Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/Tolcapone

This appears to be a text book example of the processes involved in bringing a new therapy to market. N.B. There was an interval of 9 years between the first tests on humans and formal licencing approval.

Background

Tolcapone is a drug that crosses the blood brain barrier and inhibits the enzyme catechol-O-methyl transferase (COMT). This has the efect of prolonging the utility of levadopa. It is distributed under the trade name Tasmar.

Research

1995

Dingemanse et al conducted the first test of tolcapone on humans in a double-blind, placebo-controlled, ascending-single-dose study. Doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers and adverse events, vital signs, and clinical laboratory variables were recorded. Their conclusions:-

The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.

1997

Baas et al conducted a multicentre, randomised, double blind, placebo controlled trial. 58 patients received a placebo, 60 received 100 mg tolcapone three times daily, and 59 received 200 mg tolcapone in addition to levodopa/ benserazide.

After three months with 200 mg tolcapone the, “off” time decreased by 26.2% of the baseline value, “on” time increased by 20.6%, and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg. These responses were maintained up to nine months.

With 100 mg tolcapone the, “off” time decreased by 31.5%, “on” time increased by 21.3%, and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg.

With 200 mg tolcapone the, unified Parkinson’s disease rating scale motor and total scores were significantly reduced, and quality of life scores were significantly improved.

1998

De Santi et al studied the variation of catechol-O-methyltransferase (COMT) activity in the human liver, duodenal mucosa and renal cortex, and investigated the inhibition of COMT by entacapone and tolcapone. The study included 87 samples of human liver, 94 samples of the duodenum and 72 samples of the renal cortex. The results were:-

Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P = 0.008), respectively, in the liver; consistent results were obtained with the other tissues.

Adler et al carried out a randomized, double-blind, placebo-controlled, parallel-group study with a cohort of 215 PD patients. These were given either a placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks.

Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day

2001

Factor et al compared the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease. Their conclusions:-

Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.

2004

The European Medicines Agency approved the use of Tolcapone (Tasmar) for the treatment of Parkinson's Disease on 29/04/2004

2006

Stocchi and De Pandis carried out a comprehensive review of tolcapone and concluded:-

With proper monitoring, tolcapone is an effective, well-tolerated drug useful in the management of patients with fluctuating PD.

Further Reading

1995

Dingemanse, J; Jorga, K.; Zurcher, G.; Schmitt,M.; Sedek, G,; Da Prada, M. and Van Brummelen, P. Full Text Br. J. Clin Pharmacol. 40 (3): 253–262.

Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1365105/

1996

Dingemanse, J.; Jorga, K.; Zurcher, G.; fotteler, N.; Sedek, G.; Nielsen, T. and van Brummelen, P. Full Text Eur. J. Clin. Pharmacol. 50 (1-2):47-55.

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects.

http://www.ncbi.nlm.nih.gov/pubmed/8739811

2002

Ceravolo, R.; Piccini, P.; Bailey, P. L.; Jorga, K.M.; Bryson, H. and Brooks, D. J. Abstract Synapse 43 (3) 201—207.

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

http://www.ncbi.nlm.nih.gov/pubmed/11793426

Today

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Summary

This appears to be a text book example of the processes involved in bringing a new therapy to market. N.B. There was an interval of 9 years between the first tests on humans and formal licencing approval.

Related pages

Therapy > Neuroprotection

Sub Pages:

Neuroprotective agents

Substances with possible neuroprotective properties:

Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--