 0.5, 0.2 and 0.1 ng/ml, respectively. A linear relationship (r2 > 0.99) was obtained between the concentrations of each neuroleptic drug and the detector signal. The accuracy of the quality control samples was +/- 7% for each neuroleptic drug with a precision within 9.5%, 8.1% and 13.5% for chlorprothixene, levomepromazine, and promethazine, respectively. The neuroleptic drugs were stable in acetonitrile and human serum for at least six months when stored at -20 degrees C. This method is applicable to analyze a large number of serum samples for pharmacokinetic studies of the neuroleptic drugs.

Chlorprothixene↗
PubMed1994

Circadian rhythm of tryptophan, serotonin, melatonin, and pituitary hormones in schizophrenia.

Circadian rhythm abnormalities have been described mostly with respect to manic-depressive illness; little information is available concerning circadian rhythms and schizophrenia or their influence on neuroleptic drugs. We showed previously that the MESOR of dopamine is higher in schizophrenic patients than in healthy subjects and that women who are drug-free schizophrenic have lower prolactin MESORs and lower amplitudes than healthy women. We now report the data of a cosinor analysis of tryptophan, serotonin, melatonin, and pituitary hormones in the blood of 34 healthy subjects, 90 drug-free schizophrenics, and 25 neuroleptic-treated schizophrenic patients. This data indicated a significant phase advance of serum tryptophan, prolactin, and melatonin concentrations, a trend toward a phase advance in serotonin. Thyroid stimulating hormone (TSH), and growth hormone concentrations, and decreases in the TSH MESORs among patients compared to healthy subjects. These results suggest that circadian changes, such as phase advances and alterations in MESOR, are not only present in depression but also in schizophrenia. Although neuroleptic treatment raised the prolactin MESOR and amplitude, it did not elicit any change in circadian rhythmicity among the other parameters.

Adolescent↗
PubMed1994

Autoaggressive behavior is closely related to serotonin availability in schizoaffective disorder.

Lowered serotonin turnover has been observed in impulsive hetero- and auto-aggressive behavior. Most notably the CSF 5-hydroxyindole acetic acid concentrations were decreased. However, data on CSF or blood serotonin are far from clear-cut, since similar levels in suicidal and non-suicidal patients have also been noted. Longitudinal studies of suicidal patients have revealed pronounced shifts in blood serotonin levels, whereas healthy subjects' blood serotonin levels remained stable. We investigated blood serotonin levels of female schizoaffective patients and healthy women to test whether the fluctuations correlated with changes in autoaggressive behavior. The patients were divided into three groups: nonsuicidal, acutely suicidal, and postsuicidal. Nonsuicidal and postsuicidal schizoaffective patients' and healthy women's blood serotonin levels were similar. Suicidal patients' blood serotonin levels were significantly lower than those of healthy subjects and postsuicidal patients. We interpret the serotonin augmentation after a suicide attempt as a psychobiological correlate of increased neurotransmitter function.

Adult↗
PubMed1994

Biochemical findings of negative symptoms in schizophrenia and their putative relevance to pharmacologic treatment. A review.

The most prominent biochemical finding in schizophrenic patients with negative symptoms appears to be the reduction in central dopaminergic, serotonergic and noradrenergic activity. This decrease in amine activity tends to be associated with structural brain abnormalities, i.e., cortical atrophy or enlarged ventricles. There are indications that typical neuroleptics reduce those negative symptoms of schizophrenia that are secondary to positive symptoms when these are effectively treated. However, negative symptoms of schizophrenia that occur independently of positive symptoms may also be reduced with monoamine oxidase inhibitors and atypical antipsychotic drugs, such as clozapine. The latter's efficacy seems to be related to their pharmacological profile, i.e., their interference with dopaminergic, noradrenergic and serotonergic receptor systems and metabolism.

Antidepressive Agents↗
PubMed1994

Monitoring tricyclic antidepressant concentrations in serum by fluorescence polarization immunoassay compared with gas chromatography and HPLC.

The fluorescence polarization immunoassay (FPIA) developed by Abbott to diagnose intoxication with tricyclic antidepressants was adapted for therapeutic drug monitoring and validated with chromatograpic methods to investigate its potential for this use. We compared serum concentrations of tricyclic antidepressants in vivo and in vitro obtained by FPIA with those by gas chromatography and HPLC. For amitriptyline, imipramine, clomipramine, and doxepin, the detection limit of the FPIA was 72, 71, 64, and 72 nmol/L (approximately 20 micrograms/L), respectively; that by gas chromatography was 18, 18, and 16 nmol/L (approximately 5 micrograms/L) for amitriptyline, imipramine and clomipramine, respectively; with HPLC the lower limit of detection for doxepin was 36 nmol/L (10 micrograms/L). The intra- and interassay CVs ranged from 3% to 6%. In patients being treated with amitriptyline, imipramine, clomipramine, and doxepin, at steady-state the correlation coefficients between FPIA and GC/HPLC results for split samples were 0.95, 0.92, 0.90 and 0.70, respectively. However, the slopes were close to unity only for amitriptyline and doxepin, being 0.6 for imipramine and 1.9 for clomipramine.

Antidepressive Agents, Tricyclic↗
PubMed1993

Concurrence of cortex and platelet serotonin2 receptor binding characteristics in the individual and the putative regulation by serotonin.

Changes in the central and peripheral serotonergic receptor activity have been reported to be involved in depression and suicidality. To elucidate the interdependence between central and peripheral receptor sites and their regulation by serotonin, we estimated intra-individual serotonin2 receptor binding characteristics in porcine cortex synaptosomes and in platelet membranes using 3H-LSD as ligand and ketanserin as competitor and quantified the relevant serotonin concentrations. A positive correlation between the apparent half maximal saturation concentration, KD, of the receptor in cortex synaptosomes and platelet membranes (r = 0.65, p = 0.0046, n = 18), and between the apparent maximal binding capacity, Bmax, of the receptor in cortex synaptosomes and platelets (r = 0.52, p = 0.027, n = 18) was observed. The blood serotonin concentrations correlated negatively with the maximal binding capacity, Bmax, in platelets (r = -0.77, p = 0.0002, n = 18). These results suggest that the binding characteristics of the central and peripheral serotonin2 receptor are similar, and that the platelet receptor activity may be regulated by blood levels of serotonin.

Animals↗
PubMed1993

Human brain cortex and platelet serotonin2 receptor binding properties and their regulation by endogenous serotonin.

In patients with affective disorder and suicidality up-regulation of the serotonin2 receptor has been observed in brain and on platelets. Although the pharmacological profiles of the receptor in brain synaptosomes and platelet membranes are similar, it is a matter of debate whether the platelet serotonin2 receptor reflects the characteristics of the receptor in the brain and whether serotonin regulates the receptor activity. To answer these questions we measured in healthy human subjects the platelet serotonin2 receptor activity and blood serotonin concentrations. In an attempt to find whether the serotonin2 receptor activity in brain cortex synaptosomes and on platelets is similarly expressed we investigated the receptor's binding characteristics in neurosurgical patients. The results suggest that in men and women increased platelet serotonin concentrations correlate with a decrease in platelet membrane serotonin2 receptor affinity. The affinities of the brain cortex synaptosomal and platelet membrane serotonin2 receptor correlate intra-individually. These data suggest that the platelet serotonin2 receptor affinity appears to be regulated at the cellular level by blood serotonin and that the binding characteristics of the serotonin2 receptor in brain cortex synaptosomes corresponds to that on platelets. The latter finding supports the hypothesis of the platelet as a model for neuronal function.

Adolescent↗
PubMed1993

Hyperdopaminergia in schizophreniform psychosis: a chronobiological study.

Circadian rhythm abnormalities have been described in various psychiatric disorders, but they have not received much attention in studies of schizophrenia and schizophreniform psychosis. The present study used the cosine model to determine the circadian patterns of amino acids, dopamine, and prolactin concentrations, which were analyzed over a 24-hour period in serum of healthy subjects, drug-free schizophrenic patients, and neuroleptic-treated schizophrenic patients. The mesor (the daily mean) of phenylalanine was lower in drug-free schizophrenic women than in healthy women. The mesors of the ratio of phenylalanine or tyrosine to competing amino acids were similar in healthy subjects and patients. The ratio of phenylalanine/competing amino acids showed a phase advance (i.e., earlier onset of the time of highest concentration) in drug-free patients compared with healthy subjects. Schizophrenic patients displayed a higher dopamine mesor than healthy subjects. Female drug-free schizophrenic patients had lower prolactin mesors and lower amplitudes (i.e., half of the total predictable change in rhythm) than healthy women. Compared with healthy subjects, schizophrenic patients showed a phase advance of circadian prolactin concentrations. Neuroleptics raised the prolactin mesor and amplitudes but did not elicit any phase change in amino acids, dopamine, or prolactin. These data confirm the indirect pharmacologic evidence of increased dopaminergic activity in schizophrenic patients that relates to dopamine's precursors and to the neuroendocrine regulation of prolactin.

Adolescent↗
PubMed1993

Interrelationship between blood serotonin levels and affinity of platelet imipramine binding sites in healthy subjects.

Changes in the density of the platelet imipramine binding sites have been reported for a variety of psychiatric conditions. The discrepancy in binding data between different laboratories renders the interpretation of the results difficult. In addition to differences in the way the various laboratories perform their binding assays, another contributing factor might be their mathematical evaluation. The imipramine binding site appears to be associated with the platelet serotonin uptake site, but it is not clear whether blood-serotonin concentrations are involved in its regulation. In order to elucidate serotonin's influence we determined blood serotonin and platelet imipramine binding simultaneously in 13 healthy female subjects. To optimize data evaluation we tested the applicability of the Scatchard analysis and a modification of the Marquardt iterative algorithm. Computer simulation of binding data suggests a superior goodness-of-fit when using the modified Marquardt algorithm. We observed a significant positive correlation between blood serotonin and the apparent dissociation constant (KD) of the imipramine binding site: the affinity decreased at high blood-serotonin concentrations (Pearson's r = 0.88, p < 0.0001). We interpret this phenomenon as serotonin's negative feedback regulation of the platelet imipramine binding site.

Adult↗
PubMed1992

Blood serotonin, serum melatonin and light therapy in healthy subjects and in patients with nonseasonal depression.

The 24-h rhythms of blood serotonin and serum melatonin were determined in 39 unmediated inpatients with nonseasonal affective disorder and in 14 healthy men and women after 7 days of morning bright-light (2500 lx) or dim-light (50 lx) treatment. Bright-light treatment led to a more than 50% decrease in the Hamilton Rating Scale for Depression (HRSD) score in 4/19 patients and dim light in 1/17 patients. After light treatment the mesor (the daily mean estimated by cosinor analysis) of patients' and subjects' melatonin levels did not change significantly, nor was there a correlation between phase change and decrease in HRSD score. We observed after bright- and dim-light treatment a consistent increase in blood serotonin in patients and healthy subjects, which differed significantly between healthy subjects and patients. These findings suggest the involvement of serotonergic mechanisms following light therapy.

Depressive Disorder↗
PubMed1992

Early pathological changes of endothelia in a model using LDL perfusion at physiological LDL-cholesterol concentration.

The aim of the present research was to provide further insight into the debated problem of the existence of modified LDL in vivo. For this purpose a novel model was devised for studying LDL injurious effect on endothelial cells (EC) by infusing native cholesterol rich LDL, diluted to physiological LDL cholesterol concentration. Normal rabbits were infused with LDL separated from rabbits previously fed either with standard food (I-LDL Group), 1% cholesterol (II-LDL Group) or 1% cholesterol plus probucol (IV-LDL Group). Cu++ modified II-LDL was infused as well (III-LDL Group). After dilution as above, lipid oxide (LP) significantly increased in III- and II-LDL media, as compared to I- and IV-LDL media. EC of III- and II-LDL Groups showed irregular shape and surface pattern. Further, they showed adhering clusters of monocytes, platelets and erythrocytes. Endocytic vesicles and ruthenium red-positive particles increased too. EC of IV-LDL Group were only slightly affected as compared to I-LDL Group. These data suggest that native LDL from hypercholesterolemic rabbits contain an oxidized form which is noxious to EC even when LDL is infused at physiological LDL-cholesterol concentration. This early injury is in part LP-associated and actively involves platelets and monocytes.

Animals↗
PubMed1991

Influence of high cholesterol feeding on the pattern and progression of experimental cerebral ischemia.

The aim of our research was to study if cholesterol feeding might affect the ischemic changes in the vessels surrounding infarction foci in Sephadex G-75-induced cerebral ischemia model (SG-75). One hundred-twenty-four rabbits were divided as follows: group I was given standard food for 5 weeks; group II: as group I and then injected with SG-75; group III: standard food plus 1% cholesterol for 5 weeks; and group IV: as group III and then injected with SG-75. Rabbits were sacrificed 3 h, 6 h and 2, 5 and 7 days after ischemia had occurred. Vessels surrounding infarction foci (SIF) were identified by using a 6% carbon perfusion. Samples were examined by light microscopy and transmission electron microscopy (TEM). The occurrence of hemorrhagic infarction (HI) showed a clear time/course increase in group II whereas a decrease after 2 days in group IV was observed. The rate of HI was 40% and 20% in group II and IV, respectively. SIF vessels showed red blood cells leakage in group II, whereas multiple platelet thrombi appeared in group IV. This phenomenon caused a more extensive ischemic damage, when compared to group II. By making use of a widely employed model of high cholesterol diet and of a more physiological model of cerebral ischemia devised by us, we have provided the evidence that the hypercholesterolemia-induced changes in the SIF vessels strongly affect the pattern and progression of cerebral ischemia.

Animals↗
PubMed1991

Cholesterol-rich LDL perfused at physiological LDL-cholesterol concentration induces platelet aggregation and PAF-acetylhydrolase activation.

The aim of this research was to perform an in vivo study on the relationships between lipid oxide (LP), platelet aggregation and PAF-acetylhydrolase in a model using perfusion of cholesterol-rich LDL media diluted to physiological LDL-cholesterol concentration. Normal rabbits were infused with LDL (d 1.025-1.063 g/ml) extracted from rabbits previously fed either with standard food (I-LDL group), 1% cholesterol food (II-LDL group) or 1% cholesterol plus probucol (IV-LDL group). CU2+ modified II-LDL was also infused (III-LDL group). After dilution as above, LP increased significantly in III- and II-LDL media. After perfusion, LP significantly increased in III- and II-LDL groups as compared to baseline values and to control. Compared to the I-LDL group, PAF-acetylhydrolase and platelet aggregation significantly increased in III- and II-LDL groups. These data indicate the property of cholesterol- rich LDL to activate PAF-acetylhydrolase and enhance platelet aggregation, even when perfused through a medium containing a physiological LDL-cholesterol concentration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1990

Serum amino acids, central monoamines, and hormones in drug-naive, drug-free, and neuroleptic-treated schizophrenic patients and healthy subjects.

Basal serum amino acids (including central monoamine precursors), central monoamines, and hormones were studied in schizophrenic patients (drug-naive; n = 20; drug-withdrawn for 3 or more days, n = 67; neuroleptic-treated, n = 23) and healthy subjects (n = 90) to answer the following questions: (1) Do neuroleptic-withdrawn and neuroleptic-naive patients differ on these serum measures? (2) What are the effects of neuroleptic treatment on these measures? (3) On which variables do drug-free and neuroleptic-treated patients differ? Because serum amino acid, central monoamine, and hormone levels were similar in drug-naive and drug-withdrawn patients, data from these groups ("drug-free") were combined and compared to those of healthy subjects and neuroleptic-treated patients. Asparagine, citrulline, phenylalanine, and cysteine were higher, while tyrosine, tryptophan, and the ratio of tryptophan to competing amino acids were significantly lower in drug-free schizophrenic patients than in healthy subjects. Dopamine was increased, and melatonin and thyroid hormones were decreased in drug-free schizophrenic patients compared to healthy subjects. Norepinephrine, epinephrine, and prolactin were higher in neuroleptic-treated men compared to drug-free male patients or healthy men. These results are consistent with the hypothesis of dopaminergic overactivity in schizophrenia, which might be caused by altered amino acid precursor availability and could be related to the decrease in melatonin and reduction in thyroid hormone levels.

Adult↗
PubMed1990

[Status-dependent neurochemical parameters in schizophrenic and affective diseases].

The dynamics of course, i.e., the marked psychopathological fluctuation in acute phases of schizophrenic and other idiopathic psychoses was little considered up to now in investigations referred to correlating clinical and neurochemical findings. Therefore, we selected subgroups of patients, classified as inactive or slight, moderate or severe process-active according to the operational defined actual psychopathological syndrome (Gross et al. 1988, Klosterkötter et al. 1989) at the time of taking of blood samples. We demonstrated in previous studies that the fluctuation and/or sudden development (minutes, hours, up to six days at the latest) of schizophrenic first rank symptoms and certain basic symptoms may reflect also an instability and process-activity of underlying neurochemical changes. In this study we have measured the concentrations of dopamine, noradrenaline, adrenaline, 5-HT, TSH, prolactin, HGH, melatonin, cortisol, T 3, T 4 and 28 amino acids in blood samples (examined 8 times within 24 hours) from 48 schizophrenic patients, divided in 4 subgroups (each 12 cases) with severe, moderate, slight or lacking process-activity, from 20 patients with (inactive or only slight active) depressive phases of affective psychoses and from normal controls. Marked process-active schizophrenics showed significantly higher levels of dopamine, noradrenaline and 5-HT, and significantly lower levels of TSH, compared to healthy controls and process-inactive schizophrenics with pure deficiency syndromes, that reveal a relative hypo-activity of catecholaminergic and presumably also of serotoninergic systems. In the subgroup of depressions were found decreased concentrations of noradrenaline, 5-HT, adrenaline and melatonin when compared to marked process-active schizophrenics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The influence of phototherapy on serotonin and melatonin in non-seasonal depression.

Circadian profiles of melatonin in serum and serotonin in blood were assessed before and after 7 days of artificial light treatment in 30 patients with non-seasonal depression and 12 healthy subjects. Patients and volunteers were allocated at random to either dim (50 lux) or bright light (2,500 lux) for 2 hours daily. The study has not been completed yet. Preliminary findings are presented here. Light treatment modifies marginally the circadian melatonin profiles of depressed patients and healthy subjects; however, it augments blood serotonin throughout the day. This increase is seen in all patients and healthy subjects after bright as well as dim light. These results suggest that the influence of light is more pronounced on serotonin than melatonin metabolism.

Adult↗
PubMed1990

Lymphocytes of healthy subjects and schizophrenic patients possess no high-affinity binding sites for spiroperidol.

We investigated 3H- and 125I-spiroperidol binding to lymphocytes from healthy subjects and schizophrenic patients and compared it with that to a porcine striatum dopaminergic D2-receptor preparation using identical conditions. Incubation for 60 min at 37 degrees C reduced lymphocyte 3H-spiroperidol binding to 29% of its maximal value. Binding of 3H- and 125I-spiroperidol to striatal membranes was saturable and showed high affinity; the apparent half-maximal saturation constants, KD, were 0.5 nmol/l and 1.0 nmol/l respectively for the two ligands. Lymphocyte membranes did not possess high-affinity binding sites for 3H-spiroperidol; binding to intact lymphocytes was saturable in the micromolar range; the KD values of healthy subjects and schizophrenic patients were similar. Validating all lymphocyte binding studies by parallel experiments with a striatal receptor preparation showed that human lymphocytes do not possess physiologically relevant high-affinity spiroperidol receptors.

Adult↗