cinnarizine and Parkinson-Disease--Secondary

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.

Topics: Aged; Antipsychotic Agents; Calcium Channel Blockers; Cinnarizine; Dopamine Antagonists; Flunarizine; Humans; Parkinson Disease, Secondary; Parkinsonian Disorders; Prospective Studies; Syndrome

Aged people are frequently the victims of iatrogenic diseases, especially adverse effects of drugs since they are affected by many age-related diseases and are given many drugs. Geriatric medicine in Japan has a bitter history of having produced many victims by adverse effects of cerebral vasodilators and cerebral stimulants; they included parkinsonism and depression induced by flunarizine and cinnarizine, and Reye-like encephalopathy induced by calcium hopantenate. Parkinsonism induced by sulpiride, tiapride, metoclopramide or atypical anti-psychotics, dyskinesia induced by anti-parkinsonian drugs or anti-psychotics, and psychotic symptoms induced by anti-parkinsonian drugs, anti-cholinergic drugs, anti-depressants or histamine H2 antagonists are still very common. Wernicke encephalopathy caused by intravenous glucose infusion without thiamine, central pontine myelinolysis by too rapid correction of hyponatremia are important though infrequent. Iatrogenic Creutzfeldt-Jakob disease by dura grafts is a warning against the easy use of medical materials produced with human organs or blood. Iatrogenic diseases are preventable, and geriatricians have to pay attention to the information on adverse effects of drugs and medical materials and carefully observe the early signs of iatrogenic diseases.

Topics: Aged; Cinnarizine; Creutzfeldt-Jakob Syndrome; Flunarizine; Humans; Iatrogenic Disease; Medication Errors; Nervous System Diseases; Parkinson Disease, Secondary; Psychoses, Substance-Induced; Wernicke Encephalopathy

Drug-Induced Parkinsonism (DIP) represents the second leading cause of Parkinsonism (PK) in several countries. Flunarizine and cinnarizine are some of the most common drugs that cause DIP. This paper reviews the first description of Flunarizine and Cinnarizine-Induced Parkinsonism (FCIP), as well as the subsequent literature, emphasizing epidemiological, clinical and diagnostic aspects.. We reviewed the literature on the subject, with special emphasis on the first description and the later definition of the clinical syndrome that results from chronic use of flunarizine and cinnarizine.. In 1984, De Melo-Souza reported the first description of flunarizine-induced PK in five patients. Other reports followed on FCIP, emphasizing the clinical features, which are symmetrical parkinsonism, and depression, affecting mainly elderly women.. Eighteen years after the original description, FCIP is a recognized condition with specific clinical features, and is the second most common cause of parkinsonism in many countries.

Topics: Cinnarizine; Flunarizine; Humans; Parkinson Disease, Secondary

Topics: Anticonvulsants; Antipsychotic Agents; Calcium Channel Blockers; Cinnarizine; Diagnosis, Differential; Dopamine Antagonists; Humans; Metoclopramide; Parkinson Disease, Secondary; Valproic Acid

Parkinsonism is an extrapyramidal disorder characterised by tremor, muscle rigidity, bradykinesia and postural instability. The most common cause of parkinsonism is idiopathic Parkinson disease. Another common cause is drug-induced parkinsonism. Various drugs can cause parkinsonian symptoms. Many patients exhibiting these side-effects are mistakenly treated with dopaminergic medication. We present two patients with drug-induced parkinsonism induced by sodium valproate and cinnarizine, respectively. The symptoms disappeared after they stopped taking this medication.

Topics: Aged; Aged, 80 and over; Cinnarizine; Female; Humans; Parkinson Disease, Secondary; Valproic Acid

Topics: Antipsychotic Agents; Catalepsy; Cinnarizine; Drug Design; Flunarizine; Haloperidol; Humans; Parkinson Disease, Secondary; Structure-Activity Relationship; Vasodilator Agents

Topics: Calcium Channel Blockers; Cinnarizine; Humans; Parkinson Disease, Secondary; Time Factors

Cinnarizine (1-diphenylmethyl-4-(3-phenyl-2-propenyl)piperazine) and its di-fluorinated derivative flunarizine inhibit the MgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffin granule ghosts. The concentrations giving 50% inhibition (IC50) of the MgATP-dependent generation of the pH-gradient were 5.9+/-0.6 microM (n = 6) and 3.0+/-0.3 microM (n = 5) for cinnarizine and flunarizine, respectively. The IC50 values for inhibiting the generation of the membrane potential were even lower, i.e. 0.19+/-0.06 microM (n = 6) and 0.15+/-0.01 microM (n = 4) for cinnarizine and flunarizine, respectively. Cinnarizine (10 microM) also inhibited the energy-dependent vesicular uptake of [14C]-dopamine (50 microM) by 76%, i.e. from 2.1+/-0.9 to 0.5+/-0.6 nmol/mg protein/min (n = 5, P < 0.002). Cinnarizine (10 microM) increased the MgATPase activity of the granule ghosts by 47+/-26% (n = 4) compatible with an uncoupling of the vacuolar H+-ATPase activity. The IC50-values observed for the two compounds are in the same range as their reported therapeutic plasma concentrations in vivo, suggesting that cinnarizine and flunarizine may well inhibit proton pumping and catecholamine uptake in storage vesicles also in vivo. This mechanism of action may contribute to the drug-induced parkinsonism seen as a side-effect of the two drugs.

Topics: Animals; Cattle; Chromaffin Cells; Cinnarizine; Dopamine; Energy Metabolism; Flunarizine; Parkinson Disease, Secondary; Proton-Translocating ATPases; Synaptic Vesicles; Uncoupling Agents; Vacuoles

A retrospective study was carried out to investigate the evolution of patients diagnosed with cinnarizine-induced parkinsonism (CIP) over the past 15 years. A total of 74 cases of CIP were found among 172 patients with drug-induced parkinsonism (DIP). Both CIP and other DIP were significantly more frequent in women. No clinical differences between CIP and other DIP were found. Most of the patients (66 of 74) completely recovered after cinnarizine withdrawal in 1-16 months. Eleven patients later developed Parkinson's disease; four of them had previously recovered. Five patients had tardive dyskinesia. CIP accounts for a high proportion of DIP referred to neurologists in populations in which cinnarizine is widely prescribed. The symptoms typically resolve after drug withdrawal, although complete recovery may take more than 1 year.

Topics: Aged; Cinnarizine; Dizziness; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Long-Term Care; Male; Neurologic Examination; Parkinson Disease, Secondary; Retrospective Studies; Spain; Substance Withdrawal Syndrome; Vertebrobasilar Insufficiency

Drug-induced Parkinsonism (DIP) is the second commonest cause of Parkinson syndrome, after Parkinson disease (PD) and represents between 10% and 30% of all patients with Parkinsonism.. To study the frequency and drugs responsible for DIP and to compare some of the clinical characteristics of these patients and those with PD.. A retrospective community based study in Bajo Aragon district to determine the frequency of PD and other Parkinsonism, including DIP. PD was diagnosed on the criteria proposed by the United Kingdom Parkinson's Disease Society Brain Bank and DIP on the criteria of Jiménez et al.. Calcium antagonists were the cause of 73% of the DIP, followed by neuroleptic drugs (11.5%). There were 73% women (19/26). The patients with DIP were older than those with PD when their symptoms started (p = 0.02). In patients with DIP, 48% presented with bilateral symptoms as compared with 7% in PD (p < 0.0001).. 1. Cinarizine is the main drug responsible for DIP (58%) 2. As compared with patients with PD, patients with DIP are mainly women, older, more frequently have bilateral onset of symptoms and consult the doctor sooner.

Topics: Aged; Calcium Channel Blockers; Cinnarizine; Female; Humans; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary; Retrospective Studies

The aim of the present study is to investigate whether there are geographic differences in the etiology of parkinsonism (PA).. 72% of patients with PA evaluated at movement disorders clinics in the Northern Hemisphere are diagnosed with Parkinson's disease (PD). Data regarding other regions are not available.. We reviewed the charts of all patients with PA seen at the Federal University of Minas Gerais Movement Disorders Clinic from July 1993 through October 1995. PA was diagnosed by the presence of at least two of the following: rest tremor, bradykinesia, rigidity, and postural instability. The different etiologies were diagnosed based on standard clinical criteria.. During the period of the study, PA was recognized in 338 subjects. The following clinical diagnoses were made: PD (68.9%), drug-induced PA (DIP) (13.3%), vascular PA (4.7%), Progressive supranuclear palsy (PSP) (2%), multiple system atrophy (MSA) (1.8%), others (9.7%). Cinnarizine, haloperidol and flunarizine were the commonest drugs related to DIP.. Similarly to other studies, PD accounts for about 70% of PA patients. However, there are differences between our results and previous series. DIP is much more common in the present series. This may be accounted for a more liberal use of antidopaminergic drugs in our environment, especially Calcium channel blockers. The lower frequency of MSA and PSP in our study may reflect a short follow-up, since many patients initially diagnosed with PD later are found to have Parkinson-plus syndromes.

Topics: Aged; Anti-Dyskinesia Agents; Brazil; Calcium Channel Blockers; Cinnarizine; Female; Flunarizine; Haloperidol; Histamine H1 Antagonists; Humans; Male; Middle Aged; Parkinson Disease; Parkinson Disease, Secondary

The natural course of calcium-entry blocker-induced parkinsonism was evaluated in 13 elderly patients previously exposed to cinnarizine or flunarizine or both for a median period of 7 months. Clinical assessments were carried out before drug discontinuation and twice thereafter over a period lasting < or = 7 years. None of the patients showed a full recovery of extrapyramidal signs, indicating that the long-term prognosis of the parkinsonism is less benign than previously reported. Two main patterns of clinical outcome were recognized (i.e., "remittent" and "persistent and not progressive" parkinsonism), whereas the development of a progressive disorder was observed only in one patient. No significant correlation was found between the patterns of outcome and some clinical variables, such as total duration of exposure to cinnarizine and flunarizine, cumulative drug dosages, and age at onset of parkinsonism. There was no significant difference in terms of family history of essential tremor or parkinsonism or both among patients with the two main patterns of clinical course.

Topics: Aged; Calcium Channel Blockers; Cardiovascular Diseases; Cinnarizine; Dose-Response Relationship, Drug; Female; Flunarizine; Follow-Up Studies; Humans; Male; Middle Aged; Neurologic Examination; Parkinson Disease, Secondary; Treatment Outcome

To determine the prevalence, clinical signs and course of drug-induced Parkinsonism (DIP) in a general neurology practice, as well as to study the changing pattern of drugs implicated. Retrospective study of DIP patients seen between January 1981 and December 1993. Of the 306 cases of parkinsonism seen, 56.8% were induced or aggravated by drugs. This side effects is more frequent in women and often occurs in old age. The drugs implicated most often were cinnarizine, sulpiride and flupentixol. Forty-two patients took 2 drugs simultaneously, whereas 6 took 3. The number of DIP seen increased after 1986 and then remained stable through 1993. Between 1981 and 1988, the drug most often implicated was cinnarizine, though its relative impact decreased in later years. The most frequently seen form of presentation was rigidakinetic syndrome. Neither drug nor age influenced clinical presentation. Parkinsonism disappeared completely within a mean of 5 months in 142 (82%) patients. Twenty-eight (16%) developed Parkinson's disease. Six of them were symptom-free for 12 to 72 months (mean 40 months), whereas 22 never experienced relief from parkinsonism. Sixteen suffered tardive dyskinesia, a complication that was not associated with the use of any particular drug. More than half of the cases of parkinsonism seen in a neurology practice are drug induced or aggravated, generally by psychotropic drugs. The frequency has held steady for the past 6 years. The drugs implicated change as knowledge of their inducement of parkinsonism becomes known. The clinical picture is usually reversible.

Topics: Adult; Aged; Antiemetics; Antipsychotic Agents; Cinnarizine; Female; Flupenthixol; Follow-Up Studies; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Retrospective Studies; Sex Factors; Sulpiride

Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 mumol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'- hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout the experiments. The concentrations obtained after the 30 doses were in the order of FZ > F-2 > CZ > C-2 for the plasma and of F-2 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations of C-2 and F-2 were 2.4 and 3 times higher than those of the parent drugs. Binding affinities of CZ, FZ, and their 10 metabolites for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-met hoxy- 4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 < C-2 < FZ < CZ < C-4 << F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results suggest some important roles of C-2 and F-2 in the development of parkinsonism as active metabolites during chronic medication with CZ and FZ, respectively.

Topics: Animals; Benzamides; Calcium Channel Blockers; Chromatography, High Pressure Liquid; Cinnarizine; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Administration Schedule; Female; Flunarizine; Parkinson Disease, Secondary; Rats; Rats, Wistar; Receptors, Dopamine D2; Tritium

Cinnarizine and flunarizine are piperazine derivatives with calcium antagonist and anticonvulsant properties and are used widely in the treatment of vertigo and circulatory disorders. They have been implicated recently in the aggravation, or even the induction, of parkinsonism in elderly patients. Because the aetiology of parkinsonism has been suggested as having a mitochondrial component, we have investigated the effects of both compounds on mitochondrial respiration and on the activities of the individual respiratory chain complexes. In intact mitochondria from rat liver, both drugs inhibited respiration rates, with substrates entering at Complex I (glutamate/malate) and Complex II (succinate). These effects could be explained by potent inhibitions (Ki 3-10 microM) of both complexes. Complex I is inhibited at a site near the ubiquinone-binding site, which is not competitive with respect to ubiquinone, whereas the inhibition of Complex II is apparently caused by competition with ubiquinone. Furthermore, the inhibition of NADH oxidation by flunarizine in submitochondrial particles caused an NADH-dependent generation of superoxide. These inhibitory properties of both compounds could be significant factors in the aggravation or induction of parkinsonism in elderly patients, in whom mitochondrial function already may be impaired.

Topics: Animals; Cinnarizine; Electron Transport; Electron Transport Complex II; Flunarizine; Mitochondria, Heart; Mitochondria, Liver; Multienzyme Complexes; NAD(P)H Dehydrogenase (Quinone); Oxidoreductases; Parkinson Disease, Secondary; Rats; Submitochondrial Particles; Succinate Dehydrogenase

We describe the production of an experimental model of parkinsonism induced by cinnarizine (CNZ) in three healthy sylvanna monkeys. The drug produced a severe but reversible parkinsonism in all animals. After discontinuation of CNZ, all animals recovered but the oldest one was akinetic for 6 weeks. CNZ produced a persistent reduction in HVA and 5-HIAA levels in the CSF. Our data suggest a predominant presynaptic effect on DA and 5-HT neurons; and could account for the longstanding parkinsonism induced by calcium antagonist in some patients as well as the depression observed in these subjects.

Topics: Animals; Biogenic Monoamines; Cinnarizine; Disease Models, Animal; Dopamine; Haplorhini; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Movement Disorders; Parkinson Disease, Secondary; Tremor

The risk of developing drug-induced parkinsonism (DIP) has been related to a number of factors but it remains up to now poorly defined. The aim of this survey has been to evaluate retrospectively the possible role of inherited components in 25 patients with parkinsonism induced by chronic exposure to the calcium-entry blockers cinnarizine and flunarizine. The finding of higher occurrence of a positive family history for Parkinson's disease (PD) and/or essential tremor (ET) and of higher frequency of secondary cases with PD and/or ET among close relatives of the patients as compared to age-matched controls, suggests the involvement of genetic susceptibility in developing this drug-induced disorder. DIP could be regarded as a multifactorial disease process resulting from potential neurotoxicity of drugs on a background of inherited predisposition.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Cinnarizine; Disease Susceptibility; Female; Flunarizine; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Retrospective Studies; Risk Factors

Age at onset in 24 consecutive cinnarizine-induced parkinsonism (CIP) patients referred during a 2-year period was compared with 102 newly referred cases of Parkinson's disease (PD) examined during the same period. Not only did CIP onset occur at a greater age than PD (70.6 + 1.4 years versus 60.1 + 1.1 years), but the number of CIP cases increased steadily with age, whereas the incidence of PD patients peaked between the ages of 55 and 60 years, as is usually the case. At the time of referral, 62% of CIP cases and 14% of PD cases were over the age of 70, suggesting that advanced age was not a source of referral bias. A structured questionnaire prospectively given to 24 CIP patients revealed a history of tremor in at least one family member in 56% of the cases, whereas the incidence was much lower in 124 PD cases (17%) and 102 hospitalized nonneurological patients aged over 65 (6%). Moreover, three of the CIP patients themselves had a history of essential tremor previous to the onset of parkinsonism. CIP patients had frequently been exposed to the drug for years before developing any extrapyramidal symptoms (mean exposure, 4.1 +/- 4 years; range 4 months to 15 years). Though controlled epidemiological studies are needed to evaluate the possibility that cinnarizine is increasingly prescribed in the general population with advancing age, our data suggests that aging plus a background of genetically determined essential tremor represented critical risk factors for development of this drug side effect.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Cinnarizine; Female; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Prospective Studies; Risk Factors; Statistics as Topic; Tremor

Over the last few years, cases of movement disorders induced by flunarizine and cinnarizine have been increasingly reported. We describe a series of 101 patients, whose ages ranged from 37 to 84 years (mean 69.1), developing abnormal movements frequently associated with depression, secondary to treatment with either or both drugs. Symptoms closely resembled those induced by neuroleptic drugs and remitted on drug discontinuance in all but five cases after 5-22 months' follow-up. Whether or not such undesirable side effects are attributable to calcium antagonism and/or dopamine receptor blockade, long-term treatment with flunarizine or cinnarizine should be discouraged, particularly in the elderly.

Topics: Adult; Aged; Aged, 80 and over; Basal Ganglia Diseases; Cinnarizine; Depression; Dyskinesia, Drug-Induced; Dystonia; Female; Flunarizine; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Tremor

Topics: Adult; Aged; Cinnarizine; Depression; Female; Flunarizine; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Time Factors; Tremor

Topics: Animals; Caudate Nucleus; Cinnarizine; Dopamine; Flunarizine; Male; Nifedipine; Parkinson Disease, Secondary; Rats; Rats, Inbred Strains; Receptors, Dopamine

Cinnarizine and flunarizine are selective calcium blockers that have been used to treat and prevent vertigo. We studied 15 patients who had extrapyramidal syndromes after taking these drugs. Eleven patients had parkinsonism, one with persistent akathisia as well; one had an orofacial tremor; one, acute akathisia alone; and one an acute dystonic reaction. All but one improved when the drug therapy was discontinued. Seven patients were also depressed during treatment. Cinnarizine and flunarizine must therefore be added to the list of potentially risky drugs known to induce extrapyramidal reactions and depression.

Topics: Adult; Aged; Aged, 80 and over; Brain Diseases; Cinnarizine; Female; Flunarizine; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease, Secondary; Pyramidal Tracts

12 subjects, 8 women and 4 men, presented with extrapyramidal motor signs and psychic depression after treatment with flunarizine for between 3 weeks and 15 months. One woman presented with severe symptoms and 20 months after stopping flunarizine she still had dyskinesia and akathisia. The other patients showed partial or complete improvement after withdrawal of the drug.

Topics: Aged; Akathisia, Drug-Induced; Cinnarizine; Depressive Disorder; Dyskinesia, Drug-Induced; Female; Flunarizine; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Psychoses, Substance-Induced

Topics: Aged; Cinnarizine; Female; Humans; Male; Parkinson Disease, Secondary; Prolactin