NOVEL DRUGS FOR PARKINSON'S DISEASE

PARKINSON’S DISEASE AND PARKINSONIAN SYNDROMES

0025-7125/99 $8.00

+ .OO

NOVEL DRUGS FOR PARKINSON’S DISEASE Jean Pintar Hubble, MD

Therapeutic interventions can be divided into four broad classes:

symptomatic treatments, which simply reduce or mask signs and symptoms; protective therapies, which retard or halt the underlying pathologic processes; curative strategies, in which normal tissue function is restored; and preventive interventions, in which causative risk factors are identified and eliminated. These four types of interventions are intentionally listed in this order, starting with the most fundamental to the most advanced. Symptomatic remedies represent the minimum in therapeutic success, whereas disease prevention is the therapeutic ideal. The article reviews ongoing efforts to perfect or develop new treatment strategies for Parkinson’s disease (PD) within each class. SYMPTOMATIC DRUGS

Symptomatic therapies are the most common form of treatment for both neurologic and nonneurologic illnesses. These remedies attempt to fulfill the basic dictate of traditional medicine “to relieve suffering.” In the United States, all currently available antiparkinson medications were developed and approved for use as symptomatic therapy. These drugs are designed for use as either monotherapy or adjunctive symptomatic therapy but have little, if any, beneficial effects on underlying disease cause or pathogenesis. Included among these symptomatic remedies are both the oldest and the newest antiparkinson medicines. The use of anticholinergic compounds for the treatment of PD dates back to the From the Department of Neurology, Ohio State University, Columbus, Ohio

MEDICAL CLINICS OF NORTH AMERICA VOLUME 83 * NUMBER 2 * MARCH 1999

525

526

HUBBLE

nineteenth century, whereas the catechol-0-methyl transferase (COMT) inhibitors have come into use in the late twentieth century. Despite the large number of existing drugs within this class, new drugs continue to be developed. In this section, these novel symptomatic compounds are divided into two groups on the basis of their pharmacologic actiondopaminergic drugs and nondopaminergic drugs. Novel Dopaminergic Drugs

The pathology of PD is relatively unique. Selective neuronal cells within the substantia nigra of the midbrain degenerate and die. Under normal circumstances, these cells transmit dopamine to the striatum as part of the regulation and control of body movement. Thus, striatal dopamine depletion is the primary neurochemical determinant of clinical PD.6 Most symptomatic PD drugs attempt to replenish, mimic, or enhance the effects of brain dopamine. Dopamine itself is neither well absorbed in the gastrointestinal tract nor effectively transported across the blood-brain barrier. L-dopa is dopamine precursor therapy.' L-dopa crosses the blood-brain barrier penetrating into the brain, where it is converted to dopamine via the enzyme dopa decarboxylase. For the past three decades, L-dopa has served as the mainstay of PD therapy. Its mechanism of action is elegantly simple; it transiently increases brain (striatal) dopamine levels. Its therapeutic effect is also remarkably straightforward; most PD patients experience an obvious robust benefit with the first dose of drug. The pharmacokinetics and pharmacodynamics of L-dopa therapy in PD are far more complex. These complexities coupled with the pathologic progression of PD often result in disabling complications in individuals chronically exposed to L-dopa.20Many patients develop unsustained or unpredictable responses to L-dopa along with drug-induced involuntary movements termed dyskinesia. It is hypothesized that these fluctuating L-dopa response patterns may be postponed or blunted with more continuous dopaminergic stimulation in the form of longer-acting L-dopa preparations or with the use of other dopaminomimetic drugs.3 Further complicating the understanding of the role of L-dopa in the treatment in PD is the theoretic notion that the drug may be neurotoxic and thereby accelerate nigral neuronal degeneration.I8This neurotoxicity has not been established in clinical or pathologic studies of PD. Dopamine Agonists

Because of the difficulties and concerns surrounding long-term L-dopa use, many of the more recently released PD drugs were developed as L-dopa-sparing compounds. This includes the dopamine agonist drugs, which can be used as monotherapy in early PD to postpone the need to initiate L-dopa therapy. Agonists can also be used as adjunctive therapy later in the disease to permit reduction of L-dopa dosing or

NOVEL DRUGS FOR PARKINSON'S DISEASE

527

enhancement of beneficial dopaminergic effects. Agonists directly stimulate dopamine receptors within the brain, and thus their action is independent of L-dopa. These drugs are not usually considered to be as efficacious as L-dopa in affording symptomatic relief in PD. Brain dopamine receptors are classified into five subtypes, D-1 through D-5. The efficacy of dopamine agonist drugs might be improved if a more idealized receptor subtype activation profile could be achieved. For example, the newer agonists pramipexole and ropinirole possess an order of receptor affinity more comparable to dopamine itself?, l9 An initial phase I1 clinical trial with a new highly selective D-2 dopamine receptor agonist is ongoing in the United States.28 Interest in novel dopamine agonists remains high not only because of their L-dopa-sparing property, but also because of favorable dosing characteristics. The effective dosing range of dopamine agonists is fractional to that of L-dopa. L-dopa is often administered in the range of 300 to 1000 mg/d. In contrast, the dopamine agonist pramipexole is used in the range of 1.5 to 4.5 mg/d. High potency combined with unique solubility properties allows some agonists to be rapidly absorbed through routes other than the gastrointestinal tract. For example, apomorphine is a potent, highly hydrophilic dopamine agonist that can be subcutaneously injected. Available outside the United States, it is used as rescue therapy for PD patients who experience severe akinesia as part of their fluctuating L-dopa response pattern." Apomorphine can also be rapidly absorbed across the nasal and oral m ~ c o s a . Typically '~ the clinical effects of apomorphine are evident within a few minutes of administration and wane within an hour. It is possible that PD patients in the future will carry and use apomorphine in the same fashion that sublingual nitroglycerin is used for angina. Clinical trials examining the effects of apomorphine administered via these alternative routes are in the initial stages in the United States. Transdermal absorption of antiparkinson medications may also hold some advantages. The potency and solubility of some agonists permit formulation into a skin patch to be applied daily or less often. Thus, the inconvenience of frequent divided daily dosing is avoided, and dysphagia is not a hindrance to drug therapy. Gastrointestinal upset may be less likely, and hepatic drug metabolism is negligible. Preliminary results of testing of a dopamine agonist administered in a transdermal patch for PD have been favorable, and a wider-scale investigation is underway in the United States.2More detailed information on dopamine agonists as antiparkinson therapy is provided in a separate article. Improving L-Dopa (Dopamine) Bioavailability L-dopa when administered as monotherapy has poor bioavailability and a short half-life. Less than 1% of orally administered L-dopa penetrates into brain because of rapid peripheral metabolism by the enzymes dopa decarboxylase and COMT. To improve its bioavailability, L-dopa is formulated with a decarboxylase inhibitor. In the United States, the

528

HUBBLE

decarboxylase lnhibitor carbidopa is contained in virtually all L-dopa products prescribed during the past 20 years. The concurrent use of carbidopa permits L-dopa dose reduction of approximately 70%. Nevertheless, much of an oral dose of L-dopa is still wasted despite coadministration with carbidopa. COMT in the gastrointestinal vasculature and liver converts L-dopa to 3-0-methyldopa (30MD), a metabolic by-product with no clinical benefit. The half-life and clinical effects of orally administered carbidopa and L-dopa can be increased with the addition of a COMT inhibitory drugz1 The COMT inhibitor tolcapone was approved for use in the United States. When compared to placebo, tolcapone is reported to provide the following benefits in PD patients with L-dopa-related fluctuations: increased on time, decreased of time, and reduction in daily L-dopa dosing.15In PD patients experiencing a stable response with L-dopa dosing, the addition of tolcapone significantly improved activities of daily living.34Entacapone is a peripherally acting, reversible COMT inhibitor in the final stages of clinical testing in the United States. Entacapone’s effects on motor fluctuations in PD are similar to those reported with tolcapone.z6It remains uncertain as to whether the addition of a COMT inhibitor early in the course of L-dopa therapy will prevent or lessen the likelihood of the development of motor fluctuations. This issue is being examined in an ongoing multiyear study. The coadministration of a decarboxylase inhibitor (carbidopa) with L-dopa is an unquestioned and well-established aspect of PD therapy. It is entirely possible that this practice will be expanded in future years to include COMT inhibition as an integral part of conventional Ldopa use. COMT inhibitors and their role in PD treatment are more fully addressed in a separate article. Blockade of other metabolic enzymatic, pathways can also be used to enhance the effects of L-dopa or maintain brain dopamine levels. One of the central metabolic pathways for dopamine is mediated via the enzyme monoamine oxidase type B (MAOB).The drug selegiline inhibits MAOB and is approved in the United States as adjunctive antiparkinson therapy to be used in conjunction with dopa.^^ Selegiline can permit a modest reduction in daily L-dopa dosing needs and may increase on time in patients experiencing wearing off of benefit at the end of each L-dopa dose. These L-dopa-sparing properties of selegiline are attributed to its metabolic enzyme blockade (i.e., the drug reduces the breakdown of endogenous and L-dopa-derived dopamine within the brain). Selegiline is currently available in tablet and capsular formulations. When taken in these formulations, the drug is partially metabolized in the liver to amphetamine-related compounds. These metabolic by-products may account for some of the side effects often associated with the use of selegiline, including insomnia. Studies are underway examining the safety and efficacy of alternative formulations of selegiline that do not depend on gastrointestinal absorption. Thus, hepatic first-pass drug metabolism is avoided. Another MAOB inhibitor, lazabemide, was initially tested as adjunctive therapy in PD, but it is not being actively developed at this time. The compound rasagiline also inhibits the oxida-

NOVEL DRUGS FOR PARKINSON'S DISEASE

529

tive monoamine metabolic enzymes. Rasagiline's effects in early untreated PD are being investigated. The MA0 inhibitors' putative role as neuroprotective agents is addressed subsequently. Metabolic enzyme blockade is not the only strategy being tested to improve bioavailability of L-dopa or dopamine. To bypass gastrointestinal absorption and systemic metabolism of oral formulations, L-dopa ethyl ester (LDEE) has been tested by investigators in Israel. They report that this highly soluble prodrug of L-dopa given subcutaneously or intraperitoneally produces behavioral and pharmacologic effects akin to the native compound L-dopa in parkinsonian animal model^.'^ In a small series, LDEE was offered as a form of parenteral rescue therapy in PD complicated by severe 08period^.^ NB-355 is another investigational Ldopa prodrug being evaluated in Japan.33Dopamine-releasing polymers directly instilled into the brain have also been proposed as a treatment option in PD. L-dopa prodrugs and dopamine polymers have not been widely tested to date in the United States. Novel Nondopaminergic Drugs Dopaminergic drugs are the mainstay of symptomatic pharmacotherapy for PD. Nevertheless, drugs with little or no dopaminergic action can help alleviate PD symptoms. In fact, the anticholinergic drugs were the first successful antiparkinson drugs to be introduced many decades ago. With the advent of L-dopa and dopamine agonists, the anticholinergic drugs have been relegated to a minor role in the treatment of PD because their efficacy is only modest, and side effects are .frequent. One of the most troubling side effects of anticholinergic drug therapy is cognitive impairment and confusion. This side effect is not surprising because it is well established that acetylcholine in the frontal cortex and hippocampus plays an important role in cognitive function. Furthermore, many PD patients have underlying cognitive deficits as an integral part of the disease and are at high risk for cognitive decline or confusion when exposed to anticholinergic and other drugs. Cognitive decline and dementia in PD are poorly understood. These changes in mentation are often more disabling than the motor aspects of PD and frequently culminate in placement in long-term nursing care facilities. Although dopaminergic drugs clearly improve motor function in the vast majority of patients, these compounds afford little or no beneficial effects on cognition in I'D. With the goal of treating both the cognitive and the motor deficits of PD, a novel therapeutic agent is now being developed. The nicotinic acetylcholine receptor agonist SIB-1508Y has complex pharmacologic effects stimulating the release of dopamine in the striatum and frontal cortex; norepinephrine in the hippocampus, thalamus, and frontal cortex; and acetylcholine in the hippocampus and cortex. In a parkinsonian primate model, SIB-1508Y reportedly improved motor and cognitive function when used in conjunction with low-dose d dopa.*^ Clinical studies of the effects of SIB-1508Y in PD are underway,

530

HUBBLE

representing the first concerted effort to identify a remedy for cognitive decline in PD. NEUROPROTECTIVETHERAPIES

Neuroprotective and neurorestorative therapies for PD are considered together here. Neuroprotectants halt or delay the pathologic process (i.e., nigrostriatal degeneration). Neurorestorative therapies not only halt the pathology, but also actually restore normal or near-normal function in affected surviving neurons. At least a partial understanding of disease pathogenesis is required to develop effective neuroprotective and neurorestorative therapies. In contrast, knowledge of disease cause is not absolutely necessary. The pathogenesis of I'D is not clearly delineated, but several lines of evidence suggest that nigral cells are lost via apoptosis (preprogrammed cell death) with involvement of highly reactive free radicals." MPTP and 6-hydroxydopamine are neurotoxins used to prepare animal models of parkinsonism; both toxins have been shown to produce nigral lesions via apoptosis. Genes regulate apoptosis. For example, the bcl-2 gene blocks apoptosis in human nerve cells.37It is possible that future PD neuroprotective or restorative therapies will involve genetic engineering techniques or drugs that modify brain cell apoptosis. It is important to recognize that apoptosis likely has a vital role in the maintenance of other organ systems by limiting excessive cell division and tissue growth. Interventions that produce widespread nonselective blockade of apoptosis may have deleterious clinical consequences, including neoplastic disease. Monoamine Oxidase Inhibitors The MAOB inhibitor selegiline was the first drug to merit much attention as a possible neuroprotectant in I'D. As described earlier, the drug actually received approval for use in the United States on the basis of its benefits when used as adjunctive symptomatic therapy in PD. At the doses recommended for use in I'D, selegiline selectively blocks the oxidative enzyme MAOB, which metabolizes dopamine and other related compounds. Inhibition of MAOB with selegiline prevents nigral degeneration produced by MPTP exposure in animal models of parkinsonism. This successful experimental blockade of nigral degeneration led to speculation that selegiline might delay progression of PD by halting or limiting oxidative processes injurious to human nigral cells. An attempt was made to test this hypothesis in the DATATOP (Deprenyl and Tocopherol As Treatment of Parkinson) study. Patients with early nondisabling PD were blindly assigned to take placebo, deprenyl (selegiline), the antioxidant vitamin E (a-tocopherol), or combination therapy.25 Selegiline use delayed the onset of disability and therefore the need to introduce L-dopa therapy by many months. This benefit was not sus-

NOVEL DRUGS FOR PARKINSON'S DISEASE

531

tained and could be attributed to the symptomatic benefits of the drug. Vitamin E had no effect when used alone or with selegiline in the DATATOP study. Despite the inconclusive results of the DATATOP study, selegiline and MA0 inhibitors remain of interest in I'D. Selegiline has rather complex pharmacologic actions. In addition to MAOB inhibition, it may induce the secretion of neurotrophic factors, increase the formation of the antioxidant enzyme superoxide dismutase, alter glutamate receptor activity, and block apoptosis.22Some of these effects may occur at much lower doses than those typically tested in PD (selegiline, 5 to 10 mg/d). In addition, orally administered selegiline is absorbed in the gastrointestinal tract and is partially metabolized to amphetamine-like compounds. These metabolites are potentially neurotoxic and may contribute to selegiline-related side effects. In current clinical trials, selegiline is being tested in a skin patch formulation and a tablet that rapidly dissolves on the tongue. These novel selegiline formulations do not require gastrointestinal absorption and avoid systemic metabolism. Other MA0 inhibitors that may be better tolerated or have more select pharmacologic actions have been tested in PD or are being investigated in ongoing clinical trials.24,36 Rasagiline is a selective irreversible MAOB inhibitor not metabolized to amphetamines. It is being tested as monotherapy in early nondisabling PD.16 None of the novel MA0 inhibitors or new selegiline formulations are likely to be approved for use in less than 2 to 3 years' time. Free Radical Scavengers

Free radicals are highly reactive toxic molecules that are produced by virtually every body cell type usually in response to stress or injury. For example, sunlight exposure, cigarette smoking, and infection can generate free radical formation in some cell types. In addition, cellular constituents may generate free radicals as part of normal function. Free radicals can be soaked up or scavenged by endogenous antioxidant enzyme systems or by exogenous compounds. Unchecked excessive free radical generation can lead to cell death or neoplastic cell changes. Dopaminergic neurons of the substantia nigra appear to be particularly at risk for free radical generation and damage.22Free radicals likely participate in the form of cell death known as apoptosis. For example, the compound glutathione is a free radical scavenger. Nerve cells deprived of glutathione undergo apoptosis.12 Free radical scavengers have been tested only in a limited fashion in PD. As described earlier, the antioxidant vitamin E had no apparent effect in early I'D in the DATATOP study. It is possible that drug doses were insufficient because vitamin E does not easily penetrate into the brain. OPC-14117 is another free radical scavenging compound that readily penetrates into the brain when administered orally. It appears neuroprotective in laboratory models of neurodegeneration.* Investiga-

532

HUBBLE

tional use of OPC-14117 in humans has been stopped on occasion because of elevation of liver enzymes. Large-scale testing with the compound has not been undertaken in the United States. Other free radical scavenging compounds are being developed but are most often tested in stroke and head trauma patients. Neurotrophic Factors

Neurotrophic factors are endogenous proteins essential to the survival, growth, and maturation of the developing nervous system. It has become clear that these factors also play an important role in the survival of adult neurons. Loss of neurotrophic factor activity can result in selective neuronal cell shrinkage and death via apoptosis. At least two neurotrophic factors play a role in the development and survival of substantia nigra neurons. Brain-derived neurotrophic factor (BDNF) appears to be most important in early stages of central nervous system development. Glial-derived neurotrophic factors (GDNF) appear to play a role in the survival of adult neurons in the substantia nigra. In a parkinsonian animal model, researchers have demonstrated that GDNF can protect and even rescue nigral neurons exposed to neurotoxin^.^^, 32 These laboratory results suggest that GDNF might prove useful as neuroprotective or neurorestorative therapy in PD. GDNF is a large molecule, however, which is not well absorbed via the gastrointestinal tract, and it does not readily penetrate the blood-brain barrier. It is currently being tested in PD patients at a limited number of sites in the United States; as part of this investigational protocol, patients receive GDNF directly into the lateral ventricles via a pump. Results of this preliminary study are not yet available. Neuroimmunophilin

Immunophilins are a group of proteins that serve as receptors for immunosuppressant drugs. There are two classes of immunophilins based on drug-binding properties. Immunophilin ligands, including those lacking immunosuppressant properties, can stimulate neurite outgrowth in vitro. One such ligand, GPI-1045, induces regenerative neural sprouting in neurodegenerative animal models.31GPI-1045 produces axonal resprouting of residual nigrostriatal neurons in parkinsonian animal ' models. It is anticipated that the compound will soon be tested in ID clinical trials. It offers the hope of true restorative therapy. Glutamate Antagonists

The basal ganglia-thalamocortical circuitry facilitates volitional movements and suppresses nonintended movements under normal cir-

NOVEL DRUGS FOR PARKINSON'S DISEASE

533

cumstances. Based largely on animal model work, a functional schema of the key features of the circuitry has been developedP This system proposes parallel processing, that is, the output from the striatum to the internal segments of the globus pallidus (Gpi) is separated into two pathways originating from separate putamenal cell populations. The direct pathway results in inhibition of Gpi neurons, whereas activation of the indirect pathway stimulates Gpi neurons via connections through the external segments of the globus pallidus and subthalamic nucleus. With the degeneration of the nigrostriatal pathway in PD, the mixed nigral inhibitory and excitatory influence in the putamen is lost resulting in reduction in inhibitory influences of the direct pathway and unchecked excitatory influences in the direct pathway. Ultimately, these effects are mediated through the thalamic relay nuclei. The importance of the excessive activation of the subthalamopallidal pathway (indirect pathway) is suggested in animal models of PD, in which parkinsonian signs are reduced with direct lesioning of the subthalamic nucleus. The indirect pathway is mediated via the neurotransmitter glutamate. Thus, reduction or blockade of glutamatergic activity may reduce PD symptoms or alleviate medication side effect^.^ Remacemide is an N-methylD-aspartate receptor ion-channel blocker. Remacemide in the treatment of another basal ganglia disorder, Huntington's disease, has been examined.14 In this short tolerability study, remacemide was well tolerated but offered only minimal symptomatic benefit. Studies of the effect of remacemide in both early and advanced I'D are ongoing. CURATIVE TREATMENT

Curative treatments refer to interventions that result in total remission of all clinical features of I'D because virtually normal brain function has been restored. There are no curative therapies currently available for I'D. Neurotrophic factors and neuroimmunophilin were discussed earlier as a neuroprotective or restorative therapy. Ideally, such compounds will be labeled as curative if it is demonstrated that neuronal function is restored to the extent that all I'D signs and symptoms are abolished and no symptomatic therapies are required. It is not at all clear that such high expectations are warranted at this time. Traditionally, curative therapies in medicine are surgical remedies. Examples range from the simplest procedures, such as the excision of a skin lesion, to the most complex, such as heart-lung transplantations or bone marrow graftings. Surgical interventions have been available for the treatment of PD for many years; thalamotomy and pallidotomy are examples of neurosurgical interventions intended to afford not curative but symptomatic benefit in PD. In contrast, mesencephalic (nigral) cell transplant procedures offer the possibility of cure. To date, human fetal mesencephalic transplants have provided only symptomatic benefit to subjects in clinical trials.30It is possible, however, that a truly successful transplant could offer a cure in PD. A successful transplant may depend on the quantity and quality of transplanted tissue, the technique and

534

HUBBLE

localization of implanted material, and concurrent drug administration. The role of drug therapy as adjuncts to transplant remains obscure at best. Should patients receive antirejection (immunosuppressant) drug therapy? Should antirejection drug therapy be maintained for a brief predetermined period or indefinitely? Will administration of neurotrophic compounds facilitate a clinically successful transplant? Does the reinstitution of L-dopa or other conventional I'D drugs alter the outcome of transplantation in PD? More recently, transplants in PD have been performed using pig mesencephalic t i s s ~ eThis . ~ alternative tissue source obviates many of the ethical concerns and logistical constraints inherent to human fetal tissue transplant initiatives. Nevertheless, the role of pharmacotherapy with porcine transplants in PD is just as murky. Of interest, the commercial developer of the porcine mesencephalic transplant proposes the use of a masking antibody to reduce the antigenicity of the xenograft, thereby reducing the likelihood of graft rejection. Surgical options for the treatment of I'D are more extensively reviewed in the article on surgical therapies by Arle and Alterman. PREVENTIVE THERAPIES

The noblest and most ambitious goal of both clinical and basic PD research is disease prevention. This goal requires a knowledge of disease causation; however, the cause of PD remains elusive. Aging itself is the most robust risk factor. Etiologic hypotheses suggest a variety of less potent risk factors, including environmental toxins, genetic factors, gender, diet, and head trauma or other remote brain injurylo It is quite possible that only a small percentage of PD cases will ultimately be linked to a single cause (i.e., a dominantly inherited, highly penetrant gene). The bulk of the clinical condition that is now called PD is more likely multifactorial. Perhaps a risk factor profile will emerge as in the case of cardiovascular disease. The goal of preventive treatment would then be to identify the at-risk individuals and reduce, eliminate, or alter as many PD risk exposures as is feasible. Again, using cardiovascular disease as an example, this prevention might take the form of simple exposure reduction, such as the elimination of a dietary constituent. Alternatively, it might take the form of pharmacotherapy, as in the case of cholesterol-loweringagents to minimize risk of cardiovascular disease. It may draw on the emerging field of gene therapy to correct fundamental errors in metabolic or apoptotic mechanisms. SUMMARY

Treatment options in PD have expanded remarkably in the past several years. Three new drugs were approved for use in the United States just within the 9 months preceding the preparation of this article. Several new compounds are in the pipeline. Nevertheless, the unmet needs of PD patients are readily apparent in any busy clinical practice. These needs can be posed as three deceivingly simple questions:

NOVEL DRUGS FOR PARKINSON’S DISEASE

535

1. When and how should L-dopa be started? Despite the fact that L-dopa remains the mainstay of PD therapy after 30 years’ time, lacking is a fundamental understanding of proper usage and avoidance of long-term complications. 2. What can be done about cognitive decline and dementia in PD? The current answer is nothing. Efforts are just beginning to fill this large void in knowledge and provide adequate treatment for this disabling problem. 3. How can PD be prevented? This question cannot be answered because the cause of PD remains uncertain. The dearth of substantive information available on this topic is evidenced in this article. The bulk of text appears under the heading Symptomatic Treatments, whereas only a few speculative comments can be offered under the heading Preventive Tveatmenfs. The paramount need for expanded resources and dedicated efforts to identify the causes and devise preventions must be met if advances in the treatment of PD are to be made in the twenty-first century.

References 1. Birkmayer W, Homykiewicz 0 The effect of L-3,4-dihydroxyphenylalanine(=DOPA) on akinesia in parkinsonism. Wiene Klin Wochenschr 73:787, 1961 2. Calabrese VP, Vaughan J, Lucas J, et al: N-0923, a transdermal amino tetralin D2 dopamine agonist in the treatment of Parkinson’s disease. Neurology 48:A270, 1997 3. Chase TN, Baronti F, Fabbrini G, et al: Rationale for continuous dopaminomimetic therapy in Parkinson’s disease. Neurology 39(suppl 2):S7, 1989 4. qaldetti R, Ziv I, Melamed E: Impaired absorption of oral levodopa: A major cause for response fluctuations in Parkinson’s disease. Isr J Med Sci 321224, 1996 5. Eden RJ, Costal1 B, Domeney AM, et al: Preclinical pharmacology of ropinirole (SK&F 101468-A), a novel dopamine D2 agonist. Pharmacol Biochem Behav 38:147, 1991 6. Ehringer H, Hornykiewicz 0 Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr 38:1236, 1960 7. Ellias SA, Palmer EP, Kott HS: Fetal porcine ventral mesencephalic transplantation for Parkinson’s disease: Preliminary results. Mov Disord 12:839, 1997 8. Fisher M, Arpano MM: Inhibition of stimulated human leukocyte hydrogen peroxide generation by a novel antioxidant: OPC-14117. N Engl J Med 328:176,1993 9. Goetz CG, Delong MR, Penn RD, et al: Neurosurgical horizons in Parkinson’s disease. Neurology 43:1, 1993 10. Hubble TP, Cao T, Hassanein RES, et al: Risk factors for Parkinson’s disease. Neurology 43:1693, 1993 11. Hughes AHJ, Bishop S, Kleedorfer B, et al: Subcutaneous apomorphine in Parkinson’s disease: Response to chronic administration for up to 5 years. Mov Disord 8365, 1993 12. Jenner P: Altered mitochondria1 function, iron metabolism and glutathione levels in Parkinson’s disease. Acta Neurol Scand 146(suppl):6, 1993 13. Kapoor R, Tujanski N, Frankel J, et a1 Intranasal apomorphine: A new treatment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 53:1015, 1990 14. Kieburtz K, Feigin A, McDermott M, et al: A controlled trial of remacemide hydrochloride in Huntington’s disease. Mov Disord 11:273, 1996 15. Kurth C, Adler CH, Hilaire M, et al: Tolcapone improves motor fluctuations and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations: A multicenter, double-blind, randomized, placebo-controlled trial. Neurology 48:81, 1997

536

HUBBLE

16. Marek K, Friedman J, Hauser R, et al: Phase I1 evaluation of rasagiline mesylate (TVP1012), a novel anti-parkinsonian drug, in parkinsonian patients not using levodopa/ carbidopa. Mov Disord 12:838, 1997 17. Melamed E: Effect of subcutaneous administration of levodopa ethyl ester, a soluble prodrug of levodopa, on dopamine metabolism in rodent striatum: Implication for treatment of Parkinson’s disease. Clin Neuropharmacol 19:65, 1996 18. Mena MA, Pardo B, Caserejos MJ, et al: Neurotoxicity of levodopa on catecholaminerich neurons. Mov Disord 723, 1992 19. Mierau J: Pramipexole: A dopamine-receptor agonist for the treatment of Parkinson’s disease. Clin Neuropharmacol lb(supp1 1):S195, 1995 20. Mouradian MM, Juncos JL, Fabbrini G, et al: Motor fluctuations in Parkinson’s disease: Pathogenetic and therapeutic studies. Ann Neurol22:475, 1987 21. Nutt JG, Woodward WR, Beckner Rh4, et a1 Effect of peripheral catechol-0-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology 44:913, 1994 22. Olanow CW A radical hypothesis for neurodegeneration. Trends Neurosci 16439,1993 23. Olanow CW: A rationale for monoamine oxidase inhibition as neuroprotective therapy for Parkinson’s disease. Mov Disord 8:S1, 1993 24. Parkinson Study Group: A controlled trial of lazabemide (Ro 19-6327) in untreated Parkinson’s disease. Ann Neurol 33:350, 1993 25. Parkinson Study Group: Effect of tocopherol and deprenyl on the progression of disability in early Parkinson‘s disease. N Engl J Med 328:176, 1993 26. Parkinson Study Group: Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol42:747, 1997 27. Schneider JS, Van Velson M, Menzaghi F, et al: Effects of the nicotinic acetylcholine receptor agonist SIB-1508Y on object retrieval performance in MPTP-treated monkeys: Comparison with levodopa treatment. Ann Neurol 43:311, 1998 28. Sethy VH, Ellerbrock BR, Wu H: U-95666E A potential anti-parkinsonian drug with anxiolytic activity. Prog Neuropsychopharmacol Biol Psychiatry 21:873, 1997 29. Shults CW, Kimber T, Martin D. Intrastriatal injection of GDNF attenuates the effects of 6-hydroxydopamine. Neuroreport 7627, 1996 30. Spencer DD, Robbins RJ, Naftolin F, et al: Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N Engl J Med 3271541, 1992 31. Steiner JP, Hamilton GS, Ross DT, et a1 Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models. Proc Natl Acad Sci U S A 94:2019, 1997 32. Tomac A, Lindqvist E, Lin LFH, et al: Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373335, 1995 33. Tye SJ, Rupniak NMJ, Naruse T, et a1 NB-355: A novel prodrug for L-dopa with reduced risk for peak-dose dyskinesias in MPTP-squirrel monkeys. Clin Neuropharmacol 12393, 1989 34. Waters CH, Kurth M, Bailey P, et al: Tolcapone in stable Parkinson’s disease: Efficacy and safety of long-term treatment. Neurology 49:665, 1997 35. Wessel K, Szelenyi I: Selegiline: An overview of its role in the treatment of Parkinson’s disease. Clin Invest 70:459, 1992 36. Yu PH, Davis BA, Durden DA, et al: Neurochemical and neuroprotective effects of some aliphatic propargylamines: New selective nonamphetamine-like monoamine oxidase B inhibitors. J Neurochem 62:697, 1994 37. Zong LT, Sarafian T, Kane DJ, et al: Bcl-2 inhibits death of central neural cells induced by multiple agents. Proc Natl Acad Sci U S A 904533,1993

Address reprint requests to Jean Pintar Hubble, MD Department of Neurology Ohio State University 1581 Dodd Drive, Suite 371 Columbus, OH 43210