* — II 1 1 INI II II 1 1 II 1 1 II I Mil II I II OJII Eur°Pean Patent Office <*S Office europeen des brevets (11) EP 0 835 660 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51 ) |nt. CI.6: A61 K 31 170 15.04.1998 Bulletin 1998/16 // (A61 K31/70, 31 :535) (21) Application number: 96870130.0 (22) Date of filing : 1 4.1 0.1 996 (84) Designated Contracting States: (72) Inventor: AT BE CH DE DK ES Fl FR GB GR IE IT LI LU MC Merckx, Gaston Edmond Filomena NL PT SE 2650 Edegem (BE) Designated Extension States: AL LT LV SI (74) Representative: Van Reet, Joseph et al (71) Applicant: Gevers Patents S. A., Merckx, Gaston Edmond Filomena Brussels Airport Business Park, 2650 Edegem (BE) Holidaystraat 5 1831 Diegem (BE) (54) Products containing methylcobalamin for the treatment of multiple sclerosis or other demyelinating conditions (57) Products containing methylcobalamin in an overdose corresponding to a weekly intramuscular dose higher than 1000 micrograms, preferably higher than 1 200 micrograms and corresponding more preferably to a weekly intramuscular dose of at least 1500 micro- grams, and an antidepressant enhancing the serotonin level as a combined preparation for simultaneous, sep- arate or sequential use in the treatment of multiple scle- rosis or other demyelinating conditions. < O CO CO LO CO CO o Q_ LU Printed by Xerox (UK) Business Services 2.16.1/3.4 1 EP 0 835 660 A1 Description An object of the present invention is therefore to provide a treatment of MS whereby not only the myelin The present invention relates to products contain- reconstructing effects of methylcobalamin overdoses ing methylcobalamin for the treatment of multiple sclero- can be improved but whereby the motor ability can fur- sis (MS) or other demyelinating conditions. s ther be achieved and wherein especially the observed Multiple sclerosis is a common neurological disor- side-effects of methylcobalamin overdoses can be rem- der characterised either by episodic patches of inflam- edied. mation and demyelination (relapsing remitting According to the invention, these objects can be evolution), or by a chronic progressive evolution, which reached by combining the methylcobalamin overdoses can occur anywhere in the central nervous system 10 with a simultaneous, separate or sequential administra- (CNS) almost always without any involvement in the tion of an antidepressant enhancing the serotonin level. peripheral nerves. The use of antidepressants which work by interfer- The pathogenesis of multiple sclerosis has not yet ing with the inactivation of neurotransmitters, in particu- been elucidated. Some believe that the pathogenesis lar noradrenaline and/or serotonin, for the treatment of involves local disruption of the blood brain barrier, a 15 multiple sclerosis or other demyelinating conditions has local immune and inflammatory response, with subse- already been disclosed in W096/1 1 009. In this interna- quent damage to myelin and hence to neurons. Others tional patent application, these antidepressants are suggest that an important aspect of the pathogenesis of used, in combination with precursors of said neuro- multiple sclerosis is a possible disturbance in vitamin transmitters, for compensating for the effects of nerve B12 (cobalamin) metabolism (see Reynolds EH, Linnell 20 damage caused by MS or the other demyelinating con- JC, Faludy JE - Multiple sclerosis associated with vita- ditions. Such a possible compensation of nerve damage min B12 deficiency. Arch. Neurol. 48: 808, 1991 and has for example been observed by Scott et al. (Scott, Reynolds EH, Bottiglieri T, Laundy M, Crellin RF, Kirfer CF Jr., Cashman N, Spitler LE. Experimental Allergic SG. Vitamin B12 metabolism in multiple sclerosis. Arch. Encephalitis ; Treatment with Drugs which alters CNS Neurol. 49:649, 1992). 25 Serotonin Levels. Journal of Immunopharmacology, Based on this suggestion, Kira J. et al (see Kira J, 4(3), 153-162 (1982-83)) in experimental allergic Tobimatsu S, Goto I. Vitamin B12 metabolism and mas- encephalitis (EAE) of Guinea pigs, which is an acute sive-dose methyl vitamin B12 therapy in Japanese autoimmune demyelinating disease caused artif ically by patients with multiple sclerosis. Internal Medicine Vol. immunization with Guinea pig myelin basic protein 33, No. 2, Febr. 1994), have examined the effects of 30 (GPBP). They found that this disease may more partic- high methyl vitamin B12 overdoses on motor disability ularly be due to an immune response directed against and multimodality evoked potential (MEP) abnormalities CNS serotonin receptors and that the effect of such a in six patients with chronic progressive MS. After a treat- serotonin receptor blockage could be compensated for ment for 6 months with oral daily doses of 60 mg, it by drugs, such as imipramine and tryptophan, which could be concluded that the MEP abnormalities reflect- 35 enhance CNS serotonin levels. If a serotonin receptor ing the demyelinating lesions in the afferent pathways blockage could be found in multiple sclerosis, such a were improved but the motor disability did not improve therapy could also be effective for the treatment of MS. clinically. A massive-dose methyl vitamin B12 therapy In WO 91/11009, it is further suggested to give a was therefore recommended as a possible adjunctive background course of vitamin B12, more particularly therapy to immunosuppressive treatments for multiple 40 cyanocobalamin or hydroxocobalamin, in daily amounts sclerosis. which may be for example the conventional daily The present inventor has also found that a therapy requirement for this vitamin. In the treatment examples, with vitamin B12 overdoses has a positive effect on the it was desirable for patients with chronic progressive reflexes of an MS patient indicating the occurrence of MS, to include an 8-10 week course of 1000 micro- myelin reconstruction. This effect could be achieved 45 grams of hydroxocobalamin (intra-muscular) per week with lower overdoses than the overdoses by Kira et al, at the start of the treatment with the antidepressant and for example with intramuscular (IM) doses of about then 1000 micrograms every ten days thereafter. Since 1 500 ng per week. However, even at these lower doses, it is generally known that a vitamin B1 2 deficiency leads strong side-effects of the vitamin B12 therapy were to demyelination of the nerves, this optional hydroxoco- observed comprising pains distributed over the entire so balamin background course was clearly intended to body, including pains in the feet, legs, shoulders, ears, have a positive effect on myelin reconstruction. teeth, etc. These pains occurred when administering The treatment proposed by the present invention is, hydroxocobalamin but extended and increased consid- on the contrary, first of all based on methylcobalamin erably when changing over to methylcobalamin admin- overdoses effective for achieving myelin reconstruction istration. Further, the motor ability did not improve by ss and thus for remedying nerve damage. Indeed, methyl- the vitamin B12 therapy, moreover, spasticity occasion- cobalamin appeared according to Kira et al (see supra) ally turned over in weakness and buckling reactions in to be much more effective for myelin reconstruction than the legs. hydroxocobalamin. As already mentioned hereinabove, 2 3 EP 0 835 660 A1 4 the side-effects observed by the inventor are however 3. Biological clock function of the pineal gland also much more pronounced for methylcobalamin than for hydroxocobalamin. According to the present inven- In the pineal gland (being one of the important tion, it has now been found surprisingly that a particular human biological clocks), tryptophan is converted, on group of the antidepressants, which have been sug- 5 the one hand, into vitamin B3 and, on the other hand, gested in W096/1 1009 for compensating for the effects into 5-hydroxotryptophan (5-HTP), which is further con- of nerve damage caused by MS or other demyelinating verted into serotonin. At night, the serotonin is con- conditions, was also very effective in remedying the verted into acetylserotonin and further into melatonin. side-effects of methylcobalamin overdoses, although The serotonin produced by day is an important activity, such overdoses do not lead to nerve damage but, on the w mobility and good mood promoter and immuno-protec- contrary, to nerve repair. tor whilst melatonin produced at night is an important This surprising effect can be explained on the basis recovery and protection hormone responsible for cell of a general hypothesis developed by the present inven- protection and regeneration and also for immuno-regu- tor with respect to the etiology of multiple sclerosis and lation. The working of the pineal gland biological clock is the observed side-effects of methylcobalamin over- 15 controlled by noradrenaline released at night by sym- doses. This hypothesis is based on a number of bio- patic nerve endings and acting on p-adrenergic recep- chemical working mechanisms which are already tors of the pineal gland (see Ozawa K, Segawa T. known per se and which are schematically indicated on Methyl B12 and the intracerebral signal transduction the scheme of the general hypothesis shown in the sole system. Methyl B12 Forum, "Methyl B12", Internet K.K., figure, some correlations and interactions between 20 Tokyo, 1993, pp.20-23). Ozawa et al. further explained these separated systems being described for the first the effects of methylcobalamin, which was known to be time by the present inventor. efficacious in the treatment of sleep-wake rhythm disor- ders, on the working of the biological clock as being 1. Vitamin B12 metabolism based on an acceleration or an improval of signal trans- 25 missions via p-receptors. So a lack of methylcobalamin Vitamin B12 is delivered by the food mainly in the leads to a hypo-sensitivity of the pineal gland and so to form of hydroxocobalamin. This hydroxocobalamin is a dysfunction of the biological clock. transferred to the cells through the intermediary of sev- An analogous explanation was given by Honma et eral transcobalamins and is taken up by these cells, in al (Honma K, Kohsaka M, Fukuda N, Morita M and particular by the cells of the CNS.