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Biomedical subjects

M L Rao

Publications and source records attributed to M L Rao.

At least 37 records · Page 2Linked to original sources
PubMed2001

In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients.

RATIONALE: Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. OBJECTIVES: We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. METHODS: (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. RESULTS: Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. CONCLUSIONS: There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.

Adult↗
PubMed2001

Influence of CYP2D6 genotype and medication on the sparteine metabolic ratio of psychiatric patients.

OBJECTIVE: To investigate the influence of CYP2D6 genotype and medication on the reliability of phenotyping in a naturalistic setting of psychiatric inpatients. METHODS: The phenotype of 160 psychiatric inpatients was estimated by taking the urinary metabolic ratio (MR) of the concentrations of sparteine to 2- and 5-dehydrosparteine. Genotyping identified CYP2D6*1, *3, *4, *5 and *6 alleles as well as duplication of the CYP2D6 gene. All subjects underwent detailed drug history including drug dose and therapeutic drug monitoring to control compliance and abuse of other psychotropic drugs. These data were compared with those of 195 unmedicated healthy Germans. RESULTS: The cumulative distribution of the MR in patients showed a significant shift to higher MR when compared with that of healthy subjects (P < or = 0.001). Patients medicated either with selective serotonin reuptake inhibitors (SSRIs, P < or = 0.001), antipsychotic drugs (P= 0.002) or other drugs known to be substrates or inhibitors of CYP2D6 (P < or = 0.001) showed a significantly higher mean MR than unmedicated patients. However, there was no significant effect of tricyclic antidepressants on the MR. Healthy subjects with CYP2D6 deficiency were separated by a MR of greater than 20 from those who expressed functional CYP2D6. Seven patients carrying at least one functional CYP2D6 allele revealed a MR of greater than 20, indicating the occurrence of phenocopying. CONCLUSION: The results of phenotyping may be falsified by drugs known to be substrates or inhibitors of CYP2D6; thus, this method is not sufficiently reliable. However, since we observed the phenomenon of phenocopying only in patients treated with a SSRI such as fluoxetine, fluvoxamine or paroxetine, we conclude that sparteine phenotyping of medicated patients detects CYP2D6 deficiency correctly, provided that patients treated with these SSRIs are excluded.

Adult↗
PubMed2001

Neurotoxicity of 24-hydroxycholesterol, an important cholesterol elimination product of the brain, may be prevented by vitamin E and estradiol-17beta.

24-Hydroxycholesterol, the main cholesterol elimination product of the brain is increased in serum of Alzheimer patients. This oxysterol behaves neurotoxic towards the human neuroblastoma cell line, SH-SY5Y. Here we demonstrate, that 24-hydroxycholesterol-induced neurotoxicity in differentiated SH-SY5Y cells was due to apoptosis, as indicated by DNA-fragmentation, caspase-3 activation and a decrease of the mitochondrial membrane potential. Free radicals were generated, resulting in the death of 75% of the cells within 48h; neurotoxicity in differentiated SH-SY5Y cells was partially prevented by physiological concentrations of vitamin E (50-100 microM) in that 75% of the cells survived. Physiological concentrations of estradiol-17beta (1-100nM) elicited a protective effect in differentiated cells, which was not significant; however, in undifferentiated cells a significant protection was noted by this steroid hormone. Vitamin C and melatonin did not prevent 24-hydroxycholesterol-induced neurotoxicity. These in vitro data support the in vivo observed beneficial effects reported as circumstantial evidence of vitamin E and estradiol-17beta treatment in the prevention and therapy of neurodegenerative disease.

Antioxidants↗
PubMed2001

[Olanzapine: pharmacology, pharmacokinetics and therapeutic drug monitoring].

Olanzapine is an effective and safe antipsychotic drug. Its pharmacokinetic properties are comparable to those of classical antipsychotics. Oxidative processes are mediated by the cytochrome P450 isoenzyme CYP1A2 and to a minor degree by CYP2D6. Olanzapine's main route of metabolism is by glucuronidation. Therapeutic doses result in a wide variability of serum levels; dose and serum concentration are linearly correlated. Smoking and carbamazepine induce cytochrome P450 isoenzymes and thus decrease olanzapine serum levels. Inhibition of CYP1A2 by fluvoxamine yields increased concentrations; however, clinically relevant CYP2D6 inhibition was observed only in combination with additional disposition factors, such as female gender or old age. As a rule dose adjustment is not necessary but moderate renal or hepatic impairment calls for control of serum levels to provide maximal safety during olanzapine therapy. Therapeutic drug monitoring (TDM) and toxicology studies are carried out by HPLC methods using UV or MS detection. The optimal therapeutic range of olanzapine serum levels is 20 to 40 ng/ml. Concentrations of 80 ng/ml are considered threshold for the occurrence of adverse events; however, toxicological studies showed that postmortem plasma levels are higher than antemortem levels. Lethality of high olanzapine was only observed in combination with other drugs. Moderate increases of prolactin levels were detected during administration of olanzapine. In relation to olanzapine therapy, several case reports of neutropenia and agranulocytosis appeared in the literature. Weight gain in olanzapine-treated patients does not correlate with serum levels. Olanzapine response is augmented when patients' serum levels are titrated to 20 to 40 ng/ml thereby minimizing the occurrence of side effects, thus TDM is recommended for patients treated with olanzapine.

Antipsychotic Agents↗
PubMed2001

Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients.

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Whereas cardiovascular effects have occasionally been reported during controlled studies with SSRIs, TCA treatment poses a well-known problem in this respect. To investigate the putative correlation between antidepressant dose or serum levels and adverse effects, the authors devised a naturalistic study to evaluate the tricyclic antidepressants' and SSRIs' effect on the cardiovascular system. The authors also compared antidepressant serum levels to adverse effects. Inpatients treated with TCAs or SSRIs were included; an electrocardiogram (ECG) and a Schellong test were carried out on the day patients entered the hospital and during steady-state treatment with antidepressant drugs when blood was drawn for therapeutic drug monitoring. The patient population consisted of 114 acutely depressed patients; 81 patients were treated with TCAs and 33 with SSRIs. The TCAs comprised amitriptyline (n = 43), clomipramine (n = 11), doxepin (n = 19) and imipramine (n = 8); the SSRIs comprised fluvoxamine (n = 14) and paroxetine (n = 19). In TCA-treated patients, the authors observed the same type of abnormalities in conduction and orthostatic hypotension as had been observed earlier. The authors also observed cases of first-degree atrioventricular block, prolonged QTc interval, and orthostatic hypotension in SSRI-treated patients. Thus SSRIs also appear to affect the cardiovascular system, which might pose a problem for patients with preexisting conduction disease. The authors observed a strong correlation between the decrease in systolic pressure and antidepressant serum concentration (except for clomipramine and paroxetine), suggesting that antidepressant serum level is a better correlate than dose.

Adolescent↗
PubMed2000

Pharmacogenomics and addiction to opiates.

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.

Animals↗
PubMed2000

Identical distribution of the alpha 2-macroglobulin pentanucleotide deletion in subjects with Alzheimer disease and controls in a German population.

Recently, an association between a deletion polymorphism in the alpha 2-macroglobulin gene (A2M) and Alzheimer disease (AD) has been reported. The aim of the present study was to corroborate this association in a German population of 102 AD patients and two control samples of 191 healthy subject and 160 depressed patients. The frequency of the A2M genotype in AD patients was almost identical to that in both control samples. Logistic regression analysis revealed an effect of age and the APOE genotype on AD risk, but no effect of the A2M genotype. Our findings do not support the fact that the previously reported positive association between A2M deletion polymorphism and AD modifies the disease risk in the studied population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:775-777, 2000.

Aged↗
PubMed2000

Allelic association between the D10S1423 marker and Alzheimer's disease in a German population.

Recently a full genome survey detected an allelic association between Alzheimer's disease (AD) and the D10S1423 marker on chromosome 10p12-14 (40 cM from the telomere). In this study we examined the D10S1423 marker in an ethnically homogeneous German population of 80 AD patients and two groups of controls, 168 healthy subjects and 149 depressed patients. The 234-bp allele of the D10S1423 marker showed a significant association with AD (P = 0.033). In conclusion, our results support that the D10S1423 marker is associated with an increased AD risk and provides further evidence for an AD susceptibility locus on chromosome 10.

Aged↗
PubMed2000

Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer's disease.

The conversion of brain cholesterol into 24S-hydroxycholesterol and its subsequent release into the periphery is probably an important step for the maintenance of brain cholesterol homeostasis. Recent findings suggest that plasma 24S-hydroxycholesterol may be elevated in Alzheimer's disease (AD) and vascular dementia at least at some stage of the disease, suggesting increased brain cholesterol turnover during neurodegeneration. We investigated whether plasma 24S-hydroxycholesterol concentrations depend on the severity of AD and on the apolipoprotein E (apoE) genotype. Severity of AD and inheritance of the apoE4 allele were independently associated with reduced plasma 24S-hydroxycholesterol/cholesterol ratios. The results suggest that the decrease of plasma 24S-hydroxycholesterol/cholesterol in severely affected AD patients is a peripheral marker for loss of cholesterol 24S-hydroxylase in the CNS. Inheritance of the apoE4 allele may be associated with increased apoE-mediated transport of brain cholesterol to the periphery or with decreased activity of the 24S-hydroxylase. Longitudinal studies will assess the validity of the ratio plasma 24S-hydroxycholesterol/cholesterol as a state marker for AD.

Aged↗
PubMed2000

7alpha-Hydroperoxycholesterol causes CNS neuronal cell death.

Brain cholesterol, which is synthesized in the central nervous system and also partly taken up from lipoproteins via the blood-brain barrier, is a major component of neuronal membranes. Oxidation of cholesterol leads to the formation of oxysterols, which have been shown to act cytotoxic. The influence of 7alpha-hydroperoxycholesterol, was investigated using the human neuroblastoma cell line SH-SY5Y. 7alpha-Hydroperoxycholesterol caused neuronal cell death; this neurotoxic effect was dose-dependent, within 48 h 10 microM led to 50%, 50 microM to 92% loss of cell viability, which was detected by cell morphology and Trypan blue exclusion. DNA-fragmentation or caspase-3 activity were not detectable, LDH release occurred rapidly and reactive oxygen species (ROS) were generated. Therefore we infer that 7alpha-hydroperoxycholesterol, apart from its role in atherosclerosis, leads to necrosis of neuronal cells.

Apoptosis↗
PubMed2000

Confirmation of the association between bleomycin hydrolase genotype and Alzheimer's disease.

Bleomycin hydrolase (BH), a cysteine protease from the papain superfamily, is considered to be a candidate for the beta-secretase, which is presumably involved in the production of beta-amyloid peptide. The G/G genotype of BH was identified as a significant risk factor for the development of Alzheimer's disease (AD) in subjects not carrying the apolipoprotein E epsilon4 allele (apoE-epsilon4). However, this finding was recently challenged. We studied this polymorphism in a homogenous sample of German AD patients and controls. The over-representation of the G/G genotype in AD patients could be confirmed, however it was more pronounced in apoE-epsilon4 carriers. Additional studies should be undertaken to increase the confidence that the BH polymorphism is associated with AD and to explore the relationship between BH and apoE.

Aged↗
PubMed2000

Neuropsychological and conditioned blocking performance in patients with schizophrenia: assessment of the contribution of neuroleptic dose, serum levels and dopamine D2-receptor occupancy.

Patients with schizophrenia show impairments of attention and neuropsychological performance, but the extent to which this is attributable to antipsychotic medication remains largely unexplored. We describe here the putative influence of the dose of antipsychotic medication (chlorpromazine equivalents, CPZ), the antipsychotic serum concentration of dopamine (DA) D2-blocking activity and the approximated central dopamine D2-receptor occupancy (DA D2-occupancy), on conditioned blocking (CB) measures of attention and performance on a neuropsychological battery, in 108 patients with schizophrenia (compared with 62 healthy controls). Antipsychotic serum concentration and D2-occupancy were higher in patients with a paranoid versus non-paranoid diagnosis, and in female versus male patients (independent of symptom severity). Controlling for D2-occupancy removed the difference between high CB in paranoid and impaired low CB in non-paranoid patients. Similar partial correlations for antipsychotic drug dose and serum levels of DA D2-blocking activity with performance of the trail-making and picture completion tests (negative) and the block-design task (positive) showed the functional importance of DA-related activity. High estimates of central DA D2-occupancy were related to impaired verbal fluency but were associated with improved recall of stories, especially in paranoid patients. This, the first study of its kind, tentatively imputes a role for DA D2-related activity in left frontal (e.g. CB, verbal fluency) and temporal lobe functions (verbal recall) as well as in some non-verbal abilities mediated more in the right hemisphere in patients with schizophrenia.

Adult↗
PubMed2000

No association between an intronic biallelic polymorphism of the FE65 gene and Alzheimer's disease.

The cleavage of the amyloid precursor protein (APP) into amyloidogenic components (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). FE65 is a protein that is involved in APP metabolism and may facilitate the production of Abeta. Recently, an intronic polymorphism of the gene encoding FE65 (FE65) was associated with altered risk for the development of sporadic AD. In our sample of 102 AD patients and 351 non-demented controls we did not replicate the association between FE65 and AD. Moreover, we observed no risk-modifying interaction and no linkage disequilibrium between FE65 and the gene encoding the acid protease cathepsin D (catD), which - like FE65 - is involved in APP metabolism and is also located on chromosome 11p15. We conclude that, whereas FE65 is implicated in AD pathology, the gene encoding FE65 does not appear to confer a substantial risk for AD.

Aged↗
PubMed2000

Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.

Alzheimer's disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzymatically oxidized product of cholesterol mainly synthesized in the brain. We tested the hypothesis that plasma levels of this oxysterol could be used as a putative biochemical marker for an altered cholesterol homeostasis in the brain of AD patients. Thirty patients with clinical criteria for AD, 30 healthy volunteers, 18 depressed patients, and 12 patients with vascular dementia (non-Alzheimer demented) were studied. Plasma concentrations of 24S-OH-Chol were assayed by isotope dilution;-mass spectrometry, cholesterol was measured enzymatically, and apolipoprotein E (apoE) was genotyped by polymerase chain reaction and restricted fragment length polymorphism. The concentration of 24S-OH-Chol in AD and non-Alzheimer demented patients was modestly but significantly higher than in healthy controls and in depressed patients. There was no significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls nor between AD and non-Alzheimer demented patients. The apoE straightepsilon4 allele influences plasma 24S-OH-Chol. However, this influence could be completely accounted for by the elevated plasma cholesterol in apoE4 hetero- or homozygotes. Plasma 24S-OH-Chol levels correlated negatively with the severity of dementia. AD and vascular demented patients appear to have higher circulating levels of 24S-OH-Chol than depressed patients and healthy controls. We speculate that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system. 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.

Aged↗
PubMed1999

No association between an intronic polymorphism in the presenilin-1 gene and Alzheimer disease in a German population.

A polymorphism in intron 8 of the presenilin-1 (PS-1) gene has been demonstrated to increase the risk for developing late-onset Alzheimer disease (AD). Conflicting results exist for the association between this intronic polymorphism and AD probably due to variations in the PS-1 gene among different ethnic groups. We investigated the genetic association between this intronic polymorphism in the PS-1 gene and AD in a homogenous group of German Caucasians. The control group consisted of healthy subjects and depressed patients. There were no significant differences in the distribution of the PS-1 genotypes and allele frequencies between AD patients and controls. Our data do not support an association between the intronic polymorphism of the PS-1 gene and AD and there was no interaction between the PS-1 genotype and apolipoprotein E epsilon4 allele.

Aged↗
PubMed1999

Genetic polymorphism of cathepsin D is strongly associated with the risk for developing sporadic Alzheimer's disease.

The beta amyloid peptide derives from its precursor protein via proteolytic cleavage of yet unidentified proteases (beta- and gamma-secretases). Cathepsin D is an intracellular protease with in-vitro beta-secretase-like features. An exonic polymorphism of the cathepsin D gene (alanine to valine transition at position 224, exon 2) has been associated with altered enzyme function. We tested the hypothesis that this polymorphism is associated with an increased risk for Alzheimer's disease in 102 demented patients, 191 healthy subjects, and 160 depressed patients. There was a highly significant overrepresentation of the cathepsin D*T allele in demented patients (14.2%) compared to non-demented controls (6.7%, P = 0.0012). Carriers of the cathepsin D*T allele had a 2.4-fold increased risk for developing AD than non-carriers. Carriers of the apolipoprotein E epsilon 4 allele had a 4.1 -fold increased risk than non-carriers. The odds ratio for subjects with the apolipoprotein E epsilon 4 and the cathepsin D*T allele was 5.9. Our data suggest that the cathepsin D genotype is strongly associated with the risk for Alzheimer's disease.

Aged↗
PubMed1999

The neurotoxic effect of 24-hydroxycholesterol on SH-SY5Y human neuroblastoma cells.

Neurodegenerative disorders are characterized by a massive loss of nerve cells. The neuronal cell death is accompanied by an increased cholesterol release and conversion of cholesterol into the polar metabolite, 24-hydroxycholesterol (24-OH-Chol), appears to be an important mechanism in the central nervous system for eliminating cholesterol from the brain. We tested the influence of 24-OH-Chol on SH-SY5Y human neuroblastoma cells by recording cell morphology, Trypan blue exclusion, LDH-release into the culture medium, intracellular calcium and reactive oxygen species (ROS). The exposure of SH-SY5Y human neuroblastoma cells to 50 microM 24-OH-Chol led to a 90% loss in cell viability within 30 h, the LDH-release into the medium increased rapidly after 24 h, and after 24 to 30 h we found an elevation in intracellular calcium. These results show that, in a physiological concentration range, 24-OH-Chol damages neuronal cells, thus we speculate that this oxysterol may be involved in the etiology of neurodegenerative disease.

Analysis of Variance↗