_-_L_ .... _=_ ._l __ _ n_•_· _co_o_P_E•_ • _ND Pl l.() I,~. OUNN: - ~ -~r.o r.:. · ~ _ 1•Afl~ I~~~ :____ ~OT~~

HARMALOL IN THE TREATMENT OF

PARKINSONISM . in gaet.ro-ente~s~my-an d t hus th e tota l poriod of <'loop anotbeeta 18 usually much 1688 thau with ether or chloroform. Clinical ev idence of t he lessoned tendency to aeidOllia ia found in the gron.tly reduced amo~~t of_post-opera.tive vomiting. Thie di stro68ing BY rr . .ASTLEY COOPER, lf.D .• B. S. L oND.,

,condition 18 not abolished by gas-oxygen (as used in BNOEruALtTl8 ~c u Ol'l'JOER, WEST P.Ana: JO:.,'TAL uOBP1T.u..

AND my 11e.ries), but when it occurs it is usu ally less severe

::.w~ l:~~ ,::S·arlo:~\!are~::i::a~~~t~! J . A . GUNN, M.D., D.Sc. ED IN., F .R.C.P. LOND . ,

been ent irely absent . Finally th e lessened r isk or MlOPESBOR o, P O,UU U .001.00T IN TIIJC usn·ERSITY 011' OXFORD .

reflpiratory complicat ions is an argument in fav ou.r of gas-oxygen that must carr y cons iderab le weight. A. death on the table is a tragedy; deat h from respiratory comp lica tion s in the post-operative period

:,:pi:!y <;:hi:~s 1=~si~r.0 :!t t1;f: ::r:t ~

to die from the effect.a of an anresthetio, of what possible advant age can it bo that ho should sur vive the operation onl y to end ure two or th ree weeks of acute discomfort and pai n 1 I t is not reasona ble to co~sider the relative morbidity of different agent& only m terms of deaths on t ho tabl e. A patient may davelop an ether bronchitis followed by bronoho­pneumonia, from which ho may apparently recover

,only to dev~lop a fatal ompyoma ; tho anret5tbetist, contented with th o goocl relaxation secu red during operation, may not even know or i t.8 occurrence. Could anything be more iron ica l 1

Nitrous oxide is non-uplos.i l'e . There a.re numerous factors whi ch ent er int o the

praetica.l use of gas-oxygen. Th e qu est ion of apparatus and technique are of the utmost importanc e, and perhaps not t ho least important factor is the individual. surg eon. !h e. object of this paper, bo~ever, 18 mere ly to mdicato the ran ge of oases in which gas-oxygen may be used without the need of other ~ent, and to show t hat neither practically nor theoretica lly can a carefull y controlled anoxremia be regarded a.s a contm-indi ca ti on to its use.

I must t:ako this opportunity of thanking the aur, eons whose cases are included in this seri es for their indulgent cooperati on, more especia.lly Mr. R. C. .Alexander and Mr . R. S. Molville, for whom th e bulk of t.hia work was done .

ru-:FERENCES .

] . Ya ck1ln, A. H. : Tu.E L .&.NCET, 1931, I., 123 1. !. Crile, 0. w .. an d Lower, W. E.: Sur,1ca 1 Shook and the

fi~~e&I OperaUon through Anocl·auoclo.Uo11, London,

3. Verworn. M.: Jrrltablllt.y, London, 1913. 4. Owatbmey, J . •r.: An iHthesJa , J,on don, 1925 , Iv., 125 .

;). °1l!W Oy0~t::

19t

6.BH>ola.r Theory of Llvln&' Subetanoes.

6. 'ia;f1~rfu~·: Zclt ,. pby 1Jol. Chem. , 1910 , Lsvl., and

7. Loeb, J ,, and Wasteney1 , B.: Jour. Bio l. Che.in., 1913, :r:lv.

8. WLDterat.cln, n. : Blocbcxn. Zelt .. 19H , l:r:I.

Lewin ,1 as a res ult of 1>harmacologica l experimen t&, recommen ded bani sterine, an alkaloid obta ined from Banis teria caapi, as a romedy in nervous d iseases , and reports were hi.tor made by Lowin and Scltusto r 1

an d. Ber!nger 3 as to its va.luo in par kinsonism. La.tor, ba.msterme was shown to bo identical ,vith harmino , an alka loid obtained from Peganum luirm.ala, an d reports ua to tho clinica l uso of harmin e wero mrulo by R ustigo, t Beringer an d ,vum anna,' an d others. By tho end of 1930, a considerable number of clinica l roports h ad been publish ed which genera lly went to show that harmi~1e favoumbl y influences the rigidity of th e muscle.s m post .enco1>halit ic condi t ions , but that it has little or no effect ei th er on the tremo r or on the mental conditi on .

The effect or barrnin e in relieving rigidit y of muscles in those conditions wa.s generally a.scribed , some what vague ly, to an action on the ox:trapy ramida. l

:avc:~·a ~tfre:e0~th~:r:~~!?o!~

0 i~~:::~~ p~i: o~ervations, harmin e acts i_n a manner en tirely different to that o f hyo scine, for whereas the latter h as a. de1m:85ant action on the oxtrapyra.mi dal tract , lrn.rmmo 11timu latos the motor cells or the cerebra.I cortex. _.Accordin~ to this view, ap parent ly, tho pathologi cal condi t ion in parkinson.ism is du o to a st imula tion or over .actio n of tho extra.pyrami dal tra ct.s which is subdu ed by hyos cino . Harmiu o lcavea th ese tracta uninflu enced but, by stimul atio n of tho motor cell.a. of the cort-ex, facilitates the passage of voluntary 1mpulsos throu gh tho pyra.mida.l tract. '£his exp lains sevora.l observ ation s, amon g others ~he facts that harmin e do88 not reli eve tremor, whereas 1t does p rodu ce a cu11ioua subj ective feeling of " lightness " of th e musclos, an d th at a comb ination of harmin e an d hyosc ine produ ce summa.ted benefits because th ey act d.iJl'erently and on two component& ooncernod in volw1tary movement.

,Vhetber . Halpern 's explanations are right or wrong , they certamly afford a more prec ise and reasoned e.xplanatio n of the div ergent ac tion of t hese a.lkaJoid.8 than has previously boon given. One of us, in early pharmacological experiments with ha.rmino, 1 had suggedc d that t ho convul sa.nt action pr odu ced in laborat ory- animal s by this alk aloid is due to a sti mu­lati on of th e cerebra l motor cortex.

9. Lillie, R. S. : ScleD06, 1913, x::r:::r:vll., 959 . 10. ,. ,. : Dlol. Bull., HH 6, m., No . 5.

11. &m bridgc'. 1~~oplttamlc AcUou and Nerv ous Action,

12. Macklln: TUE LA:-fCET, 1926, 11., 194 . 13. IIend enion, Y.: Arner. Jour. Pby 1lol., 1908.

u . I1f~1t~;./; roi. Roap lratloo, Sillima n :Mcrnorlal Lectures.

U. Findlay , Leona.rd: Drlt. ?ited. J oor., 1931, I., 433. 16. Cook. B. E.: '.l'w: LANCET, 1931, I., 860. 11. FuJler, O. J.: l bld., 1930, l ., 11 5.

H OSPITAL M EALS DY CoNTRAcr.- Du ring th e last three mont.h 1 the meals for th o staff of U10 Holgate Jnsti•

~tu::· .. ~:!~:'~~~~· !Z:eot ~~ 6fd.v~dh~. : n~r!~ pared with & previous e.verago o( JS,. lt is offlci&Uy .sta.ted ~bat th e fare .ha.I giv e n oompl cto 1a.tisfact.io n by re&eo n of 11' greater var iet y.

.\I arin08Co, K.reindler , and Seheim • found that h armine_. in norm al p0l"80ns as well as in those suffering from enceJ.>haliti s, lteight ens vestibular excitability , and that. 1t tends, t houg h to a. loss extent than scopolamm e, to restore to th eir normal values t he patho logical chr ona.xies of tho nerves and muscles in pa rki.nsonism. I t is ovidont th at th o prcciso method of act ion of harmine in park:insonism cannot yet bo regar ded as decided. Th e gonora.l opinion of those who ha.\•o tried it is th at it has a definite effect in improving motility . lt, s e:ffoct on the post­encoph a.litie comp lex of sympto1DS is hal'dl y compar­able to tha t of byoacine or stramo nium , an d it h as been used chi efly to suppl ement the actio n of tho latter dru gs. Some observera-e.g., Hill and Worst er ­Dr ought •- have round littl e or no benefit from it.a use

902 Tiffi LAN( ·J-:-r.1 DH . GOOPEH AND PROF. OUNN: HAR)lALOL lN" P AII KIN l'-Ol<iL5M. [OCT, 24. 1931 -- ------·-------~·--- - ---~ - - - ----- --------- -

Gunn and his co-workers have recently investigated No pain or loca l ir ritation was produced at the sit& some artificia l derivatives of hannino and harmalino. 10 of injection, an d no toxic symptoms of any kind Th ey found that , while in all compou nd s inv est igated wore produced. In raga.rd to tho nervous condition, the actions on volun tary and involuntary muscle th e on ly primary a.Iteration observed was a decreasod. were similar , there were impo rtant differences in the ir muscular rigidity. \Vith gr. 4/5, two ca&eS showed no actions on the central nervous SY13tem. This was change , three slight relaxation, and two marked sho wn especia lly by the fact that , whereas harmine relaxation. In no ca.so was the rigidity completely and harmaline produeeelonicconvulsions in labo ratory abolished. Ca.see showing definite decrease of rigidity mammals , hn.rmol a.nd ha.rmalol {which differ from showed also improved volun tary movement. In barmine and harmaline respectively in the substitution no case was the tremor lessoned, whatever its type;. of HO for CH,O group) have no such convulsive a.nd we had the impression that tho decreased rigidity effect. I t soomed of interest, t herefore, to determine enabled the tremor to manifost itself more easily in. whether harm ol and ha.rmalol would exert tho same some cases . There was no evidenco of euphoria. or typo of action in parkinsonism as harmine or of improvement in the mental condition. Ther& ha.rmaline. If, as Halpern suggests, the action of was no red uct ion in the sialorrhcea., and sweating was. harmin e in this conditio n ill due to stim ula tion of the increased in some cases . · cerebra l motor cortex, then h armo l or harma.lol ought The effect on r igidi ty reached a. maximum in about to be ineffective, unles& th e latt6r alkaloids have an 45 minutes, and began to pass off again in about action on the central nervous system in man different two hours, though slight improvement lasted a.s long. from that which they displa.y. on lower mammals as 24 hours in somo ca.sos. (rats, guinea-pigs , and rabbits). By oral administration.-No nausea or vomiting

To obt ain evi dence on this point we have made a and no toxic symptoms were llfoduood by any dose series of observa ti ons on t he effects of h armalo l in up to grs. 12, the largest given. The effects gener~lly cases ofparkinsonism following encephalitis lethargica. resembled those pro du ced by hypodermic injection The cases treated were all patients in ·west Park with the following differen ces. No marked effect.. :Mental Hosp it al, and we wlilh to thank Dr. F. L. wore produced by doses less than about grs. 8. With Golla. and Dr. Norcli:ffe Roberts for affording us every doses of grs . 8- 12 there was usually no significant facility for con du cti ng the inv estigation. For t h e cha.nge in blood pressure , sometimes there occurred &

suppl y of ha.rmalol hydrochloride we are indebted rise , sometimes a fall of blood preseure, in neither to Messrs. Boot,a, Nottingham. c~ of over IO mm. Hg. ·w ith doses of a.bout

H armalo l hydrochloride is solub le in cold water grs. 10 the effects were similar to those previously only to the extent of ~bout 1 per cent . Thi s limited described a.a occurring after hypodermic adm.inistra.­t h e dose that coul d conveniently be given by hypo- t ion. The only posit ive effect was the diminution ia. dermie injection to a.bout gr. 4/5, which wa.s given the rigidity of t he muscles. The act ion began to pw. as two injections or gr. 2,15 dissolved in 20 c.cm. of oft' usua lly in three to four hours, though in som& water. H given repeatedly by mouth t.bo drug cases slight effects were dist inguishable up to l! ma.y cause some .staining of the teeth. hours or even longer.

All the patient s were suffering from chro nie epidemic In a few cases in which harma.lol was given to encephalitis, aud roost of them showed severe patients already receiving stramonium, a. slight symptoms of parkinsonism . In attemJlting to evaluate furt ,her relaxation of musc les occurred over a.nd abov& t h e effects of ha.rma.Jol in these cases, we were con . that due to stramonium. fronted with difficulties which are familia .r to those So far a.s these preliminary observations go, they who h ave experience in t reating this ty p e of disease. tend to suggest th at harmalol produces much the sam& Also the dosag e to begin wit h had to be tentative, effect as harmine in relieving the muscular rigidity as there was no previous experience of the use of the of pa.rk.insonism. In a. few cases in which harmin& drug in man. Practica.lly all the eases had been on a.nd h arma lol were compared in the same patient, full doses of stra-monium , and t ltis t reatment had we failed to find any material difference between the to be discontinued until t he symptoms had re turne d two alka loids . The fact that harmaJol is devoid of and reached a. stat ionary state before the patient stimulant action on tho cerebra l cortex of laboratory was given harma.Jol. Observations were made on the mammals, and neverthe less has · an effect on the loeal and general reactions to the drug ; especia lly muscular r igidi ty of parkinsonism similar to that of records wore taken of the pu lse-rate and blood ha.rmine, rather throws doubt on the explanation pressure as an indi catio n of th e safety of the dosage. that th e action of these alkaloids in man is due to Gunn an d Simona.rt had sh own, in the case of labora- stim ul at ion of tho cerebral motor cortex, though tory mammals, that small doses produce a. slight this would have afforded a feasible oxpla.na.tion or the ri se of blood pressure , and larger doses a fall. As a. act ion of harmine itself. Our observations a.re too consp icuous fall of pressure was produced by doses slender to admit of profitab le conjeotures as to their only one-tenth of the lethal dose, there was every seat of action. reason to suppose that the drug cou ld be pushed with Though harmalol, like harmine , seems to ha.ve a, safety so long as there was no marked fall of blood definite effect in relieving tho r igidity of the muscle&, pressure. Ex:perionc e with har malol con firmed tl1is with conseq uent improvement in volm1ta.ry move-ant icipa.tion . . monts , it produces no general alleviation of the

R esu lt s o f Experiments. symptoms-comp lex of parkinsonism a.ta ll comparable Tho res ul ts of the experiments ca.n ho state d with that produced by hyoscine .

bri efly. Thero is little to be gained by giving the Conclusions. r esul ts or the smaller and tentative doses .

By ltypode1wLic injectio1~.- Fiiteen tests were made with doses ranging from gr. 1/10 to gr . 4/5. The smallest of these doses generally produced a. slight rise or blood pre ssure . the largest a fall of not more than 10 mm. Hg, accompanie d . usuall y by slowing of the he ar t-rate by :Lbout ten beat s per minute.

Ha.rmalol hydrochloride , in doses of gr. 4/5 hypo­derm ically or gra. 8- 12 by mouth, has a. slight but definite effect in relieving muscular rigidity in parkinsonism. It ha.s no beneficial effect on th& tremor or on the menta .l condition and does not

(Oonti-nu.ed at foot of opposite page.)

THE LAN CET,} [OCT, 24, 1931 903

CLINICAL AND LABORATORY NOTES

CASE OF ACU T E ASEPT IC MENINGI TI S.

BY I SAAC GORDON, M .B. , D.S. L OND . , U0 U8.E l ' UT 8 1C'IAN TO TJIJI: U ,01f>8 TPJ"'-I) OKSJCIUL U08l"l 'J',1.L;

ADQLPHE AnRA.H AlilS, O.D.E. , U.D. CAMIJ., F.R.C .P . LO.ND.,

PITT'B 10 1"'-N TO T UI', !10 8 l'IT ,\l ..

TnE recent publi cat ion by Dr. J. H . Gibbon .a or aome eases of acuto n.aeptio menin gitis in THE L.o. CET (July 4th , p . 12) encour ages us to describe an exa mple of this condition in au adult. Dr. Gibbens 's pat ients wore alJ under the age of 12.

A male, aged 34, in prev ious excollont hea lth , was admit ted to the Hamps tea d General Hospital on July 8th, 1931, compl aining of head ache and vo mit ­ing . His illness began suddenly on Jun e 30th with malaise, severe headache, and pains in the limb s . His doctor had observed that pyr oxia., ran gtng from 101° to 103° F., was pr esent for the first thre e day s or th e illness, and that after two da ys or gonoral improvement all his sy mptom s recurr ed with incrca.sod severity, when for th e fi.rat tim e complaint was m a.do of stiffness in th e neck and vomitin g . Lumbar puncture had been performed ; the eerebro-spinal fluid not wtd er increase d pr essure was opal escent, containing an ex0068 of protein and capable of a slight reduct ion of Fehling's solution. Th e tot a l cell count was 280 per c.mm. , with a. differential proportion of 40 pe r cent. J>Olymorph.a, 30 per cent. small mononuclear s, and 30 per cent. endo t helials . Some coliform bacilli- pr esumably a contam ination ­wore found on cu lture.

On admission, a lthough obviously very ill, he was fuJJy. eon.sciou.a with u nimp ai red cerebration. Th e temperature was 98·8 ° F., cardia c-rate 56, r espir a ­tions 20. Ph ysica l signs were incons picuous ; all

!::aJ:~:1 th:er;;:k :1r~h~n~!r~;e ~~:~le~nf;.:

sign was not elicited. The cere bro- sp inal fluid was not under pressure and exhibited the followin g characters: .Appearance, turbid with a fine clot; tota l eel! cowit 280 per c.mm., polymorph s 17 per cent., lympho cyt es 83 per cent.; tota l prot ein , 160 mg. per cent . ; globulin incre ase d; suga r within normal limits ; chlorides, 700 mg. per cent.; W a.s.ser­m&nn reaction negat ive ; no organisms identified in smear or cult ure.

(Oontinued fr()111, previous page .) relieve salivat ion. In th ese doses it is well tolerat ed. It does not produce anything Like so oomp lete a relief of all the symp tom s as is effected by th e alkaloids or t he h yosc ine group, but may be of some value as an adjnvo.nt to tho se, in tho troatment of pa:rkinsoni.sm.

REl- 'ERE NCES . l, 11r,~, L,: Arch. f, E:"['J), P at h. 11. Phann., 1928, rurxlx. ,

2, 11~,1rd Scbu at.er, P . : Deut . Med. Wooh., 1929,

S. . : Ibid., I9 28, ll, ·., 908, t: · Wll:u 1029, Iv., 61S.

&. Ibid., ~: . : T 9ll, x lvill., 83. 9. ;! Wors~::nrought., ~.~::·:::~;~~~2~:

u .. Vi. 10 Gunn and othe rs · Quart. Jour Pharm and Ph.lU'macol ,

192G, U., 525, 1930 , Ill, 1 ftDd 218 , lOSt, l v, S3

Durin g th e two day s following admiss ion, vomiting p ersis ted but terminat ed ab ruptl y, al .though headache and st iffness of the neck contiuu od. Ilra.dyca rdia and apyroxia were maintained. Examin at ion of the blood show ed the pr esenco of sligh t seco ndar y a.uremia. The to ta l leuoocytos were 16,000 ~or c.m m., of which 78 per cent. wer e po lymorph s . Improv ement bega n and ste adi ly continu ed , and within ten days a ll sympt oms had disap pew-0<1. By this time the cere bra~ spinal fluid , st ill t urbid , contni ned 250 whit e colls per c.mm ., 90 per cent. of whi ch were ly m1>hooytes. Th e tota l prote in was now 120 mg . per cent ., chlorides were 715 mg . per cent . Cultur es ste rile. A week later the fluid was clear, colourless, with eight cells per c.m m ., all lymp hocytes . Total pr ote in 95 mg . per cont ., globulin. very slightly increase d. Sugar wit hin norm al limit s, chlorid es 720 mg. per cent. La nge's colloid al gold curve O O O O O O O O O O. A final lumb ar pun ct ure wa.s performed on August 12t h . The oorebro -spina l fluid was clear and colour less without coagul um. E ight cells-al l ly mpho cytes­per c.mm. Tota l prot ein 0·035 mg. per cent. Glob ulin a faint tr ace. Sugar uormru. Chlorides 690 mg. per cent.

It should bo add ed that th e ,v a.ssermann reaction in the b lood was negat ive, Manto ux's test was nega· tive, and that a skiagram of the skull exhibited no abnormality to suggest dis e1'o8e of the s.inu.ses.

CAR C INO MA OF T H E CE RVIX

WlTH TWIN PREGNANCY A..'ID NO R.MAL DELIVERY.

BY J . L. BL ONSTE IN, )LR .C.S. ENO .

CASES of carcino ma of the cervix and pre gnancy with deliv ery per vias natura les bav e been recorded . Ustlally th ese have been diagno sed before deli very, and if not termina.tod by Cresarean hysterectomy, there b as been severe post- partum h remorrh age.

In 1913 H. B. Mylva.ga nam 1 repo rted a case of adva nced ca rcinoma. of the cervix ute ri containing twins, tr eate d by vaginal hyste recto my at the fift h month. I n this cnse pr egnan cy wa s not d iagnosed, the fcetu ses onl y being discovere d at operation. The indication for operation was the severe hremorr hages . Jn 1918 B. P. ,v at.son 2 reported a case of can cer of the cervix complic ating tripl et pregnancy, treated by Cresarea.n Wertheim hy sterecto my at th e filth month. Pr egnan cy was dia gnosed, but from the seco nd month hromorrha ges and foul vag ina.I d ischarge were present.

Th e following case appears to be unique . I was called in by a midwif e to Mrs . .A., age d 38,

a. 2 -pa.ra , on account of a prolonged first stage. The history of tho pregnancy was un eve ntful except Ior a certain amo unt of low backache. '1'hore was no histo ry of oll'emive discharge or bleed ing. Th o last menst rual period had co mmen ced on Sept . 23rd, I 930, bad lasted five day s, and labour bad begu n on April 27th, 1931. There had be en a show , but the pains were sligh t and infrequ ent . On examination the abdomen was soon to be very pe ndul ous. Twin s were eas ily di ag nosed . On vag inal exa min at ion the os wus the size of ha.If a. crown. Jt was noticed that tho cervix waa bard and irregu lar in ou tline. No

'Tm :: L M•"Cl.."1', 1913, ll. , 930. • .Amor. J our . Obet., 1018, lxx-vlll. , sa .