Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-29
2003-04-08
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S212010, C514S228800, C514S367000, C514S385000, C514S386000, C514S461000, C514S473000, C514S557000, C514S620000, C514S866000
Reexamination Certificate
active
06544998
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutical combinations of a &ggr;-aminobutyric acid (GABA) agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a sorbitol dehydrogenase inhibitor (SDI), a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, kits containing such combinations and methods of using such combinations to treat mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers. This invention also relates to additive and synergistic combinations of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug, whereby those additive and synergistic combinations are useful in treating mammals, including humans, suffering from diabetic complications such as, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts or foot ulcers.
BACKGROUND OF THE INVENTION
GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. Its receptors have been divided into two main types. The more prominent GABA receptor subtype, the GABA
A
receptor, is a ligand-gated Cl
31
ion channel that is opened after release of GABA from presynaptic neurons. A second receptor, the GABA
B
receptor, is a member of the G protein-coupled receptor family coupled both to biochemical pathways and to regulation of ion channels. (Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N. Y.,
9
th
Edition, (1996).
By gating negative chloride (Cl
31
) ions into the interior of cells, GABA inhibits the presynaptic release of neurotransmitter due to a positive voltage polarization pulse. Such inhibition is extremely common: GABA receptors can be found in 60-80% of central nervous system neurons. Subtypes of GABA receptors can be activated by the mushroom toxin muscimol (at GABA
A
) as well as the antispasmodic amino acid baclofen (GABA
B
). These compounds directly mimic the action of GABA at the receptor. Allosteric facilitation of GABA receptors occurs at several distinct sites; the compounds which bind there are used as sedatives and anxiolytics. Progabide is a prodrug which decomposes to GABA after crossing the blood/brain barrier into the central nervous system. Vigabatrin (gamma-vinyl-GABA) promotes binding of GABA by inhibiting GABA-aminotransferase (GABA-T), the enzyme responsible for degrading GABA in the synapse.
GABA agonists well known in the art include muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin®), vigabatrin, valproic acid, tiagabine (Gabitril®), lamotrigine (Lamictal®), pregabalin, phenytoin (Dilantin®), carbamazepine (Tegretol®), topiramate (Topamax®) and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of those GABA agonists. It will be recognized by those skilled in the art in light of this disclosure that other GABA agonists are also useful in the combinations, pharmaceutical compositions, methods and kits of this invention. GABA agonists have been disclosed to be useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia and spasticity. GABA agonists have also been disclosed to be useful as antidepressants, anxiolytics and antipsychotics. Further, GABA agonists have been disclosed to have utility in the treatment of pain.
S. Ao et al.,
Metabolism,
40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter,
Diabetic Medicine,
8
,
Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578, which are hereby incorporated by reference, each disclose compounds of the Formula A,
wherein R
1
through R
5
in the compound of Formula A are defined as disclosed therein. Further, U.S. Pat. No. 5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Commonly assigned International Patent Application Publication Number WO00/59510, which is incorporated herein by reference, discloses compounds of the formula
wherein R
1
through R
3
in the compound of Formula I are defined as disclosed therein. That application discloses that the compounds of Formula I have utility in the treatment of diabetic complications.
SUMMARY OF THE INVENTION
This invention is directed to pharmaceutical compositions comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug;
b. an amount of a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug; and, optionally,
c. a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to kits for achieving a therapeutic effect in a mammal comprising:
a. an amount of a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a first unit dosage form;
b. an amount of a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug and a pharmaceutically acceptable vehicle, carrier or diluent in a second unit dosage form; and
c. a container.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug;
wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to methods for treating a mammal in need of therapeutic treatment comprising administering to said mammal a pharmaceutical composition comprising
(a) an amount of a first compound, said first compound being a GABA agonist, a prodrug thereof or a pharmaceutically acceptable salt of said GABA agonist or said prodrug; and
(b) an amount of a second compound, said second compound being a SDI, a prodrug thereof or a pharmaceutically acceptable salt of said SDI or said prodrug; and, optionally,
(c) a pharmaceutically acceptable vehicle, carrier or diluent.
The methods of this invention include therapeutic treatment of diabetic complications. Diabetic complications which may be treated by the methods of this invention include, inter alia, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic microangiopathy, diabetic macroangiopathy, cataracts and foot ulcers. Humans are especially preferred mammals which are treated by the methods of this invention.
Preferred SDIs for use in the combinations, pharmaceutical compositions, methods and kits of this invention are compounds of Formula I,
prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
R
1
Benson Gregg C.
Pfizer Inc
Richardson Peter C.
Ronau Robert T.
Weddington Kevin E.
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