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.
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References
Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276: 374–9
Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism: chronic treatment with L-dopa. N Engl J Med 1969; 280: 337–45
Duvoisin RC. Hyperkinetic reactions with L-dopa. In: Yahr MD, editor. Current concepts in the treatment of parkinsonism. New York (NY): Raven Press, 1974: 203–10
Sweet RD, McDowell FH. The “on-off” response to chronic L-dopa treatment of parkinsonism. In: McDowell FH, Barbeau A, editors. Second Canadian-American Conference on Parkinson’s Disease. New York(NY): Raven Press, 1974: 331–8
Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson’s disease. Trends Neurosci; 2000; 23: S2–7
Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000; 47Suppl. 1: S2–S11
Nutt JG, Carter JH, VanHouten L, et al. Short-and-long-duration responses to levodopa during the first year of levodopa therapy. Ann Neurol 1997; 42: 349–55
Hauser RA, Koller WC, Hubble JP, et al. Time course of loss of clinical benefit following withdrawal of levodopa/carbidopa and bromocriptine in early Parkinson’s disease. Mov Disord 2000; 15: 485–9
Lees AJ, Stern GM. Sustained low-dose levodopa therapy in Parkinson’s disease: a 3-year follow-up. In: Fahn S, Calne DB, Shoulson I, editors. Experimental therapeutics of movement disorders. New York (NY): Raven Press, 1983: 9–15
Olanow CW, Schapira AHV, Rascol O. Continuous dopaminereceptor stimulation in early Parkinson’s disease. Trends Neurosci 2000; 23: S117–26
Bedard PJ, Blanchet PJ, Levesque D, et al. Pathophysiology of L-dopa: induced dyskinesias. Mov Disord 1999; 14Suppl. 1: 4–8
DeLong MR, Crutcher MD, Georgopoulos AP. Relations between movement and single cell discharge in the substantia nigra of the behaving monkey. J Neurosci 1983; 3: 1599–606
Strecker RE, Jacobs BL. Substantia nigra dopaminergic unit activity in behaving cats: effect of arousal on spontaneous discharge and sensory evoked activity. Brain Res 1985; 361: 339–50
Nutt JG, Obeso JA, Stocchi F. Continuous dopamine-receptor stimulation in advanced Parkinson’s disease. Trends Neurosci 2000; 23: S109–15
Sulla M, Hardoff R, Giladi N, et al. Gastric emptying time and gastric motility in patients with untreated Parkinson’s disease [abstract]. Mov Disord 1996; 11Suppl. 1: 167
Djaldetti R, Baron J, Ziv I, et al. Gastric emptying Parkinson’s disease: patients with and without fluctuations. Neurology 1996; 46: 1051–4
Kurlan R, Rothfield KP, Woodward WR, et al. Erratic gastric emptying of levodopa may cause “random” fluctuations of parkinsonian mobility. Neurology 1988; 38: 419–21
Pfeiffer RF, Quigley EMM. Gastrointestinal motility problems in patients with Parkinson’s disease. Epidemiology, pathophysiology and guidelines for management. CNS Drugs 1999; 11: 435–48
Pincus JH, Barry K. Influence of dietary protein on motor fluctuations in Parkinson’s disease. Arch Neurol 1987; 44: 270–2
Fabbrini G, Mouradian MM, Juncos JL, et al. Motor fluctuations in Parkinson’s disease: central pathophysiological mechanisms, Pt I. Ann Neurol 1988; 24: 366–71
Mouradian MM, Juncos JL, Fabbrini G, et al. Motor fluctuations in Parkinson’s disease: Central pathophysiological mechanisms, Pt II. Ann Neurol 1988; 24: 372–8
Chase TN, Oh JD. Striatal dopamine, and glutamate: mediated dysregulation in experimental parkinsonism. Trends Neurosci 2000; 23: S86–91
Obeso JA, Linazasoro G, Gorospe A, et al. Complications associated with chronic levodopa therapy in Parkinson’s disease. In: Olanow CW, Obeso JA, editors. Dopamine agonists in early Parkinson’s disease. Royal Turnbridge Wells. Wells Medical Limited, 1997: 11–35
Melamed E, Hefti F, Wurtman RJ. Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in parkinsonism. Ann Neurol 1980; 8: 558–63
Wachtel SR, Abercrombie ED. L-3, 4-dihydroxyphenylalanine-induced dopamine release in the striatum of intact and 6-hydroxydopamine-treated rats: differential effects of monoamine oxidase A and B inhibitors. J Neurochem 1994; 63: 108–17
Grandas F, Gancher ST, Rodriguez M, et al. Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson’s disease. Clin Neuropharmacol 1992; 15: 13–8
Bravi D, Mouradian MM, Roberts JW, et al. Wearing-off fluctuations in Parkinson’s disease: contribution of postsynaptic mechanisms. Ann Neurol 1994; 36: 27–31
Kotter R. Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. Prog Neurobiol 1994; 44: 163–96
Djaldetti R, Koren M, Ziv I, et al. Effect of cisapride on response fluctuations in Parkinson’s disease. Mov Disord 1995; 10: 81–4
Soykan I, Sarosiek I, Shifflet J, et al. Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson’s disease. Mov Disord 1997; 12: 952–7
Djaldetti R, Melamed E. Management of response fluctuations. Neurology 1998; 51Suppl. 2: S36–40
Shoulson I, Glaubiger GA, Chase TN. On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25: 1144–8
Quinn N, Parkes JD, Marsden CD. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 1984; 34: 1131–6
Mouradian MM, Heuser IJE, Baronti F, et al. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 1990; 27: 18–23
Nutt JG, Carter JH. Apomorphine can sustain the long-duration response to L-dopa in fluctuating PD. Neurology 2000; 54: 247–50
Manson AJ, Hanagasi H, Turner K, et al. Intravenous apomorphine therapy in Parkinson’s disease: clinical and pharmacokinetic observations. Brain 2001; 124 (Pt 2): 331–40
Sage JI, Mark MH. The rationale for continuous dopaminergic stimulation in patients with Parkinson’s disease. Neurology 1992; 42Suppl. 1: 23–8
Ondo W, Hunter C, Almaguer M, et al. A novel sublingual apomorphine treatment for patients with fluctuating Parkinson’s disease. Mov Disord 1999; 14: 664–8
Dewey RB, Maraganore DM, Ahlskog JE, et al. A doubleblind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov Disord 1998; 13: 782–7
van Laar T, Jansen ENH, Neef C, et al. Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson’s disease: a study of five different suppositories. Mov Disord 1995; 10: 433–9
Poewe W, Wenning GK. Apomorphine: an underutilized therapy for Parkinson’s disease. Mov Disord 2000; 15: 789–94
Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998; 64: 573–6
Verhagen Metman L, Konitsiotis S, Chase TN. Pathophysiology of motor response complications in Parkinson’s disease: hypotheses on the why, where and what. Mov Disord 2000; 15: 3–8
Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747–55
Kurth MC, Adler CH, St. Hilaire M, et al. Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson’s disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebo-controlled trial. Neurology 1997; 48: 81–7
Schwab RS, Amandor LF, Lettvin JY. Apomorphine in Parkinson’s disease. Trans Am Neurol Assoc. 1951; 76: 251–3
Cotzias GC, Mena I, Papavasiliou PS, et al. Unexpected findings with apomorphine and their possible consequences. In: McDowell F, Barbeau A, editors. Second Canadian-American Conference on Parkinson’s Disease. New York (NY): Raven Press, 1974: 295–9
Calne DB, Teychenne PF, Claveria LE, et al. Bromocriptine in parkinsonism. BMJ 1974; 4: 442–4
Teychenne PF, Pfeiffer RF, Bern S, et al. Experiences with a new ergoline (CF 25–397) in parkinsonism. Neurology 1977; 27: 1140–3
Teychenne PF, Pfeiffer RF, Bern SM, et al. Comparison between lergotrile and bromocriptine in parkinsonism. Ann Neurol 1978; 3: 319–24
Papavasiliou PS, Cotzias GC, Rosal VLF, et al. Treatment of parkinsonism with N-M-propyl-norapomorphine and levodopa (with or without carbidopa). Arch Neurol 1978; 35: 787–91
Pfeiffer RF. The pharmacology of mesulergine. Clin Neuropharmacol 1985; 8: 64–72
Weiner WJ, Factor SA, Sanchez-Ramos J, et al. Adouble-blind evaluation of ciladopa in Parkinson’s disease. Mov Disord 1987; 2: 211–7
Pfeiffer RF, Herrera LH, Glaeske CS, et al. CQP 201-403 in Parkinson’s disease: an open label pilot study. Mov Disord 1989; 4: 278–81
Pfeiffer RF, Hofman R. CQA 206-291 in Parkinson’s disease. Clin Neuropharmacol 1991; 14: 170–8
Sage JI, Duvoisin RC. Pergolide therapy in Parkinson’s disease: a double-blind placebo-controlled study. Clin Neuropharmacol 1985; 8: 260–5
Kieburtz K, Shoulson I, McDermott M, et al. A randomized dose-ranging study of the safety and efficacy of pramipexole in early Parkinson’s disease. JAMA 1997; 278: 125–30
Rascol O, Lees AJ, Senard JM,et al. Ropinirole in the treatment of levodopa-induced motor fluctuations in patients with Parkinson’s disease. Clin Neuropharmacol 1996; 19: 234–45
Hutton JT, Koller WC, Ahlskog JE, et al. Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson’s disease. Neurology 1996; 46: 1062–5
Olanow CW, Obeso JA. Preventing levodopa-induced dyskinesias. Ann Neurol 2000; 47Suppl. 1: S167–78
Fariello RG. Pharmacodynamic and pharmacokinetic features of cabergoline. Rationale for use in Parkinson. Drugs 1998; 55Suppl. 1: 10–6
Pfeiffer RF. Clinical management of Parkinson’s disease. In: Marwah J, Teitelbaum H, editors. Advances in neurodegenerative disorders Vol 1: Parkinson’s disease. Scottsdale (AZ): Prominent Press, 1998: 1–49
Rinne UK, Bracco F, Chouza C, et al. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications: results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs 1998; 55Suppl. 1: 23–30
Rascol O, Brooks DJ, Korczyn AD, et al. A five year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342: 1484–91
Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson’s disease. A randomized controlled trial. JAMA 2000; 284: 1931–8
Stahl SM, Wets KM. Recent advances in drug delivery technology for neurology. Clin Neuropharmacol 1988; 11: 1–17
Martin GE, Williams M, Pettibone DJ, et al. Pharmacologic profile of a novel potent direct-acting dopamine agonist, (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO]. J Pharmacol Exp Ther 1984; 230: 569–76
Muenter MD, Ahlskog JE, Bell G, et al. PHNO [(+)-4-propyl-9-hydroxynaphthoxazine]: a new and effective anti-Parkinson’s disease agent. Neurology 1988; 38: 1541–5
Rupniak NMJ, Tye SJ, Jennings CA, et al. Antiparkinsonian efficacy of a novel transdermal delivery system for (+)-PHNO in MPTP-treated squirrel monkeys. Neurology 1989; 39: 329–35
Coleman RJ, Lange KW, Quinn NP, et al. The antiparkinsonian actions and pharmacokinetics of transdermal (+)-4-propyl-9 hydroxynaphthoxazine (+ PHNO): preliminary results. Mov Disord 1989; 4: 129–38
Ahlskog JE, Muenter MD, Bailey PA, et al. Parkinson’s disease monotherapy with controlled release MK-458 (PHNO): double-blind study and comparison to carbidopa/levodopa. Clin Neuropharmacol 1991; 14: 214–27
Calabrese VP, Lloyd KA, Brancazio P, et al. N-0923, a novel soluble dopamine D2 agonist in the treatment of parkinsonism. Mov Disord 1998; 13: 768–74
Cagnotto A, Parotti L, Mennini T. In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study. Eur J Pharmacol 1996; 313: 63–7
Sweet RD, Wasterlain CG, McDowell FH. Piribedil, a dopamine agonist, in Parkinson’s disease. Clin Pharmacol Ther 1974; 16: 1077–82
McDowell FH, Sweet R. Actions of dopaminergic agonists in parkinsonism. In: Calne DB, Chase TN, Barbeau A, editors. Dopaminergic mechanisms. New York (NY): Raven Press. 1975: 367–71
Chase TN, Woods AC, Glaubiger GA. Parkinson’s disease treated with a suspected dopamine receptor agonist. Arch Neurol 1974; 30: 383–6
Smith LA, Jackson MG, Bonhomme C, et al. Transdermal administration of piribedil reverses MPTP: induced motor deficits in the common marmoset. Clin Neuropharmacol 2000; 23: 133–42
Montastruc JL, Ziegler M, Rascol O, et al. A randomized, doubleblind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson’s disease. Mov Disord 1999; 14: 336–41
Belluzi JD, Domino EF, May JM, et al. N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson’s disease. Mov Disord 1994; 9: 147–54
Beaulieu M, Itoh Y, Tepper P, et al. N, N-disubstituted 2-aminotetralins are potent D-2 dopamine receptor agonists. Eur J Pharmacol 1984; 105: 15–21
van der Weide J, de Vries JB, Tepper PG, et al. Pharmacological profiles of three new, potent and selective dopamine receptor agonists: N-0434, N-0437 and N-0734. Eur J Pharmacol 1986; 125: 273–83
Swart PJ, de Zeeuw RE. Extensive gastrointestinal conversion limits the oral bioavailability of the dopamine D2 agonist N-0923 in freely moving rats. Pharmazie 1992; 47: 613–5
Hutton JT, Verhagen Metman L, Chase TN, et al. Transdermal dopaminergic D2 receptor agonist therapy in Parkinson’s disease with N-0923 TDS: a double-blind, placebo-controlled study. Mov Disord 2001; 16: 459–63
Verhagen Metman L, Gillespie M, Farmer C, et al. Continuous transdermal dopaminergic stimulation in advanced Parkinson’s disease. Clin Neuropharmacol 2001; 24: 163–9
Fahn S, Parkinson Study Group. Rotigotine transdermal system (SPM-962) is safe and effective as monotherapy in early Parkinson. Parkinsonism Relat Disord 2001; 7: S55
Quinn N for the SP 511 Investigators. Rotigotine transdermal delivery system (TDS) (SPM-962): a multicenter, doubleblind, randomized, placebo-controlled trial to assess the safety and efficacy of rotigotine TDS in patients with advanced Parkinson. Parkinsonism Relat Disord 2001; 7: S66
van Laar T, van der Geest R, Danhof M. Future delivery systems for apomorphine in patients with Parkinson’s disease. In: Stern GM, editor. Parkinson’s disease. Philadelphia (PA): Lippincott Williams & Wilkins, 1999: 535–44
van der Geest R, Danhof M, Bodde HE, et al. Iontophoretic delivery of apomorphine. I: in vitro optimization and validation. Pharm Res 1997; 14: 1798–803
van der Geest R, van Laar T, Gubbens-Stibbe JM, et al. Iontophoretic delivery of apomorphine. II: an in vivo study in patients with Parkinson’s disease. Pharm Res 1997; 14: 1804–10
Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci 2001; 14: 101–14
Touitou E, Dayan N, Bergelson L, et al. Ethosomes — novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release 2000; 65: 403–18
Dayan N, Touitou E. Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs liposomes. Biomaterials 2000; 21: 1879–85
Sudo J, Iwase H, Terui J, et al. Transdermal absorption of L-dopa from hydrogel in rats. Eur J Pharm Sci 1998; 7: 67–71
Iwase H, Sudo J, Terui J, et al. Transdermal absorption of L-dopa from a new system composed of two separate layers of L-dopa and hydrogel in rats. Drug Dev Ind Pharm 2000; 26: 755–9
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The absolutely invaluable assistance of Sharon Williams in manuscript preparation is most sincerely appreciated.
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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Pfeiffer, R.F. Potential of Transdermal Drug Delivery in Parkinson’s Disease. Drugs Aging 19, 561–570 (2002). https://doi.org/10.2165/00002512-200219080-00002
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DOI: https://doi.org/10.2165/00002512-200219080-00002