| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 24, 1992 |
| PATENT TITLE |
Method for enhancing the systemic delivery of dextromethorphan for the treatment of neurological disorders |
| PATENT ABSTRACT | A method for enhancing the systemic delivery of dextromethorphan for the treatment of a neurological disorder resulting in injury to nervous tissue, which comprises administering to a patient suffering from the disorder an amount of a cytochrome P450IID6 enzyme inhibitor, sufficient to block dextromethorphan metabolism, and an amount of dextromethorphan sufficient to treat the neurological disorder. Quinidine is particularly suitable for use in the method of the invention |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 17, 1991 |
| PATENT REFERENCES CITED | Chem. Abst. 111-89742z, (1989). |
| PATENT CLAIMS |
What is claimed is: 1. A method for enhancing the systemic delivery of dextromethorphan for the treatment of a neurological disorder resulting in injury to nervous tissue, which comprises: administering to a patient suffering from said neurological disorder an amount of a cytochrome P450IID6 enzyme inhibitor, sufficient to block dextromethorphan metabolism, and an amount of dextromethorphan, sufficient to treat said neurological disorder. 2. The method of claim 1, wherein said inhibitor is quinidine. 3. The method of claim 1, wherein said neurological disorder results from ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. 4. A method for enhancing the systemic delivery of dextromethorphan for the treatment of a neurological disorder mediated by an endogenous excitatory amino acid, which comprises: administering to a patient suffering from said neurological disorder an amount of a cytochrome P450IID6 enzyme inhibitor, sufficient to block dextromethorphan metabolism, and an amount of dextromethorphan, sufficient to treat said neurological disorder. 5. The method of claim 4, wherein said inhibitor is quinidine. 6. The method of claim 4, wherein said neurological disorder results from ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease, Alzheimer's disease, or amyotrophic lateral sclerosis. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The invention relates to compounds that enhance the delivery of a drug, dextromethorphan, used in the treatment of neurological disorders. BACKGROUND OF THE INVENTION It is now known that two common amino acids, glutamate and aspartate, are the major excitatory neurotransmitters in the mammalian brain. It is estimated that between 30 and 40% of all brain neurons use these two agents to communicate. Glutamate and aspartate are referred to as excitatory amino acids (EAA's). After physical trauma or stroke (ischemia), nerve cells which use the EAA's as their neurotransmitters become hyperactive and begin to release very large quantities of the EAA transmitters. This process results in the exhaustion and death of the neurons from EAA overstimulation. The two natural neurotransmitters, glutamate and aspartate, actually become toxins in the injured brain, due to their increased release from neurons. This phenomenon has been termed excitotoxicity. U.S. Pat. No. 4,806,543 discloses the use of dextrorotatory opiate agonists such as dextrorphan and dextromethorphan to protect against this phenomenon in a number of acute and chronic neurologic disorders, including ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Dextromethorphan is known to bind to distinct receptors in the central nervous system (Tortella et al., TIPS 10:501-507, 1989; Craviso and Musacchio, Mol. Pharmacol. 23:629-640, 1983). Although these receptors have not been fully characterized, they may be responsible for the unique anticonvulsant and neuroprotective effects reported for this drug (Leander, Epilepsy Res. 4:28-33, 1989; Koyuncuoglu and Saydam, Intnl. J. Clin. Pharmacol. Ther. Tox. 28:147-152, 1990; Ferkany et al., Eur. J. Pharmacol. 151:151-154, 1988; George et al., Brain Res. 440:35-379, 1988; Choi, Brain Res. 403:333-336, 1987; Goldberg et al., Neurosci. Ltts. 80:11-15, 1987; Prince and Feeser, Neurosci. Ltts. 85:291-296, 1988; Feeser et al., Neurosci. Ltts. 86:340-345, 1988; Steinberg et al., Neurosci. Ltts. 89:193-197, 1988). Additional CNS actions may also arise from the metabolism of dextromethorphan to dextrorphan within the CNS by the cytochrome P450IID6 like enzyme localized in brain tissue (Fonne-Pfister et al., Biochem. Biophys. Res. Commun. 148:1144-1150, 1987; Niznik et al., Arch. Biochem. Biophys. 26:424-432, 1990). In spite of the potentially desirable CNS activity of dextromethorphan, very little dextromethorphan is capable of reaching the CNS because of its extensive first-pass elimination in humans (Vetticaden et al., Pharmaceut. Res. 6:13-19, 1989; Ramachander et al., J. Pharm. Sci. 66:1047-1048, 1977). Without the administration of massive doses of dextromethorphan (>750 mg/day) on a frequent basis, one cannot hope to overcome the efficient elimination of dextromethorphan in most subjects (Walker and Hunt, Clin. Neuropharmacol. 12:322-330, 1989). As a further complication, one also faces the nonlinearity in dextromethorphan elimination at higher doses. This may make individualization of therapy more difficult and the formation of toxic metabolites and/or adverse drug effects more likely (Walker and Hunt, Clin. Neuropharmacol. 12:322-330, 1989). The large first-pass elimination of dextromethorphan is accounted for primarily by its O-demethylation to dextrorphan (Vetticaden et al., Pharmaceut. Res. 6:13-19, 1989; Koppel et al., Arzneim.-Forsch. Drug Res. 37:1304-1306, 1987). This metabolite is then rapidly conjugated and eliminated in the urine. The small amounts of dextromethorphan and dextrorphan which reach the CNS are primarily responsible for its antitussive properties. The efficient elimination of dextromethorphan and dextrorphan along with their relatively short half-lives, however, limits their effectiveness and utility for treating neurological disorders. Accordingly, there is a need for the identification of pharmacologically active compounds that can inhibit the O-demethylation of dextromethorphan to dextrorphan and thereby, preclude the use of excessive dosing with dextromethorphan, with its accompanying problems. Such pharmacologically active compounds can only increase the effectiveness of dextromethorphan and dextrorphan as neuroprotective drugs. SUMMARY OF THE INVENTION The present invention provides a method for enhancing the delivery of dextromethorphan for the treatment of a neurological disorder in which excitotoxic mechanisms are implicated. The method involves administering to a patient suffering from the neurological disorder an amount of a cytochrome P450IID6 enzyme inhibitor, sufficient to block the degradation of dextromethorphan, and an amount of dextromethorphan, sufficient to treat a neurological disorder. Quinidine is particularly suitable to enhance delivery of dextromethorphan in the present invention. BRIEF DESCRIPTION OF THE DRAWING The drawing is a graph depicting the relationship between dextromethorphan plasma concentrations and dose in patients receiving 150 mg/day of quinidine concurrently. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds found to enhance the delivery of dextromethorphan to the CNS for treating neurological disorders. Both dextromethorphan and dextrorphan have neuroprotective effects. The problem is that dextromethorphan is rapidly metabolized to dextrorphan which is eliminated from the body as a sulfate conjugate. The compounds of the present invention inhibit the cytochrome P450IID6 enzyme which is responsible for the O-demethylation of dextromethorphan to dextrorphan. By means of the compounds of the present invention both dextromethorphan and its metabolite, dextrorphan, can reach the CNS without dextromethorphan having to be given in massive amounts. The preferred compound of the invention is quinidine. Quinidine is a potent and selective inhibitor of the cytochrome P450IID6 enzyme (Brinn et al., Brit. J. Clin. Pharmacol. 22:194-198, 1986; Inaba et al., Brit. J. Clin. Pharmacol. 22:199-200, 1986; Brosen et al., Pharmacol. Tox. 60:312-314, 1987; Otton et al., J. Pharmacol. Exper. Ther. 247:242-248, 1988; Funck-Brentano et al., J. Pharmacol. Exper. Ther. 249:134-142, 1989; Nielsen et al., Br. J. Clin. Pharmacol. 29:299-304, 1990). Quinidine passes the blood brain barrier very poorly (Ochs et al., Amer. Heart J. 100:341-346, 1980; Ochs et al., Clin. Pharmacol. Ther. 38:618-624, 1985) and therefore, will not be present in any significant amount to prevent the O-demethylation of dextromethorphan by the cytochrome P450IID6 like enzyme localized in brain tissue. This creates no problem in dextromethorphan's use since once present in the CNS, dextromethorphan or its metabolite is able to act effectively as a neuroprotective drug. In addition to quinidine, there are other compounds which may be effective in enhancing the delivery of dextromethorphan by inhibiting the cytochrome P450IID6 enzyme. The compounds can be drawn from the following classes of drugs: anticonvulsants, hypnotics and sedatives, antidepressants, monoamine oxidase inhibitors, antipsychotics, .beta.-adrenoreceptor blocking drugs, cardiovascular drugs, antimalarials, antihistamines, alkaloids and analgesics. Representative medications in these classes currently demonstrated to exhibit properties of the invention include the following specific compounds: amitriptyline, chlorpromazine, domperidone, haloperidol, haloperidol epoxide, pipamperone, labetalol, metoprolol, oxprenolol, propanolol, timolol, mexiletine, quinine, diphenhydramine, ajmaline, lobeline, fluoxetine hydrochloride, papaverine, yohimbine, and functionally related compounds. The O-demethylation of dextromethorphan is carried out by the human cytochrome P450IID6 in the liver (Kronbach et al., Anal. Biochem. 162:24-32, 1987; Dayer et al., Clin. Pharmacol. Ther. 45:34-40, 1989). Consequently, individuals lacking the expression of this enzyme eliminate larger quantities of dextromethorphan in their urine and little or minimal amounts of dextrorphan (Guttendorf et al., Ther. Drug Monitor. 10:490-498, 1988; Hildebrand et al., Eur. J. Clin. Pharmacol. 36:315-318, 1989). This information has provided the basis for using the dextromethorphan metabolic ratio of (urinary dextromethorphan/urinary dextrorphan) as a screening tool for identifying subjects with deficiencies in cytochrome P450IID6 expression. In the present invention, the dextromethorphan metabolic ratio and dextromethorphan plasma level are used to show the inhibition of dextromethorphan O-demethylation by quinidine with the resulting increase in dextromethorphan levels. The metabolic ratio of dextromethorphan is determined by using the following equation: ##EQU1## A metabolic ratio <0.30 indicates extensive metabolism. Both dextromethorphan plasma levels, with and without quinidine, and dextromethorphan and dextrorphan urinary levels without quinidine were determined using an HPLC assay with fluorescence detection. Dextromethorphan and dextrorphan urinary levels with quinidine were determined using a gas chromatographic-mass spectroscopy (gc-ms) assay. The method of the invention is carried out by administering to a patient suffering from a neurological disorder an amount of a cytochrome P450IID6 enzyme inhibitor such as quinidine, sufficient to block dextromethorphan metabolism, and an amount of dextromethorphan, sufficient to treat neurological disorders. The method is suitable for use in any animal species having a cytochrome P450IID6 like enzyme. Administration can be by any technique capable of introducing a compound of the invention such as quinidine and dextromethorphan into the blood stream of a patient, including oral administration and intravenous, intramuscular, and subcutaneous injections. For stroke or head trauma, the preferred method of administration is intravenous. Oral administration is the preferred method for epilepsy and neurodegenerative diseases. Typical doses in orally acceptable pharmaceutical carriers would be from 30 to 300 mg, preferably from 50 to 150 mg, for dextromethorphan, and from 50 to 500 mg, preferably from 50 to 150 mg, for compounds of the invention such as quinidine. These doses are for administration to a typical 70 kg human. Administration can be adjusted to provide the same relative dose per unit of body weight. A preferred formulation comprises dextromethorphan, quinidine, and an inert carrier suitable for use as an injectable solution or suspension. Aqueous solutions, optionally containing minor amounts of an organic solvent, such as ethanol, for use in increasing solubility, are particularly preferred. Preferred is an injectable solution containing from 30 to 300 mg, preferably from 50 to 150 mg, of dextromethorphan, and from 50 to 500 mg, preferably from 50 to 150 mg, for compounds of the invention such as quinidine. The amount utilized for any particular patient will vary depending on the body weight and particular use, as is well understood in the art. Typical concentrations in the blood stream on the order of 100 to 1000 ng/mL, preferably 250 to 500 ng/mL, for dextromethorphan and on the order of 1 to 7 mcg/mL, preferably 3 to 5 mcg/mL, for quinidine will be useful. Injectable formulations of the invention will differ from simple aqueous solutions in that they have been formulated for pharmaceutical use and therefore, will not contain pyrogens and other substances that may be present in typical laboratory solutions of organic compounds |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |