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PubMed1998

Depression in Parkinson's disease. Pharmacological characteristics and treatment.

Parkinson's disease (PD) is a common neurological illness and various degrees of depression frequently complicate its course. Risk factors for developing depression with PD include right-sided hemiparkinsonism, akinesia, increased severity of disability, anxiety and psychosis. Onset of parkinsonism at a younger age, female gender and the use of levodopa are arguable risk factors. Depression may be difficult to diagnose in patients with PD because the signs of the 2 disorders overlap. In addition, patients with atypical PD more commonly have depression than patients with classical PD presentations. Antidepressant response to antiparkinsonian treatment has been limited. Enhancement of catecholamine levels in the CNS by selegiline (deprenyl), a monoamine oxidase (MAO) type B inhibitor, has shown potential antidepressant as well as neuroprotective effects. Other MAO inhibitors have shown antidepressant efficacy in animal models but have not been well tolerated by patients with PD. A catechol-O-methyltransferase (COMT) inhibitor combined with an MAO inhibitor might synergistically maximise the levels of catecholamines in the CNS. Antidepressant medications used in patients without PD include tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), but only TCAs have been carefully studied for their antidepressant effects in PD. Electroconvulsive therapy has proven efficacy as antidepressant therapy in patients with PD, and transcranial magnetic stimulation has provided temporary relief of depression under experimental conditions. Adverse effects of polypharmacy in the attempted treatment of depression in patients with PD are common in the elderly. A 'serotonin syndrome' has occurred frequently enough to preclude the coadministration of selegiline with SSRIs or TCAs, and multiple interactions between antiparkinsonian and antidepressant medications further complicate treatment strategies in patients with PD. An algorithmic approach to the pharmacological treatment of depression is described in this article.

Aged↗
PubMed2002

Sleep disorders in Parkinson's disease: epidemiology and management.

Sleep problems are an under-emphasised cause of disability in Parkinson's disease (PD) and may be seen independently of PD, associated with primary PD pathology, or as a result of antiparkinsonian medications. Common sleep disorders include excessive daytime sleepiness, rapid eye movement (REM) sleep behaviour disorder, night-time wakefulness and restless legs syndrome. A number of strategies may be used to improve sleep cycle disturbances, and often these interventions do not require pharmacological manipulation. Restoring traditional mealtimes and scheduling activities during predicted periods of sleepiness may help alleviate daytime somnolence; the use of controlled-release levodopa preparations or administration of a catechol-O-methyl transferase (COMT) inhibitor with levodopa at bedtime may reduce periods of night-time wakefulness. Administration of clonazepam at bedtime may assist with REM sleep behaviour disorder but, because this agent can result in daytime somnolence, experimentation with dosage times is recommended. Sleep attacks are described as a sudden, unavoidable transition from wakefulness to sleep and, although rare, have been described with pramipexole, ropinirole and other dopamine agonists. Although the condition has yet to be recognised by the International Association of Sleep Disorders, patients with PD who report rapid sleep onset should be evaluated for the possibility of sleep attacks. If sleep attacks are suspected, it is reasonable to strongly caution patients regarding potentially risk-associated activities such as driving, and to consider careful withdrawal of dopaminergic therapy.

Antiparkinson Agents↗
PubMed2001

Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.

OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.

Aged↗
PubMed1999

Entacapone. A review of its use in Parkinson's disease.

UNLABELLED: Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson's disease and end-of-dose deterioration in the response to levodopa (the 'wearing off' phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson's disease. In 2 well conducted trials of 6 months' duration and smaller short term studies, treatment with entacapone (200 mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily 'on' time and decreases in 'off' time. Changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores concurred with changes in 'on' and 'off' times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials. Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug's ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation. CONCLUSIONS: The efficacy and tolerability of entacapone administered with levodopa/AADC inhibitor have not yet been compared with those of other strategies for the treatment of Parkinson's disease. However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson's disease and the 'wearing off' phenomenon.

Animals↗
PubMed2005

Tolcapone: a review of its use in the management of Parkinson's disease.

Tolcapone (Tasmar) is a selective, reversible inhibitor of peripheral and central catechol-O-methyltransferase (COMT). Results of well designed studies indicate that oral tolcapone is an effective adjunct to levodopa plus a peripheral dopa-decarboxylase inhibitor (DDCI) in patients with fluctuating Parkinson's disease. Tolcapone significantly improves levodopa-induced motor fluctuations and significantly reduces levodopa requirements. The drug is generally well tolerated, with the most commonly occurring adverse events being dopaminergic related. Thus, tolcapone is a useful option in patients with fluctuating Parkinson's disease who are receiving levodopa/DDCI and are not responding to, or are not candidates for, other adjunctive treatments.

Antiparkinson Agents↗
PubMed2003

Entacapone/levodopa/carbidopa combination tablet: Stalevo.

Entacapone (Comtess/Comtan) is Orion Pharma's original proprietary catechol-O-methyl transferase (COMT) inhibitor. Entacapone is able to slow down degradation of levodopa and improve the availability and efficacy of each levodopa dose, hence its use as a complement to levodopa/carbidopa in patients with Parkinson's disease. In order to simplify the daily dosing of these medications, Orion has developed an entacapone/levodopa/carbidopa combination tablet. Three tablet strengths are being developed so as to cover the most common clinical dosing needs. In September 2000, Orion signed a marketing and distribution agreement with Novartis for the combination tablet. Under the terms of the agreement, Orion has exclusive marketing rights for the product in Germany, the UK, Ireland, the Nordic and Baltic countries, and several Eastern European countries. Novartis has exclusive rights to the US and territories other than those markets for which Orion holds market exclusivity. Orion also has the option to co-promote the product in France, Spain and several other countries. In June 2003, the US FDA approved the entacapone/levodopa/carbidopa combination tablet (Stalevo) for the treatment of patients with idiopathic Parkinson's disease who experience signs and symptoms of end-of-dose 'wearing off'. Market launch of the product is expected toward the end of 2003 in the US. Also in June 2003, the Committee for Proprietary Medicinal Products of the European Agency for the Evaluation of Medicinal Products adopted a positive opinion of the combination tablet. In September 2002, Orion submitted an application for the approval of the combination product in the European Union. It is expected that the product will be marketed in the European Union in early 2004. Orion estimates that about two of three fluctuating Parkinson's disease patients will be able to be treated effectively with the triple combination tablet.

Administration, Oral↗
PubMed2002

Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients.

This paper lists the genotype frequencies of 50 polymorphisms of 37 genes (ALDH2, ADRB2, ADRB3, COMT, CD36, CXCR2, CCND1, COX2, CYP2A6, CYP17, CYP19, IGF1, IL-1A, IL-1B, IL-1RN, IL-1R1, IL-6, IL-8, IL-10, LEP, Le, L-myc, MPO, MTR, MTHFR, MAO-A, NQO1, OGG1, p53, p73, Se, SRD5A2, TGF-B, TNF-A, TNF-B, XPD, and XRCC1) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients. Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers, 15 polymorphisms (CD36 A52C, CXCR2 C785T, CCND1 G870A, IGF1 C/T at intron 2 and G2502T, IL-1A 46-bp VNTR, IL-1R1 C-116T, IL-6 Ins/Del 17C, IL-8 A-278T and C74T, IL- 10 T-819C, LEP A-2548G, SRD5A2 2-bp VNTR, XPD Lys751Gln, and XRCC1 Arg399Gln) and six sets of combined genotype frequencies (IL-1B C-31T and IL-1A C-889T, IL-1B C-31T and IL-1RN 86-bp VNTR, IL-1B C-31T and IL-1R1 C-116T, TNF-A G-308A and TNF-B A252G, SRD5A2 Val89Leu and 2-bp VNTR, and XRCC1 Arg399Gln and XPD Lys751Gln) were reported in this paper for the first time for Japanese. Although microarray technology will produce this kind of information in near future, this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose.

Alleles↗
PubMed2006

Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome.

OBJECTIVE: This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance. METHODS: Specifically, given SNP profiles for 43 CFS patients, together with 58 controls, we used an enumerative search to identify an ensemble of conjunctive rules that predict whether a patient has CFS. RESULTS: The accuracy of the rules reached 76.3%, with the highest accuracy rules yielding 49 true negatives, 15 false negatives, 28 true positives and nine false positives (odds ratio [OR] 8.94, p < 0.0001). Analysis of the SNPs used most frequently in the overall ensemble of rules gave rise to a list of 'most important SNPs', which was not identical to the list of 'most differentiating SNPs' that one would calculate via studying each SNP independently. The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness.

Algorithms↗
PubMed2001

Candidate gene studies of bipolar disorder.

Genetic factors undoubtedly play an important role in determining vulnerability to bipolar disorder but the task of finding susceptibility genes is not trivial. Candidate gene studies, usually employing the association approach, offer the potential to discover the genes of relatively modest effect size that are expected for a complex genetic disorder. Candidate gene approaches depend crucially on our current understanding of disease pathophysiology, and attention has consequently been focussed on a limited range of neurotransmitter systems implicated by the action of drug treatments. Despite no unequivocal, consistently replicated findings, a number of intriguing results have emerged in the literature, both for bipolar disorder in general and for subtypes such as bipolar affective puerperal psychosis and rapid cycling bipolar illness. Genes of particular current interest include those encoding the serotonin transporter, monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). As susceptibility genes are found and knowledge of aetiology advanced it is likely that many more candidate genes in novel biological systems will attract attention.

Bipolar Disorder↗
PubMed1979

[Effect of S-adenosyl-L-homocysteine of dopamine catabolism].

1.--The administration of SAH to rats, at physiologically active dose on the sleep, does not change the urinary level of MD and NM. On the other hand, the excretion of DA and NA decreases. 2.--In the brain, SAH does not modify neither the concentration of NA and NM in hypothalamus and thalamus, nor the concentration of DA and MD in corpus striatum. 3.--After intracisternally injection of [14C]DA or [3H]NA, SAH increases the level of [14C]MD and [3H]NM. 4.--Contrary to the studies in vitro, where SAH is an inhibitor of COMT, on the rat it does not seem prevent the methylation of DA and NA.

Animals↗
PubMed1999

Medical and surgical treatment of Parkinson's disease. Strategies to slow symptom progression and improve quality of life.

Despite new medical and surgical therapy, mortality rates for Parkinson's disease remain unchanged. Nevertheless, symptom progression can be slowed and quality of life improved with current methods of treatment. Levodopa is the most effective drug for Parkinson's disease, but its long-term use is associated with significant motor complications. Dopamine agonists hold promise because of more sustained stimulation of dopamine receptors and possibly an antioxidant effect. Selegiline, amantadine, and anticholinergics are still used but must be employed with caution in the elderly. COMT inhibitors may be useful adjuncts to levodopa therapy but are plagued with serious adverse effects. Goals of therapy in patients less than 60 years of age include sparing levodopa therapy and providing neuroprotection. For patients 60 years and older, goals include maintaining cognitive status and treating symptoms. Surgical treatment includes globus pallidus internal-segment pallidotomy, deep brain stimulation, and fetal nigral transplantation. These hold promise for the future.

Age Factors↗
PubMedDate not supplied

A comprehensive approach to Parkinson's disease. How to manage fluctuating motor and nonmotor symptoms.

Parkinson's disease is challenging to diagnose and treat. Patients are subject to wide fluctuations of motor status as well as an array of nonmotor complications that may be as debilitating as their motor counterparts, or even more debilitating. Levodopa remains the most effective agent for relief of motor symptoms, but long-term levodopa use is associated with development of motor complications, including severe dyskinesias. For this reason, selegiline or a dopamine agonist may be preferred as initial therapy. Carbidopa/levodopa (with or without a COMT inhibitor) can be added within 5 years or as required for relief of motor symptoms. When medical therapy can no longer provide adequate symptom control, surgical intervention needs to be considered.

Antiparkinson Agents↗
PubMed2005

[The medical records of home health care patients: a complement or alternative to an electronic file?].

Home health care services for dependant people involve participation and interventions of professionals from the health care, medico-social and social sectors. In order to ensure quality care, the flow of information must appropriately circulate between all of the various care providers. The establishment of an electronic medical file for these patients is a possible solution which has been proposed to be conducted in next years. A paper medical record is the property of the patient and offers the possibility of an alternative and complementary solution. The electronic file would use the existing available file as a starting point, and without any additional organisational structures being implicated, it allows for better coordination of the health, medical and social activities. An experimental implementation of this in the Franch-Comte region of France demonstrated the advantages and benefits of such a tool based on a logic centered upon the individual and the open sharing of practices between professionals in the medical and social sectors.

Continuity of Patient Care↗
PubMed2005

Hoarding in obsessive-compulsive disorder: clinical and genetic correlates.

OBJECTIVE: Hoarding may be an important symptom dimension in obsessive-compulsive disorder (OCD). Hoarding in OCD has been associated with poor insight, poorer response to selective serotonin reuptake inhibitors than other OCD symptom dimensions, and a distinctive psychobiological profile. The clinical and genetic correlates of hoarding in OCD therefore deserve additional investigation. METHOD: Adult OCD patients (N = 315) underwent a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV Axis I Disorders (Patient Edition) and for Diagnosis of Obsessive-Compulsive Spectrum Disorders. DNA extracted from venous blood (10-30 mL) in a Caucasian subset of the interviewed OCD patients (N = 204) and Caucasian controls (N = 169), including patients (N = 94) and controls (N = 138) of Afrikaner descent, was genotyped to investigate polymorphisms in genes involved in monoamine function and previously hypothesized to be relevant to OCD. Data were collected from 1998 through 2004. RESULTS: OCD patients with hoarding made up 18.1% of the total sample. Compared with nonhoarding OCD, OCD with hoarding was associated with a number of comorbid Axis I disorders, obsessive-compulsive personality disorder, significantly higher OCD severity scores, and more functional impairment. In subjects of Afrikaner descent, the L/L genotype of the COMT Val158Met polymorphism was significantly more common in the OCD hoarding group, with a preponderance of low activity alleles, compared with nonhoarding patients and controls. CONCLUSIONS: These data are consistent with the hypothesis that hoarding represents a unique symptom subtype in OCD with a distinctive clinical and psychobiological profile. Further work is needed to determine the psychobiological mechanisms responsible for hoarding and to replicate the genetic findings noted here.

Adult↗
PubMed2003

Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women.

Breast cancer is the most prevalent cancer among women in Western countries, and its prevalence is also increasing in Asia. The major risk factor for breast cancer can be traced to reproductive events that influence the lifetime levels of hormones. However, a large percentage of breast cancer cases cannot, be explained by these risk factors. The identification of susceptibility factors that predispose individuals to breast cancer (for instance, if they are exposed to particular environmental agents) could possibly give further insight into the etiology of this malignancy and provide targets for the future development of therapeutics. The most interesting candidate genes include those that mediate a range of functions. These include carcinogen metabolism, DNA repair, steroid hormone metabolism, signal transduction, and cell cycle control. we conducted a hospital-based case-control study on South Korea to evaluate the potential modifying role of the genetic pollymprphisms of selected low penetrance gens that are involved carcinogen metabolisms (i.e., CYP1A1, CYP2E1, GSTM1/T1/P1, NAT1/2, etc.), estrogen synthesis and metabolism (i.e., CYP19, CYP17, CYP1B1, COMT, ER-alpha, etc.), DNA repair (i.e., XRCC1/3, ERCC2/4, ATM, AGT, etc.), and signal transduction as well as others (i.e., TGF- beta, IGF-1, TNF- beta, IL-1B, IL-1RN, etc.). We also took into account the potential interaction between these and the known risk factors of breast cancer. The results of selected genes will be presented in this mini-review.

Adult↗
PubMed2000

Introduction. Time and medicine.

Although historians work with the record of events in public time, they have not developed an explicit understanding of lived time. To set the stage for the other essays in this issue of Annals, this introductory essay explores how an understanding of lived or "private" time began to emerge in the early 20th century in the works of that era's major thinkers: Henri Bergson's philosophy of duration, Emile Durkheim's social time, Sigmund Freud's five psychoanalytic temporal narratives, and Eugene Minkowski's exploration of lived time. This essay then considers the reaction against the burden of history that began with the great 19th-century historicizers: Comte, Hegel, Marx, Darwin, and Spencer. It reflects on the effort, beginning in those years, of modern artists and intellectuals to focus on the personal past in place of the overbearing burden of the historical past. New ways of experiencing the present, made possible by new communication technologies, including the telephone and telegraph, have centered on the experience of simultaneity. Norbert Wiener's cybernetics, Marshall McLuhan's globalism, and the Internet have further transformed how both the medical and lay communities experience past, present, and future, as well as near and far. The discussion concludes with consideration of Eurotransplant, an Internet-based information and action network used by physicians to coordinate organ transplantation; it is a system that integrates cybernetics, globalism, and the Internet in an everyday, real drama of the electronic age of simultaneity.

Cybernetics↗
PubMed1990

Production, circulation, and excretion of melanin-related metabolites in B16 melanoma-bearing mice.

Urinary 5-S-cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma metastasis. A method was developed for determining the eumelanin-related metabolites 5(6)-hydroxy-6(5)-methyoxyindole-2-carboxylic acids (5H6MI2C and 6H5MI2C) in small volumes of serum. We compared these indoles and 5-S-CD regarding the correlation of their production in melanoma, circulation in blood, and excretion in urine, with the weight of highly pigmented, B16 mouse melanoma. An excellent correlation was found between the serum concentration of 5H6MI2C + 6H5MI2C (r = 0.92) and 5-S-CD (r = 0.89) and tumor weight. However, the urinary excretion of 5H6MI2C + 6H5MI2C and 5-S-CD did not show any significant correlation. These results suggest that 5H6MI2C + 6H5MI2C and 5-S-CD in serum may better reflect melanoma progression than those in urine. Furthermore, comparison of the contents of these melanin-related metabolites between highly pigmented and less pigmented B16 melanomas suggests that 5-S-CD may be accumulated in pigmented melanoma by virtue of binding to melanin and that catechol-O-methyltransferase (COMT) may play a regulatory role in pigmentation.

Animals↗
PubMedDate not supplied

[Entacapone++ : a new catechol-O-methyltransferase inhibitor which improves the response to levodopa in patients with Parkinson disease and fluctuating motor function].

INTRODUCTION AND DEVELOPMENT: Selective inhibitors of peripheral catechol-O-methyltransferase (COMT) seem to be useful drugs for the treatment of patients with Parkinson's disease. When associated with levadopa and a dopa-decarboxylase inhibitor they are clearly effective in patients with progressive illness, who are particularly dependent on the plasma concentration of levadopa, or may have fluctuating motor function when the effect of the dose is wearing off. Entacapone, a prototype of this group of drugs, has been shown to modify the pharmacokinetics of levadopa in such a way that the plasma concentration of levadopa is raised (between 21% and 50% in different studies): to reduce variations in plasma level between doses, which allows some patients to reduce the total daily dose of levadopa at the same time as the response time (time 'on') increases by between 20% and 78%. CONCLUSION: Entacapone is a well tolerated drug and could form part of a regular 'triple therapy' in the patients described.

Antiparkinson Agents↗