Parkinson's and the latest Research and Drugs
Possibly up to a million people have Parkison's Disease. Research suggest there is both a genetic and environmental component. but it far from clear. It seems to affect men and women equally. The disease usually manifests itself at around fifty years old. It is a chronic, progressive disorder of the nervous system. The substantia nigra in the brain is where the loss of brain cells takes place and affects motor control. It was first described by James Parkinson in 1817.
A recent study comparing 250 new diagnosed with Parkison's to 388 without the disease found that people with both high levels of iron and manganese were nearly twice as likely to develop Parkisonson's than those with the lowest levels of the minerals in their diets. No recommendations as of yet were made for changing ones diet. Another recent mentioned oxidative stress but didn't recommend such antioxidants as alpha lipoic acid, a great antioxidant that may help reduce oxidative stress or melatonin for instance.
J Pharmacol Exp Ther. 2004 Mar 5 [Epub ahead of print] :
Levetiracetam potentiates the anti-dyskinetic action of amantadine in the MPTP-lesioned primate model of Parkinson's disease.
Hill MP, Ravenscroft P, Bezard E, Crossman AR, Brotchie JM, Michel A, Grimee R, Klitgaard H.
Manchester, M15 6SE, U.K.
Levetiracetam (LEV, Keppra) has recently been reported to have anti-dyskinetic activity against levodopa (L-DOPA)-induced dyskinesia in the MPTP-lesioned marmoset and macaque models of Parkinson's disease. Amantadine is frequently used as adjunctive therapy for L-DOPA-induced dyskinesia but adverse effects limit its clinical utility. The current study was designed to investigate whether LEV can potentiate the anti-dyskinetic action of amantadine. The anti-parkinsonian and anti-dyskinetic effects of LEV (13 and 60 mg/kg) and amantadine (0.01, 0.03, 0.1 and 0.3 mg/kg), administered alone and in combination, were assessed in the MPTP-lesioned marmoset model of L-DOPA-induced dyskinesia (n=12). LEV (60 mg/kg) and amantadine (0.3 mg/kg) administered alone significantly reduced L-DOPA-induced dyskinesia without compromising the anti-parkinsonian action of L-DOPA. Lower doses were without any significant effects. The combination of LEV (60 mg/kg) and amantadine (0.01, 0.03, 0.1 and 0.3 mg/kg) significantly decreased dyskinesia severity, without compromising the anti-parkinsonian action of L-DOPA, more efficaciously than LEV or amantadine monotherapy. These results support the concept that normalisation of different pathophysiological mechanisms (i.e. altered synchronization between neurons and enhanced NMDA transmission) has a greater efficacy. Combined LEV/amantadine therapy might be useful as an adjunct to L-DOPA to treat dyskinetic side effects and expand the population of Parkinson's disease patients that benefit from treatment with amantadine alone.
Saudi Med J 2002 Oct;23(10):1165-75
:
An evidence-based review of Dopamine receptor agonists in the
treatment of Parkinson's disease.
Deleu D, Northway MG, Hanssens Y.
College of Medicine, Sultan Qaboos University, PO Box 35, Al Khod, PC-123,
Sultanate of Oman. Tel. +968 515106. Fax. +968 513419.
E-mail:
dtodeleu@squ.edu.omApomorphine and certain ergot alkaloids (bromocriptine, lisuride and pergolide)
have been available for several decades; for the last few years, they were
joined by newer dopamine agonists (cabergoline, pramipexole and ropinirole)
most of them are non-ergolines. Each of these dopamine agonists has its own
pharmacological characteristics and occupies a place in the pharmacotherapy of
Parkinsons disease. In this evidence-based review, emphasis is put on the clinical
efficacy of dopamine agonists in early and advanced Parkinsons disease, and
where possible comparative evidence regarding their efficacy and safety is
provided. In addition, their clinical pharmacokinetics, adverse effect profiles
and most relevant interactions will be summarized.
Bromocriptine (Generic) 5 mg 100 $148.88
Bromocriptine (Generic) 2.5 mg 100 $78.99
Pergolide (Permax) 1 mg 100 $284.21
Pergolide (Permax) 0.25 mg 100 $109.99
Pergolide (Permax) 0.05 mg 30 $22.41
Mirapex (Pramipexole) 1.5 mg 90 $159.87
Mirapex (Pramipexole) 1 mg 90 $159.87
Mirapex (Pramipexole) 0.5 mg 90 $159.87
Mirapex (Pramipexole) 0.25 mg 90 $82.43
Requip (Ropinirole) 2 mg 100 $96.10
Requip (Ropinirole) 1 mg 100 $91.63
Requip (Ropinirole) 0.25 mg 100 $51.77
Ropinirole (Requip) 2 mg 100 $96.10
Ropinirole (Requip) 1 mg 100 $91.63
Ropinirole (Requip) 0.25 mg 100 $51.77
J Clin Psychopharmacol. 2003 Oct;23(5):509-13. :
Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial.
Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F, Bello J.
Department of Neurology, Consorci Sanitari Creu Roja a Catalunya, L' Hospitalet de Llobregat, Barcelona, Spain.
Asuncion.Avila@chcr.scs.es
Some of the selective serotonin reuptake inhibitors (SSRI)-induced motor side effects are mediated by stimulating 5-HT2 receptors in the basal ganglia, probably because serotonin inhibits the subsequent neuronal dopamine release. We hypothesized that nefazodone, a serotonin 2 antagonist/reuptake inhibitor (SARI) that selectively blocks 5-HT2 receptors, could disrupt the aforementioned inhibitory pathway. Therefore, increased dopamine levels in the postsynaptic milieu and an improvement in the motor symptoms in depressed patients with Parkinson disease (PD) should be observed. This study was designed to determine whether nefazodone has a dual activity as an antidepressant and as an agent capable of reducing the extrapyramidal symptoms in depressed parkinsonian patients. Depressed patients with PD were randomly assigned to 2 therapeutic groups: nefazodone or fluoxetine. Patients were evaluated by a psychiatrist and were blindly assessed by a neurologist with an array of scales. Patients on nefazodone (n = 9) showed a significant improvement over time in the total Unified Parkinson Disease Rating Scale score (UPDRS) (part II + part III) (P = 0.004) and in the UPDRS subscore part III (P = 0.003). None of these scores changed over time in the fluoxetine group (n = 7). Both, nefazodone and fluoxetine were equally effective as antidepressants: Beck Depression Inventory scores significantly improved (P < 0.001), with no significant differences between treatment groups (P = 0.97). If our results can be confirmed in a larger clinical trial, nefazodone ought to be considered over fluoxetine given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms in depressed PD patients
Parkinsonism Relat Disord. 2003 Oct;10(1):23-8. :
Depression in Parkinson's disease: clinical correlates and outcome.
Rojo A, Aguilar M, Garolera MT, Cubo E, Navas I, Quintana S.
Neurology and Intensive Care Units, Servicio de Neurologia, Hospital Mutua de Terrassa, c/Castell, 25, Terrassa, 08221, Barcelona, Spain
Depression has been shown to be more common in Parkinson's disease (PD) than in other chronic and disabling disorders. Neurochemical and functional disturbances are important etiopathogenic factors. The prevalence and clinical features associated with depression in PD remain controversial. The purpose of this study is to estimate the prevalence of depressive symptoms in our patients, as related to other clinical data, and to assess clinical outcomes of these symptoms. A series of PD patients were evaluated over a 9-year period, using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage (HY), Schwab and England Scale (SE), Mini-Mental State Examination (MMSE), and Yesavage Geriatric Depression Scale (GDS). Presence of depressive symptoms was considered if GDS score was higher than 10: mild-moderate (MD) for GDS scores between 11 and 20 and moderate-severe (SD) for GDS scores greater than 20. Three hundred and fifty-three patients were included in this study and additional follow up information was obtained for 184 patients. MD and SD were found in 40.2 and 16.7% of PD patients, respectively. Female gender, high HY, high UPDRS total and subtotal, and low MMSE and SE scores were significantly associated with depressive symptoms. According to changes in GDS score, 34% of patients remained stable, 35% showed an improvement, and 30.9% worsened in the follow up study. Gender, age, age of onset, HY, UPDRS, and PD duration are not related to depression outcome.
J Neuropsychiatry Clin Neurosci. 2003 Winter;15(1):74-7. :Links
The contribution of somatic symptoms to the diagnosis of depressive disorder in Parkinson's disease: a discriminant analytic approach.
Leentjens AF, Marinus J, Van Hilten JJ, Lousberg R, Verhey FR.
Deparment of Psychiatry, Maastricht University Hospital, The Netherlands.
a.leentgens@np.unimaas.nl
This study assessed the sensitivity of individual depressive symptoms and their relative contribution to the diagnosis of depressive disorder in patients with Parkinson's disease. The Structured Clinical Interview for DSM-IV Depression and the Hamilton and Montgomery-Asberg depression rating scales (Ham-D, MADRS) were administered to 149 consecutive nondemented patients. The contribution of the individual items of these scales to the diagnosis of "depressive disorder" was calculated by discriminant analysis. The discriminant models based on the Ham-D and MADRS scores were both highly significant. Nonsomatic core symptoms of depression had the highest correlation coefficient. Somatic items had mostly low correlation coefficients, with the exception of reduced appetite and early morning wakening (late insomnia). Nonsomatic symptoms of depression appear to be the most important for distinguishing between depressed and nondepressed patients with Parkinson's disease, along with reduced appetite and early morning awakening.
Toxicology. 2003 Jul 15;189(1-2):129-46. :
Vitamin E therapy in Parkinson's disease.
Fariss MW, Zhang JG.
Departments of Pharmaceutical Sciences and Pharmacotherapy, College of Pharmacy, Washington State University, 99164-6534, Pullman, WA, USA
Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-alpha-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T).
Neurology. 2003 Jul 8;61(1):24-28. :
Parkinsonian signs in older people: Prevalence and associations with smoking and coffee.
Louis ED, Luchsinger JA, Tang MX, Mayeux R.
Gertrude H. Sergievsky Center (Drs. Louis, Tang, and Mayeux), Departments of Neurology (Drs. Louis and Mayeux), Medicine (Dr. Luchsinger), Biostatistics (Drs. Tang and Mayeux), and Psychiatry (Dr. Mayeux), and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs. Louis and Mayeux), Columbia University, New York, NY.
BACKGROUND: Cigarette smoking and coffee consumption may reduce the risk of PD. Parkinsonian signs (tremor, rigidity, bradykinesia) occur in 30 to 40% of the elderly. OBJECTIVE: To determine whether there was an association between cigarette smoking, coffee consumption, and parkinsonian signs in a community population of older people. METHODS: Data on smoking were collected and a neurologic examination performed on 1,339 residents >/==" BORDER="0">65 years of age in the Washington Heights-Inwood community in northern Manhattan, NY. Parkinsonian signs were rated with an abbreviated Unified Parkinson's Disease Rating Scale, resulting in a parkinsonian sign score. Coffee consumption was assessed with a semiquantitative food-frequency questionnaire, and caffeine consumption was determined. Analyses were cross-sectional. RESULTS: Mean age was 76.6 years. Parkinsonian signs were present in 537 (40.1%). The odds for presence of parkinsonian signs was lower in smokers than nonsmokers (odds ratio [OR] = 0.58, 95% CI = 0.47 to 0.73). Smokers had a lower mean parkinsonian sign score than nonsmokers (p < 0.001). Coffee drinking and caffeine consumption were not associated with the presence of parkinsonian signs. The odds for presence of parkinsonian signs remained lower in smokers (OR = 0.75, 95% CI = 0.57 to 0.99) after adjusting for age, gender, ethnicity, years of education, adjusted daily caffeine consumption, and dementia. CONCLUSION: The reduced risk of parkinsonian signs in cigarette smokers could reflect a protective effect of smoking on age-related parkinsonian signs in the elderly or an aversion to smoking in elderly persons with mild parkinsonism.
Ann Neurol. 2003 Jul;54(1):93-101. :
Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study.
Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks DJ.
Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom.
Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinson's disease (PD), and a pilot clinical study using (18)F-dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2-year, randomized, double-blind, multinational study compared the rates of loss of dopamine-terminal function in de novo patients with clinical and (18)F-dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen (18)F-dopa uptake (Ki) between baseline and 2-year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region-of-interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (-13.4%; n = 68) compared with levodopa (-20.3%; n = 59; 95% confidence interval [CI], 0.65-13.06). Statistical parametric mapping localized lesser reductions in (18)F-dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, -14.1%; levodopa, -22.9%; 95% CI, 4.24-13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by (18)F-dopa PET. Ann Neurol 2003
Endocrinology. 2003 Jul;144(7):2757-60. :
Coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss in a primate model of Parkinson's disease.
Horvath TL, Diano S, Leranth C, Garcia-Segura LM, Cowley MA, Shanabrough M, Elsworth JD, Sotonyi P, Roth RH, Dietrich EH, Matthews RT, Barnstable CJ, Redmond DE Jr.
Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
tamas.horvath@yale.edu
Parkinson's disease is characterized by dopamine cell loss of the substantia nigra. Parkinson's disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.
Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.
Rektorova I I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova Z, Fiedler J, Klajblova H, Kulist'ak P, Ressner P, Svatova J, Urbanek K, Veliskova J.
First Department of Neurology, Masaryk University, St Anne's Teaching Hospital, Brno; Department of Neurology, Hospital Pardubice; Department of Neurology, Charles University, Teaching Hospital, Plzen; Postgraduate Medical School, Department of Neurology, Prague; Department of Neurology, University Hospital, Ostrava; Department of Neurology, Charles University, Teaching Hospital Kralovske Vinohrady, Prague; and Department of Neurology, Palacky University, Teaching Hospital, Olomouc, Czech Republic.
An 8-month multicentre prospective randomized study aimed at comparing the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin(R)) and pergolide (PRG; Permax(R)) as add-on to L-dopa therapy on depression [Montgomery and Asberg Depression Rating Scale (MADRS)] in 41 non-demented patients (25 men, 16 women) suffering from both mild or moderate depression and advanced Parkinson's disease (PD). The assessment was performed by a blinded independent observer. Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities of daily living (UPDRS II and VI) and depressive symptoms as measured by Self - Rating Depression Scale by Zung were evaluated in an open-label design. The average value of Zung scores decreased significantly in both groups with no statistical difference between both groups. A significant decrease in the average value of MADRS scores was present only in the PPX group. The average UPDRS scores decreased significantly with no statistical difference between both groups at the comparable average total daily dose of both preparations. In both cases, the total daily dose of L-dopa decreased significantly but the decrease was statistically more pronounced in the PRG group. Our results demonstrate the antidepressant effect of PPX in patients with PD while we can't make any conclusions with regard to antidepressant effect of PRG
J Fluency Disord. 2003 Spring;28(1):55-70. :
Parkinsonian speech disfluencies: effects of L-dopa-related fluctuations.
Goberman AM, Blomgren M.
Department of Communication Disorders, Bowling Green State University, 200 Health Center Building, 43403, Bowling Green, OH, USA
The excess dopamine theory of stuttering (Wu et al., 1997) contends that stuttering may be related to excess levels of the neurotransmitter dopamine in the brain. As Parkinson's disease (PD) patients commonly exhibit changes in dopamine levels accompanied by changes in motor performance, the present study examined disfluency in PD patients to gain information on the role of dopamine in speech disfluencies. Nine PD patients with no history of developmental stuttering were recorded once before and twice after taking their morning medication (on separate days). They read a passage and produced a monologue. Within-word and overall speech disfluencies were calculated at each recording. Through motor testing, it was inferred that participants had relatively low dopamine levels before taking medication, and relatively high dopamine levels after taking medication. There were no group changes in disfluency levels when the low-dopamine and high-dopamine states were compared. There were, however, significant differences in percent disfluencies between the PD participants and age-matched controls. The results of this study do not strongly support the excess dopamine theory of stuttering. Rather, the disfluency changes exhibited by individual participants support a hypothesis that speech disfluencies may be related to increases or decreases in dopamine levels in the brain.EDUCATIONAL OBJECTIVES: The reader will learn about: (1) the characteristics of disfluent speech exhibited by speakers with Parkinson's disease. (2) The effect of L-dopa based medications on disfluencies of Parkinsonian speakers. (3) The complex role brain dopamine levels may play in disfluent speaking behavior.
Clin Neuropharmacol. 2003 May-Jun;26(3):142-5. :
Risk of serious extrapyramidal symptoms in patients with Parkinson's disease receiving antidepressant drugs: a pharmacoepidemiologic study comparing serotonin reuptake inhibitors and other antidepressant drugs.
Gony M, Lapeyre-Mestre M, Montastruc JL; French Network of Regional Pharmacovigilance Centers.
To compare the risk of occurrence of "serious" extrapyramidal symptoms (EPS) between selective serotonin reuptake inhibitors and other antidepressant drugs in patients with Parkinson's disease (PD), the authors performed a retrospective study using the French Pharmacovigilance Database (i.e., the database recording all serious adverse drug reactions reported in France by physicians to the National French Pharmacovigilance Network). Patients with PD were identified from the case reports including at least one antiparkinsonian drug (except anticholinergics). The authors studied patients with PD exposed to at least one antidepressant (classified as imipraminics, selective serotonin reuptake inhibitors, or "other") drug. EPS were defined as aggravation of the parkinsonian symptoms. Of the76,640 case reports registered in the database between January 1, 1995, and December 31, 2000, 916 were identified as patients treated with at least one antiparkinsonian drug, including 199 treated with antidepressant drugs. Among them the authors found nine case reports of EPS (i.e., 4.5% of the patients with PD treated with at least one antidepressant). The odds ratio for EPS was 2.18 (0.47-11.35) for selective serotonin reuptake inhibitors, 1.17 (0.22-5.50) for imipraminics, and 0.74 (0.10-4.06) for other antidepressants. This study failed to find any significant difference in the occurrence of serious EPS according to the different classes of antidepressant drugs in patients with PD treated with dopaminergic antiparkinsonian drugs
Clin Neuropharmacol. 2003 May-Jun;26(3):146-50. :
High-dose ropinirole in advanced Parkinson's disease with severe dyskinesias.
Cristina S, Zangaglia R, Mancini F, Martignoni E, Nappi G, Pacchetti C.
*Parkinson's Disease and Movement Disorders Unit, Istituto di Ricovero e Cura a Carattere Scientifico IRCCS, C. Mondino, University of Pavia; and dagger University of Novara, Italy.
Levodopa (LD) is the gold standard of therapy for Parkinson's disease, but it is commonly associated with motor fluctuations and dyskinesias. Dopamine agonists are often used as adjuncts to LD in an attempt to reduce these complications. In this open-label study the authors investigated the effects of high doses of adjunctive ropinirole in 36 patients with advanced Parkinson's disease and normal cognitive status. The daily dose of ropinirole was increased from 18.4 +/- 3.5 mg to 34.7 +/- 5.5 mg, generally in four separate doses. The daily LD dose was decreased from 734.1 +/- 254.8 mg to 502.8 +/- 228.4 mg. After 12 months 25 patients were still on high doses of ropinirole whereas 11 patients had, after either the emergence of side effects or a worsening of their clinical conditions, decreased or interrupted ropinirole. At 12 months, the daily doses of LD and ropinirole were 489 +/- 243 mg and 34.6 +/- 4.6 mg respectively. There was a significant reduction in the Dyskinesia Rating Scale scores during both ON and OFF periods, indicating a reduction in dyskinesias during ON periods and a reduction in dystonias during OFF periods (p < 0.001). Both the intensity and the hours spent during OFF periods were reduced significantly (p < 0.001). Even though these results need to be confirmed through extended controlled studies, the high-dose dopamine agonist strategy is safe for patients with advanced PD in whom a marked motor response to LD (even at very low doses) is associated with severe dyskinesias, and may be used as a means of delaying surgery or as an alternative to continuous apomorphine infusion.
Clin Neuropharmacol. 2003 May-Jun;26(3):151-5. :
Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease.
Stocchi F, Berardelli A, Vacca L, Barbato L, Monge A, Nordera G, Ruggieri S.
*Institute of Neurology IRCCS "NEUROMED," Pozzilli (IS); the dagger Department of Neurological Sciences, Rome, University of Rome, "La Sapienza"; and the double dagger Institute "A. Benedetti" Vicenza, Italy.
The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.
: Clin Neuropharmacol. 2003 May-Jun;26(3):156-63. :
Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets.
Nyholm D, Askmark H, Gomes-Trolin C, Knutson T, Lennernas H, Nystrom C, Aquilonius SM.
Departments of *Neuroscience, Neurology, dagger Surgery, and double dagger Pharmacy, Uppsala University, Sweden.
Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.
Neurobiol Aging. 2003 May-Jun;24(3):491-500. :
Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion.
Khaldy H, Escames G, Leon J, Bikjdaouene L, Acuna-Castroviejo D.
Departamento de Fisiologi;a, Facultad de Medicina, Instituto de Biotecnologi;a, Universidad de Granada, Avenida de Madrid 11, E-18012, Granada, Spain
Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.
Neurosci Lett. 2003 May 8;341(3):201-4. :
Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease.
Muller T, Buttner T, Gholipour AF, Kuhn W.
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, Germany.
thomas.mueller@ruhr-uni-bochum.de
Features of Parkinson's disease (PD) include oxidative stress, nigral mitochondrial complex I deficiency and visual dysfunction, all of which are also associated with coenzyme Q(10) (CoQ(10)) deficiency. The objective of this monocenter, parallel group, placebo controlled, double-blind trial was to determine the symptomatic response of daily oral application of 360 mg CoQ(10) lasting 4 weeks on scored PD symptoms and visual function, measured with the Farnsworth-Munsell 100 Hue test (FMT), in 28 treated and stable PD patients. CoQ(10) supplementation provided a significant (P=0.01) mild symptomatic benefit on PD symptoms and a significantly (F((1,24))=8.48, P=0.008) better improvement of FMT performance compared with placebo. Our results indicate a moderate beneficial effect of oral CoQ(10) supplementation in PD patients.
J Neurol Sci. 2003 May 15;209(1-2):41-6. :
Effects of successive repetitive transcranial magnetic stimulation on motor performances and brain perfusion in idiopathic Parkinson's disease.
Ikeguchi M, Touge T, Nishiyama Y, Takeuchi H, Kuriyama S, Ohkawa M.
Third Department of Internal Medicine, Kagawa Medical University, 1750-1, Ikenobe, Miki-cho Kita-gun, Kagawa, 761-0793, Japan
We studied the effects of 0.2 Hz repetitive transcranial magnetic stimulation (rTMS) successively performed 6 times for 2 weeks in 12 patients with idiopathic Parkinson's disease (PD). Ten patients received rTMS to the bilateral frontal cortex (frontal rTMS) and six patients received rTMS to the bilateral occipital cortex (occipital rTMS). Before and after rTMS, we evaluated regional cerebral blood flow (rCBF) using 99m-Tc-ECD single photon emission computed tomography (SPECT) and clinical tests.In an analysis with statistic parametric mapping, both frontal and occipital rTMS reduced rCBF in the cortical areas around the stimulated site. The activities of daily living (ADL) and motor scores of Unified Parkinson's Disease Rating Scale (UPDRS), pronation-supination movements, and buttoning up significantly improved after frontal rTMS than before it, while occipital rTMS had no significant effects in clinical tests.The findings of the present study suggest that successive 0.2 Hz rTMS has outlasting inhibitory effects on neuronal activity around the stimulated cortical areas. Because there were no significant relations between improved clinical tests and reduced rCBF, we speculate that the indirect effects of 0.2 Hz rTMS on subcortical structures are related to improved parkinsonian symptoms. Further studies recruiting large numbers of subjects are required to confirm the efficacy of 0.2 Hz rTMS on PD.
Front Biosci. 2003 May 1;8:S391-400. :
Estrogen and Parkinson's disease.
Kompoliti K.
Department of Neurological Sciences, Section of Movement Disorders, Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, IL.
Female sex hormones, and more specifically estrogen, can have biochemical and behavioral effects on the dopaminergic system. The effects of estrogen on the dopaminergic system can be classified as either neuroprotective or symptomatic. The neuroprotective effects refer to the ability of estrogen to prevent or modulate insults to the dopaminergic system and therefore to alter the natural history of disease processes affecting the dopaminergic circuitry in the brain. With regards to the symptomatic effects, support for both suppressive and enhancing effects has been documented in humans and laboratory animals. The pre-clinical literature for neuroprotective and symptomatic effects of estrogen on the mesostriatal dopaminergic system forms the basis for studies on the influence of estrogen on the prevalence, disease progression, clinical signs, and medication effects of Parkinson's disease and other movement disorders. Understanding the role of estrogen in modulating the dopaminergic system will allow clinicians to tailor therapies for women with Parkinson's disease and optimize therapies for menstrually related symptom fluctuations. Such clarifications may also guide recommendations on the use of postmenopausal hormonal replacement therapy in women with Parkinson's disease or those genetically at risk.
Acta Neurol Scand. 2003 May;107(5):349-55. :
Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists.
Albanese A, Colosimo C.
Istituto di Neurologia, Universita Cattolica del Sacro Cuore, Rome, Italy; Istituto Nazionale Neurologico C. Besta, Milan, Italy; Dipartimento di Scienze Neurologiche, Universita degli Studi "La Sapienza", Rome, Italy.
The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson's disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed.
Mov Disord. 2003 Jun;18(6):659-67. :
Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease.
Paus S, Brecht HM, Koster J, Seeger G, Klockgether T, Wullner U.
To study the putative association of dopamine agonists with sleep attacks in patients with Parkinson's disease (PD) and their relation to daytime sleepiness, we performed a survey of 2,952 PD patients in two German counties. In 177 patients, sudden, unexpected, and irresistible sleep episodes while engaged in some activity were identified in a structured telephone interview. Ninety-one of these patients denied the occurrence of appropriate warning signs. A total of 133 patients (75%) had an Epworth Sleepiness Scale (ESS) score >10; 65 (37%) >15. Thirty-one patients (18%) had an ESS score Expert Opin Pharmacother. 2002 Oct;3(10):1481-7. :
Use of the dopamine agonist cabergoline in the treatment of movement disorders.
Marco AD, Appiah-Kubi LS, Chaudhuri KR.
Movement Disorders Unit, Mapother House, King's College Hospital, Denmark Hill, London, UK.
Cabergoline is an ergot-derived dopamine agonist used in the treatment of Parkinson's disease (PD). Both ergot and non-ergot-derived dopamine agonists directly stimulate dopamine receptors, unlike levodopa, which must undergo presynaptic breakdown to dopamine beforehand. Cabergoline has the longest half-life of the dopamine agonists currently available and is effective when given once-daily. It has been proposed that therapy with cabergoline may mimic physiological dopaminergic stimulation in PD by providing striatal intrasynaptic dopamine replacement. Its long half-life is likely to result in sustained rather than pulsatile dopaminergic stimulation, the preferred manner of treating PD. Placebo-controlled trials using cabergoline as an adjunctive therapy in PD have shown that it significantly reduces 'off' time, improves motor function and reduces levodopa requirements. Cabergoline has been shown to be as effective as other dopamine agonists in improving motor function as monotherapy in early PD, and a 5-year levodopa-controlled study indicates the superiority of cabergoline over levodopa in reducing dyskinesias. The efficacy of cabergoline in PD patients with nocturnal disabilities, restless leg syndrome and augmentation has also been demonstrated. Audits of the clinical efficacy of cabergoline indicate that it is well-tolerated and has an acceptable side effect profile.
Department of Neurology, University of Bonn, Bonn, Germany.
Eur Neurol 2003;49(1):30-3
:
Dopamine agonists induce episodes of irresistible daytime
sleepiness.
Schlesinger I, Ravin PD.
Department of Neurology, University of Massachusetts-Memorial Health Care
Center, University Campus, Worcester, Mass., USA.We assessed the prevalence and risk factors for irresistible daytime sleepiness
(IDS) in a cohort of patients with Parkinson's disease (PD) treated with
dopamine agonists. Seventy consecutive PD patients on dopamine agonists were
interviewed. IDS was experienced by 24 patients (34.3%). Fifty percent of
the pramipexole patients, 15.4% of the pergolide patients, 23.1% of the
ropinirole patients and the 2 patients on bromocriptine experienced IDS.
Patients who experienced IDS were younger (p = 0.009). Nineteen patients had
IDS while driving, 3 sustained a motor vehicle crash. Daytime somnolence (p =
0.05) and early arousals (p = 0.001) were risk factors and daytime napping (p =
0.007) and benzodiazepines (p = 0.006) were protective. Improvement was
achieved by changing the dosing schedule, the amount of agonist per dose,
discontinuing the agonist or accommodating the sleepiness. We conclude that
dopamine agonists are commonly implicated in IDS. Copyright 2003 S. Karger
AG, Basel
Lancet 2002 Nov 30;360(9347):1767-9
:
Dopamine agonist monotherapy in Parkinson's disease.
Clarke CE, Guttman M.
Department of Neurology, University of Birmingham, Birmingham, UK.
c.e.clarke@bham.ac.ukCONTEXT: Levodopa is the gold-standard therapy for Parkinson's disease.
However, long-term treatment leads to involuntary movements and response
fluctuations which add to the complexities of later disease-management. In
addition, preclinical evidence suggests that levodopa is toxic to dopaminergic
neurons. These problems have led to a move away from levodopa towards initial
monotherapy with a dopamine agonist. STARTING POINT: Positron-emission
tomography (PET) and single-photon emission computed tomography (SPECT)
tracers have been developed which may be considered surrogate markers for
remaining dopaminergic neurons. In a randomised controlled trial in patients
with early Parkinson's disease, the Parkinson Study Group used 123I-beta-CIT
SPECT (JAMA 2002; 287: 1653-61). Those patients given pramipexole had
significantly reduced loss of striatal uptake at 46 months compared with those
given levodopa (16.0% vs 25.5%). In a similar trial, Alan Whone and colleagues
used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]: A82-83). Patients given
ropinirole had significantly reduced loss of striatal uptake at 24 months
compared with those given levodopa (13% vs 20%). These studies suggest that
agonist monotherapy may be neuroprotective and/or that levodopa is toxic. This
work has been criticised as the SPECT results may have resulted from a
differential effect of the agonist and levodopa on the regulation of the
dopamine transporter, thereby influencing the imaging outcome measure. Other
criticisms include insufficient data on the use of the potential neuroprotectant
selegiline and patients on pramipexole in the SPECT study appear to have been
clinically slow progressors. Single clinical trials with each of the four modern
agonists compared with levodopa show that as monotherapy the agonists delay
the onset of involuntary movements, although at the expense of poorer
treatment of motor impairments and disability and more dopaminergic adverse
events. The only health-related quality of life data show no difference between
pramipexole and levodopa after 4 years. No information on health-economics
measures is available but agonists cost two to three times as much as levodopa.
WHERE NEXT? Young patients should be treated with agonist monotherapy
since the trials included predominantly younger patients who have a higher
incidence of motor complications. Those with significant co-morbidity, dementia,
or a short life-expectancy should be treated with the lowest dose of levodopa
required to maintain motor function. For the vast majority though, no clear
guidance can be given. Further large-scale pragmatic trials in large numbers of
patients over prolonged periods are urgently required.
BMJ 2002 Jun 22;324(7352):1483-7
:
Sleep attacks in patients taking dopamine agonists: review.
Homann CN, Wenzel K, Suppan K, Ivanic G, Kriechbaum N, Crevenna R,
Ott E.
Department of Neurology, Karl Franzens University Hospital, A-8036 Graz,
Austria.
nik.homann@kfunigraz.ac.atOBJECTIVES: To assess the evidence for the existence and prevalence of sleep
attacks in patients taking dopamine agonists for Parkinson's disease, the type of
drugs implicated, and strategies for prevention and treatment. DESIGN:
Review of publications between July 1999 and May 2001 in which sleep attacks
or narcoleptic-like attacks were discussed in patients with Parkinson's disease.
RESULTS: 124 patients with sleep events were found in 20 publications.
Overall, 6.6% of patients taking dopamine agonists who attended movement
disorder centres had sleep events. Men were over-represented. Sleep events
occurred at both high and low doses of the drugs, with different durations of
treatment (0-20 years), and with or without preceding signs of tiredness. Sleep
attacks are a class effect, having been found in patients taking the following
dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists
(apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or
piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32,
ropinirole in 38). Reports suggest two distinct types of events: those of sudden
onset without warning and those of slow onset with prodrome drowsiness.
CONCLUSION: Insufficient data are available to provide effective guidelines
for prevention and treatment of sleep events in patients taking dopamine
agonists for Parkinson's disease. Prospective population based studies are
needed to provide this information.
Neurology 2002 Feb 26;58(4 Suppl 1):S42-50
:
Long-term studies of dopamine agonists.
Hubble JP.
Department of Neurology, Ohio State University, Columbus, OH.Dopamine agonists have long been used as adjunctive therapy for the treatment
of Parkinson's disease (PD). In more recent years these drugs have also been
proved safe and effective as initial therapy in lieu of levodopa in the treatment
of PD. Long-term levodopa therapy is associated with motor complications,
including fluctuating response patterns and dyskinesia. By initially introducing a
dopamine agonist as symptomatic drug therapy, it may be possible to postpone
the use of levodopa and delay or prevent the development of motor
complications. Recently, four clinical trials have explored this hypothesis by
comparing the long-term response and side effects of levodopa with dopamine
agonist therapy. The drugs studied have included ropinirole, pramipexole,
cabergoline, and pergolide. In each of these projects, the occurrence of motor
complications, such as wearing off and dyskinesia, was significantly less in the
subjects assigned to initiation of therapy with a dopamine agonist. The addition
of levodopa could be postponed by many months or even several years.
Therefore, these long-term studies of dopamine agonists support the initiation
of a dopamine agonist instead of levodopa in an effort to postpone
levodopa-related motor complications. This therapeutic approach may be
particularly appropriate in PD patients with a long treatment horizon on the
basis of age and general good health. The extension phase of the long-term
study comparing pramipexole with levodopa is ongoing, and follow-up
information may help to establish the value of this treatment strategy.
1353-8020 2000 Nov 1;7(1):51-58
:
Dopamine agonists: the treatment for Parkinson's disease in the
XXI century?
Lledo A.
Lilly Research Centre (CNS), Erl Wood Manor, Sunninghill Road, Surrey GU20
6PH, Windlesham, UKLevodopa combined with a peripheral dopa-decarboxylase inhibitor (DCI) has
been considered the therapy of choice for Parkinson's disease (PD). Levodopa is
nearly always effective, but has a high incidence of adverse effects with long
term use, including response fluctuations (on/off phenomena) and dyskinesias.
Dopaminergic agonists, acting directly at the receptor level, would be able to
decrease the incidence of these motor complications.In progressive
neurodegenerative diseases, such as PD, modification of the rate of disease
progression (often referred to as neuroprotection) is currently a highly
debated topic. Increased oxidative stress is thought to be involved in nigral cell
death, that is characteristic of PD. This oxidative stress may be further
exacerbated by levodopa therapy. These mechanisms have been proven in vitro
and animal models, but it's relevance in humans remains speculative.Based on the
considerations above, the emerging therapeutic strategies for PD advocate
early use of dopamine agonists in the treatment of PD. A number of recent
well-controlled studies have proven the efficacy of dopamine agonists used as
monotherapy. Moreover, as predicted by animal studies, on the long term,
dopaminergic agonists induce significantly less motor complications than
levodopa.In the last 2years, three new dopamine agonists have been launched,
including ropinirole, pramipexole and cabergoline. These new agonists have been
added, as therapeutical options to well-established drugs, like pergolide,
bromocriptine or talipexole. The recently launched compounds have proven
efficacy in monotherapy and as adjunctive therapy to levodopa. Unfortunately,
only a very limited amount of comparative data among the different agonists is
available. Pergolide has proven to be a superior drug to bromocriptine as
adjunctive therapy to levodopa in a significant number of studies and is
considered the gold standard dopamine agonist. Nevertheless, none of the
recently launched compounds has compared itself against pergolide.A
comparison of monotherapy trials is difficult, because of differences in design
and populations. In a recently completed trial pergolide was statistically
significantly better than placebo in all the efficacy parameters tested, with
57% of pergolide treated patients improving over 30% in the motor section of
the UPDRS, as compared to 17% in the placebo arm. Interestingly, these results
were obtained in the absence of any other antiparkinsonian drug during the
trial. Recent monotherapy trials done with ropinirole and pramipexole achieved
also significant improvements as monotherapy, but in these cases selegeline, a
drug that causes a symptomatic improvement in PD, was allowed as
co-medications during the trial. Not all trials used the same efficacy measures,
i.e. monotherapy trials with pergolide and ropinirole used a "responder" based
analysis (responder were all patients that improved 30% or more on the motor
section of UPDRS), as well as a baseline to endpoint improvement in motor
scores. Pramipexole monotherapy trials used only the latter approach, which is
clinically less powerful than a responder analysis.Even with the difficulties
mentioned above, all the recent trials with dopamine agonists have proven that
these drugs are a useful symptomatic long term treatment for PD with or
without levodopa and that the early use of dopamine agonists reduces the
incidence of motor complications as compared to levodopa.
: Expert Opin Pharmacother 2002 Oct;3(10):1481-7
:
Use of the dopamine agonist cabergoline in the treatment of
movement disorders.
Marco AD, Appiah-Kubi LS, Chaudhuri KR.
Movement Disorders Unit, Mapother House, King's College Hospital, Denmark
Hill, London, UK.Cabergoline is an ergot-derived dopamine agonist used in the treatment of
Parkinson's disease (PD). Both ergot and non-ergot-derived dopamine agonists
directly stimulate dopamine receptors, unlike levodopa, which must undergo
presynaptic breakdown to dopamine beforehand. Cabergoline has the longest
half-life of the dopamine agonists currently available and is effective when
given once-daily. It has been proposed that therapy with cabergoline may mimic
physiological dopaminergic stimulation in PD by providing striatal intrasynaptic
dopamine replacement. Its long half-life is likely to result in sustained rather
than pulsatile dopaminergic stimulation, the preferred manner of treating PD.
Placebo-controlled trials using cabergoline as an adjunctive therapy in PD have
shown that it significantly reduces 'off' time, improves motor function and
reduces levodopa requirements. Cabergoline has been shown to be as effective
as other dopamine agonists in improving motor function as monotherapy in early
PD, and a 5-year levodopa-controlled study indicates the superiority of
cabergoline over levodopa in reducing dyskinesias. The efficacy of cabergoline
in PD patients with nocturnal disabilities, restless leg syndrome and
augmentation has also been demonstrated. Audits of the clinical efficacy of
cabergoline indicate that it is well-tolerated and has an acceptable side effect
profile.
Neurol Sci 2002 Sep;23 Suppl 2:S115-6
:
Combination of two different dopamine agonists in the management
of Parkinson's disease.
Stocchi F, Berardelli A, Vacca L, Thomas A, De Pandis MF, Modugno N,
Valente M, Ruggieri S.
Department of Neurosciences, La Sapienza University, Viale dell'Universita 30,
I-00185 Rome, Italy.An alternative approach to the symptomatic treatment of parkinsonian patients
with and without motor fluctuations is to use dual dopamine agonists. The aim of
this study was to investigate the symptomatic effect of administrating a second
dopamine agonist to parkinsonian patients already assuming pramipexole or
ropinirole. As the second dopamine agonist we chose cabergoline, a drug with a
long half life, whose pharmacological profile differs from that of the newer
non-ergot-derived dopamine-receptor agonists. In this pilot study we enrolled
27 patients: 21 patients had motor fluctuations and were receiving levodopa
plus a dopamine agonist, and 6 patients without motor fluctuations were
receiving a dopamine agonist without levodopa. This open study shows that dual
dopamine agonist therapy (cabergoline plus pramipexole or ropinirole) may be
used in the symptomatic treatment of patients with Parkinson's disease
receiving therapy with or without levodopa.
Clin Neuropharmacol 2002 Jan-Feb;25(1):1-10
:
Pergolide in the treatment of patients with early and advanced
Parkinson's disease.
Bonuccelli U, Colzi A, Del Dotto P.
Department of Neuroscience, University of Pisa, Pisa, Italy.
u.bonuccelli@neuro.med.unipi.itIntroduced on the market in 1989, pergolide, a D1/D2 dopamine receptor
agonist, is still widely prescribed for the treatment of patients with early and
advanced Parkinson's disease (PD). Initially, pergolide was introduced as an
adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor
responses and dyskinesias. Results of recent randomized controlled clinical
trials in de novo patients with PD show that pergolide is able to improve
parkinsonian symptoms when used as monotherapy. Moreover, preliminary
results of a long-term monotherapy study in early PD suggest that pergolide is
as effective as levodopa, and that a significant delay in the time of the onset of
levodopa-induced motor complications can be obtained. A number of randomized
studies have shown that pergolide is more effective than bromocriptine as
adjunct therapy to levodopa in patients with advanced PD; the greater benefit
found with pergolide could be ascribed to its action on both D1 and D2
dopamine receptors. However, controlled comparative studies with new
dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not
been performed yet. Interestingly, few open studies in patients with
complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to
improve motor fluctuations and dyskinesias through a dramatic reduction of
levodopa dosage. The side-effect profile of pergolide is similar to that of other
dopamine agonists, and complications such as sleep attack and serosal fibrosis
have been rarely reported.
Eur J Neurol 2000 May;7 Suppl 1:15-20
:
Pre-clinical studies of pramipexole: clinical relevance.
Hubble
JP.
Department of Neurology, The Ohio State University Parkinson's Disease
Center, Columbus, Ohio 43210, USA.This paper reviews the preclinical study of the novel dopamine agonist
pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given
to those properties distinguishing this drug from other dopamine agonists, the
relevance of the preclinical data to clinical trial results in early PD, and the
putative neuroprotective properties of the compound. The conventional
dopamine agonists are ergot-derived compounds that are most widely used as
adjunctive therapies in advancing Parkinson's disease (PD). Examples of
conventional agonists are bromocriptine and pergolide. Pramipexole is an
aminobenzothiazole compound, recently introduced for the treatment of both
early and advanced PD. Its nonergot structure may reduce the risk of
side-effects, considered unique to ergot drugs, such as membranous fibrosis.
Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine
receptor family. This family includes the D2, D3 and D4 receptor subtypes.
Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype
with lower affinities for the D2 and D4 receptor subtypes. The drug has only
minimal alpha2-adrenoceptor activity and virtually no other receptor agonism
or antagonism. The optimal dopamine receptor activation for the safe and
effective treatment of PD is not known. Findings in animal models and clinical
studies indicate that activation of the postsynaptic D2 receptor subtype
provides the most robust symptomatic improvement in PD. Given its
pharmacological profile, it is not surprising that pramipexole was found to be
effective in ameliorating parkinsonian signs in animal models. This therapeutic
effect has been confirmed in clinical trials in both early and advanced PD. In
early disease, it provides a clear reduction in the chief motor manifestations of
PD and improved activities of daily living. Perhaps most striking is the large
number of clinical trial patients who have remained on pramipexole monotherapy
for many months. The majority of these subjects have been maintained on
pramipexole for an excess of 24 months without requiring additional
symptomatic treatment with levodopa. This is in contrast to the general clinical
experience with older conventional agonists. Pramipexole also has a favourable
pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in
the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability
of > 90% and can be administered without regard to meals. It has no significant
effects on other antiparkinson drugs such as levodopa or selegiline. Its
excretion is primarily renal and, thus, has little or no impact on hepatic
cytochrome P450 enzymes or other related metabolic pathways. Pramipexole
has also been theorized to have 'neuroprotectant' properties. Oxyradical
generation is posited as a cause or accelerant of brain nigral cell death in PD.
Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine
synthesis and turnover which may minimize oxidative stress due to dopamine
metabolism. Furthermore, the compound has a low oxidation potential that may
serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a
new antiparkinson medication found to have unique dopamine agonist
characteristics and putative neuroprotective properties.
Neurologia 2002 Jan;17(1):7-11
:
[Usefulness of olanzapine in the levodopa-induced psychosis in
patients with Parkinson's disease]
[Article in Spanish
]
Chacon JR, Duran E, Duran JA, Alvarez M.
Servicios de Neurologia, Hospital Universitario Virgen Macarena, Sevilla,
Spain. jchaconp@supercable.esBACKGROUND: To evaluate the antipsychotic efficacy of olanzapine (OLZ)
in patients with Parkinson's disease (PD) and drug-induced psychosis (DIP)
and its repercussion on the motor function. METHODS: Ten patients (5
women and 5 men) diagnosed of PD and DIP, aged 67 years (range: 50-81),
with PD duration of 11.1 years (range: 6-23), treated chronically with
levodopa per day, received a dose of 2.5 or 5.0 mg OLZ daily. Data
concerning improvement of psychosis and worsening of motor function was
based on Positive And Negative Symptoms Scale (PANSS) and Unified
Parkinsons Disease Rating Scale (UPDRS) motor. RESULTS: Psychotic
symptoms were improved in all patients. In most of them the improvement was
almost total. Seven patients increased levodopa dose on OLZ, but significant
worsening of motor function was reported just in one patient. None of the
patients had agranulocytosis in the blood monitoring. Two patients presented
weight gain. Seven patients improved their cognitive status. CONCLUSIONS:
We conclude that OLZ at the doses studied may have efficacy for DIP which
appears in PD and does not induce worsening of motor function in most of the
patients.
Jpn J Pharmacol 2001 Mar;85(3):207-13
:
(1S,2R)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide
(PPDC), a new class of NMDA-receptor antagonist: molecular design by a
novel conformational restriction strategy.
Shuto S, Yoshii K, Matsuda A.
Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo, Japan.
shu@pharm.hokudai.ac.jpWe have found that milnacipran, a clinically useful antidepressant due to its inhibition of the
re-uptake of serotonin (5-HT) and noradrenaline, is also a non-competitive NMDA-receptor
antagonist. Based on the cyclopropane structure of milnacipran, conformationally restricted
analogs were designed and synthesized. Of these analogs,
(1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide (PPDC) is
30-fold stronger than milnacipran as an NMDA-receptor antagonist with virtually no
inhibitory effect on the neurotransmitter re-uptake. PPDC was identified as a new class of
NMDA-receptor antagonist because it has a mode of action different from that of the previous
antagonists; it selectivly binds the GluRepsilon3/GluRzeta1 and GluRepsilon4/GluRzeta1
subtype receptors in an agonist-independent allosteric manner. Functional assays of PPDC with
the Xenopus oocytes system and cultured mouse neurons under voltage-clamp conditions
confirmed that it acts as a potent NMDA-receptor antagonist. PPDC effectively protected
against NMDA-induced neurotoxicity in both cultured mouse cerebral cortex and delayed
neuronal death in a gerbil ischemic model. It was also active in a reserpine-treated mouse
Parkinsons disease model. Thus, PPDC may be a candidate for a clinically useful
NMDA-receptor antagonist, since the development of previous NMDA-receptor antagonists as
drugs has been hindered by various undesirable side effects.
: Adv Exp Med Biol 1999;467:19-27
:
Tryptophan hydroxylase regulation. Drug-induced modifications
that alter serotonin neuronal function.
Kuhn DM.
Department of Psychiatry and Behavioral Neurosciences,
Wayne State
University School of Medicine,
Detroit, Michigan, USA.
donald.kuhn@wayne.eduTryptophan hydroxylase is the initial and rate-limiting enzyme in the
biosynthesis of the neurotransmitter serotonin. A variety of drugs are known
to diminish the function of this enzyme, and possibly cause damage to
serotonin neurons. These include the substituted amphetamines
methamphetamine and 3,4-methylenedioxy-methamphetamine, as well as
L-DOPA, the most common therapy for Parkinsons Disease. In view of the
important role for dopamine in the effects of these drugs on tryptophan
hydroxylase and on serotonin neurons, we tested whether dopamine could alter
the activity of this important enzyme.
We found that dopamine-derived
quinones, but not dopamine, inactivate tryptophan hydroxylase and convert the
protein to a redox-cycling quinoprotein. This posttranslational modification of
tryptophan hydroxylase could play a role in the drug-induced reduction in
serotonin synthesis.
BMC Pharmacol 2002 Apr 2;2(1):8
:
An MCASE approach to the search of a cure for Parkinson's
Disease.
Klopman G, Sedykh A.
Chemistry Department, Case Western Reserve University,
10700, Euclid
Avenue, Cleveland, OH 44106, USA. gxk6@po.cwru.eduBACKGROUND: Parkinson's disease is caused by a dopamine deficiency state
in the fore brain area. Dopamine receptor agonists, MAO-B inhibitors, and
N-Methyl-D-Aspartate (NMDA) receptor antagonists are known to have
antiparkinson effect. Levodopa, a dopamine structural analog, is the best
currently available medication for the treatment of Parkinsons disease.
Unfortunately, it also induces side effects upon long administration time.
Thus, multidrug therapy is often used, in which various adjuvants alleviate side
effects of levodopa and enhance its antiparkinsonian action. RESULTS:
Computer models have been created for three known antiparkinson mechanisms
using the MCASE methodology. New drugs for Parkinsons disease can be
designed on the basis of these models. We also speculate that the presence of
biophores belonging to different groups can be beneficial and designed some
potential drugs along this line. The proposed compounds bear pharmacophores
of MAO-B inhibitors, dopamine agonists and NMDA antagonists, which could
synergistically enhance their antiparkinson effect. CONCLUSIONS: The
methodology could readily be expanded to other endpoints where drugs with
multiple activity mechanisms would be desirable.
Harefuah 2001 Dec;140(12):1168-71, 1229
:
[Can we apply gene therapy in the treatment of Parkinson
patients?]
[Article in Hebrew]
Sela BA.
Institute of Chemical Pathology,
Sheba Medical Center, Tel-Hashomer,
Ramat-Gan, Israel.Neurotoxicology 2001 Dec;22(6):811-7
:
Striatal dopaminergic pathways as a target for the insecticides
permethrin and chlorpyrifos.
Karen DJ, Li W, Harp PR, Gillette JS, Bloomquis JR.
Department of Entomology, Virginia Polytechnic Institute and State
University,
Blacksburg 24061, USA.Because insecticide exposure has been linked to both Parkinsons disease and
Gulf War illness, the neurotoxic actions of pyrethroid and organophosphate
insecticides on behavior and striatal dopaminergic pathways were investigated
in C57BL/6 mice treated with permethrin (three i.p. doses at 0.2-200 mg/kg)
or chlorpyrifos (three s.c. doses at 25-100 mg/kg) over a 2-week period.
Permethrin altered maximal [3H]dopamine uptake in striatal synaptosomes
from treated mice, with changes in Vmax displaying a bell-shaped curve.
Uptake was increased to 134% of control at a dose of 1.5 mg/kg. At higher
doses of PM (25 mg/kg), dopamine uptake declined to a level significantly
below that of control (50% of control at 200 mg/kg, P < 0.01). We also
observed a small, but statistically significant decrease in [3H]dopamine
uptake by chlorpyrifos, when given at a dose of 100 mg/kg. There was no
significant effect on the Km for dopamine transport. Evidence of cell stress
was observed in measures of mitochondrialfunction, which were reduced in
mice given high-end doses of chlorpyrifos and permethrin. Although
cytotoxicity was not reflected in decreased levels of striatal dopamine in
either 200 mg/kg PM or 100 mg/kg CPF treatment groups, an increase in
dopamine turnover at 100 mg/kg CPF was indicated by a significant increase
in titers of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid. Both
permethrin and chlorpyrifos caused a decrease in open field behavior at the
highest doses tested. Although frank Parkinsonism was not observed, these
findings confirm that dopaminergic neurotransmission is affected by exposure
to pyrethroid and organophosphorus insecticides, and may contribute to the
overall spectrum of neurotoxicity caused by these compounds.
Neurotoxicology 2001 Dec;22(6):725-31
:
Is methamphetamine abuse a risk factor in parkinsonism?
Guilarte TR.
Department of Environmental Health Sciences, School of Hygiene and Public
Health,
The Johns Hopkins University, Baltimore, MD 21205, USA.
tguilart@jhsph.eduParkinsons disease (PD) is a neurodegenerative disorder with increased
incidence in individuals beyond 50 years of age. The etiology of PD is
currently not known, but it appears that environmental factors may play an
important role. The molecular basis of PD is the nearly complete loss of the
neurotransmitter dopamine (DA) in the basal ganglia (caudate/putamen). The
decrease in dopamine levels is the result of degeneration of
dopamine-containing neurons in the substantia nigra. This biochemical deficit
in the nigrostriatal pathway leads to the emergence of motor impairments
typical of PD. Methamphetamine (METH) is a psychostimulant drug with
increasing use in certain segments of the population in the United States and
worldwide. In experimental animal models and human studies, METH
administration has been shown to decrease markers of dopaminergic neuron
terminal integrity in the basal ganglia. A long-standing question has been
whether the reductions in dopaminergic markers induced by METH constitute
degenerative changes or reflect drug-induced modulation. Resolving this
question is important because the irreversible loss of dopaminergic function
may increase the likelihood of Parkinsonism with advancing age.
Arq Neuropsiquiatr 2001 Sep;59(3-A):559-62
:
[Assessment of erectile dysfunction in patients with Parkinson's
disease]
[Article in Portuguese]
Lucon M, Pinto AS, Simm RF, Haddad MS, Arap S, Lucon AM, Barbosa
ER.
Faculdade de Medicina,
Universidade de Sao Paulo, Sao Paulo, SP, Brasil.Thirty men having Parkinsons disease (PD) and 30 controls were studied
prospectively by the use of the International Index of Erectile Function
(IIEF) to assess erectile dysfunction (ED). Of the patients with PD (mean age
of 59 years), 46.66% referred to the practice of sexual activity. All of the
parkinsonians were using antiparkinsonian medication. In the control group
(mean age of 63 years), 76.66% referred to the practice of sexual activity,
46.60% to arterial hypertension and 6.66% to diabetes mellitus. The median
score for the PD group according to the IIEF was 34, and that for the
controls 50. The main differences between the two groups were in the
erectile function, orgasmic function and satisfaction with the sexual
relationship. The IIEF is a multidimensional scale widely accepted to assess
the ED. The data obtained suggest that ED is more frequent among
parkinsonians and points out to the role of DP in the genesis of ED.
Mov Disord 2001 Jul;16(4):616-21
:
Effect of sleep deprivation on motor performance in patients
with Parkinson's disease.
Hogl B, Peralta C, Wetter TC, Gershanik O, Trenkwalder C.
Max Planck Institute of Psychiatry, Neurology Department,
Munich, Germany.
birgit.ho@uklibk.ac.ukAnimal research provides evidence that sleep deprivation influences the
dopamine system. Knowledge about the effect of sleep deprivation on motor
performance in patients with Parkinsons disease is scarce. This study examines
the influence of total and partial sleep deprivation compared to normal sleep
on motor state and performance in Parkinson's disease. Fifteen nondepressed
patients with Parkinson's disease underwent one night of total sleep
deprivation (TSD), one night of partial sleep deprivation (PSD) after 3 a.m.,
and one control night of normal sleep (S), performed in a random,
nonconsecutive order. Over a period of 3 hours the following morning, motor
evaluations (United Parkinson's Disease Rating Scale, [UPDRS] and tapping
rate) were performed before and every 30 minutes after intake of the usual
morning dopaminergic drug dose. All patients underwent polysomnography
apart from the sleep deprivation protocol. Mean UPDRS motor scores and
tapping velocities did not differ significantly after each of the schedules, but
a subgroup of four patients improved their motor score after partial sleep
deprivation. These data do not confirm previous findings of an overall positive
influence of sleep deprivation on motor function in Parkinson's disease.
However, the results indicate that different response types to sleep
deprivation may exist and that a subgroup of patients could benefit from
partial sleep deprivation.
Amantadine (Generic)- 100 mg- 100- $51.79
Clin Neuropharmacol 1999 Jan-Feb;22(1):30-2
:
A pilot study on the motor effects of rimantadine in Parkinson's
disease.
Evidente VG, Adler CH, Caviness JN, Gwinn-Hardy K.
Parkinson's Disease and Movement Disorders Center,
Mayo Clinic Scottsdale,
Arizona, USAThe purpose of this pilot study was to determine whether rimantadine, the
alpha-methyl derivative of amantadine, might have any antiparkinsonian
properties. In an open-label trial, 14 patients (12 de novo and 2 on levodopa
treatment) with Hoehn and Yahr stage 2 to 3 Parkinson's disease were placed
on rimantadine at doses of 100 to 300 mg/d. No patients had dyskinesias or
motor fluctuations. Ten of 14 (71%) reported a mean subjective response of
33% (range 10%-60%) to rimantadine. After treatment, there was a 13%
improvement in Hoehn and Yahr staging (p = .01) and a 20% improvement in
mean motor Unified Parkinsons Disease Rating Scale scores (p = .02). Rigidity
was the most consistently improved feature among the responders. Mean
effective dose was 256 mg/d (range 200-300 mg/d). Side effects were mild
and transient, with nausea being most common (4/14). We conclude that
rimantadine has some motor benefits in Parkinson's disease. A double-blind
placebo-controlled study is warranted to validate our findings.
Selegeline (Generic) - 5 mg -60- $81.39
Neurotoxicol Teratol 2002 Sep-Oct;24(5):675
:
Neuroprotection by propargylamines in Parkinson's disease.
Suppression of apoptosis and induction of prosurvival genes.
Maruyama W, Akao Y, Carrillo M, Kitani K, Youdium M, Naoi M.
Laboratory of Biochemistry and Metabolism, Department of Basic
Gerontology,
National Institute for Longevity Sciences,
Obu, 474-8522,
Aichi, JapanIn Parkinson's disease (PD), therapies to delay or suppress the progression of
cell death in nigrostriatal dopamine neurons have been proposed by use of
various agents. An inhibitor of type B monoamine oxidase (MAO-B),
(-)deprenyl (selegiline), was reported to have neuroprotective activity, but
clinical trials failed to confirm it.
However, the animal and cellular models of
PD proved that selegiline protects neurons from cell death. Among
selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan
(rasagiline) was the most effective to suppress the cell death in in vivo and in
vitro experiments. In this paper, the mechanism of the neuroprotection by
rasagiline was examined using human dopaminergic SH-SY5Y cells against cell
death induced by an endogenous dopaminergic neurotoxin
N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not
necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by
mitochondrial permeability transition (PT) and activated by stepwise
reactions. Rasagiline prevented the PT in mitochondria directly and also
indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor,
glial cell line-derived neurotrophic factor (GDNF). Long-term administration
of propargylamines to rats increased the activities of antioxidative enzymes
superoxide dismutase (SOD) and catalase in the brain regions containing
dopamine neurons. Rasagiline and related propargylamines may rescue
degenerating dopamine neurons through inhibiting death signal transduction
initiated by mitochondria PT.
Coenzmye q 10 may slow down Parkinson's
click here.The phase II study, led by Clifford Shults, M.D., of the University of California, San Diego (UCSD) School of Medicine, looked at a total of 80 PD patients at 10 centers across the country to determine if coenzyme Q10 is safe and if it can slow the rate of functional decline. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the October 15, 2002, issue of the 'Archives of Neurology'. (1)
"This trial suggested that coenzyme Q10 can slow the rate of deterioration in Parkinson's disease," says Dr. Shults. "However, before the compound is used widely, the results need to be confirmed in a larger group of patients?....The investigators believe coenzyme Q10 works by improving the function of mitochondria, the "powerhouses" that produce energy in cells. Coenzyme Q10 is an important link in the chain of chemical reactions that produces this energy. It also is a potent antioxidant -- a chemical that "mops up" potentially harmful chemicals generated during normal metabolism. Previous studies carried out by Dr. Shults, Richard Haas, M.D., of UCSD and Flint Beal, M.D., of Cornell University have shown that coenzyme Q10 levels in mitochondria from PD patients are reduced and that mitochondrial function in these patients is impaired. "
(http://www.iherb.com is one of the cheapest places on the net for buying supplements)
Michael J. Fox foundation
(Tasmar, also known as tolcapone, COMT inhibitor-not available
work directly on the target cells of the substantia nigra in a way that imitates dopamine.
Parlodel-generic (bromocriptine) 5 mg 100 $148.88
Parlodel (Generic) 2.5 mg 100 $78.99
, Requip (ropinirole)
Requip (Ropinirole) v 2 mg 100 v$94.22
Requip (Ropinirole) - 1 mg- 100 - $89.83
Requip (Ropinirole) - 0.25 mg- 100- $49.78
Ropinirole (Requip)- 2 mg- 100- $94.22
Ropinirole (Requip) - 1 mg - 100 - $89.83
Ropinirole (Requip) - 0.25 mg - 100 - $49.78
Results Page: 1
Permax (pergolide)
Pergolide (Permax) - 1 mg 100 $284.21
Pergolide (Permax) - 0.25 mg - 100 - $109.99
Pergolide (Permax) - 0.05 mg - 30 - $19.49
Permax (Pergolide) - 1 mg 100 - $284.21
-
Permax (Pergolide) - 0.25 mg - 100 - $109.99
Permax (Pergolide) - 0.05 mg - 30 - $19.49
Results Page: 1
and Mirapex (pramipexole dihydrocholoride)
Mirapex (Pramipexole) - 1.5 mg -90-$159.87
Mirapex (Pramipexole) 1 mg- 90- $159.87
Mirapex (Pramipexole) - 0.5 mg- 90 -$159.87
Mirapex (Pramipexole) - 0.25 mg- 90 -$82.43
Results Page: 1
work directly on the target cells of the substantia nigra in a way that imitates dopamine.
muscarinic antagonist for parkinsonian tremorArtane (trihexyphenidyl)
Trihexyphenidyl (Generic) - 2 mg -100 -$7.99
Trihexyphenidyl (Generic) - 5 mg -100 -$10.44
Cogentin (benztropine)
Cogentin (benztropine - generic)- 2 mg -100 -$9.99
Symmetrel (amantadine)-useful for tremor
Amantadine (Generic) - 100 mg -100 -$51.79
Bromocriptine -
Eldepryl -
Madopar -
Norflex -
Permax -
Sinemet -
Symmetrel -
Bromocriptine (Generic) - 5 mg -100 -$148.88
Bromocriptine (Generic) 2.5 mg -100 -$78.99
Eldepryl
Madopar
Norflex (Orphenadrine) - 100 mg- 24- $28.99
Orphenadrine (Norflex) - 100 mg- 24 -$28.99
Pergolide (Permax) - 1 mg -100 -$284.21
Pergolide (Permax) - 0.25 -mg- 100 -$109.99
Pergolide (Permax) - 0.05 mg- 30 -$19.49
Permax (Pergolide) - 1 mg- 100- $284.21
Permax (Pergolide) - 0.25 mg -100- $109.99
Permax (Pergolide) - 0.05mg -30 -$19.49
Carbidopa/Levodopa = See Sinemet - $0.00
Levodopa/Carbidopa = See Sinemet - $0.00
Sinemet (Brand Name) - 100/25 mg- 100- $59.39
Sinemet (Generic) - 100/10 mg -100- $24.93
Sinemet (Generic) - 100/25 mg- 100- $29.93
Sinemet (Generic) - 250/25 mg -100 -$29.93
Sinemet CR (Brand Name) - 100/25 mg- 100- $62.29
Sinemet CR (Brand Name) 200/50 mg- 100- $99.11
