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Biomedical subjects

M L Rao

Publications and source records attributed to M L Rao.

At least 55 records · Page 3Linked to original sources
PubMed1999

A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer's disease.

Local inflammatory processes surrounding the amyloid plaques contribute to the progression and acceleration of the Alzheimer's disease (AD)-related neurodegeneration. Interleukin-6 (IL-6) is an inflammatory cytokine with possible involvement in the local immune response occurring in the central nervous system of AD patients. We tested the hypothesis as to whether a genetic polymorphism of the IL-6 gene (IL-6) modifies the age at onset and risk for sporadic AD. Our results support an association of the C allele of the IL-6 genotype with a delayed initial onset and reduced disease risk and indicate that genetically determined alterations of the immune response may modify the course of AD.

Age of Onset↗
PubMed1999

The risk of acute suicidality in psychiatric inpatients increases with low plasma cholesterol.

Several studies suggest that the reduction of total cholesterol in blood by lipid-lowering agents is accompanied by a decrease in the incidence of coronary heart disease, but not in total mortality. Likewise, epidemiological studies show that low total cholesterol concentrations appear to be associated with an increased risk of death from suicide and injuries. There is little information with respect to acute suicidality and cholesterol in psychiatric inpatients; therefore the aim of the present study was to examine exactly this relation between plasma cholesterol and acute suicidality. The study comprised 45 acutely suicidal psychiatric inpatients, 95 nonsuicidal inpatients with affective disorder, and 20 healthy subjects. Psychopathological measures (Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Beck's Suicide Intent Scale) were established in these patients as well as the plasma concentrations of cholesterol in patients and healthy subjects. The most important finding of this study is that the risk of acute suicidality decreases with increasing total cholesterol levels irrespective of age, gender, and nutritional status (i.e., body mass index). Comparison of total cholesterol levels between age- and sex-matched suicidal and nonsuicidal patients with affective disorder supports this observation: Despite the slightly higher body mass index, suicidal patients have significantly lower cholesterol levels than nonsuicidal patients. Our findings support the notion that acute suicidality is associated with low plasma cholesterol; this observation needs to be further studied in the context of a biological marker for suicide risk.

Adult↗
PubMed1999

[A self-rating scale for adverse drug effects and its application in a study of antidepressants].

Patient's complaints about adverse drug effects in the course of antidepressant drug therapy are related to a considerable extent to their subjective experience. Therefore general assessment of adverse drug effects that relies exclusively on the investigator's rating scales appears unsatisfactory. Additional assessment with self-rating scales should record the experience which arises from patient's perception. However, there are presently no satisfactory instruments available. Therefore, we developed the Bonner Erhebungsinstrument to assess subjective adverse drug effects. We administered this rating scale on 310 occasions to 130 patients. In order to evaluate the influence of indirect and direct questions, we devised an additional instrument the Erhebungsinstrument direkt. As it turned out, patients answering direct questions stated nearly twice as many side-effects than patients answering the indirect questionnaire. A comparison of our two rating scales with the observer-rating scale UKU showed, that investigators noted 79% of the symptoms that patients mentioned, but rated only 30% as probably due to a drug effect. A statistical evaluation of the data showed an interdependence between the number of adverse drug effects in the Bonner Erhebungsinstrument and fluvoxamine's daily dose; furthermore, the number of adverse drug effects of clomipramine correlated with its serum level; dose and serum concentrations of doxepin correlated significantly with the adverse side effects. Selective serotonin reuptake inhibitors are generally considered to have fewer side effects than tricyclic antidepressants; in our investigation this turned out to be true for the symptom "dry mouth" but not for other symptoms. Thus the novel Bonner Erhebungsinstrument discriminates well between different adverse drug effects; it provides important information to assess unwanted side effects and to understand and improve patients' compliance.

Antidepressive Agents↗
PubMed1999

Chronic oral haloperidol and clozapine in rats: A behavioral evaluation.

The present study evaluated chronic oral treatment of rats with haloperidol or clozapine. Drugs were given in the drinking water for a 23-day period. Rat behavior was analyzed once a week in an open field. Rats ingested either 1.7 mg/kg haloperidol or 40 mg/kg clozapine daily. Blood serum analysis revealed concentrations of 6 ng/ml for haloperidol and 22 ng/ml for clozapine at the end of the treatment. Haloperidol decreased overall activity from the onset of treatment. Clozapine showed similar effects only on the last test day. Control animals showed a slight habituation in exploration-related parameters. In conclusion, these results indicate that oral drug administration through the drinking water is a suitable mode of noninvasive chronic treatment that led to sufficiently high drug levels to induce specific pharmacological effects in rats.

Administration, Oral↗
PubMed1999

Pharmacokinetic-pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration.

The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A three-compartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject's sensitivity to drugs and the time course of adaptation.

Administration, Oral↗
PubMed1998

Upregulation of the platelet Serotonin2A receptor and low blood serotonin in suicidal psychiatric patients.

Suicidality has been found to be associated with low pre- and postsynaptic serotonin functioning. The purpose of this study was to examine whether in acutely suicidal psychiatric inpatients, the blood serotonin concentration was related to the underlying psychiatric disorder and whether it was associated with changes in the affinity (dissociation constant, KD) or in the maximal binding capacity (Bmax) of the platelet serotonin2A receptor. We therefore determined the blood serotonin concentrations and the platelet serotonin2A receptor activities of 45 suicidal psychiatric patients and 20 healthy subjects. We found that the blood serotonin concentrations were significantly lower in suicidal patients compared to healthy subjects. In all diagnostic categories (affective disorder, schizophrenia and adjustment disorder) we noted a significantly higher maximal binding capacity of the platelet serotonin2A receptor. These findings support the notion that a reduction in the availability of serotonin and an upregulation of the serotonin2A receptors in psychiatric patients are associated with a loss of control over suicidal impulses.

Acute Disease↗
PubMed1997

[123I]IBZM SPECT in patients treated with typical and atypical neuroleptics: relationship to drug plasma levels and extrapyramidal side effects.

[123I]Iodobenzamide (IBZM) is an iodine-labeled dopamine receptor ligand and can be used to visualize brain D2 receptors in humans with single photon emission computerized tomography (SPECT). The ratio of striatal IBZM uptake to uptake in frontal cortex (ST/FC ratio) represents a semiquantitative measure of D2 receptor binding in the striatum. Our study sample included six patients treated with haloperidol (3.0-8.0 mg/day orally; one patient with an average of 0.9 mg/day intramuscularly), five patients with benperidol (9.0-15.0 mg/day orally) and nine patients treated with clozapine (200.0-600.0 mg/day orally). Typical neuroleptics (TNs) and atypical neuroleptics (ANs) were significantly different in their ST/FC ratios. The ST/FC ratios indicated that patients treated with benperidol exhibited the lowest ST/FC ratios, with increasingly higher ratios in patients on haloperidol or clozapine. We found a curvilinear relationship between the ST/FC ratios and the dose/kg body wt. of TNs and ANs on the basis of a dose-normalization according to Ki-values of the neuroleptic at D2 receptors and a weaker, but also curvilinear relationship between ST/FC ratios and normalized dosages according to clinically defined chlorpromazine equivalents. The specific uptake of IBZM did not correlate with the plasma levels of the TN haloperidol at the present dose range (0-12.4 ng/ml). For clozapine, a meaningful negative correlation between plasma levels and ST/FC ratio could be established. There was a negative continuous correlation between uptake of IBZM and extrapyramidal side effects, which is different from the threshold-based relationship between extrapyramidal side effects and IBZM uptake reported previously.

Adult↗
PubMed1997

Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy.

BACKGROUND: A dysfunction of the serotonin system may play a major role in the pathogenesis of seasonal affective disorder. Bright light therapy has been shown to be effective in the treatment of winter depression in patients with seasonal affective disorder. Light therapy-induced remission from depression may be associated with changes in brain serotonin function. METHODS: After at least 2 weeks of clinical remission, 12 drug-free patients who had had depression with seasonal affective disorder underwent tryptophan depletion in a double-blind, placebo-controlled, balanced cross-over design study. RESULTS: Short-term tryptophan depletion induced a significant decrease in plasma free and total tryptophan levels (P < .001 for both, repeated measures analysis of variance), with peak effects occurring 5 hours after ingestion of a tryptophan-free amino acid drink. It emerged that tryptophan depletion leads to a transient depressive relapse, which was most pronounced on the day after the tryptophan-depletion testing. No clinically relevant mood changes were observed in the control testing. CONCLUSIONS: The maintenance of light therapy-induced remission from depression in patients with seasonal mood cycles seems to depend on the functional integrity of the brain serotonin system. Our results suggest that the serotonin system might be involved in the mechanism of action of light therapy.

Adult↗
PubMed1997

Serotonin syndrome after lithium add-on medication to paroxetine.

A 59-year-old female patient was hospitalized on account of a depressive episode in the course of a long-standing bipolar disorder. On a combination of lithium (400 mg/day) and paroxetine (30 mg/day) she developed symptoms of shivering, high-frequency tremor of the upper and lower limbs, skin flush in the face, agitation, and slight impairment of mental focusing, suggestive of a serotonin syndrome. At this stage serum lithium and paroxetine levels were 0.63 mmol/l, and 693 ng/ml, respectively; the latter was six times higher than the upper concentrations seen in patients on this dosage of the drug. Consequently, the dosage of paroxetine was reduced to 10 mg/day, and lithium was continued. This regimen resulted in a steady-state paroxetine serum level of 390 ng/ml. The patient became symptom-free and the depressive episode attenuated, thus enabling us to discharge the patient.

Antidepressive Agents, Second-Generation↗
PubMed1996

Mean input times of three oral chlorprothixene formulations assessed by an enhanced least-squares deconvolution method.

The efficacy and quality of drug formulations are determined mainly by their bioavailability, which is defined by the rate and extent of drug absorption. The zero and first moments of the serum concentration time profile provide relevant information on the bioavailability. On the basis of the body residence time distributions, mean input times may be used as drug absorption rate parameters, but due to computational errors the statistical moments procedure is in some instances of limited value. To circumvent these problems we have developed a procedure to calculate mean input times from input profiles obtained by least-squares deconvolution. We enhanced the performance of the deconvolution method by directly generating initial estimates of one input rate for each sampling interval and compared the statistical properties of various input rate characteristics using data from a bioavailability study on four chlorprothixene preparations. The analysis of variance revealed that estimates of mean input times depended on the calculation procedure. Mean input times estimated by the least-squares deconvolution method were more reliable and less variable than those computed as differences of mean body residence times.

Administration, Oral↗
PubMed1996

Low serum levels of tricyclic antidepressants in amitriptyline- and doxepin-treated inpatients with depressive syndromes are associated with nonresponse.

Nonresponse to tricyclic antidepressant (TCA) treatment is observed in about one-third of depressed patients. The cause(s) for nonresponse - apart from disease-specific effects - might be the failure to build up sufficiently high serum TCA levels due to noncompliance, substance abuse, rapid metabolism, or low dose. We carried out a retrospective analysis relating antidepressant serum levels to patient data obtained in the naturalistic setting of the Psychiatric Hospital of the Bonn University during the introductory phase of drug-monitoring. Case reports of 110 depressed inpatients who were treated with amitriptyline or doxepin were analyzed with respect to the following: medication and comedication, daily dose, type and duration of treatment, serum TCA concentrations (analyzed by the fluorescence polarization immunoassay), age, sex, body weight, abuse of nicotine or alcohol intake, serum transaminases (ALT, alanine aminotransferase, and AST, aspartate amino transferase), gamma-glutamyltranspeptidase (gamma-GT) and creatinine, compliance, and response. The salient findings were: 1. Serum TCA concentrations increased linearly with the daily amitriptyline dose but not with that of doxepin. 2. Interindividually, there was an eight to ten-fold difference in serum TCA concentrations at steady-state with 150 mg/day of either drug; longitudinally, we observed intraindividually a coefficient of variation of 8% and 12% for amitriptyline and doxepin respectively. 3. With amitriptyline (150 mg/day), the correlation between age and serum TCA concentrations was low (r = 0.33, p < 0.055) and no correlation was found after the administration of doxepin (150 mg/day), nor was there any correlation between age and dose-adjusted serum TCA concentrations after the administration of either drug. 4. Nonresponders had significantly lower serum levels than responders. These results suggest that patients should not qualify as nonresponders unless it can be demonstrated (and it is clinically applicable) that the steady-state serum TCA levels are stable within the upper limit of the recommended therapeutic range and serum level.

Adult↗
PubMed1996

Low plasma thyroid indices of depressed patients are attenuated by antidepressant drugs and influence treatment outcome.

Decreased turnover of thyroid indices and blunting of TSH release after TRH administration has been associated with depressive disorder. A further decrease in plasma thyroid hormone; during antidepressant treatment has been reported. However, the putative association between the plasma thyroid indices' concentration and response has not been addressed. In the present study 21 depressed inpatients underwent a four-week double blind antidepressant with amitriptyline and mianserin; their plasma thyroid hormone indices (total thyroxine [TT4], free thyroxine [FT4], total triiodothyronine [TT3], free triiodothyronine [FT3], thyrotropin [TSH], and thyroglobulin [TBG]) were quantified to elucidate their involvement in depression and during antidepressant drug treatment. Depressed patients' plasma TSH, when corrected for age, was significantly lower than that of healthy subjects. During antidepressant treatment the entire patient cohort showed a significant decrease in plasma TT4 and FT4 concentrations. Responders showed a significant drop in TT4 FT4, FT3, and T4/TBG, but nonresponders only a decrease in FT4. During mianserin treatment, a decrease was observed in TT4, FT4, FT3, and T4/TBG. FT4 and FT3 baseline levels correlated positively with the improvement in the Hamilton Depression Rating Score (HDRS). These findings show that depressed inpatients' serum TSH levels are within the reference range, but significantly lower than those of healthy subjects, and those patients who turn out to be nonresponders have potentially lower availability of thyroid hormones than responders. Therefore, we hypothesize that in order to assure clinical improvement in depression, an adequate capacity of the thyroid hormone pool is necessary to compensate for the additional antidepressant-provoked decrease in serum thyroid hormone availability.

Adult↗
PubMed1996

Lymphocytopenia and thrombocytopenia during treatment with risperidone or clozapine.

The atypical antipsychotic clozapine is associated with several well-known abnormalities of blood cell count, whereas only rare reports are associated with the neuroleptic risperidone. This report describes lymphocytopenia and thrombocytopenia under treatment with risperidone which continued after changing to clozapine without other clinically significant abnormal hematological parameters. Within one week after discontinuation of both neuroleptics abnormalities of blood cell count reversed to the initial values. Abnormalities of lymphocytes or thrombocytes are rare side-effects under treatment with risperidone or clozapine.

Adult↗
PubMed1996

Pharmacokinetics of chlorprothixene after single intravenous and oral administration of three galenic preparations.

The absolute and relative bioavailability of chlorprothixene (CAS 113-59-7, Truxal) was studied in eight healthy male volunteers with three different formulations: solution, suspension and coated tablet. An intravenous infusion and an oral aqueous solution served as references. Single doses of 100 mg were administered in a randomized complete-block design with washout periods of two weeks. Serum concentrations of chlorprothixene were assayed using a high-performance liquid chromatographic method with electrochemical detection. After a 1-h infusion period the maximum serum concentration (Cmax) of chlorprothixene was 430 +/- 81 ng/ml (mean +/- S.D.) and subsequently decreased with a terminal elimination half-life (t1/2) of 25.8 +/- 13.6 h. The total serum clearance (Cl) and the apparent volume of distribution at steady state (Vss) were 867 +/- 167 ml/min and 1035 +/- 356 l, respectively. The profiles of the chlorprothixene serum concentration vs. time and the resulting pharmacokinetic parameters were similar for all orally administered formulations. The absolute oral bioavailability of 17% of the solution indicated a marked presystemic metabolism. The bioavailability of chlorprothixene relative to the oral solution was 56.4% with the coated tablet and 67.7% with the suspension. All pharmacokinetic parameters showed wide inter-subject variations, partly attributable to the respective formulation.

Administration, Oral↗
PubMed1995

Circadian rhythm of vital signs, norepinephrine, epinephrine, thyroid hormones, and cortisol in schizophrenia.

Changes in the circadian rhythmicity in vital signs, catecholamines, thyroid hormones, and cortisol have been observed in psychiatric disorders, most notably in depression. With respect to schizophrenia, the literature is scanty. We report here on the circadian parameter estimates of the vital signs, epinephrine, norepinephrine, triiodothyronine, thyroxine, thyroid stimulating hormone, and cortisol in the blood of 34 healthy subjects, 89 drug-free schizophrenic patients, and 25 neuroleptic-treated schizophrenic patients. The analyses are based on the cosine model to fit the experimental data. The circadian profiles of heart rate, blood pressure, and oral temperature are similar among schizophrenic patients and healthy subjects. Neuroleptic-treated patients have significantly higher MESORs (the daily mean) of serum norepinephrine and epinephrine than healthy subjects. The TSH MESOR is significantly lower in schizophrenic patients; the MESOR of triiodothyronine also shows a tendency to be nonsignificantly lower in schizophrenic patients compared with control subjects. The circadian serum thyroxine and cortisol profiles are similar in the three groups. The data show that the circadian profiles of vital signs in drug-free chronic schizophrenic patients who are not chronically hospitalized are similar to those of healthy subjects and that the increase in serum catecholamines and the apparent lowering in some thyroid indices might induce a down-regulation in the noradrenergic receptor system that could contribute to the pathophysiology of schizophrenia.

Adolescent↗
PubMed1995

Bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets in CYP2D6 phenotyped subjects.

The bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets were studied in 12 healthy volunteers. A 1-hour intravenous infusion served as the reference. Serum concentrations of levomepromazine were quantified with a specific high-performance liquid chromatographic method and electrochemical detection. The 2 oral formulations were bioequivalent. After oral administration of oblong and coated levomepromazine tablets the mean serum concentration versus time profiles were similar and the pharmacokinetic parameters showed wide interindividual variations. There was a 21% absolute bioavailability of levomepromazine, indicating a pronounced presystemic metabolism. The total serum clearance and the apparent volume of distribution at steady state were 48 +/- 14 l/min and 980 +/- 213 l, respectively. These pharmacokinetic parameters were also investigated with respect to the CYP2D6 polymorphism, i.e. via dextromethorphan phenotyping of 9 subjects, 3 subjects were poor metabolizers, and 6 extensive metabolizers. The Spearman's rank-ordered correlation analysis did not reveal a significant correlation between the pharmacokinetic parameters AUC, Cmax and t1/2 after oral administration of oblong and coated levomepromazine tablets and the metabolic ratios of dextromethorphan, suggesting that levomepromazine is not metabolized to any major extent by the isoenzyme CYP2D6.

Administration, Oral↗