| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 9, 1999 |
| PATENT TITLE |
Clioquinol for the treatment of Parkinson's disease |
| PATENT ABSTRACT | A new pharmaceutical composition is disclosed that comprises clioquinol, vitamin B.sub.12, and, optionally, pharmaceutical acceptable carriers and/or excipients. The use of the pharmaceutical composition removes or alleviates the side effects of clioquinol |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 13, 1998 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Price et al., Pathophysiology: Clinical Concepts of Disease Processes, 3rd ed., pp. 791-793, 1978. Haensel et al, Therapeutic use of Chelate Formers and Metal Chelates, Pharm. Ztg. 118(26) 987-90, 1973. "Idiosyncratic Neurotoxicity: Clioquinol and Bismuth," 1980, The Lancet pp. 857-858. Baumgartner et al., 1979, Neurotoxicity of halogenated hydroxyquinolines: clinical analysis of cases reported outside Japan, Journal of Neurology, Nuerosurgery, and Psychiatry 42:1073-1083. Beppu, H., 1973, "Toxicity of Clioquinol (5-chloro-7-iodo--8-hydroxy quinoline) on chick embryo dorsal root ganglia in tissue culture," 13:551-560 (w/ English abstract). Borg-Neczak et al., 1994, "Effect of 8-Hydroxy-,8-Mercapto- and 5-Chlorol-7-iodo-8-hydroxy-quinoline on the Uptake and Distribution of Nickel in Mice," Pharmacology & Toxicology 74:185-192. Bush et al., 1994, "Rapid Induction of Alzheimer A.beta. Amyloid Formation by Zinc," Science 265:1464-1467. Bush et al., 1995, "The Role of Zinc in the Cerebral Deposition of A.beta. Amyloid in Alzheimer's Disease," Amyloidogenesis pp. 607-618. Bush et al., 1995, "Zinc and Alzheimer's Disease," Science 268:1921-1923. Chaiyabutr et al., 1985, "Urinary Bladder Effects After Oral Dosages of the ntidiarrhoeal Drug (Clioquinol/Phanquinone/Oxyphenonium Bromide) in Experimental Drugs," J. Med. Ass. Thailand 68(12):649-653. Committee on Drugs, "Blindness and Neuropathy From Diiodohydroxyquin-Like Drugs," American Academy of Pediatrics, pp. 378-379. Crapper McLachlan et al., 1991, Intramuscular desferrioxamine in patients with Alzheimer's disease, The Lancet 337:1304-1308. Degen et al., 1979, "Percutaneous Absorption of Clioquinol (Vioform.RTM.)," Dermatologica 159:295-301. Esler et al., 1996, "Zinc-Induced Aggregation of Human and Rat .beta.-Amyloid Peptides in Vitro," Jounral of Neurochemistry 66(2):723-732. Fitzgerald, 1995, "Zinc and Alhzeimer's Disease," Science 268:1920-1923. Goto et al., 1982, "Impairment of Visual System of Beagles Orally Ingesting Clioquinol," The Journal of Toxicological Sciences 7:19-25. Goto et al., 1982, "Deterioration of Spinal Reflex in Beagles Orally Ingesting Clioquinol," The Journal of Toxicological Sciences 7:-12. Holtzman et al., 1996, "Developmental abnormalities and age-related neurodegeneration in a mouse model on Down syndrome," Proc. Natl. Acad. Sci. USA 93:13333-13338. Hori et al., 1987, "5-Chloro-7-Iodo-8-Hydroxyquinoline (Clioquinol) Inhibits The Nerve Growth Factor-Induced Stimulation Of RNA Synthesis In Neonatal Rat Superior Cervical Ganglion, In Vitro," The Journal of Toxicological Sciences 12:97-109. Jack et al., 1973, "Pharmacokinetics of Iodochlorhydroxyquin in Man," Journal of Pharmaceutical Sciences 62(12):1929-1932. Kaiser, 1994, "Alzheimer's: Could Thre Be a Zinc Link?," Science 265:1365. Kawahara et al., 1997, "Alzheimer's Disease Amyloid .beta.-Protein Forms Zn.sup.2+ -Sensitive, Cation-Selective Channels Across Excised Membrane Patches from Hypothalamic Neurons," Biophysical Journal 73:67-75. Kirschner et al., 1987, "Synthetic peptide homologous to .beta. protein from Alzheimer disease forms amyloid-like fibrils in vitro," Proc. Natl. Acad. Sci. USA 84:6953-6957. Kono, R., 1975, "Introductory Review Of Subacute Myelo-Optico-Neuropathy (SMON) And Its Studies Done By The SMON Research Commission," Japan J. Med. Sci. Biol. 28:1-21. Kotaki et al., 1983, "Intestinal Absorption and Metagolism of Clioquinol in the Rat," J. Pharm. Dyn. 6:881-887. Koyama ete al., 1989, "Electrophysiological changes in the fasciculus gracilus of the cat following chronic clioquinol administration," Journal of the Neurological Sciences 94:271-282. LaFerla et al., 1996, "Extracellular Deposition of .beta.-Amyloid upon p53-dependent Neuronal Cell Death in Transgenic Mice," J. Clin. Invest. 98(7):1626-1632. Meade, T.W., 1975, "Subacute myelo-optic neuropathy and clioquinol," Brit. J. prev. soc. Med. 29:157-169. Mumenthaler et al., 1979, "Transient global amnesia after clioquinol," Journal of Neurology, Neurosurgery, and Psychiatry 42:1084-1090. Muratov et al., 1983, "Interaction of Voltaren and some Pyrazolone and Aniline Derivatives with Endoperoxide Prostaglandin Synthetase," pp. 44-46 (w/ English abstract). Nakae et al., 1972, "Relation between Subacute Myelooptic Neuropathy (S.M.O.N.) and Clioquinol: Nationwide Survey," The Lancet pp. 171-173. Oakley, Jr., G.P., 1973, "The Neurotoxicity of the Halogenated Hydroxyquinolines," JAMA 225(4):395-397. Oguro, 1974, "The interference of the water-soluble organic compounds in atomic absorption spectrophotometry of calcium," Japan Analyst pp. 1375-1378. Okada et al., 1984, "Effects Of Metal-Containing Drugs Taken Simultaneously With Clioquinol Upon Clinical Features Of SMON," The Journal of Toxicological Sciences 9:327-341. O'Mahony et al., 1995, "Bone Aluminium Content in Alzheimer's Disease," Dementia 6:69-72. Ozawa et al., 1986, "Experimental Clioquinol Intoxication in Rats: Abnormalities in Optic Nerves and Small Nerve Cells of Dorsal Root Ganglia," Acta Neuropathol (Berl) 69:272-277. Pericin, 1979, "Comparison of the Acute Toxicity of Clioquinol, Histamine, and Chloroform in Different Strains of Mice," Arch. Toxicol. Supple. 2:371-373. Polites, 1996, "Transgenic model applications to drug discovery," Int. J. Exp. Path. 77:257-262. Ricoy et al., 1982, "Subacute Myelo-Optic Neuropathy (SMON)," Journal of the Neurological Sciences 53:241-251. Ross et al., 1997, "Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins," Nature Medicine 3(8):872-878. Sargeaunt et al., 1976, "In vitro sensitivity of Entamoeba histolytica to furazolidone and iodochlohydroxyquin, separate and combined," Transactions of the Royal Society of Tropical Medicine and Hygiene 70(4):54-56. Schmid et al., 1973, "Studies of the Distribution and Excretion of Clioquinol in the Animal," Arzneim.-Forsch. (Drug Res.) 23(11):1560-1566. Shigematsu, I., 1975, "Subacute Myelo-Optico-Neuropathy (SMON) And Clioquinol," pp. 35-54. Shiraki, H., 1972, "The Neuropathology Of Subacute Myelo-Optico-Neuropathy, "SMON", In The Humans," pp. 101-164. Sobue et al., 1971, "Myeloneuropathy with abdominal disorders in Japan," Neurology 21:168-173. Sobue, "Clinical aspects of subacute myelo-optico-neuropathy (SMON)," Handbook of Clinical Neurology 37:116-139. Tamura et al., 1973, "Identification Of Green Pigment And Analysis Of Clioquinol In Specimens From Patients With Subacute Myelo-Optico-Neuropathy," Clinica Chimica Acta 47:13-20. Tamura, Z., 1975, "Clinical Chemistry of Clioquinol," pp. 69-77. Tateishi et al., 1975, "Experimental Reproduction of SMON in Animals by Prolonged Administration of Clioquinol: Clinoco-Pathological Finding," 28:165-186. Tateishi et al., 1976, "Neurotoxicity of Iodoxyquinoline: A Further Study on Beagle Dogs," 28:187-195. Thomas et al., 1984, "Correlated Nerve Conduction, Somatosensory Evoked Potential And Neuropathological Studies In Clioquinol And 2,5-Hexanedione Neurotoxicity In The Baboon," Journal of the Neurological Sciences 64:277-295. Tsubaki et al., 1971, "Neurological Syndrome Associated with Clioquinol," The Lancet 696-697. Wadia, 1984, "SMON as seen from Bombay," Acta Neurol Scand 70(suppl 100):159-164. Weathersbee, A.A., 1943, "Observations On The Relative Attractiveness Of Man And Horse For Anopheles Albimanus Weideman," The American Journal of Tropical Medicine 14:25-33. Weismann et al., 1978, "Effects of Penicillamine and Hydroxyquinoline on Absorption of Orally Ingested .sup.65 Zinc in the Rat," The Journal of Investigative Dermatology 71:242-244. Wieniewski et al., 1996, "Some neuropathological aspects of Alzheimer's disease and its relevance to other disciplines," Neuropathology and Applied Neurobiology 22:3-11. Wokes et al., 1955, "Human Dietary Deficiency of Vitamin B.sub.12," The American Journal of Clinical Mutrition 3(5):375-382. Yamanaka et al., 1973, "Uncoupling of Oxidative Phosphorylation of Rat Liver Mitochondria by Chinoform," J. Biochem. 73:993-998. Yoshimura et al., 1992, "The Same Chemicals Induce Different Neurotoxicity When Administered in High Doses for Short Term or Low Doses for Long Term to Rats and Dogs," Molecular and Chemical Neuropathology 16:59-84. Zaks et al., "Spasmolytic and Anti-Inflammatory Activity of 8-Hydroxyquinolines," p. 47 (English abstract). |
| PATENT CLAIMS |
What is claimed is: 1. A method of treating a subject having or suspected of having Parkinson's disease comprising administering to the subject an amount of clioquinol effective to treat or delay the onset of Parkinson's disease. 2. The method according to claim 1 wherein the clioquinol is (a) administered for one to three weeks, followed by (b) a period of one to four weeks during which clioquinol is not administered. 3. A method of treating a subject having or suspected of having Parkinson's disease comprising administering to the subject (a) an amount of clioquinol effective to treat or delay the onset of Parkinson's disease; and (b) vitamin B.sub.12. 4. The method according to claim 3 wherein a pharmaceutical composition comprising clioquinol is administered for one to three weeks, followed by a period of one to four weeks during which a pharmaceutical composition comprising vitamin B.sub.12 is administered and clioquinol is not administered. 5. The method according to claim 3 wherein the amount of vitamin B.sub.12 is effective to inhibit a detrimental side effect of clioquinol administration. 6. The method according to claim 3 wherein the clioquinol and vitamin B.sub.12 are comprised in a single pharmaceutical composition. 7. The method according to claim 3 wherein the clioquinol and vitamin B.sub.12 are administered sequentially. 8. The method according to claim 3 wherein the clioquinol and vitamin B.sub.12 are administered substantially simultaneously. 9. The method according to claim 5 wherein a pharmaceutical composition comprising clioquinol is administered for one to three weeks, followed by a period of one to four weeks during which a pharmaceutical composition comprising vitamin B.sub.12 is administered and clioquinol is not administered. 10. The method according to any one of claims 1 to 9 wherein the subject is human. 11. The method according to claim 1 or 3, wherein the clioquinol is administered in an amount of 10 to 250 mg. 12. The method according to claim 1 or 3, wherein trace metals and/or prosthetic groups are administered together with or subsequent to the administration of clioquinol. 13. The method according to claim 1 or 3, wherein the clioquinol is administered intermittently. 14. The method according to claim 2, wherein trace metals and/or prosthetic groups are administered during the period of one to four weeks during which clioquinol is not administered. 15. The method according to claim 1, wherein the clioquinol is administered for up to ten years. 16. The method according to claim 1 or 3, wherein the clioquinol is formulated for oral administration. 17. The method according to claim 1 or 3, wherein the clioquinol is formulated for parenteral administration. 18. The method according to claim 1 or 3, wherein the clioquinol is formulated for intradermal administration. 19. The method according to claim 1 or 3, wherein the clioquinol is formulated in a capsule. 20. The method according to claim 1 or 3, wherein the clioquinol is purified. 21. A pharmaceutical composition comprising an amount of clioquinol effective to treat or delay the onset of Parkinson's disease, and vitamin B.sub.12. 22. The pharmaceutical composition according to claim 21, which further comprises a pharmaceutically acceptable carrier. 23. The pharmaceutical composition according to claim 21, wherein the amount of clioquinol is 5 to 250 mg. 24. The pharmaceutical composition according to claim 21, wherein the amount of clioquinol is 10 to 50 mg. 25. The pharmaceutical composition according to claim 21, wherein the amount of vitamin B.sub.12 is 5 .mu.g to 2 mg. 26. The pharmaceutical composition according to claim 23, wherein the amount of vitamin B.sub.12 is 5 .mu.g to 2 mg. 27. The pharmaceutical composition according to claim 21, wherein the amount of vitamin B.sub.12 is 0.5 mg to 1 mg. 28. The pharmaceutical composition according to claim 21, wherein the composition is formulated for parenteral or intradermal administration. 29. The pharmaceutical composition according to claim 21, wherein the composition is formulated for oral administration. 30. The pharmaceutical composition according to claim 21, 22, or 23, wherein the pharmaceutical composition is formulated as a pill. 31. The pharmaceutical composition according to claim 21, 22, or 23, wherein the pharmaceutical composition is formulated as a tablet. 32. The pharmaceutical composition according to claim 21, 22, or 23, wherein the pharmaceutical composition is formulated as a capsule. 33. The pharmaceutical composition according to claim 21, 22, or 23, wherein the pharmaceutical composition is formulated as a suppository. 34. The pharmaceutical composition according to claim 21, 22, or 23, wherein the pharmaceutical composition is formulated for oral administration with an emulsifying agent. 35. The pharmaceutical composition according to claim 34, wherein the emulsifying agent is N-(4'-stearoylamino-phenyl)-trimethylammonium methyl sulfuric acid. 36. The pharmaceutical composition according to claim 21, 22 or 23, wherein the clioquinol and vitamin B.sub.12 are each purified. 37. The pharmaceutical composition of claim 32, wherein the clioquinol and vitamin B.sub.12 are each purified. 38. A kit comprising in one or more containers an amount of clioquinol effective to treat or delay the onset of Parkinson's disease, and an amount of vitamin B.sub.12 effective to inhibit a detrimental side effect of clioquinol administration. |
| PATENT DESCRIPTION |
1. INTRODUCTION The present invention is directed to methods of treatment and prevention of Parkinson's disease by administering the chelating agent clioquinol. The clioquinol may be administered in combination with vitamin B.sub.12. 2. BACKGROUND OF THE INVENTION 2.1. Parkinson's Disease Despite enormous therapeutic advances, Parkinson's disease (PD) continues to be one of the most common causes of disability in the elderly. In patients with typical Parkinson's disease, the results of magnetic resonance imaging are usually normal. However, when a high field strength, heavily T2 weighed magnetic resonance imaging is used, a wider area of lucency in the substantia nigra is seen, indicative of increased accumulation of iron. In general, iron in the substantia nigra area has been reported in many publications as being causative of or at least contributory to the development of Parkinson's disease. Iron is known to be a catalyst for the fenton reaction, by which the generation of reactive oxygen free radicals occurs. Iron is typically found within cells in the iron storage molecule ferritin. Once stored in ferritin, iron is generally unavailable as a catalyst for the production of free radicals. Research has been focused on the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin) model of Parkinson's disease based on the advances in the neuropathology and neurochemistry of the disease. This toxin selectively damages the dopaminergic neurones of the substantia nigra when oxidized to MPP+. Anti-oxidants prevent the oxidation of MPTP to MPP+ and have been investigated clinically for the treatment of Parkinson's disease. It has been also postulated that endogenous or exogenous toxins, including metabolites of dopamine, generate hydroxyl radicals and hydrogen peroxide, which are known neurotoxic substances. These toxins interfere with normal mitochondrial metabolism. Abnormalities have also been reported in the complex I (NADH:ubiqinone oxidoreductase). 2.2. Clioquinol Clioquinol has been formulated and administered in various ways, at various doses (Ozawa et al., 1986, Acta Nueropathol (Berl) 69:272-277; Yamanaka et al., 1973, J. Biochem. 73:993-998; Sobue et al., 1971, Neurology 21:168-173; Tamura et al., 1973, Clinica Chimica Acta. 47:13-20; Jack and Riess, 1973, J. Pharm. Sci. 62(12):1929-1932; Baumgartner et al., 1979, Journal of Neurology, Neurosurgery, and Psychiatry 42:1073-1083, Kono, 1975, Japan. J. Med. Sci. Biol. 28:1-21; Sargeaunt and Lumsden, 1976, Transactions of the Royal Society of Tropical Medicine and Hygiene 70(1):54-56; Nakae et al., 1973, Lancet 171-173; Mumenthaler et al., 1979, Journal of Neurology, Neurosurgery, and Psychiatry 42:1084-1090; Schmid et al., 1973, Arzneim.-Forsch. (Drug Res.) 23(11):1560-1566; Oakley, 1973, JAMA 225(4):395-397; David et al., 1943, American J. Trop. Med. 24:29-33; Thomas et al., 1984, Journal of the Neurological Sciences 64:277-295; Yoshimura, 1992, Molecular and Chemical Neuropathology 16:59-84; Nakae, 1974, Japan Public Health Journal 15:607-611; Tateishi, 1973, Japan Public Health Journal 15:187-196; Degen et al., 1979, Dermatologica 159:295-301; Goto et al., 1982, J. Toxicological Sciences 7:1-12). Clioquinol (5-chloro-7-iodo-8 hydroxyquinoline) was previously frequently used for the treatment of various disorders, such as amoebiasis and non-specific infectious diarrhea (Kono, 1975, Japan J. Med. Sci. Biol. 28:1-19, Meade, 1975, Brit. J. Prev. Soc. Med. 29:157-169). However, the use of clioquinol was stopped in Japan when the Japanese Government officially banned the sale in September 1970. The ban was motivated by the presumption that clioquinol caused subacute myelo-optico-neuropathy (SMON). Subsequently, clioquinol was withdrawn from the market in most other countries of the world on the recommendation of the World Health Organization. SMON develops with an acute or subacute onset preceded by abdominal disorders and is characterized by dysesthesia of the legs, sensory disturbances, a variable degree of motor weakness, and visual loss. Corresponding to these clinical findings, SMON reveals pathologically symmetrical degeneration in peripheral nerves, spinal cord, posterior column, cardiac-spinal tract, and optic nerves. The occurrence of SMON was confined to Japan even though clioquinol was prescribed worldwide and not only in Japan. In the published literature no systematic pathological features resulting from the administration of clioquinol have been described other than the cases of SMON in Japan. Although, in March 1972, the SMON Research Commission in Japan established a guideline for the treatment of SMON, wherein vitamin B.sub.12 was recommended to be administered as part of a supply of various vitamins (Jap. Med. Sci. Biol. 28 Suppl. (1975)), it was never recognized that the deficiency of vitamin B.sub.12, at least to some extent, might be responsible for SMON. Actually, the effect of vitamin B.sub.12 in the treatment of SMON has been contested by Okuda, K. ("On vitamin B.sub.12 metabolism in SMON patients years after the onset." Report of SMON Research Commission in 1972 (1973) 86), who reported that the vitamin B.sub.12 level in the serum of SMON patients is normal. It was also observed that there may be pathological differences between SMON and B.sub.12 deficiency (Ricoy et al., 1982, J. Neurol. Sci. 53:241-251.) Hence, it was supposed that the administration of vitamin B.sub.12 would not produce any improvement in the symptoms and signs of SMON. After the withdrawal of clioquinol from the market there was a dramatic disappearance of new cases of SMON. At present, clioquinol is used topically due to its antibacterial and anti-fungal activity in skin infections. Clioquinol has recently been shown to be effective in the treatment of Heliocobacter pylori (see International Publication No. WO 95/31199, dated Nov. 23, 1995) and neurotoxic injury (see International Publication No. WO 97/09976, dated Mar. 20, 1997 of Washington University). The chelating ability of clioquinol is known for Fe, Co, Ni and Zn (Kidani et al., 1974, Jap. Analyst 23:1375-1378). Using mass spectrophotometry the coordination number for clioquinol for Co(II), Ni(II), Cu(II) and Zn(II) is 2, whereas the coordination number for Fe(III) is 3. Reportedly, injected preparations of clioquinol have crossed the blood-brain-barrier, leaving concentrations thereof in the brain on the order of 20 .mu.l/ml when administered at dosages of 10-20 mg/kg (Tateishi et al., 1973, Psychiat. Neurol. Jap. 75:187-196 and Tamura, 1975, Jap. J. Med. Sci. Biol. Suppl 28:69-77). The concentration of clioquinol was also found to be high in such areas of the brain as the hippocampus. Using microautoradiographic techniques, clioquinol has been shown in monkeys to form zinc chelates in the hippocampus. The Zn(II) chelates were mainly found in the terminal axodendritic boutons of the mossy fibres. Unconjugated clioquinol has an extremely rapid penetration into the nervous system when injected intravenously, with the ability to cross the blood-brain-barrier (Shiraki, 1979, In: Intoxications of the Nervous System. Part II. Handbook of Clinical Neurology, Vinken et al. eds., North Holland Publishing Co., New York, pp. 115-139). Citation or discussion of a reference hereinabove shall not be construed as an admission that such is prior art to the present invention. 3. SUMMARY OF THE INVENTION The present invention provides methods of treating or preventing Parkinson's disease by administering clioquinol alone or in combination with vitamin B.sub.12. Also according to the present invention, a pharmaceutical composition is provided, which comprises clioquinol, vitamin B.sub.12, and, optionally, pharmaceutically acceptable carriers. 4. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the NMR spectra of three solutions. Solution a contained vitamin B.sub.12 (hydroxycobalamin), at a concentration of 2.6 mM. Solution b contained a mixture of 2.6 mM vitamin B.sub.12 and 10 mM clioquinol glucuronide (mole ratio of about 1:4). Solution c contained 10 mM clioquinol glucuronide. FIG. 2 depicts the right half of FIG. 1 expanded for easier comparison of the resonance positions. FIG. 3 depicts the left half of FIG. 1 expanded for easier comparison of the resonance positions. 5. DETAILED DESCRIPTION OF THE INVENTION In the following the invention will be explained in further detail. The present invention provides methods of treating or preventing Parkinson's disease by administering clioquinol or a combination of clioquinol and vitamin B.sub.12. The relationship between SMON and clioquinol has been investigated and an explanation of the development of SMON as a consequence of clioquinol administration has been discovered. Thus, a further object of the present invention is to remove or alleviate or prevent at least some of the side effects that occur when clioquinol is administered. This object is achieved through the co-administration of vitamin B.sub.12 with clioquinol. In the following the invention will be explained in further detail. The proposed mechanism of action of the invention is not intended to limit the invention to said mechanism. It is known that clioquinol is excreted through the kidneys as glucuronide or sulfate derivatives (Kotaki et al.: "Enterohepatic circulation of clioquinol in the rat", J. Pharmacobiodyn. 1984 June; 7(6):420-5 and Jurima et al.: "Metabolism of 14C-iodochlorhydroxy-quinoline in the dog and the rat", J. Pharmacobiodyn. 1984 March; 7(3):164-70), e.g., as the compound methyl(5-chloro-7-iodo-quinolyl-2',3',4'-tri-O-acetyl-glucopyranosid)urona te. For short, this compound is referred to as clioquinol glucuronide in the following. The detoxification of hydrophobic substances, such as clioquinol, in the body predominantly occurs in the liver. Therefore, it is believed that the clearance of clioquinol happens as follows: Clioquinol is converted to clioquinol glucuronide in the liver. Following the formation, the water soluble clioquinol glucuronide is secreted to the bile. The bile enters the intestine, wherein a major amount of the clioquinol glucuronide is evacuated in the stool. A certain amount of the clioquinol glucuronide is resorbed from the intestine to the blood. The clioquinol glucuronide is filtered from the blood in the kidneys and appears in the terminal urine. By treating mice with clioquinol and subsequently administering a radioisotope of vitamin B.sub.12 ([.sup.57 Co]-cyanocobalamine), it is shown in Example 1 below that the concentration of vitamin B.sub.12 in the brain and the liver of the clioquinol-treated mice remains at a normal level, whereas the concentration of the radioisotope of vitamin B.sub.12 is decreased in the kidney of such mice compared to the normal level. This finding suggests a metabolism of vitamin B.sub.12 being dependent on clioquinol. Further, the finding suggests that the kidneys are the target organs, wherein the clioquinol dependent metabolism occurs. In order to investigate a possible interaction between clioquinol glucuronide and vitamin B.sub.12, an experiment was designed, wherein clioquinol glucuronide and vitamin B.sub.12 were mixed in water. The mixture was analyzed by .sup.1 H NMR. The .sup.1 H NMR spectra, see FIGS. 1-3, show that some of the resonances of vitamin B.sub.12 (corresponding to the benzimidazole moiety) have shifted, and the same is observed for two resonances of the clioquinol glucuronide (corresponding to the quinoline moiety). It is believed by applicant that similar results would be expected using free clioquinol, however clioquinol cannot be dissolved in aqueous solutions for NMR testing. The results indicate a hydrophobic interaction between clioquinol glucuronide and vitamin B.sub.12, possibly between the benzimidazole moiety of the vitamin B.sub.12 and the quinoline moiety of clioquinol glucuronide. Vitamin B.sub.12 is normally resorbed actively from the renal plasma after it has been filtered. In that way the body recovers most of the vitamin B.sub.12 that would otherwise have been lost in the urine. It has recently been demonstrated that the resorption of vitamin B.sub.12 is mediated by the action of the membrane protein megalin (Moestrup et al., Proc. Natl. Acad. Sci. 1996; 93(16):8612-7). The megalin is shown to have a strong affinity towards the binding of a complex formed by vitamin B.sub.12 and the transport protein transcobalamin. Based on the new finding reported herein, viz. that vitamin B.sub.12 binds to clioquinol glucuronide, it is believed that vitamin B.sub.12 does not bind to the megalin protein and/or the transcobalamin when it is already bound to the clioquinol glucuronide. Thus, the resorption of vitamin B.sub.12 will fail and the body will suffer from vitamin B.sub.12 deficiency after a certain time period of clioquinol administration if the body is not supplied with enough new vitamin B12 through the normal diet. At present, it is believed that clioquinol and A.beta. competitively chelate zinc and other heavy metals. Clioquinol is regarded as the stronger chelator and will, therefore, predominately capture the heavy metal ions. Thus, A.beta. from precipitated zinc-A.beta. will be resolubilized into the surrounding fluid because clioquinol will capture the zinc ions. The complex of clioquinol and zinc will penetrate the blood-brain-barrier and be cleared from the organism. Since clioquinol is a relatively strong chelator, it may also chelate metal ions from enzymes or prosthetic groups. Therefore, it might be desirable to supplement trace metal ions or prosthetic groups to clioquinol treated patients, especially when establishing prolonged clioquinol treatments. Vitamin B.sub.12 contains cobalt. Since the only source of vitamin B.sub.12 is microorganisms, only microorganisms and species eating microorganisms contain vitamin B.sub.12. Thus, diets low in meat and/or microorganisms will evidently cause vitamin B.sub.12 deficiency. If persons are supplied with diets with a too low content of vitamin B.sub.12, the administration of clioquinol will worsen the condition as the resorption of B.sub.12 is prevented by the competitive binding of clioquinol with megalin. The fact that the Japanese diet in the 1960s predominantly consisted of vegetables and cereals, especially rice (Kromhout D., et al.: "Food consumption pattern in the 1960s in seven countries", Am. J. Clin. Nutri. 49:889-894, 1989), may explain why the SMON disease was confined to Japan. The present invention solves the problem of clioquinol induced vitamin B.sub.12 deficiency and the subsequent development of SMON by the co-administration of vitamin B.sub.12 and clioquinol. Compositions, formulations, and kits for such co-administration are provided. 5.1. Treatment of Parkinson's Disease In a specific embodiment, the invention provides a method of treating or preventing Parkinson's disease (PD) with clioquinol or with a combination of clioquinol and vitamin B.sub.12. Clioquinol is believed to have the ability to penetrate the blood-brain barrier, to effectively chelate heavy metals to prevent the generation of hydroxyl radicals and hydrogen peroxide, and to prevent oxidation of molecules found in the brain, including MPTP. A role for an increase of oxidative stress in the mechanism of Parkinson's disease development is implicated by the finding that in all stages of Parkinson's disease, patients exhibit increased iron levels, decreased ferritin levels, and reduced glutathione (glutathione acts as a free radical scavenger by serving as a reducing agent). Without intending to be bound by any mechanism, the aim of using a chelating agent such as clioquinol is to chelate or clear the iron that has been accumulated in the brain and, in particular, in the substantia nigra. In this way, iron catalyzed free radical production can be minimized and the oxidation of MPTP or other molecules inhibited. Clioquinol may be administered in any appropriate amount in any suitable galenic formulation and following any regime of administration. Preferably, the amount of daily administration will be from 10 mg to 750 mg clioquinol depending on the condition of the patient. A typically daily dosage is 100 mg. Alternatively, from 10 mg to 250 mg, or, from 5 mg to 250 mg, preferably 100 mg clioquinol, three times daily, may be administered. A daily dosage of up to 750 mg for a period of two weeks is considered to present no risk of neurotoxicity or other side effects. In another embodiment, the daily dose of clioquinol is less that 100 mg. For methods which include the administration of vitamin B.sub.12, a typical daily dose of vitamin B.sub.12 is, for example, 5 .mu.g to 2 mg, preferably 0.5 to 1 mg. The actual administered amounts of clioquinol and vitamin B.sub.12 may be determined by a supervising physician. For the prevention of the onset of the symptoms and signs of Parkinson's disease, or for the delay of the symptoms and signs in the evolution of the disease, daily clioquinol dosages of 100 mg or less can be administered for long periods, viz. up to ten years. By way of example, but not limitation, methods of the invention can be used for: 1) patients diagnosed with PD at any clinical stage of the disease, 2) the prevention of PD in patients with early or prodromal symptoms or signs, and 3) the delay of the onset or evolution or aggravation of the symptoms and signs of PD. The methods of the invention will be, for example, useful for the treatment of PD, the improvement or alleviation of any symptoms and signs of PD, the improvement of any pathological or laboratory findings of PD, the delay of the evolution of PD, the delay of onset of any PD symptoms and signs, the prevention of occurrence of PD, and the prevention of the onset of any of the symptoms and signs of PD. The actual administered amount is to be decided by the supervising physician and may depend on multiple factors, such as, the age, condition, file history, etc. of the patient in question. If clioquinol is going to be administered for a prolonged period, it is preferably administered intermittently. In a first period clioquinol may be administered, e.g., for one to three weeks followed by a wash-out period, which may provide for the lessening of any unwanted side effects of clioquinol. The duration of the wash-out period may be one to four weeks. After the wash-out period the first period may be repeated. If vitamin B.sub.12 is to be administered, such administration may take place during the clioqinol administration period, during the wash-out period, or during both periods. The long-term intermittent therapy will provide not only for the treatment of Parkinson's disease, but also for the prophylactic inhibition of the development of Parkinson's disease. The intermittent administration of clioquinol will also reduce the toxicity potential of the drug, which means that the treatment may be extended throughout the evolution of the disease. Prior to administration to humans, efficacy of the clioquinol formulation is preferably shown in animal models. Any animal model for Parkinson's disease known in the art can be used. The subject, or patient, to be treated using the methods of the invention is an animal, e.g., a mammal, and is preferably human, and can be a fetus, child, or adult. 5.2. Pharmaceutical Compositions The pharmaceutical compositions according to the present invention preferably comprise one or more pharmaceutically acceptable carriers and the active constituents. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In a preferred embodiment, the clioquinol and/or vitamin B.sub.12 in the pharmaceutical composition is purified. It will be appreciated that the amounts of clioquinol and vitamin B.sub.12 required for said treatment or prevention will vary according to the route of administration, the disorder to be treated, the condition, age, and file history of the subject, the galenic formulation of the pharmaceutical composition, etc. Preferably, the clioquinol used in the invention is of high purity, such as that provided by Spectrum Quality Products, specification: USP 23; however any suitable preparation of clioquinol can be used in the methods and compositions of the invention. Preferably, the vitamin B.sub.12 used in the invention is of high purity, such as that provided by Hoffman La Roche, Ltd., specification: pharmaceutical grade; however any suitable preparation of vitamin B.sub.12 can be used in the methods and compositions of the invention. In general, a suitable (therapeutically effective) amount of clioquinol in the pharmaceutical composition is, for example, 5 to 250 mg, preferably 10 to 50 mg. A suitable amount of vitamin B.sub.12, effective to inhibit clioquinol related side effects, in the pharmaceutical composition is, for example, 5 .mu.g to 2 mg, preferably 0.5 to 1 mg. The actually administered amounts of clioquinol and vitamin B.sub.12 may be decided by a supervising physician. Clioquinol and vitamin B.sub.12 can be in the same composition for administering in combination concurrently, or in different compositions for administering concurrently but separately, or sequentially. Therapeutic formulations include those suitable for parenteral (including intramuscular and intravenous), oral rectal or intradermal administration, although oral administration is the preferred route. Thus, the pharmaceutical composition may be formulated as tablets, pills, syrups, capsules, suppositories, formulations for transdermal application, powders, especially lyophilized powders for reconstitution with a carrier for intravenous administration, etc. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. The carriers in the pharmaceutical composition may comprise a binder, such as microcrystalline cellulose, polyvinylpyrrolidone (polyvidone or povidone), gum tragacanth, gelatine, starch, lactose or lactose monohydrate; a disintegrating agent, such as alginic acid, maize starch and the like; a lubricant or surfactant, such as magnesium stearate, or sodium lauryl sulphate; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; and/or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. Therapeutic formulations suitable for oral administration, e.g., tablets and pills, may be obtained by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing clioquinol and vitamin B.sub.12, and compressing this mixture in a suitable apparatus into tablets having a suitable size. Prior to the mixing, the clioquinol may be mixed with a binder, a lubricant, an inert diluent and/or a disintegrating agent and the vitamin B.sub.12 may be mixed with a diluent, a lubricant and/or a surfactant. Alternatively, the vitamin B.sub.12 may be omitted. In a preferred embodiment, free-flowing clioquinol powder is mixed with a binder, such as microcrystalline cellulose, and a surfactant, such as sodium lauryl sulphate until a homogeneous mixture is obtained. Subsequently, another binder, such as polyvidone, is transferred to the mixture under stirring. When a uniform distribution is obtained an aqueous solution of vitamin B.sub.12 is added under constant stirring. This mixture is passed through granulating sieves and dried by desiccation before compression into tablets in a standard compressing apparatus. In a second preferred embodiment, free-flowing clioquinol powder is mixed with surfactants and/or emulsifying agents, such as Sapamine.RTM. (N4'-stearoyl amino phenyl)-trimethylammonium methyl sulfuric acid) and lactose monohydrate until a uniform distribution of the constituents is obtained. A second preparation containing a disintegrating agent, such as maize starch, is added to the clioquinol mixture under continuous stirring. Such a second preparation may be prepared by adding excess boiling water to a maize starch suspended in cold water. An aqueous solution of vitamin B.sub.12 is added to the clioquinol mixture. The final mixture is granulated and dried as above and mixed with maize starch and magnesium stearate and finally compressed into tablets in a standard apparatus. A tablet may be coated or uncoated. An uncoated tablet may be scored. A coated tablet may be coated with sugar, shellac, film or other enteric coating agents. Therapeutic formulations suitable for parenteral administration include sterile solutions or suspensions of the active constituents. An aqueous or oily carrier may be used. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Formulations for parenteral administration also include a lyophilized powder comprising clioquinol and vitamin B.sub.12 that is to be reconstituted by dissolving in a pharmaceutically acceptable carrier that dissolves vitamin B.sub.12 and clioquinol, e.g., an aqueous solution of carboxymethylcellulose and lauryl sulfate. When the pharmaceutical composition is a capsule, it may contain a liquid carrier, such as a fatty oil, e.g., cacao butter. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. In yet another embodiment, the therapeutic compound can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)). In one embodiment of the pharmaceutical composition according to the invention, the active constituents, i.e., vitamin B.sub.12 and clioquinol, are comprised as separate entities. The two entities comprising vitamin B.sub.12 and clioquinol, respectively, may be administered simultaneously or sequentially. For example, clioquinol can be administered, followed by vitamin B.sub.12 administered within a day, week, or month of clioquinol administration. If the two entities are administered sequentially, the entity comprising clioquinol is preferably administered for one to three weeks followed by a wash out period of one to four weeks during which the entity comprising vitamin B.sub.12 is administered, but not the entity comprising clioquinol. After the wash out period, the treatment can be repeated. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. |
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