Parkinson Disease: Nutt JG

Nutt JG. · No affiliation provided · Neurology. · Pubmed #10822422 No free full text.

This publication has no abstract.

Nutt JG. · Department of Neurology, Oregon Health & Science University, Parkinson Disease Research, Education and Clinical Center, Portland VA, Oregon, USA. · Mov Disord. · Pubmed #18781675 No free full text.

Abstract: The pharmacokinetics and pharmacodynamics of levodopa are dominated by two features: the short plasma half-life of the drug and the portion of the antiparkinsonian response that parallels the plasma levodopa levels, the so-called short-duration response. These features are the basis of motor fluctuations that complicate long-term therapy with levodopa. Motor fluctuations will predictably improve with measures that prolong the elevations of plasma levodopa or prolong the efficacy of dopamine synthesized from exogenous levodopa. Because dyskinesia is closely linked to the short-duration response and conceivably part of the short-duration response, it is less clear that dyskinesia will be improved by therapeutic strategies that reduce motor fluctuations.

Peterson AL, Nutt JG. · Parkinsons Disease Research, Educational and Clinical Center, Portland Veteran's Administration Medical Center, Portland, Oregon 97239, USA. · Neurotherapeutics. · Pubmed #18394569 No free full text.

Abstract: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

Nutt JG. · Parkinson Center of Oregon, Oregon Health & Science University, Portland, Oregon 97239-3098, USA. · Mov Disord. · Pubmed #16958130 No free full text.

Abstract: Continuous dopaminergic stimulation (CDS) is a treatment strategy hypothesized to avoid or reduce the motor complications of long-term levodopa therapy, motor fluctuations, and dyskinesia, by preventing or reversing sensitization induced by pulsatile dopaminergic stimulation. The CDS hypothesis is itself based on several hypotheses. First, tonic dopaminergic stimulation is physiological. Second, sensitization is undesirable and should be reversed. Third, reduction of off time and dyskinesia can be induced simultaneously. Finally, clinical studies substantiate the CDS hypothesis. The evidence for these hypotheses is reviewed, and the need for randomized clinical trials that rigorously test the CDS hypothesis is emphasized.

Nutt JG, Wooten GF. · Department of Neurology, Oregon Health and Science University, Portland 97239, USA. · N Engl J Med. · Pubmed #16148287 No free full text.

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Samii A, Nutt JG, Ransom BR. · Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA. · Lancet. · Pubmed #15172778 No free full text.

Abstract: Parkinson's disease is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. The disease is attributed to selective loss of neurons in the substantia nigra, and its cause is enigmatic in most individuals. Symptoms of Parkinson's disease respond in varying degrees to drugs, and surgery offers hope for patients no longer adequately controlled in this manner. The high prevalence of the disease, and important advances in its management, mean that generalists need to have a working knowledge of this disorder. This Seminar covers the basics, from terminology to aspects of diagnosis, treatment, and pathogenesis.

Nutt JG. · Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, OP32, Portland, OR 97201-3098, USA. · Exp Neurol. · Pubmed #14637071 No free full text.

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Gold BG, Nutt JG. · Center for Research on Occupational and Environmental Toxicology, Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97201-3098, USA. · Curr Opin Pharmacol. · Pubmed #11786313 No free full text.

Abstract: Parkinson's disease treatments can be divided into three categories: symptomatic, protective and restorative. This review focuses on the restorative and neuroprotective actions of a new class of potential therapeutic agents, neuroimmunophilin ligands. To date, however, short-term treatments with two such compounds in a non-human primate model and in patients with Parkinson's disease have been disappointing.

Nutt JG. · Department of Neurology, Oregon Health Sciences University, Portland, Oregon 97201, USA. · Adv Neurol. · Pubmed #11553997 No free full text.

This publication has no abstract.

Nutt JG. · Department of Neurology, School of Medicine, Oregon Health Sciences University, Portland, OR 97201-3098, USA. · Parkinsonism Relat Disord. · Pubmed #11489675 No free full text.

Abstract: Motor fluctuations and dyskinesia are common complications of long-term levodopa therapy. The neural and molecular mechanisms underlying their development are partially understood. A variety of clinical strategies may reduce the unpredictability of motor fluctuations and reduce their impact. Prevention of these complications remains an elusive goal.

Nutt JG, Obeso JA, Stocchi F. · Dept of Neurology, Oregon Health Sciences University, Portland 97201, USA. · Trends Neurosci. · Pubmed #11052228 No free full text.

Abstract: Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of the motor fluctuations and dyskinesia that complicate long-term L-dopa therapy of Parkinson's disease. As a corollary to this hypothesis, continuous dopamine-receptor stimulation can avoid or reverse these complications. Such continuous stimulation is unlikely to mimic completely the normal function of the dopaminergic system, but should avoid the supra-physiological swings in extracellular dopamine that accompany intermittent L-dopa dosing. The concern is that this continuous stimulation might induce tolerance rather than sensitization to some effects of L-dopa. Open clinical trials support the value of continuous dopaminergic stimulation in Parkinson's disease with established motor complications, but rigorous studies, although experimentally difficult, are needed.

Obeso JA, Olanow CW, Nutt JG. · Dept of Neurology and Neurosurgery, Neuroscience Center, Clínica Universitaria and Medical School, Pamplona, Spain. · Trends Neurosci. · Pubmed #11052214 No free full text.

Abstract: Parkinson's disease (PD) is an age-related neurodegenerative disorder with an average onset age of 60 years. In the United States, approximately one million persons suffer from PD, and there are 60,000 newly diagnosed cases every year. The estimated cost of PD to society is $27 billion per year. Based on United States Census Bureau projections, it is estimated that the frequency of PD will increase fourfold by the year 2040, making it an even larger burden on patients, their families and society.

Nutt JG. · Department of Neurology, School of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA. · Ann Neurol. · Pubmed #10762144 No free full text.

Abstract: Levodopa-induced dyskinesia (LID) is a major impediment to the successful therapy of Parkinson's disease. The development of LID is facilitated by dopaminergic denervation but may not require denervation. Repeated levodopa dosing is necessary to induce dyskinesia, implying the development of sensitization to levodopa. There is inconclusive evidence on whether repeated dosing lowers the threshold (shifts the levodopa-dyskinesia response curve to the left), increases the severity of dyskinesia (increases the maximum effect that is initially zero) or induces more complex changes in the dose-response curve. Once a patient develops LID, the severity of LID is not dose responsive, but the duration of dyskinesia is. Clinically, it is very difficult to separate the antiparkinsonian and dyskinetic effects of levodopa. Whether this separation is possible with more selective agonists with antiparkinsonian effects that are equipotent to levodopa is unknown. The fact that selective stimulation of the pallidum does not separate antiparkinsonian and dyskinetic actions implies that they are closely related anatomically and physiologically.

Nutt JG, Carter JH, Carlson NE. · Department of Neurology, and Public Health and Preventative Medicine, Division of Biostatistics, Oregon Health and Science University, Portland, OR 97239, USA. · Arch Neurol. · Pubmed #17353373 links to  free full text

Abstract: OBJECTIVE: To determine if repeated dosing with methylphenidate hydrochloride (MPD) (Ritalin; Novartis Pharmaceuticals, East Hanover, NJ), an inhibitor of the dopamine transporter, would augment the effects of oral levodopa in patients with Parkinson disease. DESIGN: The study was a double-blind, randomized, placebo-controlled crossover trial. SETTING: The trial was conducted at the General Clinical Research Center (GCRC) as an inpatient study. Subjects Thirteen people with idiopathic Parkinson disease and a fluctuating motor response to levodopa were recruited from movement disorder clinics as a convenience sample. One subject was excluded because he did not have a 10% increase in tapping speed in response to levodopa. The remaining 12 subjects completed the protocol. INTERVENTIONS: A 0.4-mg/kg dose of MPD was administered orally at 8 am, noon, and 4 pm in conjunction with the subjects' normal oral antiparkinsonian medications. Oral levodopa dosage was decreased as clinically feasible during the first 4 days in the GCRC during open-label administration of MPD and hourly monitoring of parkinsonism and vital signs between 7 am and 8 pm. Subjects were discharged taking their usual antiparkinsonian medications without MPD. They returned 1 and 2 weeks later to the GCRC for 1 day of hourly monitoring of their response to the medication regimen derived during the 4 days in the GCRC, once with MPD and once with identical-appearing placebo, in a randomized sequence and double-blind conditions. MAIN OUTCOME MEASURES: The main outcome measure was the duration of "on" time between 9 am and 8 pm measured by an increase in tapping speed by 10% over the average of the 7 am to 8 am predosing tapping speed measurements. Secondary measures were estimates of "on" time obtained with the timed walking task, tremor scores, and dyskinesia scores. In addition, averages of hourly tapping speeds, walking speed, tremor scores, dyskinesia scores, vital signs, and analog scale scores for mood, anxiety, and fatigue between 9 am and 8 pm were examined. Adverse events on the double-blinded days were compared. RESULTS: Methylphenidate tended to increase the time "on" as measured by tapping (P = .09) but not by walking time or dyskinesia scores (P = .40 and .42, respectively). Methylphenidate tended to increase average tapping speed, decrease time to perform walking task, decrease tremor, and increase dyskinesia score but only the decrease in tremor reached significance. Neither the investigators nor the subjects could reliably identify active drug. Methylphenidate was well tolerated. CONCLUSIONS: The effects of 0.4 mg/kg of MPD 3 times per day on the motor response to levodopa were small and variable and judged to be clinically insignificant. Trial Registration clinicaltrials.gov Identifier: NCT00359723.

Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M. · Toronto Western Hospital, University of Toronto, Ontario, Canada. · Ann Neurol. · Pubmed #16429411 No free full text.

Abstract: OBJECTIVE: Glial cell line-derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open-label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin). METHODS: Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin 15 microg/putamen/day or placebo. The primary end point was the change in Unified Parkinson Disease Rating Scale (UPDRS) motor score in the practically defined off condition at 6 months. Secondary end points included other UPDRS scores, motor tests, dyskinesia ratings, patient diaries, and (18)F-dopa uptake. RESULTS: At 6 months, mean percentage changes in "off" UPDRS motor score were -10.0% and -4.5% in the liatermin and placebo groups, respectively. This treatment difference was not significant (95% confidence interval, -23.0 to 12.0, p = 0.53). Secondary end point results were similar between the groups. A 32.5% treatment difference favoring liatermin in mean (18)F-dopa influx constant (p = 0.019) was observed. Serious, device-related adverse events required surgical repositioning of catheters in two patients and removal of devices in another. Neutralizing antiliatermin antibodies were detected in three patients (one on-study and two in the open-label extension). INTERPRETATION: Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased (18)F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way this negative outcome.

Chan PL, Nutt JG, Holford NH. · Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. · J Pharmacokinet Pharmacodyn. · Pubmed #16320101 No free full text.

Abstract: The purpose of this analysis is to describe how levodopa pharmacokinetic and pharmacodynamic parameters change over the first 4 years of long-term levodopa treatment in patients with Parkinson's disease. Twenty previously untreated Parkinsonian patients were admitted to the general clinical research center (GCRC) for 4 days at the beginning of long-term levodopa therapy and 6, 12, 24 and 48 months later. On each GCRC admission, patients received a 2 hr IV infusion of levodopa on day 1 and day 4 with no oral levodopa between the infusions. After the first GCRC admission patients were treated with oral levodopa dosed for optimal control of Parkinsonism. Motor function was measured by finger tapping rate. A pharmacokinetic-pharmacodynamic model incorporating 3 effect compartments was used to fit the individual plasma levodopa concentrations and tapping rates. Motor function before the first levodopa infusion (E0(1)) improved over the first 20 months and subsequently returned to the initial baseline at the start of the study. A similar pattern was seen in motor function before the second infusion (E0(2)) after the 3 days levodopa withdrawal, with a decline predicted to fall below the initial baseline at the start of the study by 6 years. Eight patients showed an increase in maximum tapping rate with levodopa (E(max)) approaching a steady state after 16 months. Ten patients showed an increase in E(max) with a peak at 31 months. One patient showed a linear decrease and another patient did not change over the 48 months. Longitudinal progress models were used to describe the time course of pharmacokinetic and pharmacodynamic parameters over 4 years. Peak treatment benefit, defined as the difference between E(max) and E0(1) or E0(2) (D(max)1 or D(max)2), increased with time particularly after the 3-day levodopa withdrawal. Deterioration of pre-dose motor function (E0) as disease progresses coupled with a greater amplitude of response due to levodopa (D(max)) could be a key factor contributing to motor fluctuations associated with long-term levodopa treatment.

Nutt JG, Carter JH, Sexton GJ. · Department of Neurology, Oregon Health and Science University, Portland, OR 97239-3098, USA. · Ann Neurol. · Pubmed #15174010 No free full text.

Abstract: The dopamine transporter (DAT) may be the single most important determinant of extracellular dopamine concentrations. The importance of DAT in Parkinson's disease (PD) in which DAT may be reduced by 50 to 70% is unclear. We have examined the effects of methylphenidate (MPD), an inhibitor of DAT, administered alone or with levodopa, on parkinsonism measured with tapping and walking speeds, dyskinesia, subjective effects, and vital signs. MPD in oral doses of up to 0.4 mg/kg was well tolerated. Administered alone, MPD produced no objective improvement of parkinsonism. MPD, 0.4 mg/kg orally, coadministered with 2-hour levodopa infusions at 0.5 or 1.0mg/kg/hr increased the percentage of patients responding to the 0.5mg/kg/hr dose and prolonged the response to levodopa infusions as measured by tapping and walking speeds. Dyskinesia was prolonged in proportion to the increase in antiparkinson actions but severity was not increased. MPD decreased the hypotensive response to levodopa. In conclusion, MPD appeared to have no effect given alone but potentiated the effects of levodopa, particularly doses at threshold for clinical effects. These observations indicate that the residual DAT is functional in PD and is a potential target for symptomatic therapy of PD.

Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER, Lozano AM, Penn RD, Simpson RK, Stacy M, Wooten GF, Anonymous00009. · Oregon Health & Science University, Portland 97201-3098, USA. · Neurology. · Pubmed #12525720 No free full text.

Abstract: OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Camicioli R, Lea E, Nutt JG, Sexton G, Oken BS. · Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA. · Clin Neuropharmacol. · Pubmed #11479391 No free full text.

Abstract: We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.

Heikkinen H, Nutt JG, LeWitt PA, Koller WC, Gordin A. · Research Center, Orion Pharma, Orion Corporation, Espoo, Finland. · Clin Neuropharmacol. · Pubmed #11391126 No free full text.

Abstract: We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Rascol O, Nutt JG, Blin O, Goetz CG, Trugman JM, Soubrouillard C, Carter JH, Currie LJ, Fabre N, Thalamas C, Giardina WW, Wright S. · Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Médecine, 37 Allées Jules Guesde, 31073 Toulouse Cedex, France. · Arch Neurol. · Pubmed #11176963 links to  free full text

Abstract: BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Nutt JG, Carter JH. · Department of Neurology, School of Medicine, Oregon Health Sciences University, Portland 97201-3098, USA. · Neurology. · Pubmed #10636162 No free full text.

Abstract: The authors investigated the ability of daytime infusions of apomorphine, a D-1 and D-2 dopamine agonist, to sustain the long-duration response (LDR) in seven subjects with fluctuating PD in whom L-DOPA was discontinued for 3 days. Apomorphine maintained the LDR to the extent that it kept the subjects "on" during the day. This observation suggests that the LDR can be a postsynaptic effect, independent of dopamine storage.

Rascol O, Blin O, Thalamas C, Descombes S, Soubrouillard C, Azulay P, Fabre N, Viallet F, Lafnitzegger K, Wright S, Carter JH, Nutt JG. · Clinical Investigation Centre, Department of Pharmacology, INSERM U455, University Hospital, Toulouse, France. · Ann Neurol. · Pubmed #10360765 No free full text.

Abstract: Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.

Jacobs JV, Nutt JG, Carlson-Kuhta P, Stephens M, Horak FB. · Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA. · Exp Neurol. · Pubmed #19061889 No free full text.

Abstract: Freezing of gait (FoG) is an episodic, brief inability to step that delays gait initiation or interrupts ongoing gait. FoG is often associated with an alternating shaking of the knees, clinically referred to as knee trembling or trembling in place. The pathophysiology of FoG and of the concomitant trembling knees is unknown; impaired postural adjustment in preparation for stepping is one hypothesis. We examined anticipatory postural adjustments (APAs) prior to protective steps induced by a forward loss of balance in 10 Parkinson's disease (PD) subjects with marked FoG and in 10 control subjects. The amplitude and timing of the APAs were determined from changes in the vertical ground-reaction forces recorded by a force plate under each foot and were confirmed by electromyographic recordings of bilateral medial gastrocnemius, tibialis anterior and tensor fascia latae muscles. Protective steps were accomplished with a single APA followed by a step for control subjects, whereas PD subjects frequently exhibited multiple, alternating APAs coexistent with the knee trembling commonly observed during FoG as well as delayed, inadequate or no stepping. These multiple APAs were not delayed in onset and were of similar or larger amplitude than the single APAs exhibited by the control subjects. These observations suggest that multiple APAs produce the knee trembling commonly associated with FoG and that FoG associated with a forward loss of balance is caused by an inability to couple a normal APA to the stepping motor pattern.

Goetz CG, Nutt JG, Stebbins GT. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Mov Disord. · Pubmed #19025759 No free full text.

Abstract: We developed and tested a rating scale aimed to capture the essential features of dyskinesia in Parkinson's disease (PD). Although several scales assess selected attributes of PD-dyskinesias, no comprehensive rating tool exists. Available rating scales were evaluated by the investigators and patient focus groups. Modifications were finalized into the Unified Dyskinesia Rating Scale (UDysRS). The UDysRS has four parts: I: Historical Disability (patient perceptions) of On-Dyskinesia impact (maximum 44 points); II: Historical Disability (patient perceptions) of Off-Dystonia impact (maximum 16 points); III: Objective Impairment (dyskinesia severity, anatomical distribution over seven body regions, and type (choreic or dystonic) based on four activities observed or video-recorded (28 points); IV: Objective Disability based on Part III activities (maximum 16 points). For clinimetric testing, 70 PD patients with all severities of dyskinesia were interviewed and videotaped. Twenty movement disorder experts rated the videotapes with the UDysRS. Internal consistency was examined with Cronbach's alpha. Inter- and intra-rater reliability was evaluated with generalized weighted and nonweighted Kappa coefficients, and intraclass correlation coefficients. Both subjective (Sections I and II) and objective (Sections III and IV) demonstrated high internal consistency (alpha: 0.915, 0.971). Interrater reliability for the objective sections was acceptable for all items and likewise for intrarater reliability except for right leg. Reliable factor structures were found for both subjective (six factors) and objective sections (five factors). The UDysRS is a clinimetrically sound rating scale for dyskinesia in PD, demonstrating acceptable levels of internal consistency and inter- and intra-rater reliability. Testing scale responsivity to treatment interventions is planned.