Composition comprising methylphenidate and another drug

Details Composition comprising methylphenidate and another drug Composition comprising methylphenidate and another drug

2000-06-19

2002-10-22

Salimi, Ali R. (Department: 1648)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S009200, C424S490000, C435S004000, C435S007400, C435S007710, C435S007910, C514S649000, C514S922000, C514S438000

Reexamination Certificate

active

06468504

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new composition comprising methylphenidate and another drug, and also to new ways of using known drugs including d-threo-methylphenidate (abbreviated herein as dtmp).
BACKGROUND OF THE INVENTION
Methylphenidate is a known drug (although it is a controlled substance). It is used primarily to treat hyperactive children.
Methylphenidate is a chiral molecule. The properties of the enantiomers have been investigated to some extent, although the drug is still administered as the racemate. It is generally thought that dtmp is the active material, and that its antipode (ltmp) is metabolised more rapidly.
Methylphenidate is often administered in conjunction with other drugs. It is known that the concurrent administration of two drugs that act or are metabolised through the same metabolic pathway can block that pathway, leading to drug interaction.
Racemic methylphenidate is known to interact clinically with a variety of drugs, such as the tricyclic antidepressants (TCAs), necessitating reduction in the TCA dosage when co-administered to prevent drug interaction (Physicians Desk Reference, Guide to Drug Interactions, 1994).
It is generally believed that the separate enantiomers of chiral therapeutic drugs exhibit different toxicological profiles, with one usually being the main cause of the toxic effects of drug interactions; see Ariens, Schweiz. Med. Wochenschr. 120(5): 131-134 (1990). The basis for this is that each enantiomer will exhibit different preferences for the pathways of enzyme metabolism, e.g. the cytochrome P
450
pathways, and therefore co-administered drugs are blocked at different sites of metabolism.
SUMMARY OF THE INVENTION
It has been discovered that, surprisingly, both dtmp and ltmp similarly inhibit metabolism of other drugs by the cytochrome P
450
systems, in human microsomes. Further, the racemate is shown to have a greater inhibitory profile than either of the enantiomers, suggesting an interaction between the two. Administration of dtmp, substantially free of ltmp, will substantially reduce the inhibition of P
450
isozymes. This has beneficial effects for patients undergoing concurrent administration of other drugs. To avoid the resultant risk of drug-drug toxicity, the present invention involves the administration of that other drug and dtmp. The two drugs used in this invention may be administered sequentially, concurrently or simultaneously, by the same or separate means.
The discovery is based on data showing that, surprisingly, dtmp administration results in less toxicity in the mouse liver than racemic methylphenidate, possibly due to less inhibition of hepatic cytochrome P
450
enzymes. The experiments and data are summarised below. The invention is thus of particular utility in that proportion of the population in which the relevant enzymes have reduced efficiency, or that are receiving the cross-reacting drugs, e.g. SSRIs, in therapy of, say, anxiety or depression.


REFERENCES:
patent: 5733756 (1998-03-01), Zeitlin et al.
Patrick, K.S. et al. (1987) “Pharmacology of the Enantiomers of the threo-Methylphenidate”The Journal of Pharmacology and Experimental Therapeutics241(1):152-158.
Eckerman, D.A. et al. (1991) “Enantioselective Behavioral Effects of threo-Methylphenidate in Rats”Pharmacology Biochemistry&Behavior40(4):875-880.
Aoyama, T. et al. (1994) “Pharmacokinetics and Pharmacodynamics of (+)-threo-Methylphenidate Enantiomer in Patients with Hypersomnia”Clinical Pharmacology&Therapeutics55(3):270-276.
Arëns, E.J. (1991) “Racemic Therapeutics-Ethical and Regulatory Aspects”Eur. J. Clin. Pharmacol. 41:89-93.
Arëns, E.J. (1990) “Stereoselectivity in Pharmacodynamics and Pharmacokinetics”Schweiz. Med. Wochenschr. 120(5):131-134.
Tyndale, R.F. et al. (1991) “Neuronal Cytochrome P450IID1 (Debrisoquine/Sparteine-Type): Potent Inhibition of Activity by (−)-Cocaine and Nucleotide Sequence Identity to Human Hepatic P450 Gene CYP2D6”Molecular Pharmacology, An International Journal40(1):63-68.
Rapport, M.D. et al. (1993) “Methylphenidate and Desipramine in Hospitalized Children: I. Separate and Combined Effects on Cognitive Function”J. Am. Acad. Child. Adolesc. Psychiatry32(2):333-342, **abstract only.
Licamele, W.L. et al. (1989) “The Concurrent Use of Lithium and Methylphenidate in a Child”J. Am. Acad. Child Adolesc. Psychiatry28(5):785-787, **abstract only.
Grob, C.S. et al. (1986) “Suspected Adverse Methyphenidate-imipramine Interactions in Children”J. Dev. Behav. Pediatr. 7(4):265-267, **abstract only.
Drimmer, E.J. et al. (1983) “Desipramine and Methylphenidate Combination Treatment for Depression: Case Report”Am. J. Psychiatry 140(2):241-242, **abstract only.

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