the introduction of dihydroxyphenylalanine ( levodopa ) to the treatment of pd was a major scientific and clinical breakthrough in the treatment of this devastating disease .
second , comes the realization that an understanding of biochemical deficits can provide a clue as to how replacement , therapy could be successfully employed in neurodegenerative diseases , providing significant symptomatic benefit , if not a cure .
dopa had an enormous impact on attempts to treat other neurodegenerative disorders , particularly ad .
unfortunately , in spite of miraculous effects on patients with early and advanced pd and the motor benefits afforded to them , it soon became clear that dopa does not slow the neurodegenerative process and its effects are purely symptomatic .
consequently , the dopa dose required to control the motor manifestations must , be gradually increased as the disease progresses .
it quickly became clear also that , of the two dopa isomers , only the levorotatory stereoisomer , levodopa , produced therapeutic benefits , and chemical means to separate the two isomers were developed . in practice , only levodopa is now used in the treatment of pd , resulting in an improved safety profile . soon after came the recognition that some of the adverse effects associated with the drug were the result of peripheral - rather than central - conversion of levodopa into da , which , unlike levodopa , has significant autonomic activity .
since da does not cross the blood - brain barrier ( bbb ) , any da produced in the peripheral nervous system docs not contribute to the clinical benefits afforded by levodopa , and actually causes significant , adverse events , particularly gastrointestinal and other autonomic disturbances . the enzyme involved in the transformation of levodopa to da , ie ,
l - amino acid decarboxylase ( l - aad , initially called dopa decarboxylase ) is widespread in the body , with high concentrations in the liver .
two agents were developed that could inhibit , it , and both are still in use : carbidopa and benserazide . at .
present , practically all patients who require treatment with levodopa receive it as a fixed - dose combination with one of these inhibitors . of course , it is essential that levodopa be converted into da in the brain , and so the l - aad inhibitor should not cross the bbb .
the inhibition of peripheral l - aad has another result , which was initially unappreciated : it prolongs the biological half - life of levodopa ( and therefore also of da in the brain ) .
early on in pd , there is a dramatic beneficial effect of levodopa , described as the  honeymoon . 
as the disease advances and additional da neurons arc being lost , there is a need to compensate for this by increasing the daily dose of levodopa .
this is first , manifested by shortening of the duration of action of individual levodopa doses , called  end - of dose  effect or wearing off .
later on , other manifestations appear , including  peak of dose  dyskinesias and erratic responses to levodopa ( so - called unexpected  on - off ,  or yo - yoing ) ( table i ) . while the exact mechanism responsible for this erratic response is still elusive , it is at least partly dependent upon pharmacokinetic factors such as plasma levels of levodopa . in particular , the phenomenon of wearing off , where the initial prolonged response to individual doses of levodopa is no longer maintained , limits the patients ' independence .
wearing off probably results from impaired capacity of the nigrostriatal da neurons and their terminals to uptake , store , and release da .
blockade of peripheral l - aad , which prolongs the biological half - life of the drug , can only incompletely compensate for this .
gait instability ( late ) depression ( early or late ) cognitive decline ( early or late ) autonomic dysfunction ( mainly constipation ) nonmotor problems ( eg , dementia , autonomic dysfunction ) fluctuations and/or drug - induced complications short duration response : delayed or partial  on ,  wearing off , dyskinesias levodopa remains the  gold standard  of pd therapy .
however , several key symptoms of pd fail to respond to levodopa , or have a limited or unsatisfactory response ( table ii ) .
as discussed above , the long - term use of levodopa often leads to complications later in the disease ; wearing - off , dyskinesias , freezing episodes , and unpredictable  on - off  fluctuations are the most , problematic .
the pathogenesis and pathophysiology of these complications remain unclear , but it has been suggested that they are related to the toxicity of levodopa or its metabolites .
the pharmacokinetic and pharmacodynamic changes that take place as the disease progresses may be major contributors .
it has also been speculated that the complications may derive , at least in part , from the toxic effects of levodopa or da oxidative metabolites .
since levodopa alleviates the symptoms of the disease , accurate assessment of the patient 's real condition and monitoring of disease progression are problematic . at present ,
the only way to assess progression or deterioration is by withdrawing levodopa for a period exceeding 2 weeks .
obviously , this is not a practical solution particularly in the advanced stages of the disease and therefore our ability to monitor the rate of disease progression is limited .
positron emission tomography ( pet ) and single - photon emission computed tomography ( spect ) techniques are being developed and have shown significant correlations with global severity of pd . 

catechol - o - methyltransferase ( comt ) is a ubiquitous enzyme that breaks down levodopa before it can be converted to da , as well as da itself .
comt inhibitors prolong the availability of a single dose of levodopa , without , delaying the onset of its effects , frequently reducing the total amount , of levodopa needed .
the present , indication for comt inhibition is as an adjunctive therapy to levodopa in advanced pd patients who have developed wearing off or  on - off  fluctuations .
however , comt treatment in the earlier stages of pd may also be worthwhile by preventing or delaying motor complications .
comt inhibition as a new treatment , strategy for pd has been recently comprehensively reviewed . 
 
two comt inhibitors have been widely tested so far : tolcapone and entacapone . although motor fluctuations such as  off  periods are frequently reduced or eliminated by the use of tolcapone or entacapone , peak dose dyskinesias can be enhanced or precipitated , requiring a reduction in individual doses of levodopa .
tolcapone was recently removed from the market in most , countries due to presumed hepatic toxicity . however , the exact relationship to drug exposure is still ambiguous . on the basis of the rarity of these adverse events ,
some practitioners believe that its withdrawal was premature , arguing that the drug is possibly superior to entacapone ( although a direct comparison between the two has not been performed ) .
entacapone has a brief duration of action of approximately 2 h , ie , it has to be consumed with each levodopa dose ( or even more frequently ) .
preparations containing levodopa , entacapone , and a decarboxylase inhibitor in a single tablet or capsule could be beneficial , especially for patients who are treated with other drugs as well .
long - acting derivatives or sustained - release formulations of entacapone could also be advantageous .
da agonists ( daas ) have been an important tool in the treatment of pd for almost 40 years .
ttttc first , study of daas by calne et al constituted a milestone in pd therapy .
these drugs were introduced shortly after the discovery of levodopa and were initially thought to represent second- or even third - line agents .
ttttis was because they were effective in patients who had developed intolerance to - or side effects of - levodopa .
their initial use demonstrated not only their efficacy against rigidity and tremor , but also their dopa - sparing effects .
the possibility of reducing the dose of levodopa gradually became more important as the complications of chronic levodopa therapy were recognized , particularly dyskinesias and motor fluctuations .
the ability to replace some of the levodopa dose with a daa resulted in amelioration of these motor disturbances , also proving that they are not necessarily an unavoidable development in chronic pd .
attempts to use a daa as monotherapy in advanced cases of pd were deserted due to poor efficacy and the existence of side effects , while the trend toward using a daa as early therapy increased : by delaying the initiation of levodopa treatment , motor complications can be prevented .
several novel daas were tested and their utility was unquestionably demonstrated , although these studies proved that .
however , as the disease progresses , stronger da stimulation is required and , as increased daa dosages become limited by side effects , supplementation with levodopa becomes necessary , albeit again with the danger of the development of motor complications . 
 
although there is no doubt , that daas can be used initially as monotherapy , the number of patients in whom this treatment can be maintained over long periods remains unclear . according to available data
20% of patients , and in 50% after 5 years . 
  while the ergot derivatives are clearly efficacious in pd , their use has been complicated by several side effects .
it was realized that ergots are  dirty  drugs , with the potential to interact with several types of receptors in the central nervous system , as well as in the periphery .
the development , of the synthetic daas piribedil , ropinirole , and pramipexole was an important further step . however , these agents shared a number of side effects .
it thus became clear that , while pleuropulmonary fibrosis may be specific to ergot derivatives , most of the complications of these therapies are class effects .
the motor fluctuations that characterize prolonged levodopa therapy are thought ( but . not proven ) to be related to the short , plasma half - lives of individual levodopa doses ( t1/2=90 min).thc clinical benefit from individual doses is longer , at least , in early stages of the disease , due to the buffering capacity of surviving da neurons , which transform levodopa to da , store it , and then release it in a tonic , rather than phasic , pattern .
the fact that daas do not depend on da neurons is a theoretical advantage , particularly at advanced stages of the disease when very few da neurons survive .
however , this advantage is related to their longer duration of action , typically 4 to 6 hours ( and much longer for cabergoline ) . if the nonsustained level of da stimulation is responsible for the development of motor fluctuations , these complications should be significantly delayed if cabergoline is to be used in de novo cases .
several studies have suggested that daas have additional beneficial properties , such as antioxidant or antiapoptotic effects .
notably , all these studies were performed in vitro , and therefore had a very short duration and used doses with unclear relationship to the clinical situation .
there are no available data indicating that daas have relevant antioxidant or antiapoptotic effects in routine clinical use in humans , or indeed that oxidative stress plays a major role in the pathogenesis of pd.the early addition of a daa prevents ( or at .
least delays ) the appearance of motor complications , but . whether this should be regarded as a neuroprotective effect
furthermore , even if daa can slow the progressive loss of da neurons in the substantia nigra , it would be very difficult , to prove it .
if daas do slow the progression of pd , a possible mechanism could be stimulation of presynaptic da receptors .
probably all da terminals contain receptors that mediate the synthesis and release of da by negative feedback .
reduction in the rate of da synthesis can thus be expected to slow the ongoing damage to da neurons .
most ( and probably all ) daas reduce the rate da of synthesis , but there is limited information on their relative efficacy in this regard . theoretically , a drug with relatively strong presynaptic stimulation ( relative to postsynaptic d2 stimulation ) , such as talipexole , should be preferred , although it is difficult to see how that advantage can be demonstrated in pd patients .
currently used daas include the  ergot - derived  or  ergoline  drugs bromocriptine , cabergoline , lisuride , and pergolide , with chemical structures based on ergot , a plant alkaloid . the newer ,  non - ergot  synthetic daa , piribedil , pramipexole , and ropinirole - chemically unrelated to ergot - are being promoted vigorously .
side effects typical of all daas ( as well as levodopa ) include nausea , vomiting , dizziness , and orthostatic hypotension . at higher doses
, daas may induce confusion , hallucinations , and psychosis , although these usually appear in the advanced stages of the disea.se .
sedation and insomnia are other reported side effects of some daas , as well as of levodopa , and are probably not associated with any specific agonist .
attention has recently been drawn to somnolence as a possible adverse effect of daas ( including levodopa ) .
events of a compelling urge to sleep ( so - called  sleep attacks  ) have been observed in patients treated with daas .
this needs to be considered and explained to the patient , particularly if he or she is involved in activity in which the somnolence , even if not excessive , could endanger them or others .
some of the side effects specifically linked to the ergot derivatives include digital or coronary vasospasm , as well as pleuropulmonary and retroperitoneal fibrosis .
these are not associated with the newer and safer non - ergot daas piribedil , ropinirole , and pramipexole . 
 
it has been found to reduce daily levodopa doses by 30% in a multicenter phase 2b trial in mild - to - severe pd .
apomorphine is the most , potent daa , and the only one that stimulates effectively both da d1 and d2 receptors ( as does da itself ) .
however , its therapeutic effect is hampered by its complex interindividual pharmaco - kinetics and pharmacodynamic variability and its narrow therapeutic range .
subcutaneous injections are very helpful , particularly for patients with prolonged  off  episodes .
is technically complex to use and expensive . in order to overcome these difficulties , several attempts to create individualized controlled delivery systems for apomorphine
in a recent study , a carboxymethyl cellulose powder of apomorphine was tested as intranasal sustained - release formulation .
these newer delivery systems will hopefully enhance its use as a rescue medication in severe cases .
there are at least , five types of da receptors , namely d1 , d2 , d3 , d4 , and d5 .
the role of d1 stimulation in the therapy of movement disorders , and particularly pd , has been debated for years .
bromocriptine is a d1 antagonist , pergolide a d1 agonist , while ropinirole and pramipexole do not interact with d1 receptors at all .
since all these daas have similar efficacy in pd , the role of d1 receptors in pd therapy is questionable .
however recent , reports suggest that the specific drstimulating drug , abt-431 , is also effective in pd .
thus , there arc several remaining issues in daa therapy ( table iii ) . 

the efficacy of selegiline in the treatment , of pd is based on the assumption that inhibition of the monoamine oxidase b ( maob ) enzyme may prevent .
da neurotoxicity . the extensive datatop ( deprenyl and tocopherol antioxidative therapy of parkinsonism ) study demonstrated the safety and beneficial symptomatic effects of selegiline in early pd , but
it is possible that at higher therapeutic doses , maob inhibitors will not only ameliorate disease symptoms , but .
could also provide neuroprotection , which has been demonstrated in vitro with equivalent drug concentrations .
a new formulation of selegiline dissolves instantly in the mouth , eliminating the first - pass effect , in the liver , so that therapeutic levels are reached at an eighth of the daily regular dose of selegiline .
tms reduces the concentrations of amphetamine , the unwanted metabolite of selegiline , which otherwise limits the maximal tolerated dose .
rasagiline , another maob inhibitor , is presently being evaluated in clinical trials in the usa , europe , and israel . at .
doses up to 2 mg / day , rasagiline shows good safety and tolerability . it has a similar pharmacological profile to selegiline , but without amphetamine as a metabolite .
amantadine has been used for the treatment of pd for several decades , even though its mechanism of action is obscure .
recently , it was shown to function by inhibiting n - methyl - d - aspartate ( nmda ) receptors and found to be effective in reducing dyskinesias .
mcmantinc , a related drug , also functions as a neuroprotective agent through this mechanism .
memantine is used in germany as an antispastic drug and also to treat dementia , and is presently being evaluated for its effectiveness in pd , on the basis of preliminary results .
the antiglutamatergic effect of amantadine and memantine also suggests a neuroprotective action , and memantine is now actively promoted in ad .
although motor symptoms are the cardinal features of pd , most if not all patients will also manifest symptoms in other spheres . depression is particularly common and frequently antedates the motor disorder .
clinical experience shows that tricyclic antidepressants and selective serotonin reuptake inhibitors are very efficacious in this condition , with a dose and adverse event , profile similar to that of other patients .
amitriptyline , which has a marked antimuscarinic action , may adversely affect the constipation , while reducing the severity of parkinsonian tremor .
cognitive deterioration in pd may start , even before motor symptoms appear ( and is then trcndily termed
 dementia with lewy bodies  ) , but more frequently characterizes the advanced stages of the disease .
it is therefore not surprising that treatment with acetylcholinesterase inhibitors is effective in demented patients with pd .
delusions and hallucinations , usually visual , are frequent in advanced pd , particularly in demented patients .
obviously , classical neuroleptics can not be used since by blocking da receptors the parkinsonian symptoms would be exacerbated .
clozapine in particular is helpful in this situation , though its side effects and particularly the need for hematological monitoring are disadvantageous .
ouetiapine may be as useful , but other socalled  atypical neuroleptics ,  and particularly olanzapine , are quite likely to induce motor exacerbation .
the most significant , of all is constipation , which commonly antedates the diagnosis and is frequently exacerbated by the antiparkinsonian drugs .
clinical experience again suggests that , the usual therapies ( eg , sildenafil for penile erectile dysfunction ) arc useful .
the management of pd is quite easy at the initial stages of the disease , where all dopaminomimetic drugs , as well as amantadine or selegiline ( or an antimuscarinic agent if tremor is the main problem ) , can be very efficacious .
as the disease advances , however , the motor complications become increasingly more severe and difficult to control , and require expertise and individual tailoring . at this stage , it is sometimes necessary to resort to functional neurosurgery . unfortunately , no drugs are yet available that slow the rate of progression of pd . the initial therapy for the motor symptoms should constitute a daa , which all have similar efficacy , though non - ergot daas arc probably safer . as the disease progresses and these agents become insufficient , levodopa can be added .
there is no clear role for selegiline and amantadine . in spite of the fact that these drugs are definitely effective and relatively safe
 parkinson 's disease ( pd ) is a common neurodegenerative disease . 
 while its cause remains elusive , much progress has been made regarding its treatment . 
 available drugs have a good symptomatic effect , but none has yet been shown to slow the progression of the disease in humans . 
 the most efficacious drug is levodopa , but it remains unclear whether the symptomatic benefit is associated with neurotoxic effects and long - term deterioration . the long - term problem associated with levodopa is the appearance of dyskinesias , which is significantly delayed among patients treated with dopamine agonists as initial therapy . 
 less clear is the role of other drugs in pd , such as monoamine oxidase inhibitors ( maois ) , including selegiline and rasagiline , the putative n - meihyl - o - aspartaie ( nmda ) receptor antagonists amantadine and memantine , and the muscarinic receptor blockers . 
 all these may be used as initial therapy and delay the use of dopaminergic drugs , or can be added later to reduce specific symptoms ( tremor or dyskinesias ) . 
 advanced pd is frequently associated with cognitive decline . to some extent , this can be helped by treatment with cholinesterase inhibitors such as rivastigmine . 
 similarly , hallucinations and delusions affect pd patients in the advanced stages of their disease . 
 the use of classical neuroleptic drugs in these patients is contraindicated because of their extrapyramidal effects , but atypical drugs , and particularly clozapine , are very helpful . 
 the big void in the therapy of pd lies in the more advanced stages . 
 several motor symptoms , like postural instability , dysphagia , and dysphonia , as well as dyskinesias , are poorly controlled by existing drugs . 
 new therapies should also be developed against autonomic symptoms , particularly constipation . 
Levodopa
COMT inhibitors
DA agonists
Other drugs
Treatment of nonparkinsonian symptoms
Conclusion