Sinemet

Sinemet contains the active ingredient levodopa and is known under several different brand names. Its main use is in Parkinson’s disease where it relieves the symptoms and the pain. Mainly it reduces tremor and muscle stiffness, common symptoms of the illness. Levodopa is in fact the precursor of dopamine and gets converted to it once in the body. Since it is known that symptoms are caused by dopamine depletion in the brain, administering it helps to reduce them. The medication is also used in non-Parkinson patients to relieve similar symptoms in cases of chemical poisoning and encephalitis. When administered alone, levodopa is destroyed by vitamin B6 in the body and its effectiveness is limited; this is why it is often prescribed or manufactured in combination with carbidropa, an inhibitor of this process. Nausea appears to be the most common side effect of the medication.

Neurologia. 2005 May;20(4):180-8.
[Optimization of use of levodopa in Parkinson's disease: role of levodopa-carbidopa-entacapone combination.]
[Article in Spanish]
Castro A, Valldeoriola F, Linazasoro G, Rodriguez-Oroz M, Stochi F, Marin C, Rodriguez M, Vaamonde J, Jenner P, Alvarez L, Pavon N, Macias R, Luquin M, Hernandez B, Grandas F, Gimenez-Roldan S, Tolosa E, Obeso J.
Servicio de Neurologia. Hospital Xeral de Galicia. Santiago de Compostela.

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the <<pulsatile>> dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of <<wearing off>> fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in <<de novo>> patients is underway. At present, the combination levodopa-carbidopaentacapone is indicated when levodopa is judged necessary. Neurologia 2005;20(4):180-188.

Prescrire Int. 2005 Apr;14(76):51-4.
Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect.
[No authors listed]

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.

Mov Disord. 2005 Feb 22.
Long-term efficacy and safety of pramipexole in advanced Parkinson's disease: Results from a European Multicenter Trial.
Moller JC, Oertel WH, Koster J, Pezzoli G, Provinciali L.
Department of Neurology, Philipps-University Marburg, Germany.

A double-blind, placebo-controlled study with a subsequent open-label phase was conducted in 354 patients with Parkinson's disease (PD) and motor fluctuations under individually adjusted therapy with levodopa. During the double-blind phase 174 patients received pramipexole and 180 placebo. In agreement with previous studies, pramipexole treatment improved UPDRS sum scores of parts II and III by 30% and off times by approximately 2.5 hours per day. Differences between the treatment groups became significant at a daily dose of 0.75 mg of pramipexole dihydrochloride. We, furthermore, performed post hoc analyses with respect to resting tremor and depression. Patients with pronounced resting tremor derived a clear benefit from pramipexole treatment compared with placebo. In addition, pramipexole significantly improved the subitems motivation/initiative and depression in a subpopulation with increased Unified Parkinson's Disease Rating Scale I scores at the time of inclusion. There were 262 patients who were subsequently enrolled into the open-label study featuring a maximum duration of up to 57 months. Statistical analysis revealed good long-term efficacy and tolerability of pramipexole. Overall, only a low prevalence of somnolence was found. In summary, this study provides additional level I evidence of the usefulness of pramipexole, suggests a particular tremorlytic and a possible antidepressant action of this compound, and addresses for the first time its efficacy and safety during long-term administration in advanced PD. (c) 2005 Movement Disorder Society.

J Psychiatr Res. 2005 May;39(3):241-250.
Psychometric schizotypy modulates levodopa effects on lateralized lexical decision performance.
Mohr C, Krummenacher P, Landis T, Sandor PS, Fathi M, Brugger P.
Department of Neurology, Functional Brain Mapping Laboratory, University Hospital Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland; Rehabilitation Clinic, University Hospital Geneva, Geneva, Switzerland; Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Emergence of psychotic thought has been related to a breakdown in left-hemisphere language dominance. Dopamine (DA) is implicated in both psychotic pathology and modulation of the semantic system. The present study explored whether controlled DA administration modulates basic language functions: (1) in general and/or (2) as a function of schizophrenia-associated thought. Forty healthy men performed a tachistoscopic lexical decision task. Participants' performance was also analyzed as a function of their positive (magical ideation, MI) and negative (physical anhedonia, PHYSAN) schizotypal features. Half of the subjects received 200 mg levodopa, the other half a placebo. Our findings showed that pharmacological treatment per se did not influence task performance, but influenced laterality patterns as a function of participants' schizotypal features. In the placebo, but not in the levodopa group, right hemisphere language contribution increased as a function of increasing MI scores. In the levodopa, but not in the placebo group, superior left hemisphere lexical decision performance was related to increasing PHYSAN scores. The findings from both substance groups suggest that in the healthy brain, a DA agonist restores left-hemispheric dominance for language by reducing right-hemispheric contribution with respect to a positive schizotypal trait and by increasing left-hemispheric specialization with respect to a negative schizotypal trait. We conjecture that the healthy brain compensates through intact neurochemical mechanisms an increased DA concentration, in particular for persons with elevated positive psychotic-like features.

J Commun Disord. 2005 May-Jun;38(3):187-96.
The effects of levodopa on word intelligibility in Parkinson's disease.
De Letter M, Santens P, Borsel JV.
Department of Oto-Rhino-Laryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.

Dysarthria is a common manifestation in patients with idiopathic Parkinson's disease. This study investigated the effects of levodopa on intelligibility in patients with Parkinson's disease. Ten participants were tested during on- and off-states using the Yorkston and Beukelman intelligibility test (1980). Intelligibility as scored by a panel of speech therapists was significantly improved in the on-condition. No correlation was found, however, between intelligibility and overall severity of the disease or severity of the motor problems. EDUCATIONAL OUTCOMES:: As a result of this activity the participant will be able to discuss the effects of levodopa on intelligibility in patients with Parkinson's disease.

J Psychiatr Res. 2005 May;39(3):241-250.
Psychometric schizotypy modulates levodopa effects on lateralized lexical decision performance.
Mohr C, Krummenacher P, Landis T, Sandor PS, Fathi M, Brugger P.
Department of Neurology, Functional Brain Mapping Laboratory, University Hospital Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland; Rehabilitation Clinic, University Hospital Geneva, Geneva, Switzerland; Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Emergence of psychotic thought has been related to a breakdown in left-hemisphere language dominance. Dopamine (DA) is implicated in both psychotic pathology and modulation of the semantic system. The present study explored whether controlled DA administration modulates basic language functions: (1) in general and/or (2) as a function of schizophrenia-associated thought. Forty healthy men performed a tachistoscopic lexical decision task. Participants' performance was also analyzed as a function of their positive (magical ideation, MI) and negative (physical anhedonia, PHYSAN) schizotypal features. Half of the subjects received 200 mg levodopa, the other half a placebo. Our findings showed that pharmacological treatment per se did not influence task performance, but influenced laterality patterns as a function of participants' schizotypal features. In the placebo, but not in the levodopa group, right hemisphere language contribution increased as a function of increasing MI scores. In the levodopa, but not in the placebo group, superior left hemisphere lexical decision performance was related to increasing PHYSAN scores. The findings from both substance groups suggest that in the healthy brain, a DA agonist restores left-hemispheric dominance for language by reducing right-hemispheric contribution with respect to a positive schizotypal trait and by increasing left-hemispheric specialization with respect to a negative schizotypal trait. We conjecture that the healthy brain compensates through intact neurochemical mechanisms an increased DA concentration, in particular for persons with elevated positive psychotic-like features.

Acta Neurol Scand. 2004 Sep;110(3):188-95.
Levodopa effect on [18F]fluorodopa influx to brain: normal volunteers and patients with Parkinson's disease.
Kumakura Y, Danielsen EH, Reilhac A, Gjedde A, Cumming P.
PET Centre, Aarhus University Hospitals and Centre for Functionally Integrated Neuroscience, Aarhus, Denmark.
OBJECTIVES: Levodopa is the immediate precursor of dopamine and the substrate for DOPA decarboxylase, an enzyme subject to regulation in living brain. To test whether this regulation changes in disease, we used Positron Emission Tomography (PET) with parametric mapping to measure the effect of levodopa on the net clearance of [(18)F]fluorodopa to brain (K, ml/g/min). METHODS: Five patients with early Parkinson's disease with pause of medication for 3 days and six age-matched healthy volunteers were studied in a baseline condition and after levodopa challenge. RESULTS: Levodopa (200 mg as Sinemet) increased the magnitude of the net clearance K in the left and right putamen of the healthy volunteers by 11% relative to the baseline condition. In contrast, resumption of medication with levodopa did not significantly alter the magnitude of K in putamen of the Parkinson's disease patients. Compartmental analysis was used to probe the physiological basis of the activation of K: levodopa treatment increased by 15% the apparent distribution volume of [(18)F]fluorodopa in cerebellum (, ml/g) of both patients and control subjects, without significantly altering the unidirectional blood-brain clearance (, ml/g/min) or the relative activity of DOPA decarboxylase (, min(-1)) in putamen. CONCLUSION: We conclude that levodopa treatment increases the distribution volume of [(18)F]fluorodopa in brain, increasing its availability for utilization in dopamine terminals. We speculate that levodopa act as a direct beta-adrenergic agonist at receptors regulating the permeability of the blood-brain barrier to levodopa. However, the PET analytical method was without sufficient power to detect the consequent increase in magnitude of K in brain of only five Parkinson's disease subjects.

Mov Disord. 2004 May;19(5):513-7.
Drug adherence in Parkinson's disease.
Leopold NA, Polansky M, Hurka MR.
Division of Neurology, Department of Medicine, Crozer-Chester Medical Center, Upland, Pennsylvania 19013, USA. naleopold@comcast.net
Physicians modify drug schedules in response to their patients' clinical responses. Failure to relieve patients' symptoms or the emergence of drug-related side effects may reflect nonadherence to a prescribed drug schedule rather than incorrect therapeutic physician decisions. Using a medication questionnaire and a computerized medication event monitoring system (MEMS) to monitor medication use, nonadherence of drug use was examined in subjects with Parkinson's disease (PD). We report that prescription nonadherence in PD subjects was common and approximated that reported in other chronic diseases. During a 28-day observation period, only 4 of 39 subjects had complete schedule adherence, i.e., no missed, extra, or mistimed doses. Using a questionnaire, 24.3% of subjects acknowledged missing any doses but the computerized MEMS recorded that 51.3% of subjects missed at least one dose per week and 20.5% of subjects missed three or more doses per week. Mistiming of doses was admitted by 73% of subjects but 82.1% had recorded mistimed doses. Of multiple sociodemographic and disease-related items examined, only gender and level of education were statistically related to nonadherence. Copyright 2004 Movement Disorder Society

Mov Disord. 2004 Feb;19(2):228-30
Exercise-induced dystonia as a preceding symptom of familial Parkinson's disease.
Bruno MK, Ravina B, Garraux G, Hallett M, Ptacek L, Singleton A, Johnson J, Singleton A, Hanson M, Considine E, Gwinn-Hardy K.
Parkinson's Unit, Division of Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. brunom@ninds.nih.gov
Paroxysmal exercise-induced dystonia can occur with Parkinson's disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise-induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, sequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype-phenotype studies in this and similar families may give clues to pre-symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future.

Surg Neurol. 2004 Feb;61(2):201-3; discussion 203.
Split spinal cord malformation in an elderly patient: case report.
Quinones-Hinojosa A, Gadkary CA, Mummaneni PV, Rosenberg WS.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
Split spinal cord malformations (SCM) typically present in childhood and rarely in adulthood. Very little is known about the SCMs in the elderly, and the diagnosis can be easily missed. A 73-year-old woman with a childhood history of scoliosis and late ambulation milestones presented with a 2-year history of worsening low back pain and progressive difficulty walking. She had a mild gait disturbance with 4/5 weakness in left ankle dorsiflexion. Magnetic resonance imaging revealed a bifid spinal cord contained in a single thecal sac and a tethered cord with low-lying conus at L3. The patient was taken to the operating room and a soft-tissue median septum, as well as all other adhesions, was removed. The filum terminale was identified, coagulated, and divided. Six weeks later, the patient reported decreased back pain, improvement in ambulation, and markedly decreased used of narcotics for her back and leg pain. Her left ankle dorsiflexion strength improved to 4+/5. This patient had two hemicords encased in a single dural tube separated by a nonrigid, fibrous median septum and an associated tethered cord. Adult presentation of SCM is extremely rare. This case highlights the need to consider split cord malformation and tethered cord in the differential diagnosis not only for adults but also the elderly presenting with back pain, scoliosis, and difficulty walking.

Clin Neuropharmacol. 2004 Jan-Feb;27(1):17-24.
Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/carbidopa.
Almeida L, Vaz-da-Silva M, Silveira P, Falcao A, Maia J, Loureiro A, Torrao L, Machado R, Wright L, Soares-da-Silva P.
Department of Research and Development, BIAL, S Mamede do Coronado, Portugal.
This study investigated the tolerability and the pharmacokinetic and pharmacodynamic interactions between single oral administration of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg), a novel catechol-O-methyltransferase (COMT) inhibitor, and standard carbidopa/levodopa 25 mg/100 mg (Sinemet 25/100) in healthy adult volunteers. This was a single-center, double-blind, placebo-controlled, randomized, crossover study with 5 single-dose treatment periods with a washout period of 2 weeks between doses. During each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Sinemet 25/100. Tolerability was assessed by recording adverse events, vital signs, continuous EKG, and clinical laboratory parameters. Pharmacokinetic parameters of levodopa and 3-O-methyl-levodopa (3-OMD) were determined. The activity of soluble COMT in erythrocytes was also measured. Eighteen subjects (10 men and 8 women) participated in the study. The drug combination was well tolerated, with the adverse events reported being transient and generally mild in severity. Mean levodopa Cmax values were attained at 0.8 to 1.8 hours postdose. Thereafter, plasma levodopa levels declined with a mean t1/2 that increased in a manner that depended on the dose of BIA 3-202. The increase in systemic exposure to levodopa (AUC0-infinity) occurred at all doses of BIA 3-202, attaining its maximum at 200 mg BIA 3-202 (95% conficence interval, 1.43-1.73). The mean Cmax and AUC0-infinity values of 3-OMD decreased dose proportionally in BIA 3-202-treated subjects, with differences being statistically significant for all the doses tested. Maximum COMT inhibition occurred between 0.8 and 2.0 hours postdose, and ranged from 56 (50 mg) to 85% (400 mg). Time to return to baseline COMT activity ranged from 6 (50 mg) to 18 hours (400 mg), following the same dose-dependent tendency. In conclusion, the novel COMT inhibitor BIA 3-202 increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard levodopa/carbidopa.

Mov Disord. 2004 Jan;19(1):22-8.
Quality of life in early Parkinson's disease: impact of dyskinesias and motor fluctuations.
Marras C, Lang A, Krahn M, Tomlinson G, Naglie G; Parkinson Study Group.
Division of Neurology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinson's disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM-PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients. Copyright 2003 Movement Disorder Society

Pharm Res. 2003 Sep;20(9):1466-73.
Novel gastroretentive dosage forms: evaluation of gastroretentivity and its effect on levodopa absorption in humans.
Klausner EA, Lavy E, Barta M, Cserepes E, Friedman M, Hoffman A.
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
PURPOSE: To design novel expandable gastroretentive dosage form (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers. METHODS: Thin (<0.07 cm), large-dimensioned (> or = 5 x 2.1 cm), multi layer dosage forms (DFs) with different rigid polymeric matrices an mechanical properties were folded into gelatin capsules and wer administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa GRDF were compared to Sinemet CR in a crossover design. RESULTS: The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity (> or = 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDF rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR. CONCLUSIONS: The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.

Rev Med Chil. 2003 Jun;131(6):623-31.
Pharmacokinetic comparison of Sinemet and Grifoparkin (levodopa/carbidopa 250/25 mg) in Parkinson s disease: a single dose study
Chana P, Fierro A, Reyes-Parada M, Saez-Briones P.
Unidad de Movimientos Anormales, Servicio de Neurologia y Neurocirugia, Hospital DIPRECA.
BACKGROUND: There are doubts wether generic medications have the same bioavailability and efficacy compared with the original drugs developed by pharmaceutical companies with research capabilities. AIM: To compare the pharmacokinetics and clinical (motor) responses of Sinemet and Grifoparkin (generic carbidopa/levodopa 250/25 mg) in patients with advanced Parkinson's disease. PATIENTS AND METHODS: Patients were randomly assigned to Sinemet (15 patients 62 +/- 12 years old; mean disease duration 11 +/- 7 years) or Grifoparkin (15 patients, 64 +/- 11 years old; mean disease duration 12 +/- 4 years) groups. Medication and food were withheld 12 h before the study. Fifteen blood samples were collected (starting 9 AM) immediately before (sample 1, t = 0 min) and after (samples 2-15, t = 20-360 min) oral administration of a single dose of Sinemet or Grifoparkin, and plasmatic L-DOPA was quantified using HPLC with electrochemical detection. Additionally, each patient was clinically evaluated every 20 minutes, using the tapping test and the unified Parkinson's disease scale Hoehn & Yarh. RESULTS: Tmax (time at which the maximal L-DOPA concentration was reached) were 69 +/- 12 min and 64 +/- 11 min for Sinemet and Grifoparkin respectively (NS). Cmax (maximal L-DOPA concentration reached) was 3161 +/- 345 ng/ml for Sinemet and 3274 +/- 520 ng/ml for Grifoparkin (NS). The t1/2 (half life time), CL (clearance) and volume of distribution (Vd) values calculated were 159 +/- 32 min, 51.7 +/- 5.1 1/h and 3.6 +/- 1.2 l/kg for Sinemet and 161 +/- 48 min, 58.7 +/- 8 l/h and 3.0 +/- 0.7 l/kg for Grifoparkin (NS). UPDRS-III value for the best "on state" and for the worst "off state" were 23 +/- 11 and 50 +/- 19 for Sinemet and 20 +/- 7 and 46 +/- 13 for Grifoparkin respectively (NS). CONCLUSION: The results obtained showed that both drugs are bioequivalent in patients with advanced Parkinson's disease.

Ann Neurol. 2003 May;53(5):558-69.
Randomized trial of pallidotomy versus medical therapy for Parkinson's disease.
Vitek JL, Bakay RA, Freeman A, Evatt M, Green J, McDonald W, Haber M, Barnhart H, Wahlay N, Triche S, Mewes K, Chockkan V, Zhang JY, DeLong MR.
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Thirty-six patients with Parkinson's disease (PD) were randomized to either medical therapy (N = 18) or unilateral GPi pallidotomy (N = 18). The primary outcome variable was the change in total Unified Parkinson's Disease Rating Scale (UPDRS) score at 6 months. Secondary outcome variables included subscores and individual parkinsonian symptoms as determined from the UPDRS. At the six month follow-up, patients receiving pallidotomy had a statistically significant reduction (32% decrease) in the total UPDRS score compared to those randomized to medical therapy (5% increase). Following surgery, patients' showed improvement in all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, gait and balance. Drug-induced dyskinesias were also markedly improved. Although the greatest improvement occurred on the side contralateral to the lesion, significant ipsilateral improvement was also observed for bradykinesia, rigidity and drug-induced dyskinesias. A total of twenty patients have been followed for 2 years to assess the effect of time on clinical outcome. These patients have shown sustained improvement in the total UPDRS (p < 0.0001), "off" motor (p < 0.0001) and complications of therapy subscores (p < 0.0001). Sustained improvement was also seen for tremor, rigidity, bradykinesia, percent on time and drug-induced dyskinesias.

Ann Neurol. 2003;53 Suppl 3:S87-97; discussion S97-9.
Neuroprotection in Parkinson's disease: clinical trials.
Stocchi F, Olanow CW.
Department of Neuroscience and Neuromed, University La Sapienza, Rome, Italy.
Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.