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monoamine oxidase.8 It has no antiparkinsonian effectwhen given alone, but will enhance the effect of levo-dopa. A major contribution to the study of Parkinson’sdisease has been the recognition of two types of mono-amine oxidase, A and B, in the human brain.9,10 Levo-dopa can be safely combined with the B substrate inhibi-tor deprenyl, and dietary restrictions are unnecessary.Deprenyl prolongs the action of levodopa and seems toact as a sustained-release preparation, being particularlyhelpful for clinical features such as difficulty in turningin bed at night and early-morning stiffness and immobi-lity." When deprenyl is added to treatment, the dose oflevodopa can be reduced.12 At present, deprenyl is notgenerally available.Bromocriptine has proved of great value in the treat-

ment of hyperprolactinaemia and acromegaly. On p. 735Dr CALNE and his co-workers record their long-term ex-perience with this agent in parkinsonism. Bromocrip-tine, together with other ergot derivatives, causes potentdopamine-receptor stimulation in animals, althoughsome ergot-related drugs make parkinsonism worse

rather than better, or damage the liver.13,14 In man, bro-mocriptine is rapidly absorbed and plasma levels reacha peak about 2 hours after oral dosage.15 The plasmahalf-life of bromocriptine is three to four times longerthan that of levodopa, and in animals the effect on mobi-lity is similarly prolonged. The dopamine stimulanteffect of bromocriptine results from both a presynapticand a postsynaptic action, and can be prevented byinterference with dopamine synthesis.16 The clinical re-sponse to bromocriptine is rapid and occurs within thefirst week of treatment. The response to a single dose issustained for several hours. The most effective dosage inparkinsonism, usually between 20 and 150 mg daily, isoften much higher than that necessary to suppress pro-lactin levels in the blood. This dosage must be achievedgradually. Bromocriptine 3-3—10 mg daily is about equi-valent to levodopa 100 mg plus a decarboxylase inhibi-tor." Two groups of parkinsonian patients are possiblecandidates for bromocriptine. Patients who remain naus-eated on levodopa despite the addition of decarboxylaseinhibitors and antiemetics can sometimes tolerate bro-

mocriptine without sickness. Others with end-of-doseakinesia on levodopa, and who cannot achieve a stableresponse despite splitting of the levodopa into frequentsmall doses, may achieve a smoother response to bro-mocriptine.15 Levodopa may still be needed as well, sincebromocriptine seems to be a little less potent. Bromo-criptine will not prevent response swings due to freezing,and in most patients has no advantage over levodopa.With the high dosages of bromocriptine used to treatparkinsonism, side-effects are common, as Dr CALNE

8. Elsworth, J. D., and others. cited in Lees et al., ref. 11.9. Knoll, J., Magyar, K. in Monoamine Oxidase—New Vistas (edited by E.

Costa and M. Sandler); p. 393. New York, 1972.10. Glover, V., Sandler, M., Owen, F., Riley, G. J. Nature, 1977, 265, 80.11. Lees, A. J., Shaw, K. M., Kohout, L. J., Stern, G. M., Elsworth, J. D.,

Sandier, M., Youdim, M. B. H. Lancet, 1977, ii, 791.12. Birkmayer, W., Riederer, P., Ambrozi, L., Youdim, M. B. H. ibid. 1977, i,

439.13. Teychenne, P. F., Pfeiffer, R., Bern, S. M., Calne, D. B. Neurology, 1977,

27, 1140.14. Lieberman, A., Miyamoto, T., Battista, A. F., Goldstein, M. ibid. 1975, 25,

459.15. Parkes, J. D. in Advances in Drug Research, Vol. 12 (edited by A. B. Sim-

monds); p. 247. London, 1977.16. Johnson, A. M., Loew, D. M., Vigouret, J. M. Br. J. Pharmac. 1976, 56, 59.17. Gerlach, J. Acta neurol. scand. 1976, 53, 189.

and his co-workers show. Psychiatric disturbance andvisual and auditory hallucinations are more frequentwith bromocriptine than with levodopa, possibly owingto the lysergic-acid-amide part of the molecule. Thesesymptoms can persist for several weeks after drug with-drawal. Dyskinesias with bromocriptine and levodopaare similar in nature and intensity. Symptomatic pos-tural hypotension is more common with bromocriptinethan with levodopa, and a few subjects faint after asingle dose. Bromocriptine, like amantadine but unlikelevodopa, occasionally causes ankle oedema and livedo,but no antiparkinsonian drug other than bromocriptinecauses increased skin temperature and redness. Some ofthese effects may be due to stimulation of peripheral vas-cular receptors. Dopamine causes vasodilatation in thecoronary, mesenteric, and renal circulation,’8 but levo-dopa seldom causes obvious vascular changes in theskin. Long-term bromocriptine treatment seems to befree from biochemical and haematological toxicity,except for the transient increases in serum-transaminaselevels recorded this week by the Bethesda workers. Uter-ine tumours have been associated with long-term bro-mocriptine treatment in rats, but careful screening hasnot shown this to happen in women.19 Dr CALNE and hiscolleagues recommend annual gynaecological examina-tion for all women on long-term bromocriptine.

About 10-20% of all patients are unresponsiveto antiparkinsonian drugs. This is sometimesbecause the diagnosis is wrong or because the drugis not absorbed. The therapeutic range of plasmadopa and bromocriptine concentrations has notdefinitely been established, but in patients who re-spond well peak plasma-dopa levels are usuallybetween 1 and 5 fLmol per litre and bromocriptinelevels are 2-15 ng per ml.ls Most people who donot respond to levodopa likewise do not respond tobromocriptine. None of the drugs alters the naturalhistory of parkinsonism, although levodopa willprolong life for several years. Until the cause of thedisease is recognised and prevention or cure

becomes possible, the major advances in treatmentare likely to be refinements of levodopa therapy.The agonist to replace dopamine has not yet beenfound.

Vitamin K and the Newborn

IN a characteristic editorial footnote, GELLISonce wrote: "Despite all the arguments andcounter arguments of the past, we believe that theweight of evidence clearly indicates the benefits tobg derived from the routine administration at thetime of delivery of a small dose of vitamin K to allnewborn infants. There seems to be no justificationwhatsoever for withholding this preparation andwe would earnestly hope that the subject will notbe reopened for at least another 10 years. Twenty

18. Goldberg, L. I. Pharmac. Rev. 1972, 24, 1.19. Besser, G. M., Thorner, M. O., Wass, J. A. H., Doniach, I., Canti, G., Curl-

ing, M., Gradziniskas, J. G., Setchell, M. E. Br. med. J. 1977, ii, 868.

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years would be even better."’ Ten years have now

elapsed and the subject has been reopened. VANDOORM et al .2 failed to find P.I.V.K.A.-II in 43cord plasma samples and concluded that healthybabies were unlikely to become vitamin-K defi-cient. They also suggested that generalised bleedingcould be due to a hitherto unrecognised heparin-like inhibitor. P.I.V.K.A.-II is short for a "proteininduced by vitamin K absence like factor II"-anabnormal precursor of prothrombin found only invitamin-K deficiency. The relevance of cord-bloodfindings in a condition which typically arises one ortwo days after birth is questionable,3,4 but the dis-covery of this abnormal prothrombin at last offersscope for a specific diagnostic test for vitamin-Kdeficiency.

Haemorrhagic disease of the newborn is definedas a bleeding disorder in the first few days of lifecaused by a deficiency of vitamin K and character-ised by a deficiency of the four known vitamin-K-dependent clotting factors-namely, factors II

(prothrombin), VII, IX, and X.5 To this might beadded the quick and readily shown correction byvitamin K. Thus, to deny the role of vitamin K inhaemorrhagic disease of the newborn is to addsemantic chaos to laboratory confusion.

Fortunately the clinical syndrome is secure. It doesnot include babies with superficial bleeding into thescalp or under the periosteum, conditions primarilydue to direct birth injury. Nor does it include in-tracranial haemorrhages in preterm babies, inwhom the primary defect is not one of coagula-tion.6 It is confined to otherwise healthy babies whohave not received vitamin K at birth and who bleed

mostly from the stomach, intestine, umbilical

stump, and needle or operation sites on the secondor third day.The condition is now fortunately uncommon and

there is a temptation to ascribe its low incidence tothe widespread use of vitamin K routinely at birth(or at least in those mostly at risk) and to the intro-duction of improved methods of cord occlusion.Estimates of the extent of vitamin-K prophylaxis,the number of treated and untreated babies who

actually bleed, and the proportion with laboratoryevidence of vitamin-K deficiency vary widely.SMITH gave an incidence of about 1 in 200 to 1 in400 births. SUTHERLAND et al. found moderate orsevere bleeding in 1.7% of untreated full-termbabies compared with 0-4% in those given vitaminK; moreover, severe bleeding was virtually con-

1. Gellis, S. S. Year Book of Pediatrics; p. 291. Chicago, 1969.2. van Doorm, J. M., Muller, A. D., Hemker, H. C. Lancet, 1977, i, 852.3. Edson, J. R. ibid. 1977, ii, 187.4. Aballi, A. J. ibid. p. 559.5. Committee on Nutrition, American Academy of Pediatrics. Pediatrics, 1961,

28, 501.6. Chessels, J. M., Wigglesworth, J. S. Archs Dis. Childh. 1972, 47, 564.7. Smith, C. H. Blood Diseases of Infancy and Childhood; p. 655. St. Louis,

1966.8. Sutherland, J. M., Glueck, H. I., Gleser, G. Am. J. Dis. Child. 1967, 113,

524.

fined to babies who were entirely breast-fed. It haslong been evident that physiological hypopro-thrombinaemia, like physiological jaundice, is a

common basis on which other causes may be super-imposed and that vitamin-K administration cannotbe expected to prevent all forms of haemorrhagicdisease. Prenatal factors, possibly dietary, mayaccount for its occurrence in lower socioeconomicgroups.9 Drugs taken by the mother may also playa part-notably, phenobarbitone and phenytoin,"oral anticoagulants, phenylbutazone, and rifampi-cin." The normal full-term infant is born with lessthan 50% of the adult plasma levels of factors 11,VII, IX, and X, and these continue to decline forthe first three days.9 Administration of vitamin-Kto the mother is not invariably beneficial, whereasadministration to the baby prevents the decline inthe days after birth.12 Adverse conditions includestarvation before or after birth and difficultdeliveries, especially Ventouse extraction, whichplace an additional stress on an imperfect coagula-tion mechanism. Haemorrhagic disease occurs whenthe concentrations of the vitamin-K-dependent fac-tors fall below 25%. Ideally, prevention should aimto influence those conditions responsible for anexcessive fall. Extreme depression of prothrombinactivity is found in breast-fed babies who have notbeen given any vitamin K or cow’s milk comple-ment, since human milk is deficient in vitamin Kand inhibits colonisation of the intestine byorganisms capable of synthesising the vitamin."This has important clinical implications in view ofthe current emphasis, even for premature and low-birth-weight babies, on human milk to the exclu-sion of any kind of artificial complement, and es-pecially in view of the growing demand for earlydischarge at a time when the infant’s clotting fac-tors are at their lowest concentration.

Historically, vitamin K (Koagulation vitamin)acquired its name with the discovery that chickensfed on a diet free from ether-soluble componentsbled to death.14 Since then, vitamin K has been iso-lated in three main forms. Vitamin K1 (phytona-dione) is the naturally occurring fat-soluble vita-min found mainly in green leafy vegetables;vitamin K2 (menaquinone) is the form synthesisedby intestinal bacteria; and vitamins K3 (mena-dione) represent water-soluble derivatives such asthe phosphate (’Synkavit’) and sulphate (’Hyk-inone’). These derivatives have been accused ofcausing excessive jaundice and also haemolysis inglucose-6-phosphate dehydrogenase deficient in-fants and are no longer used in the neonatal period,although these adverse effects were almost cer-

9. Aballi, A. J., Lópes-Banús, V., Lamerens, S. de, Rosengvaig, S. ibid. 1959,97, 524.

10. Mountain, K. R., Hirsh, J., Gallus, A. S. Lancet, 1970, i, 265.11. O’Reilly, R. A. A. Rev. Med. 1976, 27, 245.12. Aballi, A. J., de Lamerens, S. Pediat Clins. N. Am. 1962, 9, 785.13. Keenan, W. J., Jewett, T., Glueck, H. I. Am. J. Dis. Child. 1971, 121, 271.14. Dam, H. Biochem. Z. 1929, 215, 475.

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tainly due to excessive dosage.15 Phytomenadione(’Konakion’) is a synthetic preparation of vitaminK, for oral and parenteral use, the recommendeddose for newborns being 1 mg by intramuscular in-jection. Its effectiveness in correcting a vitamin-K-dependent coagulation-factor deficiency in a matterof hours is beyond dispute but arguments about itsprophylactic use in all babies at birth will continuewhile the incidence of haemorrhagic diseaseremains low. An aspect commonly overlooked isthat of cost, this one small item of routine preven-tion costing about 100 000 in materials alone inthe U.K. A rational compromise would be to ensureselective prevention of hsemorrhagic disease in allthose at risk-namely, preterm and low-birth-

weight infants, those who have had difficult births,those destined for early discharge or to be whollybreast fed, those with inadequate intakes or onantibiotics, those with evidence of bruising or

bleeding, and those needing surgery. A programmeof selective vitamin-K prophylaxis should appeal tothose clinicians who rightly question the wisdom ofinjecting the majority of normal babies unneces-sarily.

SELF-MONITORING OF BLOOD-GLUCOSE

IN an era of elaborate electronic and mechanicaldevices, revolutionary yet simple techniques may beunder-rated. Such was the case with ’Dextrostix’, the glu-cose-oxidase-based reagent strip for measuring blood-glucose launched by Ames in 1964; it caused hardly astir. To ease reading of the colour of the strip, Amesthen introduced a reflectance meter, but reaction was

again muted. Critics complained of inaccuracy andinstability, so this device was replaced in 1974 by themore accurate but less portable ’Eyetone’ meter; a simi-lar combination of reagent strips and meter, the ’Reflo-test’ system, was introduced by Boehringer. Yet, despitethe simplicity, cheapness, speed, and accuracy of thesemethods-they measure a blood-glucose within 90

seconds, can be as accurate as standard laboratorymethods, yet cost less than lOp a time-they have notbecome a popular method of blood-glucose analysis. Fewgeneral practitioners do their own measurements,though the advantages to patient and health service areobvious.

This week’s Lancet has two papers about an appli-cation of these sticks and meters which is perhaps evenmore useful-self-monitoring of blood-glucose by dia-betic patients as a means to better diabetic control. Dia-betics have traditionally been taught to "balance" theirinsulin dose by measurement of urine glucose, but therenal threshold for glucose has made this difficult. Theaverage diabetic has been faithfully testing and chartinghis urine for years, mainly to please his doctor andpartly, perhaps, because he believes that this is thepunishment he is given for contracting diabetes. In re-ality he, like the patient cited by Dr Sonksen and his col-leagues, finds that regulating his insulin dose on the

15. Meyer, T. C., Angus, J. Archs Dis. Childh. 1956, 31, 212.1. West, T. E. T., Judd, S. L., Sönksen, P. H. Diabete Metab. 1977, 3, 165.

results of his urine tests is like driving a car in a 30m.p.h. restricted area when its speedometer does notread below 70 m.p.h. How can urine testing possibly beuseful? If the blood-glucose is to be kept anywhere nearthe normal range there will be no glycosuria. How thenis the diabetic best able to tell whether his blood-glucoseis 1 or 10 mmol/1? Obviously by measuring it ratherthan by guessing. The St. Thomas’ and Nottinghamgroups both found that self-monitoring of blood-glucoseenabled patients to adjust the balance of short and inter-mediate insulins to reduce or eliminate swings in blood-sugar. The day profiles collected by the Nottinghamworkers indicate that postprandial peaks of hyperglycae-mia can virtually be eliminated on conventionalregimens of twice-daily soluble and isophane insulin.Even though the average blood-sugars were lower,hypoglycaemic attacks were less frequent-presumablybecause swings of blood-sugar were less. 70% of patientspreferred blood tests to urine tests.

If one accepts that good diabetic control is not onlya "good thing" but can delay or prevent diabetic compli-cations-and the experimental evidence is now stronglyin favour of this-then patients should wherever pos-sible be taught to adjust their insulin dose on the basisof blood rather than urine glucose measurements. Thismeans that reagent strips must be made available to pa-tients on prescription from their general practitioner,and a suitable meter produced which is cheaper andmore appropriate for home use than the existing twomains-operated machines.

LIPID-STORAGE MYOPATHIES

THE lipid-storage disorders, an indispensible part ofevery medical student’s list of differential diagnoses, in-volve the accumulation in lysosomes of complex lipidssuch as sphingomyelin (in Niemann-Pick disease) or glu-cocerebroside (in Gaucher’s disease). In each case a hy-drolytic enzyme is lacking, required for further metabo-lism. A new group of lipid-storage disorders has latelybeen recognised which involves cellular accumulation ofneutral fat, the common triglyceride.1,2 Skeletal muscleis the tissue most obviously affected. The material ac-cumulates not in any cell organelle but in cytoplasmicvacuoles, and these vacuoles take up dyes such as oil-red-O which are soluble in neutral fat. The patients areusually children or young adults. Of 13 cases 8 werewomen and 5 men, and the commonest complaint wasof muscle weakness in the arms and legs and easy fati-guability ; some had muscle pain or cramps.l,3-14 At least4 patients had myoglobinuria.4,s.lo Serum-creatine-phos-phokinase was abnormal in less than half the patients

1. Engel, A. G., Siekert, R. G. Archs Neurol. 1972, 27, 174.2. Chanarin, I., Patel, A., Slavin, G., Wills, E. J., Andrews, T. M., Stewart,

G. Br. med. J. 1975, i, 553.3. Bradley, W. G., Hudgson, P., Gardner-Medwin, D., Walton, J. N. Lancet,

1969, i, 495.4. Engel, W. K., Vick, N. A., Glueck, C. J., Levy, R. L. New Engl. J. Med.

1970, 282, 697.5. Dimauro, S., Dimauro, P. M. M. Science, 1973, 182, 929.6. Johnson, M. A., Fulthorpe, J. J., Hudgson, P. Acta neuropath. 1973, 24, 97.7. Engel, A. G., Angelini, C. Science, 1973, 179, 899.8. Jerusalem, F., Spiess, H., Baumgartner, G. J. neurol. Sci. 1975, 24, 273.9. Markesbery, W. R., McQuillen, P., Procopis, P. G., Harrison, A. R., Engel,

A. G. Archs Neurol. 1974, 31, 320.10. Bank, W. J., DiMauro, S., Bonilla, E., Capuzzi, D. M., Rowland, L. P. New

Engl. J. Med. 1975, 292, 443.