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Cyanocobalamin-A Case for Withdrawal

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Cyanocobalamin-A Case for Withdrawal 686 Journal of the Royal Society of Medicine Volume 85 November 1992 Cyanocobalamin- a case for withdrawal: discussion paper A G Freeman MD FRCP Meadow Rise, 3 Lakeside, Swindon SN3 IQE Keywords: anaemia, pernicious; optic neuropathies; chronic cyanide intoxication; hydroxocobalamin; cyanocobalamin It seems evident that controversy still surrounds the reduced ability to detoxify the cyanide in the tobacco- treatment of pernicious anaemia and other vitamin smoke to which they are exposed'0. B12 deficiency disorders. The long quest for the 'anti- Patients with tobacco amblyopia who have normal pernicious anaemia factor' in the liver seemed to serum vitamin B12 levels need not continue therapy have ended in 1948 when pure cyanocobalamin was with intramuscular hydroxocobalamin once their isolated. This was found to be very active thera- visual acuity and visual fields have returned to peutically when given by intramuscular injection and normal providing they abstain from further smoking. was non-toxic in extremely high doses'. However, those patients who have low serum vitamin Lederle, in a recent commentary2, advocates that B12 levels or evidence of -defective vitamin B12 patients with pernicious anaemia should now be absorption will need to continue-indefinitely with treated with oral cyanocobalamin. He is not without hydroxocobalamin irrespective of their smoking support in that 40% of patients with pernicious habits as will all patients with pernicious anaemia anaemia in Sweden are being similarly treated3. and other vitamin B12 deficiency disorders who are He further states that such!- treatment is cheap at risk of developing- optic neuropathy if they and effective, produces clinical and haematological are smokers. remissions, and that most patients would prefer There is certainly no place for either oral or it if given the choice. He considers that a wider intramuscular cyanocobalamin in the treatment of appreciation of its effectiveness would be of value to such patients in that hydroxocobalamin and not physicians and that this is 'Medicine's best kept cyanocobalamin, is a powerful cyanide antagonist. secret' and that 'it is time to let the secret out'. Because confusion still persisted among doctors It is now known that there are at least four forms of over the various commercial forms of vitamin B12 vitamin B12 (cobalamin), ie cyanocobalamin, hydroxo- available for therapeutic use and their adverse effects cobalamin and two coenzymes forms which are in neuro-ophthalmological disorders, we presented a biochemically active, namely methylcobalamin and case for withdrawal of cyanocobalamin in favour of adenosylo-cobalamin4. hydroxocobalamin and submitted t-his in 1970 tothe Evidence has been presented that oral treatment Committee on Safety of Medicines'2. with vitamin B12 cannot replace body stores in As no action was taken by the manufacturers, we patients with Addisonian pernicious anaemia where asked again in 1978 'Svhy has cyanocobalamin not there is a lack ofgastric intrinsic factor due to an auto- been withdrawn?'. We laid particular emphasis on the immune gastritis causing malabsorption of vitamin fact- that some patients fail to respond to treatment B12 or in those who have undergone total gastrectomy- because, although hydroxocobalamin had been pres- or ileal resection. Such patients will require life-long cnbed, cyanocobalamin had been administered instead. parenteral vitamin B12 therapy. The, diagnosis may then be questioned, treatment In the United Kingdom, intramuscular hydroxo- stopped and the patient with tobacco amblyopia be cobalamin has replaced cyanocobalamin as it is condemned to a life of poor sight'3. retained in the body longer than cyanocobalamin and In 1981, the Committee on Safety ofMedicines drew thus for maintenance therapy needs only be given at attention to our thesis that hydroxocobalamin is intervals of 3 months5-7. effective in treatment of certain bptie neuropathies, In strongly opposing any treatment for pernicious of which tobacco amblyopia is an example, but anaemia other than parenteral hydroxocobalamin on cyanocobalamin is not. Since tobacco amblyopia may a life-time basis once the diagnosis has been confirmed occur in patients with pernicious anaemia it is clearly I would emphasize that hydroxocobalamin is also a preferable to use hydroxocobalamin routinely instead potent cyanide antagonist whereas cyanocobalamin is of cyanocobalamin'4. This view is supported by not. Thus oral or intramuscular cyanocobalamin Linnell and co-workers who, in support of our is ineffective in the treatment ofpatients with tobacco contention, stated that there was no condition in amblyopia or retrobulbar neuritis in pernicious which it has been claimed that cyanocobalamin was anaemia, examples ofoptic neuropathy due to chronic preferable to hydroxocobalamin and that there cyanide intoxication8. was no place for its continued use15. Despite these Healthy smokers with normal vision have raised recommendations it appears that cyanocobalamin has cyanocobalamin levels and raised plasma and urinary not been withdrawn for therapeutic use'6. thiocyanate levels, products of effective cyanide Even the World Health Organization's Committee detoxication as compared with the levels in healthy on the selection of essential drugs listed only cyano- non-smokers9. Patients with tobacco amblyopia, even cobalamin'7, thus placing an incalculable number if they smoke more than their healthy counterparts, of patients with tobacco and tropical amblyopia have much lower levels of plasma cyanocobalamin and optic neuropathy in pernicious anaemia at and thiocynate in their body fluids indicative of a risk. Journal of the Royal Society of Medicine Volume 85 November 1992 687 Since our original work on the aetiology oftobacco References amblyopia'8 and retrobulbar neuritis in Addisonian 1 Matthews DM, Linnell JC. Vitamin B12: an area of pernicious anaemia19 more than 30 years ago, I have darknss BAM 1979ii:5333-5 - been particularly concerned with the neuro-ophthal- 2 Lederle FA. Oral cobalamin for pernicious anaemia. mological manifestations of deficiency diseases and JAMA 199426b94-5- 3 Berlin R. Written communication, Nov. 1989 (cited by degenerative neuropathies. Clinical and laboratory Lederle FA, JAMA 1991;265:94-5) studies on the pathogenesis of such disorders have 4 Matthews DM. Distribution ofcobalamins in the animal been continued in many centres and the precise role body. In: Zagalak B, Friedrich W, eds. Vitamin B12: ofchronic cyanide intoxication has merited plarticular Proceedings ofthe 3rd European Symposium. Berlin: De attention. As a result of the development and Gruyter, 1979:681-94 application of the chromo-bioautographic method of 5 Drugs and Therapeutics Bulletin 1984;22:43-4 estimating individual plasma-cobalamins in neuro- 6 Chipping PM. Vitamin B12 deficiency. Prescribers' J ophthalmological disorders, it may in the future be 1988;28:117-24 possible to identify patients at risk in genetically 7 British National Formulary. March 1991:296-7 determined disorders, such as Leber's optic atrophy, 8 Freeman AG. Optic neuropathy and chronic cyanide Isuch intoxication: a review. J R Soc Med 1988;18:103-6 and thus initiate effective prophylactic measures 9 Wilson J, Linnell JC, Matthews DM. Plaacqbalmin as stopping smoking and giving hydroxocobalamin' in neuro-ophthalmelogal diseases. Lancet 1971i:777-8 intramuscularly before the onset ofirreversible visual 10 Wilson J, Matthews D)4. Metabolic inter-relationships failure8.' between cyanide, thiocyanate and vitamin B12 in Besides being present in tobacco-smoke and alcohol, smokerse and non-smokers. Cltn Sci 1966;#31:1-7 cyanide has a world-wide distribution in the plant 11 k'6ulds WS, Bronte-Stewart JM, ChiAolm IA. Serum kingdom. Optic neuropathy, often afsdciated with thiocyahate concentrstions intobaccb amblyoia. Nature nerve deafness, my6lopathy -with yramidal tract (A,tnd) 1968;218:586 involvement, and sensory ataxia, is particuiilAiy 12 Foulds WS, Freeman AG,- Phillips CI, Wilson J. prone to occur in tropical and subtropical counthes Cyanocobalamin: a casefor withdrawal. Lancet 1970;:35 13 Freeman AG, Wilson J, F'ou1ds WS, Phillips CI. Why where nutrition is poor and the indigenouds popu- has cyanocobalamin, not been withdrawn? Lancet lation suffers from a low protein and sulphur- 1978;i:777-8 containing amino acid intake ind high cyanide 14 Commitee pn Safety of Medicines, Current problems, exposure from a dietary source such as unprocessed July 1981:6 cassava roots20. 15 Linnell JC, Matthews DM, England JM Therapeutic Ifthe indiscriminate dumping of industrial cyanide misuse of cyanocobalamin. Lancet 1978ii:1053-4 waste continues unchecked with the inherent risk of 16 Monthly Index ofMedical Specialities, January 1991:178 pollution of food and water supplies there' may well 17 Terry SI, Nicholson GD. Survival of cyanocobalamin. come a time when more widespread chronic cyanide Lancet 1978i-:848 neurotoxicity occurs in the'Western hemfsphere from 18 Heaton JM, McCormick AJA, Freeman AG. Tobacco amblyopia: a clinical. manifestation of vitamin B12 a dietary source in persons with-a genetic or acquired deficiency.-Lancet 1958ji:286-90 error of cyanide or vitamin B12 metabolism2l. 19 Freeman AG, Heaton JM. The aetiology ofretrobulbar Looking to the future, it is possible that other neuritis in Addisonian pernicious anaemia. Lancet cyanide antagonists, with the obvious advantage 'of 196i1i:908-11 oral administration, will becbme available. In this 20 Osuntokum BO, Osuntokun 0. Tropical amblyopia. Am event, all patients with tobacco and nutritional J Ophthalmol 1971;72:708-16 amblyopia and optic neuropathy, myelopathy or 21 Freenan AG. Chronic cyanide intoxication. BZM neuropathy ofobscure origin, should be very carefully 1981;282:1321 screened for evidence ofvitamin B12 deficiency before 22 Freeman AG. Food and cyanide. BMJ 1972ii:49 embarking on any therapy other than intramuscular hydroxocobalamin22. (Accepted 18 November- 1991).
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