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Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and daily “OFF” time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25–50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily “OFF” time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive–compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa–dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms in individuals with advanced Parkinson's disease (PD) and enables physicians to reduce doses of antiparkinsonian drugs. We investigated possible predictive factors for the successful reduction of antiparkinsonian drug dosage after STN-DBS. We evaluated 33 PD patients who underwent bilateral STN-DBS. We assessed rates of reduction of the levodopa-equivalent daily dose (LEDD) and levodopa daily dose (LDD) by comparing drug doses before vs. 6-months post-surgery. We used correlation coefficients to measure the strength of the relationships between LEDD and LDD reduction rates and preoperative factors including age, disease duration, preoperative LEDD and LDD, unified Parkinson's Disease Rating Scale part-II and -III, levodopa response rate, Mini-Mental State Examination score, dyskinesia score, Hamilton Rating Scale for depression, and the number of non-motor symptoms. The average LEDD and LDD reduction rates were 61.0% and 70.4%, respectively. Of the variables assessed, only the number of psychiatric/cognitive symptoms was significantly correlated with the LEDD reduction rate. No other preoperative factors were correlated with the LEDD or LDD reduction rate. A wide range of preoperative psychiatric and cognitive symptoms may predict the successful reduction of antiparkinsonian drugs after STN-DBS.

Complex I (NADH dehydrogenase) and complex IV (cytochrome-c-oxidase) of the mitochondrial electron transport chain are reported to be affected by drugs used to treat psychiatric or neurodegenerative diseases, including antidepressants, antipsychotics, anxiolytics, mood stabilizers, stimulants, antidementia and antiparkinsonian drugs. We conducted meta-analyses examining the effects of each drug category on complex I and IV. The electronic databases Pubmed, EMBASE, CENTRAL and Google Scholar were searched for studies published between 1970 and 2018. Of 3105 screened studies, 68 articles covering 53 drugs were included in the meta-analyses. All studies assessed complex I and IV in rodent brain at the level of enzyme activity. Meta-analyses revealed that selected antidepressants increase or decrease complex I and IV, antipsychotics and stimulants primarily decrease complex I but increase complex IV, whereas anxiolytics, mood stabilizers, antidementia and antiparkinsonian drugs preserve or even enhance both complex I and IV. To determine potential contributors to the drug effects, we meta-analyzed the drugs' neurotransmitter receptor profiles and found that affinity to adrenergic, dopaminergic (D1/2), glutaminergic (NMDA1,3), histaminergic (H1), muscarinic (M1,3), opioid (OP1-3), serotonergic (5-HT2A, 5-HT2C, 5-HT3A) and sigma receptors contributed most to the effects. We discuss the drug effects in relation to pharmacological mechanisms of action that might have relevance for clinical and research applications. Funding: No specific funding. Declaration of Interest: J.J.M. receives royalties for commercial use of the C-SSRS from the Research Foundation of Mental Hygiene. The remaining authors declare no competing interests. Keywords: meta-analysis; psychotropic drugs; NADH dehydrogenase; cytochrome-c-oxidase

International audience; Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson's disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.

Using molecular simulations, we study the adsorption and diffusion of an antiparkinsonian drug known as amantadine (or 1-aminoadamantane) in different single-walled carbon nanotubes (SWCNs) with di...

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine.

Ethopropazine (EP) or profenamine is a phenothiazine derivative, N 10 -(2-diethylaminopropyl)phenothiazine (Figure.1), used as an antiparkinsonian drug that has anticholinergic, antihistamine, and antiadrenergic actions. Transition metal complexes of ZnBr2, CdBr2, CdI2, and HgBr2 have been synthesized using EP as the main ligand and purified by recrystallization in MeOH. These products have been characterized based on their elemental analysis, molar conductance, magnetic susceptibility, IR and 1 H-NMR data. The molecular formulations of the new mononuclear complexes have been found to be(Zn(C19H24N2S.HCl)2)Br2,(Cd(C19H24N2S.HCl)2)Br2,(Cd(C19H24N2S.HCl)2)I2 and(Hg(C19H24N2S.HCl) (C19H24N2S.HBr) (OH2)) Br2, where the ligand, EP = C19H24N2S. All the complexes show an ionic ratio of 1:2 in acetonitrile solutions. Molecular structures have been proposed. The four-coordinate complex cations of(Zn(C19H24N2S.HCl)2) Br2,(Cd(C19H24N2S.HCl)2)Br2, and(Cd(C19H24N2S.HCl)2)I2 contain an sp

The physico-chemical properties and in vivo efficacies of two nanoparticulate systems delivering the antiparkinsonian drug bromocriptine (BC) were compared in the present study. Monoolein Aqueous Dispersions (MADs) and Nanostructured Lipid Carriers (NLCs) were produced and characterized. Cryogenic transmission electron microscopy (cryo-TEM) and X-ray diffraction revealed the morphology of MAD and NLC. Dimensional distribution was determined by Photon Correlation Spectroscopy (PCS) and Sedimentation Field Flow Fractionation (SdFFF). In particular, BC was shown to be encapsulated with high entrapment efficiency both in MAD and in NLC, according to SdFFF combined with HPLC. Two behavioral tests specific for akinesia (bar test) or akinesia/bradykinesia (drag test) were used to compare the effects of the different BC formulations on motor disabilities in 6-hydroxydopamine hemilesioned rats in vivo, a model of Parkinson's disease. Both free BC and BC-NLC reduced the immobility time in the bar test and enhanced the number of steps in the drag test, although the effects of encapsulated BC were longer lasting (5h). Conversely, BC-MAD was ineffective in the bar test and improved stepping activity in the drag test to a much lower degree than those achieved with the other preparations. We conclude that MAD and NLC can encapsulate BC, although only NLC provide long-lasting therapeutic effects possibly extending BC half-life in vivo.

Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.

A prospective study carried out in the Netherlands showed that the most important risk factor for motor function deterioration in Parkinson's disease (PD) during hospital admission was medication error, including both incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs.1 Indeed, one of the reported reasons for omitting or delaying levodopa administration has been medication unavailability on time where needed, that is, in medical wards where the patient is admitted. Skelly et al in a recent study carried out in Derby Hospital (National Parkinson Foundation Centre of Excellence for Parkinson’s Disease) report that even in a ward specially designed to treat patients with PD, with an enhanced stock of anti-PD medications, 2.5% of all doses were not administered because the drug was not available on time.2 It is likely this problem is compounded in other nonspecialized wards and especially in smaller hospitals. To counteract this problem, Parkinson's United Kingdom “Get it on time campaign,”3 among others, has suggested that all commercially available antiparkinsonian drugs should be available in all hospital wards and on time. Given the data described previously, this seems unfeasible, especially in small hospitals where having available all the anti-PD drugs would certainly result in the expiration of many of these drugs before they are used. We think a possible solution can be found in Skelly et al’s reflections: “The available stock was not used as flexibly as we had hoped: e.g. doses of modified release medications were omitted rather than a temporary switch to available standard release drugs.”2 (p. 1246) We agree and propose a therapeutic interchange protocol (Figure 1) where the unavailable PD drug is first converted to the equivalent levodopa dose according to published dose equivalency.4 Then an immediate release levodopa dose could be administered until the original drug is available. Immediate release levodopa is cheap. Thus, having it in each hospital ward is a realistic approach. Figure 1. An example of applying the proposed protocol to prevent Parkinson’s disease (PD) drug omissions. It has to be kept in mind that dose equivalencies proposed by Tomlinson et al were developed to compare dose intensities of antiparkinsonian drugs in clinical trials rather than to use them in clinical practice and were catalogued by the authors as mere approximations. Paraphrasing Magdalinou et al5: “PD medications should be regarded as important as insulin is for diabetics.” (p. 540) Using short-acting insulin instead of the patient’s chronic insulin treatment is now routine clinical practice in hospitals. Although there may be some limitations to this approach, we think changing to an equivalent dose of immediate release levodopa could help to prevent PD drug omissions and delays.

Background: L-dopa is an important antiparkinsonian drug. It is a precursor of dopamine and the other catecholamines. Potentially, administration of L-dopa could lead to increased urinary excretion of catecholamines and their metabolites to abnormal amounts. The current study aimed to determine these excretions in patients with Parkinson's disease (PD) receiving L-dopa compared with suitable controls. This is the first assessment of the effect of exogenous administration of L-dopa on urinary free metadrenalines. Methods: Using one-way analysis of variance (ANOVA), urine catecholamines and metabolites, expressed as mmol per mole creatinine, were compared in: patients with PD who were receiving L-dopa; patients with PD but not receiving L-dopa; and patients without PD who were being investigated for the presence of phaechromocytoma but were found not to have the disease. Results: Significantly higher values for urinary dopamine, homovanillic acid, free normetadrenaline and free metadrenaline were found in patients with PD receiving L-dopa compared with the other two control groups. In all the patients with PD, these four analytes were significantly correlated with daily dose of L-dopa. Conclusion: L-dopa therapy can result in production of false positives for urinary excretion of dopamine, homovanillic acid, free normetadrenaline or free metadrenaline and thereby decrease the diagnostic value of these measurements in identifying phaeochromocytoma and related tumours.

To assess whether there is an association between initial use of serotonergic antidepressants and changes in antiparkinsonian drug treatment.A retrospective cohort study was performed with the PHARMO record linkage system. All patients from 1994 until 2004 of 40 years or older who were first time users of an antidepressant and who had used a levodopa-containing drug at least 180 days before initiation of the antidepressant were included. The maximum follow-up time was 180 days. The first change in antiparkinsonian drug treatment, defined as an increase in the daily dosage of any antiparkinsonian drug, the start of a new antiparkinsonian drug or a change in the dosage form during the follow-up period, was taken as an endpoint. Antidepressants were classified in two ways: according to their class [selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or other antidepressants] or by the extent of their inhibition of serotonin reuptake (high, intermediate or low).A total of 221 patients was included in our study. The adjusted hazard ratio for a change in antiparkinsonian drug treatment was 0.7 (95% CI 0.3-1.5) comparing SSRI with TCA users, and it was 0.9 (95% CI 0.4-2.1) comparing users of other antidepressants with TCA users. The adjusted hazard ratio for a change in antiparkinsonian drug treatment was 0.6 (95% CI 0.3-1.4) comparing users of antidepressants with high versus low extent of inhibition of serotonin reuptake, and it was 0.7 (95% CI 0.3-1.4) comparing users of antidepressants with intermediate versus low extent of inhibition of serotonin reuptake.Based on these observations, we found no evidence to be more cautious using SSRIs or serotonergic antidepressants compared to other antidepressants in patients with Parkinson's disease.

1202 patients suffering from Parkinson’s disease switched from other dopamine agonists to pramipexole under open conditions either abruptly or in an overlapping, gradual manner. Mostly insufficient effectiveness motivated the switch. The investigators gave equal preference to either an abrupt or an overlapping switch to pramipexole in this observational study. There was a tendency in favour of the overlapping switch procedure in those patients who were on a relatively higher dose of a dopamine agonist before the switch. The switch was performed because the investigators expected the effect of pramipexole on tremor, motor functions and depression/anhedonia to be better compared with previous dopamine agonists. The main reasons for switching to pramipexole (anti-tremor effect, anti-depressive/anti-anhedonic effect) as given by the physicians at baseline came up to expectations.

Transdermal delivery of dopamine agonists (DA) is a promising therapeutic concept, which aims to ameliorate frequency and intensity of motor fluctuations in patients with Parkinson’s disease (PD). We treated 8 PD patients with unpredictable on-off phenomena with lisuride patches (release: 2–5/μg lisuride base/cm2/hour in mice) in addition to their preexisting antiparkinsonian drug regime up to a period of 8 days. In order to quantify the intensity and frequency of motor fluctuations, we determined the motor changing rate (MCR), which corresponds to the patient’s self rating of motor function, performed every thirty minutes, divided through the number of scored intervals minus 1. Additional lisuride patch application significantly (p = 0.023) improved the MCR compared to baseline. Relevant side effects were transient skin irritations in four patients. Our observational study demonstrates the safety, tolerability and efficacy of transdermal lisuride delivery in the treatment of motor complications.

Despite clinical experience with levodopa for more than three decades, the role of this agent in the treatment of Parkinson's disease (PD) has not been well defined. Clearly the most effective antiparkinsonian drug, levodopa, is associated with emergence of motor complications, particularly fluctuations and dyskinesias, as well as other side effects. In addition to these limitations, there is an ongoing debate about the potential neurotoxic effects of levodopa, suggested by some in vitro studies. However, there is no support for levodopa-induced neurotoxicity from in vivo studies. This review discusses possible mechanisms of levodopa-related complications and therapeutic strategies for their prevention and management.

A 42-year-old man had suffered from Parkinson's disease for 5 years. Levodopa was effective, but the wearing-off phenomena were severe. Because of relatively low levels of serum copper and ceruloplasmin, D-penicillamine was administered. D-penicillamine increased plasma levodopa concentrations, thereby improving his parkinsonian symptoms. We propose that D-penicillamine facilitates levodopa absorption and, hence, the efficacy of the antiparkinsonian drug.

Dopaminergic drugs exert their action through activation of dopamine D1 and D2 receptors [1]. Changes of dopamine receptor density or affinity following antiparkinsonian drug therapy is suggested to underlie the development of long-term treatment complications in patients with PD [2]. However, evidence for this has not been provided.

The authors review management issues in Parkinson’s disease (PD) and provide an overview of the current pharmacological management strategies, with a specific focus on safinamide. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using levodopa, dopamine agonists, and inhibitors of dopamine-metabolizing enzymes. Currently under investigation for use in the treatment of PD, safinamide has multiple modes of action including monoamine oxidase B inhibition. It is well absorbed orally, has a long plasma half-life, and does not have liver enzyme-inducing or liver enzyme-inhibiting activity. Peak plasma concentration occurs 2–4 hours after single oral doses. Safinamide as monotherapy and as an adjunct to dopamine agonists improves Unified Parkinson’s Disease Rating Scale motor scores. One randomized, placebo-controlled trial involving 168 patients given a median safinamide dose of 70 mg/day (range 40–90 mg/day) significantly increased the proportion of responders – defined as patients improving their Unified Parkinson’s Disease Rating Scale motor scores by 30% or more from baseline – after 3 months (37.5% for safinamide versus 21.4% for placebo; P < 0.05). Safinamide increased “on” time with no or minor dyskinesia compared with the placebo in another trial, but dyskinesia severity was not reduced. Safinamide was well tolerated, with an adverse effect profile similar to that of the placebo. Further Phase III trial data for safinamide efficacy is awaited, and will be of interest in a comparison with other developments in PD therapeutics: modified formulations of available compounds, new drug classes such as adenosine receptor antagonists, and gene-based therapies.

Antiparkinsonian drugs used for 117: chronic schizophrenic patients receiving long-term neuroleptic treatment were withdrawn. Seventy-eight (66.7%) of the 117: patients were without akathisia and/or parkinsonism at least for 6: weeks after the antiparkinsodan drug withdrawal. A double-blind study of clonazepam was carried out for 22: patients and clonazepam was effective on 8: patients (100%) with akathisia and on 3: patients (75%) with parkinsonism. The authors conclude that these data support the need for discontinuous use of antiparkinsonian medication during the long-term neuroleptic therapy of chronic schzophrenic patients and the effectiveness of clonazepam in managing antiparkinsonian drug withdrawal-induced akathisia and parkinsonism.

Four case reports are described in which adjunctive alprazolam was administered to schizophrenic or schizoaffective patients who satisfied criteria for the syndrome of “negative symptoms”. The addition of alprazolam to ongoing neuroleptic and antiparkinsonian drug treatment produced substantial clinical benefit in only one of these cases, and that benefit was not replicated in a second trial in this case. These results are discussed in comparison to previously reported findings in other alprazolam-treated “negative symptom” patients.

The clinical potency of 3 drugs, apomorphine, N-propylnorapomorphine, and bromocryptine, have been found to be closely correlated to their potencies in competing for 3H-haloperidol and 3H-spiroperidol both of which label the dopamine receptor. This correlation indicates that the direct binding assay may be used to predict clinical potencies of anti-parkinsonian drugs, and indicates that agonists as well as antagonists compete potently for 3H-neuroleptic binding.

Mesulergine, an 8-alpha-aminoergoline, is now proven to be of utility in the clinic as an antiparkinsonian drug. However, the molecule itself shows in vitro and in vivo antidopaminergic properties. Mesulergine is rapidly metabolized into several pharmacologically active DA agonists. The influence of mesulergine on central DA metabolism in rats is dependent on the route of drug administration. It was possible to determine the different metabolites of this drug in plasma as well as in rat striatum. A correlation between the actual present concentration of the parent drug and DAergic metabolites and the net action on striatal DA metabolism was found. It may be concluded that mesulergine itself lacks DAergic activity but occupies DA receptors and is very rapidly metabolized into potent DA agonists.

Studies on the effect of budipine in Parkinson’s disease were started in 1976 (Brandt and Oppel 1979; Oppel and Umbach 1977). We have investigated budipine’s influence on akinesia and tremor in akinesia tests, pulmonary function tests, and by quantitative tremor measurements (Oppel and Umbach 1977). Budipine was administered in combination with other antiparkinsonian drugs. The major result fo these tests was that budipine had an outstanding effect on tremor, whereas the effect on akinesia was not significant.

Administration of antiparkinsonian drugs in humans is often succeeded by a complex pattern of mental, motor, and vegetative effects. To elucidate these interactions, reliable and objective multidimensional approaches to different physiologic subsystems are required (Meyer-Delius and Schaffler 1975; Schaffler et al. 1975). An outstanding aspect of ambulant treatment with such drugs is possible impairment of vigilance, motor systems, and performance, because of their importance for everyday life, working and car driving.

Neurological examinations of 27 outpatients receiving lithium carbonate maintenance therapy for recurrent affective illness revealed that most of the patients receiving lithium for more than 8 months had cogwheel rigidity. The data suggest a positive correlation between the duration of lithium maintenance and the severity of cogwheeling. Intravenous administration of benztropine, an antiparkinsonian drug, did not abolish or significantly ameliorate this symptom.

The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml X min-1 X kg-1 and 24 l X kg-1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.

Budipine is a new antiparkinsonian drug which has been shown to ameliorate the major parkinsonian symptoms such as tremor, akinesia, and rigidity. It may have some influence on dopamine release and uptake and may also possess anticholinergic properties and exert definite stimulatory effects on the serotonergic receptors (Menge and Brand 1982).

It has recently been found that tremor in patients on long-term lithium therapy has a lower frequency than that of normal physiological tremor and is likely to have an extrapyramidal component (Tyrer et al, 1981). Other extrapyramidal signs and symptoms have been found with chronic lithium therapy (Shopsin and Gershon, 1975; Baastrup et al, 1976; Branchey et al, 1976; Asnis et al, 1979). These extrapyramidal effects differ from the pseudoparkinsonism produced by antipsychotic drugs in that they do not respond to antiparkinsonian drug treatment (Schou, 1970; Tyrer et al, 1980).

To the Editor.— In the recent article, "Myoclonus in Familial Restless Legs Syndrome" ( Arch Neurol 33:368, 1976), Boghen and Peyronnard refer to symptoms including an unpleasant sensation in the legs and an associated urge to move them, occurring at rest and relieved by walking. I wish to point out the similarity between the clinical manifestations of the familial restlesslegs syndrome and those of phenothiazineinduced akathisia. The latter is characterized by an inability to sit still, intolerance of inactivity, continuous agitation and restless movement, rocking and shifting of weight while standing, and shifting of legs and tapping of feet while sitting. 1 The use of antiparkinsonian drugs has been recommended in the treatment of phenothiazineinduced akathisia. 2 A trial of an antiparkinsonian drug, such as procyclidine, in the treatment of familial restless legs syndrome might be worthwhile.