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Drug holiday and management of Parkinson disease

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Abstract

Chronic treatment of parkinsonism with levodopa or levodopa/carbidopa is associated with problems that include dyskinesia, on-off phenomena, hallucinosis, and possible loss of therapeutic efficacy. We studied the effects of a period of transient drug withdrawal (drug holiday) in 16 patients who manifested these complications of chronic levodopa therapy. Patients were evaluated daily before, during, and after the period of drug withdrawal. Eleven of the 16 patients exhibited enhanced motor responsiveness after the holiday and required only half of the initial daily dose for improved motor performance. Most levodopa-induced side effects decreased after the holiday. Hallucinosis was ameliorated in all cases. The frequency of on-off phenomena and myoclonus also diminished. Sensitivity to levodopa-induced dyskinesia was not affected by the drug holiday. Because most patients required lower dosage after the holiday, dyskinesias were no longer present. These observations suggest that parkinsonian patients who suffer complications of chronic levodopa therapy may benefit from a period of drug withdrawal.

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... The results appeared to support the idea of dopamine receptor resensitization upon reduction of levodopa dosage. LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES Weiner et al. (1980) reported on the short term effects of a period of transient complete drug withdrawal, i.e. drug holiday, in 16 patients who manifested severe complications of chronic levodopa therapy. Eleven of the 16 patients exhibited enhanced motor responsiveness after the holiday and required only half of the initial dose for improved motor performance. ...
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... "Drug holiday" in which all anti-PD drugs were discontinued for up to 2 weeks; [23][24][25][26][27] 3. ...
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... "Drug holiday" in which all anti-PD drugs were discontinued for up to 2 weeks; [23][24][25][26][27] 3. ...
... Drug holidays have demonstrated to improve psychosis, and some patients sustained a hallucination-free state for <12 months [25][26][27]. However, these holidays have their set of restrictions and are considered to be physically and psychologically debilitating [22,24,32]. ...
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Chapter
After more than a decade levodopa (combined with a peripheral decarboxylase inhibitor) remains the standard treatment for Parkinson’s disease (PD) with up to 90% of patients responding. However, levodopa does not halt the advance of the underlying disease, but by improving mobility, it delays the onset of fatal complications (Marsden and Parkes, 1977; Yahr et al., 1972). Thus, after 2–5 years many PD patients have increased disability. The increased disability may manifest itself by the reappearance of old symptoms, i.e., symptoms present before levodopa treatment, or by new symptoms, symptoms not present before levodopa treatment. Most of the new symptoms are disease manifestations seen only because patients live longer (postural instability, dementia), and some of the symptoms may result from the chronic effects of levodopa itself (dyskinesias, diurnal oscillations in performance).
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Acute administration of neuroleptic drugs causes blockade of cerebral dopamine receptors. It has been discovered that chronic administration of neuroleptic drugs may have different effects on cerebral dopamine systems. Initial antagonism of dopamine mediated behaviour, such as stereotypy, disappears and may be replaced by supersensitivity to dopamine agonists. Changes also occur in biochemical indices of dopamine receptors, such as in the number and affinity of specific binding sites identified by 3H-ligands labelling D-2 receptors, and in dopamine-stimulated adenylate cyclase activity. All these changes occur obviously in the striatum in response to chronic administration of a range of neuroleptic drugs. Lesser changes take place in the mesolimbic dopamine system. What happens in the mesocortical dopamine pathways is unknown. The consequence of such adaptive responses to chronic neuroleptic therapy may be of importance to understanding of tardive dyskinesia and schizophrenia.
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This article reviews the side-effects of levodopa therapy in Parkinson's disease. First the pharmacokinetic aspects of levodopa are dealt with. Then the side-effects are successively discussed. Finally the therapeutic possibilities for the side-effects will be covered. An attempt has been made to give both proponents and opponents of a certain therapy their due to make it clear to the reader that for the time being uniform therapeutic recommendations are not always possible. The typical characteristics and circumstances of every individual patient should be considered before any advice can be given.
Article
Administration of drugs that reduce the influence of dopamine at its receptor site can lead to postsynaptic supersensitivity, whereas treatment with dopamine (DA) agonists can cause postsynaptic subsensitivity. Both unaltered and enhanced postsynaptic responses to DA have been shown after pretreatment with DA agonists. In the present manuscript pretreatment with apomorphine, a dopaminergic agonist, is shown to induce either increased or reduced locomotor activity. When a drug-free period between successive injections was allowed, apomorphine induced an enhanced locomotor response, whereas a reduced response occurred when each dose was injected before the previous apomorphine dose had been completely metabolized. Pretreatment with both high (1 and 3 mg/kg) and low (0.05 mg/kg) apomorphine doses enhanced the response. Apomorphine treatment that caused enhanced locomotor responses did not modify the stereotypy response to the drug. Similar enhanced or reduced response were found in rats with partial lesions of the nigrostriatal system. These altered responses to DA agonists may have important clinical consequences. The present data also suggest the existence of a different DA systems for locomotor and stereotypy actions of dopaminergic agonists.
Article
The contribution of the peripheral and central pharmacokinetic mechanisms of levodopa to the pathogenesis of the motor fluctuations that complicate its long-term administration was studied in 28 parkinsonian patients. The rate of levodopa clearance from the general circulation, its plasma half-life, and apparent volume of distribution were indistinguishable between patients with the on-off or the wearing-off phenomenon and those with a stable response to levodopa or those who had not been previously treated with levodopa. Peripheral pharmacokinetic factors are thus unlikely to account for the development of these response fluctuations. Conversely, the efficacy half-time of levodopa differed markedly among the four response groups studied and may provide a quantitative index of central mechanisms that favor the development of the wearing-off and on-off phenomena. Although symptom duration was the best predictor of the severity of untreated parkinsonism, levodopa dose correlated best with response half-time. The wearing-off phenomenon may primarily reflect the loss of buffering capacity caused by degeneration of the dopamine neurons, while the development of the on-off phenomenon appears to require additional postsynaptic changes, possibly at the receptor level.
Article
The duration of the antiparkinsonian action of levodopa was studied in 48 patients with various response patterns to the oral administration of the dopamine precursor. Deterioration in motor scores after abrupt cessation of a steady-state intravenous levodopa infusion occurred at two successive rates: an initial rapid phase followed by a terminal slower phase. Efficacy half-time decreased and initial efficacy decay slope increased with progression of levodopa response groups from never treated to stable responders, and then to fluctuating responders of the wearing-off type and finally of the on-off type. Efficacy half-time exceeded plasma levodopa half-life in the 2 nonfluctuating groups, approximated it in those patients with wearing-off responses, and was significantly shorter in patients with fluctuations of the on-off type. The half-times for the decline in antiparkinsonian efficacy and dyskinesia severity differed significantly, suggesting different pharmacological mechanisms. Motor fluctuation severity correlated best with initial efficacy decay slope, and both were best predicted by parkinsonian symptom severity. The dyskinesia decay rate correlated most closely with levodopa dose. These results support the view that progressive dopamine neuron degeneration reduces the brain's ability to buffer shifts in levodopa availability attending its periodic oral administration; the clinical result is wearing-off phenomenon. The on-off phenomenon as well as dyskinesia apparently reflects additional secondary changes related to levodopa therapy and occurring postsynaptically.
Article
D2 dopamine receptor densities were measured in postmortem samples of the caudate nucleus and putamen from 36 parkinsonian patients. The relationship between the age of the patient, duration of the disease, and duration of L-dopa therapy versus density of brain D2 dopamine receptors was examined using [3H]spiperone. Receptor density in parkinsonian tissues was constant over the age range of 56 to 90 years, as was the case for control tissues. Density did not change with duration of disease up to 24 years. Treatment with L-dopa did not cause progressive reduction in receptor density. The diminished clinical response in the final stages of Parkinson's disease is not due to receptor dropout, and must depend on other factors.
Article
Visual hallucinations are a well recognized unwanted effect of treatment with levodopa. Although many individual cases have been reported, there has only been one review previously published about this finding, and this did not discriminate age groups. We present five cases and briefly review the literature. It is important to enquire specifically about visual hallucinations in patients on levodopa therapy at follow up, as this otherwise potentially reversible side effect may be overlooked.
Article
This chapter discusses the interplay between the laboratory and the clinic in analyzing the biological bases of parkinsonism arid formulating a rational approach to its treatment. There is a discussion regarding the syndrome, its accompanying neuropathology, and the current modes of treatments. Two animal models of parkinsonism are reviewed. Models involving 6HDA and MPTP represent a considerable advantage over previous pharmacological and surgical models of parkinsonism. Lesions can be made that are neurochemically specific; they can be restricted to the brain or even to individual dopamine (DA) projections; and they are permanent. Most important, they result in a collection of neurological impairments that parallel the clinical syndrome to a remarkable degree. Destruction of the nigrostriatal bundle (NSB) in adult animals produces akinesia, rigidity, and sensory neglect, large lesions are required before these neurological deficits occur, such deficits do not occur when comparable lesions are made in very young animals. Instead, a quite different syndrome emerges and after exposure to stressors, adult preclinical animals with moderate DA depletions show behavioral dysfunctions that are similar to those seen after more extensive lesions.
Article
We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30 MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
1. Normally during walking, the heel strikes the ground before the forefoot. Abnormalities of foot strike in idiopathic Parkinson's disease may be amenable to therapy: objective measurements may reveal response which is not clinically apparent. Occult changes in foot strike leading to instability may parallel the normal, age-related loss of striatal dopamine. 2. The nature of foot strike was studied using pedobarography in 160 healthy volunteers, aged 15 to 91 years. Although 16% of strikes were made simultaneously by heel and forefoot, there were no instances of the forefoot preceding the heel. No significant effect of age on an index of normality of foot strikes was detected (P greater than 0.3). 3. The effect on foot strike of substituting placebo for a morning dose of a levodopa/carbidopa combination was studied in a double-blind, cross-over trial in 14 patients, aged 64 to 88 years, with no overt fluctuations in control of their idiopathic Parkinson's disease in relation to dosing. On placebo treatment there was a highly significant (P = 0.004) reduction in the number of more normal strikes, i.e. heel strikes plus simultaneous heel and forefoot strikes. The effect appeared unrelated to the corresponding difference between active and placebo treatments in plasma concentration of levodopa or a metabolite of long half-time, 3-O-methyldopa (3OMD). However, it correlated negatively (P less than 0.05) with the mean of the 3OMD concentrations. 4. It appears that some abnormalities of foot strike due to Parkinson's disease are reversible. Employing test conditions, designed to provoke abnormalities of foot strike, might be useful in screening for pre-clinical Parkinson's disease.
Article
Patients with rare diseases are a major challenge for healthcare systems. These patients face three major obstacles: late diagnosis and misdiagnosis, lack of proper response to therapies, and absence of valid monitoring tools. We reviewed the relevant literature on first-generation artificial intelligence (AI) algorithms which were designed to improve the management of chronic diseases. The shortage of big data resources and the inability to provide patients with clinical value limit the use of these AI platforms by patients and physicians. In the present study, we reviewed the relevant literature on the obstacles encountered in the management of patients with rare diseases. Examples of currently available AI platforms are presented. The use of second-generation AI-based systems that are patient-tailored is presented. The system provides a means for early diagnosis and a method for improving the response to therapies based on clinically meaningful outcome parameters. The system may offer a patient-tailored monitoring tool that is based on parameters that are relevant to patients and caregivers and provides a clinically meaningful tool for follow-up. The system can provide an inclusive solution for patients with rare diseases and ensures adherence based on clinical responses. It has the potential advantage of not being dependent on large datasets and is a dynamic system that adapts to ongoing changes in patients’ disease and response to therapy.
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We sought to determine if tolerance developed to the antiparkinsonian effects of apomorphine and, if so, what temporal factors influenced its development. Seven patients with parkinsonism and motor fluctuations received short (6-hour) and long (22- to 31-hour) apomorphine infusions. Tolerance was evaluated by comparison of the responses to test doses of apomorphine that were administered before and after each infusion. The responses to the test doses that followed either infusion were reduced by 35% after the short infusion and by 68% after the long infusion, although plasma apomorphine levels were similar to or higher than levels achieved with preinfusion test doses. The duration of improvement in parkinsonism after discontinuation of the long infusion was briefer than that after the short infusion. We conclude that tolerance to apomorphine occurs in parkinsonism, and the loss of response is greater after longer periods of drug administration.
Article
Levodopa-induced dyskinesias are a common complication of chronic dopaminergic therapy in patients with Parkinson's disease (PD). The overall prevalence of levodopa-induced dyskinesias ranges from 40%-90% and is related to the underlying disease process, pharmacologic factors, and to the duration of high dose levodopa therapy. The mechanisms underlying the emergence of levodopa-induced dyskinesias are unknown, although most investigators favor the theory that striatal dopamine receptor supersensitivity is directly responsible for the development of these abnormal movements. In laboratory animals, the pineal hormone melatonin has been shown to regulate striatal dopaminergic activity and block levodopa-induced dyskinesias (Cotzias et al., 1971). Since the pineal gland is known to be a magnetosensitive organ and as application of external magnetic fields has been shown to alter melatonin secretion, we studied the effects of application of external artificial weak magnetic fields in a Parkinsonian patient with severe levodopa-induced dyskinesias ("on-off"). Application of weak magnetic fields with a frequency of 2 Hz and intensity of 7.5 picotesla (pT) for a 6 minute period resulted in a rapid and dramatic attenuation of Parkinsonian disability and an almost complete resolution of the dyskinesias. This effect persisted for about 72 hours after which the patient regressed to his pretreatment state. To ascertain if the responses elicited in the laboratory were reproducible, the patient was instructed to apply magnetic fields of the same characteristics daily at home. These subsequent treatments paralleled the initial response with a sustained improvement being maintained during an observation period lasting at least one month. This case demonstrates the efficacy of weak magnetic fields in the treatment of Parkinsonism and motor complications of chronic levodopa therapy.
Article
In the present investigations continuous intraduodenal infusion of levodopa has been given to patients with advanced Parkinson's disease during 6 months (seven patients) and 2.5 years (two patients). The plasma concentration and the effects on motility have been studied at the start, at 3 and 6 months and after 2.5 years. The individually titrated steady state plasma concentrations (Css) for satisfactory mobility was found to be decreased by the time, and already after 1 month of intraduodenal infusion Css was decreased by about 50%. The obtained data indicate an increased sensitivity with time to levodopa, interpreted as a consequence of disappearing tolerance by the controlled drug delivery. Blood pressure and heart rate were studied in spontaneous hypertensive rats during continuous administration of l-propranolol. A maximum reduction in heart rate of about 20% was seen, but no tolerance was observed. All animals showed, however, rebound effects that were at a maximum 3 days after drug withdrawal. Different PK/PD models have been fitted to the data and an indirect effect model seems to be the most appropriate.
Article
Local cerebral blood flow (CBF) in the steady state and after intravenous administration of levodopa (1 mg/kg) was measured by xenon-enhanced computed tomography in patients with Parkinson's disease (PD, n = 16), progressive supranuclear palsy (PSP, n = 6), olivopontocerebellar atrophy (OPCA, n = 5), and arteriosclerotic parkinsonism (AP, n = 7). Three patterns of local CBF changes following levodopa were observed: (1) diffuse CBF increases, especially in striatum and thalamus, as found in patients with PD; (2) no significant changes in CBF, as in patients with OPCA and AP; and (3) CBF reductions in basal ganglia and thalamus, as seen in patients with PSP. The CBF increases after levodopa in PD may be secondary to metabolic activation of the nigrostriatal dopaminergic system. The poor CBF responses in patients with OPCA, AP, and PSP appeared to reflect degeneration of the dopamincrgic neurons and dopamine receptors to various degrees. The CBF increases, especially in striatum and thalamus, tended to be greater (not significant) among responders to oral levodopa therapy. Levodopa-induced CBF measurements may be useful for the differential diagnosis of parkinsonian syndromes of various etiologies, but are not necessarily sufficient for predicting outcomes of long-term levodopa therapy.
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Most reviews of the psychiatric problems seen during the chronic therapy of parkinsonism have focused primarily on nonaffective psychosis and related disorders. This chapter will include both these disorders and alterations in affect or mood.
Article
The role of levodopa in the treatment of dysphagia in Parkinson's disease (PD) has recently been questioned. There are good reasons, however, to "question the question." In this essay, evidence from published literature and clinical experience is presented, as well as a critical review of the first meta-analysis to explore this issue. The evidence presented supports the traditional view that PD dysphagia is responsive to levodopa.
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A 62-year-old man with a 6-year history of Parkinson’s disease, treated with Sinemet 25/250 mg b.i.d. and Amantadine 100 mg. b.i.d., was brought to the ER by Emergency Services personnel. The patient’s family had become alarmed when he did not answer the telephone that morning. They came to his home and found him on the floor, confused and unable to rise. It was estimated that the patient had been disabled for a period of 18–24 hours. On physical exam, the patient was a thin cachetic man, somewhat disoriented, displaying diffuse tremor, pinrolling movements, and stiff facial expresion. Blood pressure, supine, was recorded at 140/80, heart rate 90/min. Upon sitting, blood pressure was 90/60 and heart rate 116/min. The patient was also noted to have a marked deformity of the right hip which was extremely painful on attempted rotation. X-ray of the right hip revealed a fracture of the femur. Laboratory data was remarkable for a hematocrit of 47%, and BUN/ creat. of 41/1.3. Chest x-ray within normal limits. He was scheduled for open reduction and internal fixation of the right hip as soon as possible.
Article
Drug-induced psychosis represents one of the more serious adverse effects of therapy for Parkinson’s disease. Risk factors include dementia, a history of psychiatric illness, advancing age, and the dose and duration of treatment with dopamine-enhancing agents. The pathophysiological basis of drug-induced psychosis has not been established. Chronic changes in both the dopaminergic and serotonergic systems have been implicated in producing these symptoms. Management options include the reduction and/or elimination of medications used for symptomatic control of the illness. However, with the attendant risks of an unacceptable reduction in mobility and, in rare cases, life-threatening complications, therapeutic alternatives are required. Treatment with atypical antipsychotic agents, such as clozapine and risperidone, presents such an avenue. Nonpharmacological treatments, including electroconvulsive therapy (ECT), may also play a role in the management of these patients.
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Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DA D2 agonists and thus seem related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80-99% denervation, a persistent aberrant signal develops in D2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of l-dopa therapy reduced the aberrant D2 signal. With a high degree of denervation, l-dopa enhanced another aberrant signal, this time in the D1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models.
Chapter
Therapy with levodopa (LD), the amino acid precursor of dopamine (DA), has been the most successful pharmacologic strategy for improving parkinsonian disability. Since its introduction in the 1960s, LD continues to impress clinician and patient alike with its almost metaphysical prowess at “awakening” paralyzed movement, unlocking rigidity, and stilling the “cruel restlessness” of shaking in parkinsonism (Sacks 1983). The degree of improvement with LD can be so dramatic that some clinicians would regard this response as a diagnostic feature of Parkinson’s disease (PD). There are few other examples of symptomatic therapy for neurodegenerative disease as effectively targeted for the essential pathophysiology as is LD against PD. In the last two decades, use of LD has become so pervasive that it is virtually impossible to study the natural history of PD without the intervening factor of LD therapy.
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With the introduction of high dosage d,l-dopa therapy for Parkinson’s disease by Cotzias et al. (1967) only a few side effects were reported, namely gastrointestinal, faintness, and hematologic changes. The last appeared to be due to the presence of the dextrorotatory isomer of dopa since it has not been reported as a complication of subsequent treatment with the levorotatory form. In their next publication, using levodopa, Cotzias et al. (1969) now listed mental effects and involuntary movements, in addition to anorexia, nausea, and vomiting. The mental effects listed were irritability, anger, hostility, paranoia, insomnia, and an awakening effect. The dyskinesias were chorea, myoclonus, hemiballism (ipsilateral to the side of a prior thalamotomy), and dystonia. These adverse effects subsided with lowering of the dosage.
Chapter
For 15 years now, levodopa has been the most effective drug in the treatment of Parkinson’s disease, particularly in combination with a peripheral decarboxylase inhibitor. Administered in the presynaptic area, L-dopa restores the deficient dopaminergic activity by raising intraneuronal dopamine levels, but eventually loses its therapeutic efficacy as a result of progressive destruction of the dopaminergic neurons and hence reduced transformation of L-dopa into dopamine. Temporary insufficiencies of dopamine at the respective brain receptors lead to abnormal movements, oscillations in performance, occasional psychosis, and deficits in mental integrative function. In addition, a dopa-resistant state limits treatment efficacy. Dopamine agonists, i.e., drugs that bypass the degenerating nigrostriatal neurons and directly stimulate the striatal receptors, are considered a valuable alternative. Given in conjunction with L-dopa, the major advantage of these drugs lies in their ability to reduce the on-off effects as the duration of dose action is prolonged. However, the frequently inadequate therapeutic response derives from the fact that it is not possible to give sufficient doses of the drug because of side effects. The search for other drugs is thus desirable, particularly for the treatment of advanced Parkinson’s disease, where dopaminergic agents have already been in use for several years. The present 5-year study deals with the clinical effectiveness of budipine against advanced Parkinson’s disease, previously treated over a long period of time with L-dopa in combination with a decarboxylase inhibitor, which led to marked side effects, in particular, on-off phenomena.
Article
Clozapine may suppress levodopa-induced hallucinations and delusions, without significant worsening of Parkinsonism. A mild degree of drug-related dyskinesias usually does not require special treatment. For more severe dyskinesias 2 approaches can be taken. First, a reduction of the maintenance dose of levodopa until the severity of dyskinesias becomes mild enough to be tolerated. Secondly, the concomitant use of a selective dopamine D2 receptor antagonist, such as tiapride, if a reduction of levodopa dosage worsens Parkinsonism. However, tiapride may partially block the anti-Parkinsonian effects of levodopa. The most common adverse effects of other anti-Parkinsonian drugs are gastrointestinal [selegiline (deprenyl), dopamine agonists] and psychiatric (dopamine agonists, amantadine, anticholinergics) effects. Pleuropulmonary change and retroperitoneal fibrosis are rare complications of long term treatment with bromocriptine, and a controlled release formulation of the drug has been developed in an attempt to reduce the overall incidence of adverse effects. Because of their common adverse effects, anticholinergics should be used with care and are contraindicated in patients with narrow angle glaucoma and/or prostate hypertrophy with dysuria.
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Levodopa is a most effective but rather difficult therapeutic agent in the treatment of Parkinson's disease. Parkinson's disease is almost invariably progressive and no previous treatment, except in rare individual cases, has altered this course. Before levodopa became available, almost 90% of patients with primary parkinsonism (paralysis agitans) were either dead or seriously disabled after 16 yr, and in the mature adult it increased the chances of dying nearly 3 fold. In the present study, levodopa therapy for 5 yr in adequate doses in patients with primary parkinsonism was accompanied by a dramatic decrease (to 35%) in the proportion of patients dead or seriously disabled after 16 yr; and it appears to have increased life expectancy to normal range. In certain cases patients with Parkinson's disease have had only modest or transient response to levodopa; most of these appear to have one or more different pathological substrates and necessitate a redefinition of the parkinsonian syndrome. The high incidence of organic dementia and depression also requires a redefinition of the underlying processes in Parkinson's disease. While levodopa has also opened up many new approaches to basal ganglia physiology and pharmacology, it does not appear to be leading to the ultimate solution of Parkinson's disease. Other approaches are necessary to determine why the large pigmented cells in the substantia nigra, and certain other cells in the central nervous system, die prematurely.
Article
The degeneration of the substantia nigra that characterises Parkinson's disease may cause an alteration in sensitivity of striatal dopamine receptors. The development of denervation supersensitivity has been held to be responsible for some of the effects of chronic levodopa therapy. The rotating rodent is an animal model commonly used to study the phenomenon of striatal dopamine receptor supersensitivity, and to investigate drugs which may prove to be beneficial in the treatment of Parkinson's disease. We have investigated as to whether long-term oral administration of levodopa to mice with unilateral destruction of striatal dopaminergic nerve terminals influences dopaminergic receptor denervation supersensitivity as judged by the circling response following systemically administered levodopa. It does not do so and the relevance of these findings to the treatment of Parkinson's disease is discussed.