DSM LDME LDME LDME

Letterstothe Editor

tobe thetreatmentofchoiceinthissubgroup ofpatients.

KRAY-CHAUDHURI RJ ABBOTT PAHMILLAC The Department ofNeurology, Leicester Royal Infirmary, Leicester,UK Correspondenceto:DrRay-Chaudhuri,Research Fellow, National Hospital of Nervous Diseases, Autonomic Unit (EEG Department), Queen Square, London WC1N 3BG, UK

1 Stibe CMH, Lees AJ, Kempster PA, Stern GM.

Subcutaneous apomorphine in parkinsonian on-offoscillations. Lancet1988;i:403-6.

2 Ray-ChaudhuriK,CritchleyP,AbbottRJ, Pye IF, Millac PAH.Subcutaneousapomorphine for on-offoscillations in Parkinson's disease.

Lancet 1988;ii:1260.

3 Horowski R. Psychiatric side effects of high dose lisuride therapy in parkinsonism. Lancet 1986;ii:510.

4 Strian F, Micheler E, Beukert 0. Tremor inhibition in parkinson syndrome after apomorphine administration under L-dopa and decarboxylase inhibitor basic therapy.

Pharmakopsychiat1972;5:198-205.

5 Chiara DG, Gessa GL. Pharmacology and neurochemistry of apomorphine. In: Gara HiniS,GoldinA,Hawking F, Kapin IJ, eds.

Advances inpharmacologyandchemotherapy, Vol 15. London Academic press, 1978, 87-160.

Subcutaneous and sublinguallevodopa methylesterinParkinson's disease Subcutaneous continuous infusionsorinter- mittentinjectionsof the dopaminereceptor

agonist apomorphine have provedto bean

effectivetreatmentformotorfluctuationsin patients with Parkinson's disease receiving long term levodopa treatment.'2 Levodopa itself is impractical for chronic parenteral

treatment because ofits low solubility and high acidity. The highly soluble levodopa methyl ester(LDME), however, mightbea more suitable candidate for parenteral application3anditslongerhalf-lifecompared withthat ofapomorphinecould be of clinical advantage. We have therefore investigated thepossibilityofadministeringLDME both by the subcutaneous and, following a

previousanecdotalreport,4bythesublingual

route.

Five sublingual and five subcutaneous dosesof LDMEweregiventosevenpatients with idiopathic Parkinson's disease and motor fluctuations. Theirmeanagewas 59

years, mean duration of disease 12 (4-22)

years, meanduration oflevodopa therapy95 (1 5-19)yearsandmeanstageof Hoehn and Yahr 3-4 when "off" and 2-4 when "on".All patientswereknowntorespondtotheir first morning dose of 100 or 200mg of oral levodopa plusdecarboxylaseinhibitor within 15 to30minutes and themeandurationof effectwas135(90-120)minutes.Ontestdays the morning dose was replaced by 1 ml of LDME (equivalent to 200mg levodopa) either injected subcutaneously or given sublingually. Patients were given 50mg of oralbenserazideonehour before theLDME challenge.Subcutaneous doseswereinjected intwoboluses of 0 5 mleach into different sites of the abdominal wall. Withsublingual applications patientswereinstructedtokeep theliquidunderneath theirtongueaslongas

possibleandspitit outas soon astheyfelt forcedto swallow. Motorassessments were

carriedoutusingthe modified Websterscale at baseline and at the time of maximum therapeutic effectaswellasunilateral hand

tapping

tests10minutes before andevery10 minutes afteradministrationofLDME until drugeffectshadcompletelywornofforupto one and a half hours when there was no

clinical effect.

Two patients switched "on" with sub- cutaneousLDME with the^samequalityand duration of

therapeutic

effectseenafter their orallevodopadoses. The timefrom

injection

tofull switch"on"was60minutes in both patients.Twopatientshadnoeffectoverthe entireobservationperiodof 90minutes and another oneexperiencedonset-of-dose

dys-

kinesiascontinuingfor 110minutes without

everswitchingfully"on".One of the^respon- ders then receivedasecondinjectionwhich afteralatencyof 80minutesproducedsome

clinical effects withaninferior"on"-quality lastingforonly 15minutes. Allpatientshad

burning

sensationsattheinjectionsitewith rapidly developing nodules which slowly disappearedovertwo tofour

days.

Sublingual LDME ^was ineffective in all patients who managed to keep the

liquid

underneaththeirtonguesforanaverageof 13 (5-20) minutes. No local side effects were

observed.

Thecausefor theunpredictable response tosubcutaneous LDME is unclear. Therate

ofde-esterificationofLDME andresulting absorptionoflevodopaisinfluenced bypH,

temperatureanddistribution and activity of

esterases.'Different individual conditionsat

thesubcutaneousinjection sitemaytherefore beresponsiblefor thevaryingclinical effects observed. As the local toxic reactiontosub- cutaneousLDME^{was seen}in bothrespon- ders and non-responders it isunlikelytobea

Cortical nicotinic receptors in Alzheimer's disease and Parkinson's disease

Cognitiveimpairment and centralcholinergic dysfunction are common features of Alzheimer's disease (AD) and Parkinson's disease (PD). Degeneration of subcortico- corticalcholinergicsystemsand reductionsin cortical pre-synaptic cholinergic markers, such as choline acetyltransferase (CAT) activity, have been consistentlydemonstrated in AD and PD.'2 Most investigations of muscarinic cholinergic receptors in the

neocortex indicate that receptorbinding is unchangedinADandincreased inPD.34The statusofnicotinic cholinergicreceptorsisless clear. We have examined nicotinic receptor binding and CAT activityin thecortexinAD andPD.

Braintissuewasobtainedatnecropsyfrom

tenpatientswith AD and fromtenmatched control subjects with no evidence of

major

^reasonforpoor

absorption.

The failure of

sublingual LDME

to

produce

clinical effects

provides

noevidence for

absorption through

the oralmucosa.

Although

the number of

patients

in this trialwassmallweconclude that due tothe

variability

and

unreliability

^{of clinical res-}

ponse subcutaneous LDME is

unlikely

to

becomea

practical

treatmentfor

fluctuating

Parkinson's disease.

Wegratefullyacknowledge Chiesi

Farmaceutical,

Parma,Italyforproviding levodopa methylester solution.

BKLEEDORFER AJLEES GMSTERN

Department ofNeurology,

TheMiddlesexHospital,

MortimerStreet,

London WIN8AA,UK

Correspondenceto:Dr Lees.

1 StibeCMH,KempsterPA,Lees AJ, Stem GM.

Subcutaneous apomorphine inparkinsonian on-offoscillations. Lancet1988;i:403-6.

2 PoeweW,KleedorferB, GerstenbrandF,Oertel W. Subcutaneous apomorphine in Parkin- son'sdisease.Lancet1988,i:943.

3 Cooper DR,MarrelC,Testa B,etal.L-dopa

MethylEster-a candidatefor chronicsystem

delivery ofL-dopa in Parkinson's disease.

ClinNeuropharmacol1984;7:89-98.

4 Stocchi F, Ruggieri S, Carta A, et al. New

strategies in the treatment of Parkinson's disease. In: Dahlstrom A, Belmaker RH, Sandler M, eds. Progress in Catecholamine Research,Vol42,Pt C:ClinicalAspects.New York:Liss,1988:13-17.

5 Marrel C, BossG, TestaB,etal.Levodopa

estersaspotentialpro-drugs. PtII.Chemical andenzymatic hydrolysis. Eur JMed Chem

1985;5:467-70.

neurological

or

psychiatric diseases,

andfrom

ten

patients

with

PD,

five of whom were

clinically

demented

according

toDSM III

criteria,

andtenmatched controls. AD and PDwereconfirmed

neuropathologically.

The Parkinsonian

patients

had been treated with

levodopa

up tothe time of death. Patients with AD and controls hadnotreceivedany medication that is knowntoaffect the central

nervous system.

Using

washed membrane

homogenates

we

performed

saturation

analysis

fornicotinicreceptorswith

(-)-[3H]-

nicotine

(concentrations

05-64

nM)

in the frontal ^cortex

(Brodmann

area

8)

and

temporal

cortex

(Brodmann

area 38). Non-

specific binding

was defined

by

unlabelled nicotine.Protein concentrations andenzyme activities were measured

by

standard

techniques.

CAT

activity

was reduced in the frontal and

temporal

cortexof

patients

withAD and demented and non-demented patients with PD

(table).

Cortical maximal densities of Table Mean(SEM) maximal nicotinic receptorbindingin thecortex

Control AD Control PD

(n= 10) (n= 10) (n= 10) (n= 10)

Age (year) 79-8(2-4) 82.7(2-3) 731(5-5) 73-7(25)

Deathtobrain

removal(h) 40 5(6-0) 42-6(6-2) 19-6(24) 18-1(2-7)

CAT activity

infrontal cortex 4-0(0 7) 1-8(04)* 4-2(0-4) 2-3(0-4)*

intemporalcortex 4-4(0-3) 1-4(03)* 4-5(0-2) 2 5(0-3)*

(-)-['H]-nicotinebinding

infrontal cortex 21 7(1-3) 11-0(1-4)* 23-1(1-1) 12 2(13)*

intemporalcortex 26-9(1-1) 11 5(1-2)* 25-0(1-1) 13-3(0 9)*

Wilcoxon's rank-sumtext:*p <0 05.

CATactivityinnmol/h/mgprotein;nicotinebindingas

B.,,,

in

fmol/mg

protein.

373

Letterstothe Editor nicotinic receptors ' were substantially

reduced in both AD and PD. There wereno changes of the equilibrium dissociation constants(KD).

The exact cellular location of nicotinic cholinergic receptors in the cerebral cortex is not known. The parallel changes in these receptors andCAT activity in AD and PD suggestthat they are located pre-synaptically ondegenerating cholinergic axons. This view is consistent with the finding that nicotine stimulates the release ofacetylcholine from cholinergic terminals in the cortex.5 The present results point to the potential for stimulation of the remaining nicotinic receptors as a treatment of the cholinergic deficit in AD and PD andprovidearationale for atherapeutic trial of selective nicotinic agonists.

This study was supported by the Medical Research Council, the Parkinson's Disease Society and the Research Funds of the Bethlem Royal and Maudsley Hospitals and King's College Hospital. KWL was supported by the Deutsche Forschungs- gemeinschaft. Brain tissue specimens were obtained from the Parkinson's Disease Society Brain Bank in London and the MRC Brain Bank inCambridge.

KWLANGE FRWELLS MNROSSOR PJENNER CDMARSDEN InstituteofNeurology and The NationalHospitalforNervousDiseases, London WCIN3BG, andDepartment of Pharmacology, King'sCollege, University of London, London SW36LX, UK Correspondenceto: DrLange.

1 Perry EK,CurtisM,Dick DJ, et al.Cholinergic correlates ofcognitive impairmentinParkin- son's disease: comparison withAlzheimer's disease. J NeurolNeurosurgPsychiatry 1985;

48:413-21.

2 Rossor MN, Garrett NJ, Johnson AL, MountjoyCQ,RothM,Iversen LL. Apost- mortemstudyof thecholinergicand GABA systems in senile dementia. Brain 1982;

105:313-30.

3Ruberg M,PloskaA, Javoy-AgidF, Agid Y.

Muscarinicbindingand choline acetyltrans- feraseactivityinParkinsonian subjects with reference to dementia. Brain Res 1982;

232:129-39.

4 Lange KW,Wells FR, Rossor MN, Jenner P, MarsdenCD.Brainmuscarinic receptors in Alzheimer's and Parkinson's diseases. Lancet 1989;ii:1279.

5 RowellPP,Winkler DL.Nicotinic stimulation of

[3H]acetylcholine

release from mouse cerebralcortical synaptosomes. J Neurochem 1984;43:1593-8.

Industrial exposure to cobalt causing optic atrophy and nerve deafness: a case report

A 48 year old man presented with a seven monthhistory of progressive bilateral deaf- nesswithtinnitus and occasional vertigo and asix month history of visual failure. He had been exposed to raw cobalt powder for 20 months, working 50 hours a week. He stop- ped work in November 1988. In spite of face masks, someof the powder was inhaled. He smoked tencigarettes a day and drank two

pints of lager a week. There was nodrug exposure or family history of note. On examination his visual acuity was 6/36 in the right eye and 6/60 in the left eye. The temporal margins of the discs were pale.

Hearing was impaired bilaterally. Full haematological investigation, chest radio- graph and CT brain scan were normal. CSF showed a raised protein of 70 mgs/100 ml with oligoclonal IgG banding. Syphilis serology was negative. Blood cobalt was 234jgm/1 (normal <2) in February 1989, falling to 14 7

ygm/l

by May 1989.Twenty four hoururinary cobaltwas 119pgm/24hr (normal <51) in February 1989. VERs in February1989 wererighteye125ms, lefteye 126 5 ms, in May1989, 118ms onbothsides, and inFebruary1990, 109msonboth sides.

By January 1990 the visualacuity improved to6/12 bilaterally.

Audiometry improved from December 1988 toFebruary1990asshown. Thepatient felthis hearing was backtonormalbytheend of 1989.

Cobalt is a relatively rare metal. Today most of it is produced as a by-product of copperorsilverproduction.Cobalt iswidely used in themakingof hard metals inindustry, forexample, drilltipsand gas turbine blades.

Itis alsoused in medicine. The metalalloy, vitallium, is a strong and corrosionresistant metal used for prostheses in replacement bone surgery, for example, hip and knee

joints.'

Cobalt has also been usedclinically in the treatmentof certain types ofanaemia;when giventonormalandanaemicpatientsit has producedareticulocytosis. Medically,ithas beenusedas anantidote for certain types of poisoning,suchascyanide, andas apoten- tiatorof the action of antibioticsorhydrocor-

Rightear

dBHL Tests conductedon6 December1988

1 , I ., , , I ,

40

---

Tests conductedon 1 February1990 dBHL

6C° ^{- -- -f--f--}

80 __

100-- - F--f

120

140 125 250 500 1000 2000 4000 8000 Frequency(Hz)

tisone. Radiumhasvirtually beenreplacedby Cobalt 60forradiotherapy.'

Many adversereactions have been reported following its clinical use, although thereare remarkably few reports of severe poisoning as a result ofindustrial exposure. Reactions to cobalt have included anorexia, nausea and vomiting, diarrhoea, precordial pain, cardiomyopathy, skin rashes, flushing, nerve deafness, renal damage, hypothyroidism, asthma and pulmonaryfibrosis and possible optic atrophy.'` Despite the long list of adverse reactions, the complications that developed in this case, optic atrophy and nervedeafness, have never been reported to occurtogether.

Licht, Oliver and Rachmilewitz4 described theonly previouscasereportofopticatrophy possibly secondary tocobalt chloride. The patient,a32 yearoldJewish man,wasfound tohave a pancytopenia with a hypercellular bone marrow of unknown aetiology. The anaemia responded to courses of cobalt chloride given on fourdifferent occasions. On twooccasions the drug had to be discontinued because of nausea and vomiting. On the fourthoccasion, aftera fifteen weekcourseof cobaltchloride, thepatient began to complain ofdeteriorating vision. Ophthalmological fin- dings and fluroscein angiography indicated the presenceofoptic atrophyand abnormal choroidal perfusion. Their patient had received a total dose of 73g of cobaltchlor'ide over aperiodofthree years.Followingcessa- tion of the drug there was no further deterioration invision despite the progres- sion of the underlying disease, suggesting that theopticatrophy may have been due to cobalttoxicity.

Gardner'

studied17patients with anaemia and uraemia treated with cobalt chloride.

Leftear

_ __ T -rT T r

I

- -

--I

-1

^{- -}

- -I I f-

^-

I-I- I----

-

+ I - -I

I -I F- IF

- -~I 4--F--

- -I- -I- In

- - - -~~1- -4

Frequency (Hz)

Figure Audiograms showing improvement of hearing after withdrawalfrom cobalt exposure.

I II IIII II

I I I 11 I I

374

I