LEADING ARTICLE

Drugs Aging 2002; 19 (8): 561-570 1170-229X/02/0008-0561/$25.00/0 © Adis International Limited. All rights reserved.

Potential of Transdermal Drug Delivery in Parkinson’s Disease Ronald F. Pfeiffer Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA

Abstract

There has been a growing recognition that pulsatile stimulation of dopamine receptors may be an important mechanism in the generation of the motor fluctuations that often develop and compromise the effectiveness of long-term levodopa administration in persons with Parkinson’s disease (PD). This has prompted investigation of treatment approaches that might provide more constant, and therefore physiological, dopamine receptor stimulation. Frequent levodopa administration, controlled-release levodopa preparations, inhibitors of levodopa metabolism, and duodenal, subcutaneous and even intravenous infusions of levodopa or dopamine agonists have all been employed with this goal in mind, but all have limitations. Transdermal drug delivery is a treatment approach that is not only capable of providing a constant rate of drug delivery, but is also non-invasive and relatively simple to use. However, developing a drug to be delivered transdermally for the treatment of PD has been anything but easy. Levodopa and many dopamine agonists are not sufficiently soluble to be administered via the transdermal route, and blind alleys have been encountered thus far in the investigation of suitably soluble drugs. Nevertheless, investigation continues and yet another candidate drug, rotigotine (N-0923), is currently under active investigation. Techniques designed to enhance skin permeation and thus improve the effectiveness of transdermal drug delivery are also potential sources for future treatment advances.

In the heady days of the late 1960s, following the dramatically successful introduction by Cotzias and colleagues[1] of the technique of gradual levodopa titration to massive, but clinically effective doses, the idea that Parkinson’s disease (PD) had finally been conquered was prevalent. However, this evanescent mirage of misplaced optimism soon evaporated, as the first descriptions of dyskinesia and, later, other types of levodopa-induced motor fluctuations began to emerge.[2-4] Over the ensuing years it has become increasingly evident that the long-term use of levodopa is often accompanied by

a variability and unpredictability in response to levodopa doses; this may run the gamut from no response at all to delayed, partial, distorted or even exaggerated responses which can become increasingly precipitous, unpredictable and incapacitating as time and disease severity march inexorably onward.[5,6] This review examines the proposed mechanisms of motor fluctuations in the levodopa-treated PD patient, and how such fluctuations can be circumvented, with particular emphasis on the potential of transdermal drug delivery.

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1. Motor Fluctuations The first whisper of the emerging motor fluctuation cacophony is often the gradual appearance of a diminished duration of effectiveness of individual levodopa doses. When levodopa is first initiated, individuals typically demonstrate what has come to be called the ‘long duration response’ in which they derive a smooth, sustained improvement from a dose of levodopa and are even able to miss doses without any discernible deterioration of function.[7,8] However, after a variable period of time, the duration of effectiveness of a dose of levodopa begins to noticeably contract and it becomes necessary to administer the drug more frequently to maintain benefit. With the further passage of time, the ‘wearing off’ of levodopa efficacy can become increasingly abrupt and unpredictable; at times the transition from functional to immobile may unfold within seconds, making it impossible for the individual to prepare for the ‘off’ period. As these changes are occurring, individuals taking levodopa may also begin to display involuntary movements that typically appear when the effectiveness of a dose of levodopa is at its peak. The movements are usually choreiform in character, although other types of movements may also occur.[6] The percentage of patients with PD receiving levodopa displaying these motor fluctuations grows over time. By 3 years of treatment, 30 to 33% have begun to experience motor fluctuations; by 5 years this has mushroomed to over 50% and by 10 years of levodopa treatment 70 to 80% are experiencing motor fluctuations. This rises to almost 100% in persons whose PD appeared before the age of 45 years.[9-11] Discerning and dissecting the mechanisms responsible for the development of such motor fluctuations has been the goal of intense investigation by numerous basic scientists and clinicians, and in recent years a clearer picture of these processes has come into focus. Central to this has been the recognition that normal functioning of the nigrostriatal dopaminergic system is characterised by sustained, tonic firing of the dopamine (DA) neurons with periodic interruptions by phasic bursts of ac© Adis International Limited. All rights reserved.

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tivity triggered by sensory stimuli.[12-14] However, in attempting to explain the genesis of motor fluctuations, both peripheral and central factors have been hypothesised and, indeed, both may be operative. 1.1 Gastric Emptying

Impaired gastric emptying, with consequent delay in levodopa reaching its absorptive sites in the small intestine, has been documented in PD and appears to be more frequent in individuals who are experiencing motor fluctuations.[15,16] It is easy to conceptualise how such a delay in absorption might lead to a delayed, or even an occasional failed, response to a dose of levodopa.[17,18] Moreover, interference by dietary protein with levodopa absorption at intestinal sites can also lead to diminished effectiveness of levodopa doses.[19] However, it is more difficult to account by peripheral mechanisms alone for the progressively shorter duration of efficacy of levodopa doses over time and the progressively more prominent dyskinesias that all too often eventually contaminate the response to levodopa. To explain these phenomena, changes within the central nervous system (CNS) seem more probable. 1.2 Presynaptic Mechanisms

Levodopa is a prodrug that must be converted to DA within the CNS to be effective. This conversion is normally accomplished within DA neurons, which convert the levodopa to DA, store the DA in vesicles, release it into the synapse upon proper signal, and then recycle the DA by transporting it back into the neuron where it is repackaged for later reuse. It is this ability to recycle DA that presumably accounts for the prolonged effect of doses of levodopa in patients with early PD, an effect that far exceeds its plasma half-life. As more and more DA neurons die as part of the progressive neurodegenerative disease process, the ability of the surviving DA neurons to provide a compensatory buffer and maintain the physiological tonic supply of DA to the synapse progressively erodes. Eventually, insufficient numbers of DA neurons remain Drugs Aging 2002; 19 (8)

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to carry out the ‘job’ of converting levodopa to DA in sufficient quantity at a constant rate.[5,20-23] As this state of affairs develops, it appears that other types of cells take up the burden and convert levodopa to DA.[24,25] However, these cells do not contain appropriate storage mechanisms for DA, and the DA thus formed promptly leaks out of the cells into the synaptic cleft. Here it stimulates DA receptors in a burst of activity and is then destroyed, since it can not be reclaimed and recycled by the adoptive, non-dopaminergic neuron. Thus, the synaptic environment in the striatum evolves from a setting of constant, tonic dopaminergic stimulation to one characterised by bursts of activity provoked by levodopa administration followed by lulls in synaptic activity until the next levodopa dose arrives.[22] The emergence of a dosedependent levodopa response of diminishing duration, with end-of-dose wearing off of efficacy, sometimes labelled the ‘short duration response’, fits well with this presynaptic or ‘storage’ hypothesis. However, the development of dyskinesia is not adequately explained and it has recently become clear that the story doesn’t end there. 1.3 Postsynaptic Mechanisms

Apomorphine, a DA agonist that directly stimulates postsynaptic DA receptors and whose function, therefore, is largely independent from presynaptic control, also displays a progressive shortening of duration of action with advancing PD, similar to that observed with levodopa.[26,27] This, then, suggests that postsynaptic factors must also be important in the development of motor fluctuations. Recent studies strongly suggest that the unphysiological pattern of pulsatile stimulation of striatal postsynaptic receptors eventually induced by prolonged levodopa treatment leads to a cascade of further ‘downstream’ changes within the postsynaptic neuron, away from the DA receptor itself. DA receptors in the striatum are found primarily on medium spiny neurons (MSN), which constitute over 90% of striatal neuronal cells.[28] These MSN, which utilise γ-aminobutyric acid © Adis International Limited. All rights reserved.

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(GABA) as their neurotransmitter, receive at their dendrites in the striatum not only dopaminergic input from nigrostriatal neurons, but also glutamatergic input from cortical neurons. Accumulating evidence suggests that pulsatile stimulation of striatal DA receptors on the MSN may secondarily induce changes in the phosphorylation of nearby glutamate [primarily N-methyl-D-aspartate (NMDA)] receptors. These changes result in upregulation of these receptors and consequent overactivity of the striatal MSN, driven by cortical glutamatergic activity.[22] It is these changes, then, that are felt to be primarily responsible for the development of dyskinesia and perhaps other aspects of the levodopainduced motor fluctuations that develop during the course of PD treatment. 2. The Role of Continuous Dopaminergic Stimulation Actual proof of the concept that continuous dopaminergic stimulation prevents the emergence of motor response fluctuations is still lacking. However, the realisation that pulsatile stimulation of DA receptors may be one root of the motor fluctuations that ultimately mar the effectiveness of levodopa therapy has led to a number of treatment approaches that share the goal of providing a more natural, continuous delivery of DA (or at least DA stimulation) to the striatal DA receptors. Medications that hasten gastric emptying have been employed in attempts to reduce some of the peripherally mediated factors influencing levodopa delivery to the brain. Cisapride and domperidone have been shown to effectively perform such a function.[29,30] Taking levodopa on an empty stomach, separated from potentially competing dietary protein, is also routinely used in PD management. More rapidly dissolving prodrugs have also been tested with the idea that more rapid dissolution of the tablet will facilitate gastric egress and intestinal arrival of the drug. Levodopa ethylester is an example of such a pharmacological approach.[31] However, most attention has been targeted toward more directly providing a constant level of Drugs Aging 2002; 19 (8)

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striatal dopaminergic stimulation in the effort to ameliorate dyskinesia and other motor fluctuations. Constant intravenous (IV) infusion is one such approach. The IV infusion of levodopa completely circumvents the vagaries of intestinal levodopa absorption and presumably results in a relatively constant rate of delivery of levodopa, and thus DA, to striatal sites. Levodopa IV infusions have, indeed, been shown to produce a gradual improvement in dyskinesia and a reduction in motor fluctuations.[14,32-34] The same is true for IV infusions of the direct DA agonist, apomorphine.[35,36] However, constant IV infusion is not a practical management strategy for treatment that will span years, and perhaps decades. Duodenal delivery of levodopa has also been employed as a strategy that, while still cumbersome, is less problematic than IV infusion of levodopa. This technique has been used successfully for up to 4 years with significant, sustained improvement in motor fluctuations.[37] However, direct duodenal drug delivery is still unwieldy and necessitates placement of a percutaneous endoscopic gastrostomy (PEG) tube, rendering it less than ideal for routine clinical use. Apomorphine is a direct DA agonist that, because of its high degree of solubility, is suitable not only for IV delivery but also for use by other parenteral routes. Sublingual,[38] nasal[39] and rectal[40] delivery modes have been used, but by these avenues constant delivery is neither achievable nor intended, and these routes might be conceptualised primarily as a means of temporarily rescuing individuals in the throes of an ‘off’ period. Subcutaneous delivery of apomorphine by intermittent injection is widely used in some parts of the world as rescue therapy,[41] but apomorphine is also amenable to constant subcutaneous infusion via pump. This technique of apomorphine delivery has, in fact, been successfully employed in individuals for up to 8 years or more.[42] Nevertheless, the requirement for proper use and management of needles and pumps makes this a technique of drug delivery that is somewhat limited in its applicability to patients who are particularly motivated, mechanically © Adis International Limited. All rights reserved.

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adept and conscientious. Subcutaneous administration of another dopamine agonist, lisuride, has similar limitations. Oral administration of drug is a time-honoured and highly accepted mode of medication delivery. However, to attain any semblance of constant delivery of drug, either a drug with a very long halflife, a tablet with an effective controlled-release mechanism, or very frequent drug administration is necessary. Several controlled-release levodopa preparations have been marketed (Sinemet CR®, Madopar HBS®1), but neither is capable, at least in standard dosage regimens, of producing a truly sustained delivery of levodopa to the CNS.[43] Attempts to further prolong the clinical effect of levodopa by inhibiting its metabolism (or that of DA itself) with either catecholamine-O-methyltransferase (COMT) or monoamine oxidase inhibitors have been primarily directed toward reducing end-of-dose wearing-off of levodopa efficacy. [44,45] Recent attention has centred on the COMT inhibitor, entacapone.[44] It is not yet known whether these drugs, in combination with levodopa, can provide a level of constant DA receptor stimulation sufficient to reverse or avoid the synaptic and intracellular changes responsible for the development and maintenance of motor fluctuations.[10] Very frequent, typically hourly, administration of levodopa ground up and administered as a suspension (so-called ‘liquid levodopa’) is also occasionally used in treating individuals who have developed intractable motor fluctuations. However, most individuals are unable or unwilling to put up with the onerous task of the preparation and the inconvenience of the hourly administration. Following the introduction of levodopa into routine clinical use it soon became apparent that progressive DA neuronal loss was not going to be arrested by levodopa and that, with progressive neuronal loss, the ability to convert, store and release DA was also going to be compromised. This led to the exploration of avenues to bypass the ail1 Use of tradenames is for product identification only and does not imply endorsement.

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ing DA neurons and directly stimulate the DA receptors on the still intact and functioning MSN in the striatum. Apomorphine, the first agonist to be used in PD,[46] was found to be unsuitable for oral use.[47] Bromocriptine was then the first to be successfully employed,[48] followed by a long line of other agonists that have undergone clinical trials, some successfully, others not.[49-59] This flurry of developmental activity has led to the introduction of four additional DA agonists to routine clinical use as oral medications for the treatment of PD: pergolide, pramipexole, ropinirole and cabergoline. In addition to their ability to directly stimulate DA receptors, the DA agonists have the advantage of relatively long half-lives compared with the 60 to 90 minutes for levodopa.[60] Of the available agonists, only cabergoline has a sufficiently long half-life to possess the potential to approximate a pattern of constant DA receptor stimulation. Its half-life is about 65 to 110 hours,[61] compared with a range of 6 to 27 hours for the other agonists,[62] and this long half-life permits once daily administration. Cabergoline has been found to be effective in reducing both dyskinesia and motor fluctuations,[59] but it is not known whether, as monotherapy, it can actually forestall their development. As is also true with the other DA agonists, the clinical efficacy of cabergoline is not equal to that of levodopa. Thus, a significant proportion of persons (though by no means all) placed on it or other agonists require levodopa supplementation within several years.[63-65] One potential additional practical problem with the use of an ultra-long– acting agent such as cabergoline lies in the probability that adverse effects are likely to be prolonged, should they occur. 3. Transdermal Drug Administration The appeal of transdermal administration of medication as a means of achieving a constant rate of drug delivery is well recognised[66] and the technique has been applied successfully in the treatment of a number of disease processes. Nitroglycerin (glyceryl trinitrate) patches for coronary artery © Adis International Limited. All rights reserved.

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disease, clonidine patches for hypertension, scopolamine patches for motion sickness, and nicotine patches for smoking cessation are all examples of currently used transdermal treatment approaches. With a transdermal system, a constant supply of drug can be delivered, even though the half-life of the drug might be quite short; moreover, the drug can be easily removed should adverse effects develop. Levodopa itself has generally not been regarded as a candidate for transdermal administration because it has poor solubility and stability, but several DA agonists have demonstrated a capability for transdermal absorption. 3.1 Naxagolide

The naphthoxazine derivative, naxagolide [(+)4-propyl-9-hydroxynaphthoxazine (PHNO, MK458)] is a very potent DA agonist that was the subject of some excitement and extensive testing in the 1980s in both animals and humans. The excitement was generated by the discovery that naxagolide was an extremely potent DA agonist in various in vitro and in vivo test systems.[67] It was also known to be soluble in both aqueous and lipid media, making it a candidate for transdermal application. Subsequent testing demonstrated that, in addition to being effective when administered via the oral route,[68] naxagolide also produced clinical improvement in both primates and humans when applied transdermally.[69,70] A delay of 4 to 6 hours, correlating with rising plasma naxagolide concentrations and reflecting the time for naxagolide to permeate the epidermis below the skin patch and reach the dermal capillaries, was noted between patch application and onset of clinical benefit.[70] Clinical response and plasma concentration elevations persisted for several hours after removal of the patches, also reflecting the reservoir provided by the skin and subcutaneous tissues. Adverse effects generated by naxagolide were similar to those produced by other DA agonist drugs, including drowsiness. Despite its initially promising performance, testing of naxagolide was eventually abandoned Drugs Aging 2002; 19 (8)

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because its effectiveness was judged to be insufficient for monotherapy.[71] Toxicity might also have played a role in this decision.[72] 3.2 Piribedil

Another ‘veteran’ DA agonist, whose scrutiny as a potential agent for the treatment of PD dates back to the early 1970s, is piribedil (ET-495). Piribedil is a non-ergot piperazine derivative and a dopamine D2 family agonist that has a preferential effect on the D3 receptor subtype.[73] Initial studies in the 1970s demonstrated antiparkinson efficacy, but a short duration of action and a relatively high incidence of adverse effects limited the clinical usefulness of piribedil.[74-76] However, interest in the drug was resurrected following the recognition that these drawbacks of piribedil could be overcome by transdermal application of the drug.[77,78] In marmosets rendered parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride), transdermally applied piribedil (by paste or patch) produced a dose-related increase in locomotor activity and reversal of motor deficits that was prolonged up to five times that seen with oral administration.[77] The nausea characteristic of oral administration of the drug was also avoided with the transdermal route. In addition to improvement in motor function, animals also displayed an increased level of vigilance and awareness, with enhanced responsiveness to environmental stimuli. This observation contrasts starkly with the drowsiness often observed with other DA agonists and its basis is unexplained. Evaluation of transdermally applied piribedil was also undertaken in humans in a randomised, double-blind, placebo-controlled study involving 27 patients.[78] However, no pharmacological effect of piribedil was evident in any of the parameters studied. Adverse events were actually seen more frequently in the placebo group than in the groups receiving piribedil. The study was quite brief in that treatment duration was only 3 weeks. The investigators speculated that the absence of any demonstrable benefit from piribedil might be a result of the brevity of treatment, or that insuf© Adis International Limited. All rights reserved.

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ficient doses may have been employed. Plasma piribedil concentrations achieved in the study were below those that had been found to be the therapeutic range in previous studies of IV piribedil administration. Nevertheless, development of the transdermal piribedil dosage form was stopped following this study, since it was realised that the size of skin patch that would be necessary to deliver adequate amounts of the drug would be impractical.[78] 3.3 Rotigotine

Despite these disappointments, the search for an effective and well-tolerated candidate drug for transdermal PD treatment continues. Yet another DA agonist has been the object of extensive testing over recent years and is still under active investigation. Rotigotine (N-0923) is a non-ergot aminotetralin derivative that, along with most other DA agonists employed or tested in PD, predominantly stimulates the D2 receptor.[79-81] It is the (–)-enantiomer of the racemic agonist, N-0437.[79] In animal models, it produced responses predictive of antiparkinson activity in humans, but it was found to undergo extensive gastrointestinal and first pass hepatic metabolism that rendered it inactive when administered orally.[82] Because of its lipid solubility and ability to penetrate the skin, it was felt to have potential as an agent delivered via the transdermal route. In initial studies in humans it was administered to nine patients in a series of 30-minute IV infusions as a dose-finding exercise, followed by a 4hour infusion.[72] All nine patients displayed improvement in motor function, that ranged from 27 to 95%, while receiving rotigotine. The primary adverse effects noted were hypotension and nausea. In a subsequent study, a transdermal delivery system in the form of an adhesive matrix patch was used. 85 individuals with PD receiving levodopa treatment were enrolled in a randomised, parallelgroup, double-blind, placebo-controlled multicentre trial to examine the efficacy and tolerability of rotigotine over a 21-day period.[83] Participants in the study received either placebo or 1 of 4 doses Drugs Aging 2002; 19 (8)

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of transdermal rotigotine. During the treatment phase, levodopa dosage was reduced if possible and any DA agonist medications previously being taken were discontinued. Patches were worn 14 hours each day. Of the original 85 patients, 82 actually initiated treatment, 73 completed the study, and 67 were judged to be evaluable. Reduction in levodopa dosage that achieved statistical significance and surpassed 25% was noted at the two highest dosage levels (33.5 and 67mg per day), and five patients receiving rotigotine (plus one placebo recipient) were able to completely discontinue levodopa. No improvement or deterioration in motor function was noted in any treatment group. This suggested to the investigators that rotigotine was sufficiently effective to compensate for and allow reduction or elimination of other dopaminergic therapy, at least in some patients. Adverse effects were generally mild and typical for a DA agonist. In a second study involving 10 levodopa-treated patients with advanced PD, a modified transdermal system (rotigotine CDS) which increased drug delivery 3-fold compared with the earlier patch of similar size was utilised. Rotigotine was administered for a period of 4 weeks (2 weeks escalation; 2 weeks maintenance), while patients were evaluated by a blinded examiner.[84] During the treatment period levodopa dosage was reduced if possible. Seven of the ten patients successfully completed the trial, and in these individuals levodopa dosage was reduced over 50% (median levodopa dosage was reduced from 1400 to 400 mg/day). Reduction in both ‘off’ time and dyskinesia was also noted in most patients. Adverse effects, typical of dopaminergic drugs, resolved with reduction in levodopa dosage; mild skin reactions in the form of itching, erythema at the patch site or rash were common. The authors of both of these studies encouraged additional trials and, indeed, two additional doubleblind trials, one evaluating rotigotine as monotherapy in early PD and one evaluating rotigotine in advanced PD, have recently been completed, but results have only been published in abstract form.[85,86] In the monotherapy trial,[85] which was © Adis International Limited. All rights reserved.

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of 12 weeks’ duration, improvement in motor function was evident in the two highest dosage groups (13.5 and 18 mg/day). In the study performed in individuals with advanced PD,[86] somewhat higher dosages were used (up to 27 mg/day). What appeared to be a dose-dependent reduction in ‘off’ time was documented, but no statistically significant difference from the placebo group was present. Further studies, presumably larger and longer, evaluating rotigotine are being planned and, thus, rotigotine remains an unfolding story. 3.4 Other Transdermal Systems

The transdermal systems discussed thus far have been essentially passive systems in which a drug is soluble enough to diffuse across the skin and enter the dermal capillaries. An embellishment upon this approach is to assist a drug in its passage across the skin by means of transdermal iontophoretic transport, which entails the use of a small electrical current to produce electrorepulsive and electro-osmotic forces that drive the drug across the skin, producing a current-dependent delivery system.[87] Such an approach has been used in preliminary studies with apomorphine, both in vitro and in patients with PD, and the feasibility of such an approach has been demonstrated.[88,89] In ten individuals with PD, apomorphine did not show any absorption following passive application to the skin for 1 hour, but measurable plasma concentrations were present when iontophoretic current was applied along with the apomorphine for the same time duration.[89] A potential advantage of this type of system is that the flux of drug can be controlled not only by the patch size, but also by the current density, which could allow for more elegant individualisation of drug delivery than is possible with passive transdermal delivery systems. Other means of improving transdermal drug delivery via skin permeation enhancement remain largely unexplored in the setting of PD. Other physical or electrical methods, chemical enhancers, and vesicular carriers all represent potential avenues of investigation[90] and, indeed, some preDrugs Aging 2002; 19 (8)

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liminary steps have been made. An ethosomal (composed of phospholipid, ethanol and water) carrier system has been shown to produce superior skin penetration of trihexyphenidyl (benzhexol) compared with a standard liposomal system,[91,92] while hydrogel systems have demonstrated the ability to enhance levodopa transdermal absorption.[93,94] Whether these novel systems will be refined and translated into further clinical studies that might provide feasible and affordable treatment approaches in the treatment of PD is unknown. 4. Conclusion In many respects the sentence above echoes and summarises the experience thus far with transdermal delivery systems in the treatment of PD. As the role that pulsatile stimulation of DA receptors may be playing in the generation of motor fluctuations is increasingly recognised, the theoretical rationale for delivering drugs as continuously as possible continues to grow stronger. So also does the clinical evidence supporting this approach. However, the practicality of developing a delivery system that is capable of providing reliable, constant drug delivery without undue complexity that might confuse the patient, and without invasiveness that might endanger the patient, has been very elusive. Transdermal drug delivery is a potential answer to this dilemma. Success in developing such transdermal systems will require a combination of masterful knowledge of the pharmacokinetic/pharmacodynamic profiles and skin permeability characteristics of candidate molecules, along with the ability to design an efficient delivery carrier. In summary, the technique of transdermal delivery of drug possesses tremendous promise as an ideal delivery system for the pharmacological management of PD. It can only be hoped that, in time, it might actually be able to ‘deliver’ on this promise. Acknowledgements The absolutely invaluable assistance of Sharon Williams in manuscript preparation is most sincerely appreciated. © Adis International Limited. All rights reserved.

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No sources of funding were used to assist in the preparation of this manuscript. The author has received research grants from Pharmacia, Teva, Mylan/Bertek, Cephalon, Merck-Germany and is on speakers bureaus for Pharmacia, Novartis and GlaxoSmithKline.

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Correspondence and offprints: Dr Ronald F. Pfeiffer, Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA. E-mail: [email protected]

Drugs Aging 2002; 19 (8)