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PubMed1982

Enzymatic O-methylation of catechols and catecholamines.

The reactivity of a number of catechols and catecholamines with regard to the enzymatic O-methylation by catechol-O-methyltransferase (COMT) was studied. The reaction was carried out in a vial at a temperature of 37 degrees C, the vial contained a certain concentration of one catechol(amine), catechol-O-methyltransferase (the enzyme), S-adenosylmethionine (the methyldonor), MgCl2 (a cofactor) and buffer pH = 7.85. After certain time intervals samples were taken, the reaction was stopped in acid. The catechol(amine) concentration decrease and the product concentration increase were determined by injecting the samples directly into an HPLC connected with a fluorimeter, giving the opportunity of estimating the mass balance. Vmax, Km, C3/C4 ratio (= ratio of 3-O- and 4-O-methylated product formed) and the reaction rate at low substrate (catecholamine) concentration (= Vmax. [S]/Km)-which appears to be related to log P - are given. It is conjectured that V at low substrate concentration is especially determined by the polarity of the catechol(amine) while Vmax is primarily determined by other physico-chemical properties like steric conformation (L-dopa vs DL-dopa; L-adrenaline vs DL-adrenaline).

Catechol O-Methyltransferase↗
PubMed1993

Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS.

In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.

Animals↗
PubMed2003

Current researches on breast cancer epidemiology in Korea.

As a cause of death in women, breast cancer ranks second to stomach cancer in Korea. Age-standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s. There are big differences in the incidence rates for breast cancer compared with Western countries. Epidemiological features, trends in morbidity and mortality, various age-specific incidence curves, migrant study results, and analysis of the risk factors, however, suggest that the incidence of breast cancer might be further increasing in Korea. The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis. These include older age, family history of breast cancer, early menarche, late menopause, late full-term pregnancy, and never a breast feeding. Both the establishment of high-risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer. Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea, and the five-year survival rate has been estimated as 80-83%. Recent studies on the identification of susceptibility factors such as genetic polymorphisms of GSTM1/T1/P1, COMT, CYP2E1, CYP19, CYP17, ER-alpha, XRCC1, XRCC3, RAD52, TGF-alpha, TNF-alpha, IL-1B, IL-1RN, CDK7 etc. that predispose individuals to breast cancer by gene-environment or gene-gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy.

Biomedical Research↗
PubMed2004

The genetic relationship of personality to major depression and schizophrenia.

Since ancient times, dimensions of personality have been linked with the liability to psychiatric illness. In modern times, several research approaches suggest that personality and the liability to psychiatric illness such as schizophrenia and major depression (MD) are influenced by many of the same genes. If this is true, it could shed light on the genetic architecture of psychiatric illness. It could also validate the use of personality measures in unaffected relatives in linkage and association studies of psychiatric illness. This approach could potentially increase statistical power to detect genetic effects. The personality trait neuroticism (N) may be genetically related to MD, while schizotypal traits may be genetically related to schizophrenia. Twin studies have reported that most of the covariation between N and MD is due to shared additive genetic factors. Adoption studies have demonstrated that the biological offspring of schizophrenic mothers are more likely to have schizotypal personality disorder than are children of control mothers. At the current time, only one genome wide scan of N has been published, which does show some overlap in linkage results with genome scans of MD. However, this should be replicated and more rigorously studied. At the present time, there are no established susceptibility genes for MD. When these are established, it will be necessary to assess their relationship with N. Currently, no genome scans of schizotypy have been published. Furthermore, although several putative susceptibility genes for schizophrenia have been reported and replicated, only one--catechol-O-methyltransferase (COMT)--has been tested in schizotypy.

Major Depressive Disorder↗
PubMed2005

Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method.

Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMT and ALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

Aldehyde Dehydrogenase↗
PubMed2000

Costs in the treatment of parkinsonism.

Parkinson's disease imposes a considerable economic burden on our society. Apart from the direct costs for therapy, the indirect costs of the disease are estimated to be substantially higher. Unfortunately, only the high costs of current medication are usually considered, when financial aspects are discussed. An ideal therapy should ameliorate the symptoms of the disease and achieve a high quality of life. but the prognosis should also be improved. Cost estimates have to be extended throughout the course of the disease. We recommend a treatment schedule which is expected to result in a favorable cost profile when the entire course of the disease, is considered. L-Dopa monotherapy in working patients is obsolete. During the course of the disease dopamine agonists, amantadine, budipine, COMT inhibitors and selegiline will be used.

Antiparkinson Agents↗
PubMed2000

Workshop III: late motor complications of Parkinson's disease.

The aim in the current treatment of Parkinson's disease is to delay L-Dopa administration and to keep the L-Dopa dosage as low as possible. Such a treatment strategy can delay the onset of late motor complications and reduce their severity. L-Dopa remains the most potent anti-parkinsonian medication, but its use for the initial therapy of Parkinson's disease is limited to elderly patients. In all other cases, dopamine agonists, budipine, amantadine and selegiline are primarily used. With the occurrence of late motor complications continuous dopamine receptor stimulation becomes essential. In this situation, combination therapy has to be individualized, with dopamine agonists playing a key role. In addition, COMT inhibitors, budipine, amantadine and selegiline may be used. Anticholinergic drugs are of very limited importance in the current treatment of Parkinson's disease.

Antiparkinson Agents↗
PubMed2004

Screening for candidate gene regions in narcolepsy using a microsatellite based approach and pooled DNA.

Narcolepsy is a complex sleep disorder characterized by excessive daytime sleepiness and cataplexy. Mutations in genes of the hypocretin (orexin) neurotransmitter system cause narcoleptic symptoms in animal models. The absence of hypocretin in the cerebrospinal fluid of human patients is hypothesized to originate from destruction of hypocretinergic cells in the hypothalamus, the cause of which remains unknown. Due to strong HLA association autoimmune models of narcolepsy pathogenesis are still mostly favored. Genetic predisposition factors other than HLA are likely to play a role in causing the disorder. We screened three sets of gene regions ( n=254) for association with narcolepsy using a microsatellite based approach and pooled DNA: genes related to immunity, particularly apoptosis; genes related to regulation of circadian rhythmicity; genes coding for several factors of neurotransmission. In relation to apoptosis an association was found for the BAG1 gene region. Interestingly, microsatellites representing four genomic regions related to neurotransmission revealed association with narcolepsy: COMT, DRD2, GABBR1, and HTR2A. These results, although exploratory and still to be confirmed in independent samples, support a complex pathogenetic model for narcolepsy, including disturbances of neurotransmission rather than involvement of autoimmunity.

Alleles↗
PubMed2002

[Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes].

Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified.

Bipolar Disorder↗
PubMed2003

A bitter pill. Overview of ecstasy (MDMA, MDA) related fatalities.

RATIONALE: The issue of ecstasy-related fatalities has extensively attracted the attention of both the media and the general public, but less so of the scientific literature. OBJECTIVES: The aim of the present review is to focus on the epidemiological, clinical and pharmacological issues related to ecstasy fatalities. RESULTS: Possibly due to a number of different reasons, the rates of ecstasy-related deaths seem to have peaked in recent years. MDMA metabolism is regulated by the levels of CYP2D6 and COMT (both exhibit some genetic polymorphism), and range of activity of these enzymes may account for some inter-individual differences in terms of toxic responses to the drug. A small increase in MDMA dosage can lead to a significant rise in drug plasma concentration. Due to their tolerance to MDMA psychoactive effects, some individuals may binge with dosages that may be the cause of serious concern. In experienced users, a reverse tolerance phenomenon can also be observed. Together with ecstasy, most of the misusers take a number of different compounds and the possible rationale of this style of consumption is commented upon here. Frequently, the lethal complications observed after acute MDMA administration can be the consequence of the occurrence of a serotonin syndrome and/or of sympathomimetic overstimulation (both conditions are exacerbated by environmentally induced overheating). CONCLUSIONS: A number of methodological problems can contribute to making difficult the interpretation of the role played by ecstasy in so-called ecstasy-related deaths, especially so if accurate information is not available.

Amphetamine-Related Disorders↗
PubMed2004

Genetic features of antidepressant induced mania and hypo-mania in bipolar disorder.

RATIONALE AND OBJECTIVES: The present study investigated possible genetic association between some polymorphisms possibly involved in antidepressant response and the occurrence of manic or hypo-manic switches during antidepressant treatment. METHODS: We retrospectively examined 169 individuals with a diagnosis of bipolar disorder (BP) type I ( n=103) and II ( n=66), who presented at least one sudden manic or hypo-manic episode (according to DSM IV criteria) during antidepressant therapy, that occurred within a period of 3 weeks from the beginning of the treatment and without any interposed period of well being ("manic switch"). They were compared with a sex, age, and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects, who never showed switches. We then randomly selected from the whole sample ("switched" and "not switched") a sub-sample of patients not under mood stabiliser treatment at the time of the index episode (65 "switched" and 117 "not switched") and compared them with a sex, age and ethnicity matched group of 133 subjects, randomly selected from our pool of major depressed patients, who did not present manic switches. The functional polymorphism in the upstream regulatory region of the serotonin transporter (SERTPR), tryptophan hydroxylase (TPH), G-protein beta 3 subunit (Gbeta3), monoamine oxidase A (MAO-A), catechol- O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) gene variants were analysed using PCR-based techniques. RESULTS AND CONCLUSIONS: The distribution of the genetic polymorphisms was not significantly different between switched and not-switched patients ( P>0.006-Bonferroni corrected). Moreover, no significant difference was found between switched and not switched sub-samples and the sample of major depressed subjects. Further studies are required to investigate other possible related genetic variants influencing the timing of manic-depressive cycle.

Adult↗
PubMed2001

L-dopa induces dyskinesia in normal monkeys: behavioural and pharmacokinetic observations.

RATIONALE: L-Dopa induces dyskinesias during the treatment of Parkinson's disease and also in primates with nigrostriatal lesions produced by MPTP, but it is claimed that L-dopa does not provoke dyskinesia in humans or monkeys with an intact or mildly damaged nigrostriatal system. OBJECTIVES: This study assessed the behavioural and pharmacokinetic effects of chronic oral administration of L-dopa plus carbidopa alone, or with co-administration of the peripheral COMT inhibitor entacapone, to normal macaque monkeys. Repeated high dose L-dopa administration was shown to induce marked dyskinesias in monkeys with an intact nigrostriatal system, and the threshold for dyskinesia expression was increased by peripheral catechol-O-methyltransferase inhibition with entacapone. METHODS: Six groups of normal macaque monkeys (n=8 per group; Macaca fascicularis) were treated with L-dopa (20, 40 or 80 mg/kg) plus carbidopa (5, 10 or 20 mg/kg) with or without the catechol-O-methyltransferase inhibitor entacapone (20, 40 or 80 mg/kg), or with entacapone alone (80 mg/kg), by oral administration once daily for 13 weeks. RESULTS: Eleven of 16 animals receiving high dose L-dopa (80 mg/kg plus carbidopa 20 mg/kg PO with or without entacapone 80 mg/kg PO for 13 weeks) gradually developed reproducible and idiosyncratic combinations of chorea, athetosis and dystonia maximal at 60-100 min after L-dopa administration, which progressively intensified over the course of the study. The dyskinesias observed were similar in type and distribution to L-dopa-induced dyskinesia observed in patients with Parkinson's disease and in MPTP-treated primates. The occurrence of dyskinesia correlated with plasma concentrations of L-dopa, with animals displaying the most severe dyskinesias having significantly higher plasma concentrations of L-dopa one hour after dosing than animals with mild or moderate dyskinesia or no dyskinesia. Co-administration of entacapone with L-dopa plus carbidopa significantly lowered peak plasma concentrations of L-dopa and this was reflected by a decrease in the severity of dyskinesias, with only one animal receiving entacapone and high dose L-dopa plus carbidopa showing severe dyskinesia, while four receiving high dose L-dopa plus carbidopa alone did so. CONCLUSIONS: These results show for the first time that chronic oral L-dopa administration can provoke dyskinesias in primates independently of nigrostriatal damage, and that this effect is dose related.

Animals↗
PubMedDate not supplied

Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man. A study using a stable isotope techique.

OBJECTIVE: This study investigated the pharmacokinetics of the catechol-O-methyltransferase (COMT) inhibitor entacapone by giving simultaneously stable non-radioactive isotope 13C-entacapone intravenously (i.v.) and unlabelled entacapone orally. In comparison with a crossover design, the simultaneous i.v. and oral administration made it possible to minimise intra-individual variation, sample size and the duration of the study and still obtain accurate pharmacokinetic data. METHODS: Eight healthy male volunteers were enrolled in this study. They were given a 20-mg i.v. dose of 13C-entacapone as a 1-mg/ml infusion at a constant rate of 5 mg/min over 4 min and a 100-mg dose of unlabelled entacapone orally immediately after the infusion. Blood samples were drawn at -5 (before onset of infusion), 0 (upon termination of infusion), 2, 5, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after the tablet ingestion. Urine during the 48 h after dosing was collected in fractions. Concentrations of 13C-entacapone and entacapone in plasma samples and urine fractions were determined using gas chromatography-mass spectrometry. RESULTS: The decay of i.v. 13C-entacapone in plasma was tri-exponential and its pharmacokinetics were described using an open three-compartment model. The volume of the central compartment (Vc) and the volume of distribution at steady state (Vss) were 0.08+/-0.03 l/kg and 0.27+/-0.10 l/kg, respectively. Total plasma clearance (Cltot) averaged 11.7+/-1.9 ml/min kg(-1). The half-lives for the distribution phase and for the rapid and terminal elimination phases (t1/2alpha, t1/2beta and t1/2gamma) were 0.05+/-0.01 h, 0.38+/-0.16 h and 2.40+/-1.70 h, respectively. The terminal elimination phase accounted for only 9% of the total area under the plasma concentration-time curve (AUC), which was 409 +/- 98 ng h/ml after the i.v. dose. Oral entacapone was absorbed rapidly with a time to reach the peak concentration (tmax) of 0.9+/-0.4 h, a maximum concentration (Cmax) of 457+/-334 ng/ml and an AUC of 497+/-118 ng h/ml. During the 48 h after dosing, the recovery of free and conjugated unchanged 13C-entacapone in urine was 38.1+/-7.2% of the i.v. dose and the recovery of free and conjugated unchanged entacapone 13.3+/-3.9% of the oral dose. The bioavailability of oral entacapone was 25% based on the AUC values and 35% based on urinary excretion. CONCLUSION: The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.

Administration, Oral↗
PubMed1996

Simultaneous inhibition of catecholamine-O-methylation by entacapone and neuronal uptake by imipramine: lack of interactions.

OBJECTIVE: We have evaluated the effects of simultaneous inhibition of catechol-O-methyltransferase (COMT) by entacapone and of neuronal monoamine reuptake by imipramine on haemodynamics and catecholamine metabolism, and the safety and tolerability of the drug combination in healthy women. METHODS: In a randomized, single-dose, single-blind, cross-over study, 12 healthy women were given placebo, entacapone (200 mg), imipramine (75 mg) or entacapone and imipramine in combination. Heart rate, blood pressure, systolic time intervals, and plasma concentrations of catecholamines and their metabolites were measured at rest and during exercise. RESULTS: The only drug-related effect on haemodynamics was an increase in heart rate during exercise after imipramine. The increase in heart rate after the combination of entacapone and imipramine was similar to that after imipramine alone. Entacapone alone had no effects on haemodynamics. Imipramine and entacapone had no significant effects on the plasma concentrations of noradrenaline and adrenaline. No interactions between entacapone and imipramine were detected.

Adrenergic Uptake Inhibitors↗
PubMed2005

Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes?

Schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies.

Bipolar Disorder↗
PubMed2002

New drugs in the future treatment of Parkinson's disease.

During the last few decades, there has been a remarkable progress in our understanding of the biology of Parkinson's disease (PD), which has been translated into the development of numerous antiparkinsonian drugs. There are different therapeutic strategies for patients in an early stage versus patients in a late stage of the disease. The current therapeutic arsenal includes levodopa preparations, MAO-B inhibitors, dopamine agonists, COMT inhibitors and several other compounds that target non-dopaminergic systems. Much interest is focused on the potential neuroprotective effect of the already available drugs, as well as on new research approaches for the development of disease-modifying agents. These include mainly anti-glutamategic compounds, anti-apoptotic and antioxidative agents. Future therapy might include targeted delivery of trophic factors or genes involved in the pathogenesis of the disease. Apart from the classic levodopa-associated motor complications, such as dyskinesias and response fluctuations and psychosis, many other problems of advanced disease should be focused upon and solved including fatigue, freezing of gait, postural instability, depression, anxiety and panic attacks, sleep disturbances, autonomic dysfunction and sensory complaints.

Animals↗
PubMed2003

The relevance of preclinical studies for the treatment of Parkinson's disease.

An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).

Antiparkinson Agents↗
PubMed2005

Optimising levodopa therapy for the management of Parkinson's disease.

Levodopa remains unrivalled in providing symptomatic benefit for the treatment of Parkinson's disease (PD). However, wearing-off and dyskinesia have been associated with chronic therapy using traditional levodopa formulations. The onset of these motor complications arises, in part, due to the limited pharmacokinetic profile of traditional levodopa and not as a direct consequence of levodopa per se. Clinical trials addressing these issues have suggested that providing less pulsatile and more continuous dopaminergic stimulation by improving the pharmacokinetic profile of levodopa may overcome the onset of these motor complications. It can, therefore, be suggested that the onset of dyskinesia may be prolonged if levodopa is administered in a more continuous manner by administering it as a combination of levodopa/DDCI and COMT inhibitor.

Antiparkinson Agents↗