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PubMed1992

Catechol-O-methyltransferase inhibition increases striatal L-dopa and dopamine: an in vivo study in rats.

We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa. Acute administration of Ro 40-7592 increased basal levels of l-dopa and dihydroxyphenylacetic acid (DOPAC) and decreased basal homovanillic acid (HVA) levels, but did not affect basal dopamine levels. In rats treated with Ro 40-7592, l-dopa administration produced a greater increase in striatal levels of l-dopa, dopamine, and DOPAC than it did in controls, while HVA formation was attenuated. We conclude that inhibition of COMT activity promotes central dopamine synthesis and release following administration of pharmacologic doses of l-dopa.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers.

Tolcapone is a potent, reversible inhibitor of catechol O-methyltransferase (COMT) intended for use as an adjunct to levodopa therapy for Parkinson's disease (PD). Findings from the first pharmacokinetics/pharmacodynamics and tolerability studies of tolcapone in volunteers are reviewed. Following linear and dose-proportional pharmacokinetics, tolcapone is rapidly absorbed and eliminated after single- or multiple-dose (i.e., tid) administration. Onset of COMT inhibition is rapid, substantial, and reversible, and is not affected by the co-administration of levodopa/decarboxylase inhibitor (levodopa/DCI). When given together with levodopa/DCI, tolcapone increases the relative bioavailability and plasma elimination half-life of levodopa, without affecting its peak plasma concentration. This leads to more stable plasma levels of levodopa, and the formation of 3-O-methyldopa is effectively reduced. Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.

Antiparkinson Agents↗
PubMed1993

Sustained increase in adrenergic activity in gerbil striatum following transient ischemia.

We investigated the changes in striatal monoaminergic functions, focusing on the release and metabolism, in a cerebral ischemic model induced by a 5-min bilateral occlusion of the carotid arteries (BOCA) and reperfusion in anesthetized gerbils. In the microdialysis study, the striatal extracellular level of dopamine (DA) markedly increased (144-fold) immediately after BOCA. Although norepinephrine (NE) and 5-hydroxytryptamine (5-HT) could not be detected in the dialysates throughout the baseline period, they increased to detectable levels after BOCA. On the contrary, the tissue contents of NE and 5-HT decreased or tended to decrease up to 4 hr following reperfusion. Striatal DA contents did not show any changes in the early period after ischemia-reperfusion and slightly increased at 4 hr or later. Tissue contents of 3-methoxytyramine (3-MT), a metabolite of DA by catechol-O-methyltransferase (COMT), increased 0 and 5 min after reperfusion. Normethanephrine (NMN), which is a metabolite of NE by COMT, also increased not only 5 min after but also up to 4 hr after ischemia-reperfusion, indicating a sustained increase in NE release. These results suggested that the neuronal activity of NE, which is supposed to exert a protective effect on ischemic damage, was enhanced for a longer period than that of DA after transient ischemia.

Animals↗
PubMed2000

The role of entacapone in the management of Parkinson's disease.

Catechol-O-methyltransferase (COMT) inhibition is an important advance in the treatment of Parkinson's disease. This consensus statement provides guidelines for the optimal use of the only currently available COMT inhibitor, entacapone (Comtess, Orion Pharma (UK) Ltd, Newbury, Berkshire).

Antiparkinson Agents↗
PubMed2002

Entacapone in the management of Parkinson's disease.

Entacapone is one of a new class of drugs, the catechol-O-methyltransferase (COMT) inhibitors, which expand the therapeutic options for Parkinson's disease by extending the action of levodopa. Entacapone is used in conjunction with levodopa and provides benefit to patients who suffer from motor fluctuations. Side effects include worsening of the dyskinesias associated with peak doses of levodopa, hypotension, constipation and urine discoloration. Unlike tolcapone, an earlier COMT inhibitor, entacapone does not require liver function monitoring.

Antiparkinson Agents↗
PubMed2003

Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson's disease.

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson's disease (PD). They extend the duration of action of levodopa. As a result, they increase 'on' time, decrease 'off' time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.

Antiparkinson Agents↗
PubMed2004

Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology.

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency polymorphisms has steadily increased over the last years. Evidence based on meta-analyses of individual case-control studies is accumulating, defining specific individual variations in disease susceptibility. For example, genetic variations of the estradiol metabolism have been described as significant contributors to disease susceptibility with variations depending on ethnic background. In the field of obstetrics and gynecology, the genetic contribution of polymorphic markers to a series of disorders has been characterized. These disorders include recurrent pregnancy loss, pre-eclampsia, endometriosis, breast cancer, and hormone replacement therapy (HRT)-related complications such as thrombosis. Among other genetic markers, thrombophilic genetic variants, such as the Factor V Leiden and prothrombin G20210A polymorphisms, as well as genetic variants of cytochrome P450 (CYP) enzymes, for example, CYP19 and CYP1B1, have been established as genetic risk markers and disease modifiers of recurrent and sporadic pregnancy loss and HRT-independent and -dependent breast cancer, respectively. In addition, meta-analyses of data in the literature established the TGFBR1*6A, GSTP I105V, and TP53 R72P polymorphisms, as well as the GSTM1 gene deletion as low-penetrance genetic risk factors of sporadic breast cancer. With respect to genetic modulation of therapeutic effects, beneficial effects of estrogen replacement therapy and HRT are modulated by the carriage of single nucleotide polymorphisms, for example, osteoprotection and blood lipid changes by the estrogen receptor-alpha (ER-a) PvuII polymorphism. Polymorphisms of the catechol-O-methyltransferase (COMT), ER-alpha, IL-1 receptor antagonist, and Factor V genes have been demonstrated to modulate the timing of natural menopause. Lastly, a strong genetic contribution of polymorphisms to the development and the clinical course of endometriosis has been established with data pointing to polymorphisms of the COMT, GST, NAT-2, and ER-alpha genes as susceptibility markers. In summary, the available evidence points to a number of polymorphisms of a wide variety of genes as strong hereditary determinants of the susceptibility to benign and malignant gynecologic and obstetric conditions.

Female↗
PubMed1999

Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease.

Tolcapone is a selective peripheral and central catechol-O-methyltransferase (COMT) inhibitor recently approved as adjunctive therapy in patients with idiopathic Parkinson's disease who are already being treated with a levodopa-peripheral dopa decarboxylase inhibitor (DDI) combination. Tolcapone potentiates and prolongs the effect of levodopa in the central nervous system (CNS) by enhancing levodopa's delivery to the CNS and slowing dopamine's central metabolism. A short terminal disposition half-life of 2 hours mandates dosing 3 times/day. Dosage adjustment is generally unnecessary in the presence of mild to moderate renal and hepatic impairment. Coadministration of tolcapone with levodopa-DDI results in significant amelioration of the wearing-off and on-off phenomena and frequently allows significant levodopa dosage reduction. In patients with stable disease, tolcapone improves "on" time. As might be expected from its potentiation of levodopa effects, dopaminergic side effects are prominent with this agent. Although the main objective of drug treatment in Parkinson's disease remains clinical improvement with an optimum dose and frequency of levodopa administration, tolcapone may prove a useful adjunct to such therapy, especially in the presence of the wearing-off and on-off phenomena. The relative merits of this agent vis-a-vis dopamine receptor agonists are somewhat unclear at present. However, recent guidelines from the American Academy of Neurology suggest that a COMT inhibitor be added to levodopa-dopamine agonist therapy in patients with advanced disease.

Antiparkinson Agents↗
PubMed1990

The O-methylation of catechol oestrogens by pig conceptuses and endometrium during the peri-implantation period.

Pig conceptuses display a surge in oestrogen and catecholoestrogen synthetic activity during the peri-implantation period. However, the pathways of catecholoestrogen metabolism in pig conceptuses and endometrium are unknown. O-Methylation is an important route of catecholoestrogen metabolism. Therefore, the O-methylations of 2- and 4-hydroxy-oestradiols (2- and 4-OH-oestradiol) by cytosol of pig conceptuses and endometrium during the peri-implantation period were studied. Kinetic studies performed in tissues obtained on day 13 of pregnancy (day 0 = first acceptance of the male) indicated that the O-methylation of 2-OH-oestradiol displayed simple Michaelis-Menten kinetics in both tissues. In blastocysts, the apparent Michaelis constant (Km) and maximum velocity (Vmax) for the O-methylation of 2-OH-estradiol were 1.4 mumol/l and 11.27 pmol/mg protein per min respectively, and when 4-OH-oestradiol was used as substrate, the values were 2.53 mumol/l and 9.86 pmol/mg protein per min respectively. The apparent Km and Vmax values for the O-methylation of 2-OH-oestradiol in endometrium were 0.77 mumol/l and 19.6 pmol/mg protein per min respectively, and for the O-methylation of 4-OH-oestradiol were 2.44 mumol/l and 10.38 pmol/mg protein per min respectively. Ontogenesis of catechol-O-methyltransferase (COMT) in conceptuses and endometrium was studied from day 10 to day 19 of pregnancy. Conceptus COMT activity was lowest on day 10 and increased gradually to day 19 of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Periovulatory changes in catfish ovarian oestradiol-17beta, oestrogen-2-hydroxylase and catechol-O-methyltransferase during GnRH analogue-induced ovulation and in vitro induction of oocyte maturation by catecholoestrogens.

In the catfish Heteropneustes fossilis and Clarias batrachus, ovarian oestrogen-2-hydroxylase (OE-2-H) activity increased significantly at 8 h after the injection of an ovulatory dose (0.15 microg/g body weight) of a mammalian GnRH analogue ([d -Ala(6)-Pro(9)]-LHRH ethylamide) and was restored to the 0 h (control) level after egg-stripping at 16 h. On the other hand, ovarian oestradiol-17beta (OE2) level and catechol-O-methyltransferase (COMT) activity decreased significantly at 8 h. While the OE2 level was restored to the 0 h level, COMT activity increased significantly at 16 h. Changes in ovarian OE2 level and enzymes indicate higher synthesis of 2-hydroxylated catecholoestrogens and their degradation during the periovulatory period. Under in vitro conditions, the synthetic catecholoestrogens (CEs, 2- and 4-hydroxylated oestradiol17beta and oestrone (OE1)) induced germinal vesicle break down (GVBD) in a dose- (0.01-10 microg/ml) and duration- (1-36 h) dependent manner, the mean values of the responses being in the order 2-OH OE2>4-OH OE2> 2-OH OE1>4-OH OE1. The CE-induced GVBD response (8 h induction) was not blocked by prior and subsequent incubations with steroid synthesis inhibitors (cyanoketone, epostane and aminoglutethimide) up to 36 h, suggesting that de novo steroidogenesis is not essential for the response. The percentage of GVBD response to 2-h induction by CEs was significantly inhibited by actinomycin D (a transcriptional inhibitor) and cycloheximide (a translational inhibitor), indicating the involvement of both RNA and protein synthesis. The CE-induced 8-h stimulation of GVBD was mildly blocked by propranolol, the beta-adrenergic inhibitor, suggesting the response was partly mediated through a beta-adrenergic receptor mechanism. Incubations with phentolamine, an alpha-adrenergic inhibitor, did not interfere with the CE-induced GVBD response. The results demonstrate CE-related enzymatic changes in teleost (catfish) ovaries and maturation-inducing substance activity of CEs.

Animals↗
PubMed2026

Investigating the mechanisms of PhIP-induced colorectal cancer through network toxicology, machine learning, and molecular dynamics simulation.

BACKGROUND: Over the past few years, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)- a compound from grilled or processed meats-has emerged as a major player in cancer development, especially colorectal cancer (CRC). This work dives into its potential links to CRC and uncovers the key genes that bridge this connection. METHODS: We tapped into various databases to pinpoint target genes tied to PhIP and CRC, then ran protein-protein interaction (PPI) analyses for visualization. Next, we explored underlying mechanisms through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. To nail down predictions, we tested 107 machine learning pipelines and picked the best one, validating its accuracy and the core genes' prognostic value across datasets. Next, molecular docking and dynamics simulations probed the interactions between these genes and PhIP. Finally, cell proliferation was assessed using Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays, and polymerase chain reaction (PCR) was performed to validate the expression levels of the hub genes. RESULTS: Our analysis identified 39 overlapping genes, from which a machine learning model (glmBoost + Enet) identified six candidate targets: CDK4, CEBPB, COMT, SOX9, TIMP1, and TOP2A. To prioritize these, a hierarchical screening framework was applied. Molecular docking and dynamics simulations identified CDK4, COMT, and TIMP1 as the most stable interactors with PhIP. Functional assays confirmed that PhIP treatment significantly enhanced the proliferation of CRC cells. Crucially, quantitative PCR (qPCR) validation in multiple CRC cell lines identified TIMP1 as the primary target, showing the most consistent and significant upregulation upon PhIP exposure. CONCLUSIONS: In essence, these genes drive PhIP is role in CRC, offering novel insights into its molecular pathways. This could reshape how we tackle food-related pollutants, paving the way for better prevention and targeted therapies.

Colorectal cancer (CRC)↗
PubMed2002

Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease.

Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored.

Animals↗
PubMed2004

Pharmacogenetics of antihypertensive drug responses.

The blood pressure (BP) response to any single antihypertensive drug is characterized by marked interindividual variation, and the known predictors of response are of limited value in identifying the optimum drug for an individual patient. Analysis of genetic variation has the potential to improve our understanding of determinants of antihypertensive drug response in order to individualize drug selection. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Classic pharmacogenetic investigations have identified variations in single genes that have a large effect on antihypertensive drug metabolism and are inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6 gene, encoding a cytochrome p450 family member involved in phase I drug metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these polymorphisms have major effects on the pharmacokinetic profiles of both commonly used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have not been shown to influence variation in the antihypertensive effect of these drugs at conventional doses. Interest is now focused on identifying genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Using a candidate gene approach, such polymorphisms have been identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone system (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE), beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1), angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful. New genome-wide scanning techniques may lead to the identification of genes previously unsuspected of influencing drug response. Additional requirements for pharmacogenetic approaches to become clinically useful are the characterization of the effects of haplotypes and multi-locus genotypes on drug response, and consideration of gene-by-environment interactions. Such studies will require huge sample sizes and novel statistical methods, but the theoretical and technical framework is in place to make this possible.

Animals↗
PubMed1987

Metabolism of 6,7-dimethoxy 4-(4'-chlorobenzyl)isoquinoline. II. Role of liver catechol O-methyltransferase and glutathione.

1. On i.v. administration to rats of 14C-6,7-dimethoxy 4-(4'-chlorobenzyl)isoquinoline (PV2) 23% dose of 14C was excreted in urine and 72% in faeces. The pattern of metabolites showed ten 14C-PV2 derivatives and unchanged PV2. Seven metabolites have been characterized by comparison with authentic compounds e.g. the ketone of PV2, the N-oxide PV2, the demethylated metabolites 6-hydroxy-PV2, 7-hydroxy-PV2 and 6,7-dihydroxy PV2, the benzyl ring-hydroxylated metabolites, 3'-hydroxy-PV2 and 6,7,3'-trihydroxy-PV2. Unchanged PV2 and its metabolites are excreted both free and conjugated. 2. Enzymic O-methylation of 6,7-dihydroxy-PV2 by liver catechol-O-methyl transferase (COMT) in vitro produced 6-hydroxy,7-methoxy-PV2. After blockade of COMT by pyrogallol in vivo, the excretion of 6,7-dihydroxy-PV2 was increased and the excretion of 6-hydroxy, 7-methoxy-PV2 decreased. 3. Hydroxylation of the benzyl ring of PV2 and its metabolites indicates the formation of an intermediate epoxide followed by glutathione conjugation. After glutathione depletion in vivo by diethyl maleate (DEM) liver covalent binding of 14C-PV2 metabolites was increased and biliary excretion of benzyl ring-hydroxylated PV2 metabolites decreased. Replacement of glutathione depletion by a cysteine derivative restored liver covalent binding and the excretion of PV2 metabolites to levels similar to those observed in control rats, indicating that glutathione conjugation may be an important metabolic pathway for the detoxication of PV2 and its metabolites in vivo.

Animals↗
PubMed1997

Genomic sequence and mapping of a methyljasmonate-induced O-methyltransferase from barley (Hordeum vulgare L.).

We have isolated a genomic clone corresponding to a caffeic acid O-methyltransferase (COMT) from barley (Hordeum vulgare L.) using a cDNA for a previously described jasmonate-regulated mRNA showing homology to COMT. Primer extension was used to characterize the 5' end of the mRNA while the 3' end, intron/exon structure and other features of the sequence were deduced by comparison to the cDNA sequence and/or conserved motifs. The gene is mapped to chromosome five and is absent in the barley cultivar Morex. Southern and northern analyses suggest that no differences in genomic structure and jasmonate inducibility exist between the barley cultivar Salome (source of the cDNA clone) and Igri (source of the genomic clone). This genomic clone is thus suitable for promoter studies with respect to jasmonate induction.

Acetates↗
PubMed1994

Kinetics of the reversible tight-binding inhibition of pig liver catechol-O-methyltransferase by [2-(3,4-dihydroxy-2- nitrophenyl)vinyl]phenyl ketone.

The inactivation of partially purified pig liver catechol-O-methyltransferase (COMT) by [2-(3,4-dihydroxy-2-nitrophenyl)vinyl]phenylketone has been studied. The results demonstrated that COMT is inhibited in a reversible tight-binding fashion with an apparent Ki of 0.2 microM. IC50 values were determined at different concentrations of both substrates of the enzymatic reaction, pyrocatechol and S-adenosyl-L-methionine (AdoMet). The plot of IC50 versus pyrocatechol concentration gave a straight line, suggesting competitive inhibition. However the nitrocatechol derivative showed an uncompetitive inhibition pattern when measured as a function of AdoMet concentration.

Animals↗
PubMed1978

Biochemical activities of the derivatives of dehydrodicaffeic acid dilactone.

Activities of derivatives of dehydrodicaffeic acid dilactone (DDCAD) to inhibit catechol-O-methyltransferase (COMT), cyclic AMP phosphodiesterase (PDE) and DOPA decarboxylase (DDC) were examined. Among those tested, 2,6-bis-(5',6'-dibromo-4'-hydroxy-3'-methoxyphenyl)-3,7-dioxabicyclo-[3,3,0]-octane 4,8-dione was found to be the strongest inhibitor of both COMT and PDE. There were no derivatives which showed a stronger inhibition against DDC than the original compound, DDCAD.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

[Recent advances in Parkinson disease].

OBJECTIVE: To evaluate the latest advances in the diagnosis and symptomatic pharmacological treatment of patients with Parkinson's disease at different stages. DEVELOPMENT: In this article we summarize the criteria for clinical diagnosis of Parkinson's disease based on recent clinico-pathological studies. We evaluate the different therapeutic options at early and late stages of the illness in view of the results of recent, controlled, double-blind studies in which the efficacy of new dopaminergic agonists (carbergolin, pramipexol and ropinirol) and catechol-O-methyl-transferase enzyme inhibitors (COMT; entacapone and tolcapone) are compared with placebo and with established treatments (e.g. levodopa and bromocryptin). CONCLUSIONS: Levodopa is still the most important advance yet made in the treatment of Parkinson's disease, but new dopaminergic agonists and COMT inhibitors are useful additions to the possibilities available for the treatment of early and late stages of the illness and may be included in modern guidelines for treatment.

Antiparkinson Agents↗