clinical trial of cafilon and ritalin in the treatment of obesity

391

CLINICAL TRIAL OF CAFILON AND RITALIN IN THE TREATMENT OF OBESITY

By OLIVER FITZGERALD, M.D., M.Sc.

Visiting Physician, St. Vincent's Hosp~tal, Dublin; Lecturer in Therapeutics, University College, Dublin;

and L. (J~. McELEARNE¥, M.D., M.R.C.P.I.

Late University T.t~tor, St. Vi~acent's Hospital, Dublin.

T HE importance of weight reduction for obese patients is at present widely accepted. The outlook for the obese patient is roughly in inverse proportion to the percentage overweight, according to

the statistics of the Metropolitan Life Assurance Company (1951), ranging from 33½ per cent. higher mortality for those 20 per cent. overweight to a 100 per cent. higher rate for the 50 per cent. overweight group. The magnitude of the obesity problem may be gauged by the fact that at least 15 million adults in the U.S.A. over 30 years of age are estimated to be 10 per cent. overweight, and indeed it may well be said that obesity presents a challenge to preventive medicine.

The methods of weight reduction are fairly widely agreed upon. The keystone in any programme must be a reduction in calorie intake. With regard to diets in obesity the important thing is a decrease in the total calorie intake without upsetting the proper balance of the diet and depriving the patient of essential vitamins and minerals.

In obese subjects reducing diets are often accompanied by anxiety and depression, and it is here that the anorexigenic mood-elevating drugs have proved invaluable. The amphetamine group is the main one in this category, viz. 1-amphetamine, d-amphetamine and meth-amphetamine. Harris is concludes that these compounds induce weight loss primarily by facilitating a diet of lower calorific value, and secondarily by increas- ing calorie expenditure through voluntary overactivity. The present evidence is that they. cause reduction of appetite by a central action, but whether they inhibit specifically an "appetite centre " or not remains unanswered. Tolerance to the amphetamines and side-effects may be seen, especially in older patients. These include insomnia and restless- ness, so that patients are advised not to take these compounds late in the evening. Amphetamine addiction is uncommon in these islands, but Masaki ~7 reports it as a formidable problem in Japan. McNair 2° reports favourably on the use of a combination of Rauwolfia and amphetamine as an appetite-suppressant for obese patients. It was free of side-effects and had some mood-elevating action.

Thyroid has long been used to facilitate weight loss in obese subjects, but there is now general agreement that thyroid should be used only if there is concomitant hypothyroidism. Many obese patients take extra exercise under the erroneous impression that it will result in weight loss. A 250 lb. man must climb 20 flights of stairs to account for one slice of bread, or walk 26 miles to rid himself of 1 lb. of fat2 Extra exercise is a poor substitute for proper dieting.

392 I R I S H J O U R N A L OF M E D I C A L S C I E N C E

Rostalski 21 and Berneike 4 repor t on the use of a more recent compound in t rea t ing obesity. I t is 2-phenyl-3-methyl-tetrahydra-1, 4 oxazine hydrochloride or " Pre tud in ", and they claim it has an appet i te-suppressant action without any undesirable side-effects.

I t s formula is as follows :

CH3 I CH NH

< ) o Cl4z

Thomas and Wick 25 have reviewed its pharmacology. I t s mode of action is unknown, but in clinical pract ice it causes reduct ion of calorie intake by producing earl ier sat isfaction of the appet i te without causing any appa ren t in ter ference with the normal enjoyment of meals. A few side reactions have been noted by other invest igators; these include dryness or an unpleasant taste in the mouth, urt icaria, slight overstimu- lat ion with dizziness, nausea and headache and a slight rise in blood pressure. Koenig is secured an average weight loss of 2 lb. weekly in a group on Pre lud in and he, as well as others, comment favourably on the mild elevation of mood it induces. No habi tuat ion or addiction has been noted with Preludin.

We repor t below our experiences with two newer compounds which we have been s tudying with regard to thei r effects in a group of obese subjects. Par t i cu la r a t tent ion was pa id to a number of points, viz., how mood and appet i te were affected, and whether the pat ient lost weight.

The first of these compounds will be re fe r red to as " Cafilon ". I t is a combination of the two substances whose formulae are shown below with 20 rag. of R /381 and 30 mg. of R/382.

The ephedrine molecule was the s ta r t ing point for both, and as can be seen the side-chain has undergone various addit ions and modification.

Ep]~ e d r i n e :

~ --C14--C14 --NH I I !

OH CH3 CH3

R / 3 8 1 :

cz~s HGL

O CHz

Phenyl-ethylacetic acid (phenylme~hyl)-morpholino-N-ethanolester hydrochloride.

C L I N I C A L

R / 3 8 2 :

T R I A L OF C A F I L O N AND R I T A L I N 393

N C N'CI-13

< ? + ) . o = _ _ , ,

CNz,, OC --N-CHs 0 CHz

Phenyl methyl .morphol ino-(dimethylchloro) xanthinate. This combination of substances R /381 /382 is re fer red to a s " Cafilon "

The two consti tuents act centra l ly in a synergistic manner with an effect considerably milder "~han the st imulat ing amines. In addit ion they antagonise one another peripheral ly, thus mutual ly cancelling the effects on blood pressure or the cardiovascular system. I t is not a sympa- thomimetric compound and may be safely used in pat ients with cardiovascular disorders. Hengen and Siemer 14 have reviewed its pharmacology and note its mild, central-s t imulat ing action free of any circula- to ry effects. They claim it has an appet i te-depressant action, and that it is the least toxic of the psycho-analeptics with this appet i te-reducing action. F r o m data made available to us (in which the i r toxic effects are compared) Cafilon was apparen t ly less toxic than the amphetamines, Preludin, Rital in or Caffein. (Hengen. I~) Balg and Frohl ieh 2 noted a reduction in appet i te and a mean weight loss of 2 lb. pe r week when Cafilon was used in a group of obese subjects. Burger ' s results confirm this2 H a a f TM has noted the beneficial effects of the psycho-analeptic action of Cafilon in a group of pat ients t reated by deep x-ray for mal ignant disease.

Suda ~" has used Cafilon in doses of 100 mgs. daily in 10 tuberculous patients, with elimination of some of the undesirable t iredness and mental torpor. The tuberculous process was unaffected and weight loss was not seen. The usual tuberculostatic drugs were used and no side- effects f rom ~he Cafilon were noted, even a f t e r several weeks.

The second of these compounds is " Rital in ", and i t has the s t ructura l formula shown below:

Rital in :

, ~ - - CI.I--COOCI'I3

phenyl-(oe-piperidyl)-acetic acid methyl ester hydrochloride. I t is claimed to be a central nervous st imulant with an action inter-

mediate between those of caffein and amphetamine. I t is claimed to


have a smoother action than the amphetamine group and tha t it has not any depressant effect on appeti te. Rital in has been studied in the U.S.A. and on the Continent of Europe. Stier 23 has used l~italin in the treatment of depressive states wi th good results, and Drassdo and Schmid t ' noted an improvement in menta l capaci ty and in psychic effect in pat ients on Ritalin. Geller 1~ (1955) found Rital in effective and reliable in the t r ea tment of depression, but noted tha t t rue manic-depressives and involutional depressives must be excluded f rom t rea tment by Ritalin. Meier e~ al. 18 have suggested tha t Rital in would be of value, in t rea t ing hypnotic intoxication, and Ferguson 9 has used Rital in with success to combat depression result ing f rom the use of Reserpine in a group of psychiatr ic patients. A prepara t ion combining Ritalin. and Reserpine is now available. In addition, Ferguson noted the abolition of drowsi- ness and " stuffed-nose " in the Reserpine-treated group. He also repor ted on the successful use of the combination of drugs in improving behaviour in a group of senile patients. 9

I f the formulae for Ritalin, Cafilon and Pre lud in are compared with those of the amphetamines shown below i t can be seen tha t there is some chemical s imilar i ty between them all, as all contain the following basic grouping :

< • .~--EH

A~nphetamine:

. < , , H H C,H 3 H

d-Amphetamine:

14 H~C 14 H

Methamphetamine :

H 14 CI4~ (;H3

Method of Trial:

Thirty-one pat ients commenced the trial. They were selected as most were a t tending the hospital dietetic clinic wi th a view to weight reduction. Before commencing any drugs all pat ients were put on a 1,200

CLINICAL TRIAL OF CAFILON AND R I T A L I N 395

calories diet for one or two weeks and the effect observed. This com- parat ively generous diet was continued throughout the tr ial period. Placebo tablets similar to the t r im substances were used dur ing the trial. The patients commenced with either Cafilon or its p lacebo-- the hospital pharmacist selected whether a pat ient received the drug or its placebo. I f a pat ient received the placebo for the first period, he later received the tr ial compound and vice versa.

Later, the patients were changed to Ritalin and its placebo; these were used similarly to the Cafilon and its placebo. We were aware in which group each patient was, but did not know whether he was re- ceiving the tr im substance or the inert preparation. A record of what each patient received was kept by the hospital pharmacist and was later made available to us. Each patient was interviewed by one o£ us at every hospital visit. A record of any subjective change, with a record of weight and other pertinen~ observations such as mood or appetite, was made at each visit. Blood counts, blood pressure readings and liver function tests were carried out on all patients who volunteered for the trial. Each patient received drug and placebo for an equal length of time, but as the tr ial was carried out on extern patients, many of whom were i r regular in their attendances, it was not feasible for all patients to have drug and placebo for the same number of days. Each pat ient received each of the tr ial substances (including placebo) for approxi- mately two weeks.

Dosage Used: Cafilon 50 mg. drag~es. One tablet half-an-hour before breakfas~ and

mid-day meals. We advised that Cafilon should not be taken later than 3 p.m. in case it might interfere with a pat ient ' s sleep. RitMin (10 mg.) tablets were used in a similar manner to avoid any elemen~ of suggestion. Placebo were used in like manner.

Results: Twenty-five patients completed the trial. The remaining six were not

included as their records were incomplete or the pat ient had defaulted. In assessing ~he results, par t icular attention was paid to a number of points, viz., whether the patient 's weight increased or decreased, and the amount of change in weight; how the patient 's mood was affected; how appetite was affected; whether there were any side-effects and whether tolerance to the drug appeared.

The blood counts, blood pressure readings and liver function tests showed no deviation from the normal. Ne pat ient showed any evidence of tolerance developing to ei ther drug. The effect on weight can be seen in Figures I and II.

I t will be observed that the greatest weight loss occurred with Cafilon. The difference in weight loss between it and its placebo wa~ highly significant (p < 0.0001).

When Carl]on and Ritalin were compared there was also a considerable difference in the weight loss induced by Cafilon compared with Ritalin. This difference was significant (p ~ 0.0001) and suggests, of course, that the Cafilon is a more powerful weight-reducing substance than Ritalin. I t should be noted that the Cafilon pai r of tablets was t r ied before ~hc

396 I R I S H J O URNAL OF M E D I C A L S C I E N C E

r~ 2;

I c.

3

2

I

0

1

2

3

,t

S

6

1

4~

• I,~fht ~ai. (Ib*)

~1 No c~*ng*

, I

3

1

o

1

z

$

4

C & f t t o n C a f t t o n P t t c c b o

[ ] I o . . .

I.ml No chan~,

_, !

& ?

Figure 1.

R I t a l i a R I t IL l l n P lace I~o

INDIVIDUAL CASE. Weight change of individual patients recorded as a noraogram.

Ritalin pair; therefore, the early and possibly easily induced weight loss produced by a diet might be expected to be somewhat greater ~han that occurring later when the Ritalin test pair was used. However, the differenee does appear to be so great that it is hardly likely to be due to these factors and must be in part due to the drugs tested. In support of this view it will be noted tha~ there was hardly any difference between the two placebos (p =0-07). There was some weight loss induced by Ritalin itself (perhaps due to a combination of a reducing diet and extra activity); bu~ the difference between Ritalin and its placebo is not so great as that between Cafilon and its placebo, though that difference was significant (p = 0.0001).

Only seven patients noted a decrease in appetite while on Ritalin.

C L I N I C A L T R I A L OF C A F I L O N AND R I T A L I N 397

FIGURE I I .

g

Y

6

5

4"

3

2

1

o

6

5

4

I

~'o 0 5

6 4 ; [ 3

Comparison, of ,dr~s a s x f r , ~ q u e n c I j nomocrsm

of lot. cBAn~. .

1 o

6

8

4

3

2

t

o

I

I

! |

I

!

gLtatLn & RttatLn Ptac tSo

- t .o ,~ +. o-~1

rl

I l

i

. . . . . . . . . " ~ h D|ffar~nce I~ta~en ~wo Placebos • "- 0 . 5 6 ± 0-36

i

P~ ffarenca between, lot. cht.n~ s ~ r C~fflon ~nct RttsLin as x fra~]u~nCy .omo~ram - t-~e ~ o-39

. i l

Differe.'ce I~t~)ma~ the chanSe produced txj C~filon Snd Placebo ma fregatnc~j .omo~rzm - 2 - 4 +- 0 . 4 g

I I • *3 *2 41 0 - i -2 -3 " -4-5 - 6 - - T - 8 -9

No. of lbs. lost or gained.


Rital in appeared to have a grea ter mood-elevating and " pepping-up '~ effect than Cafilon. Due to these effects the pat ients may have found their diets more tolerable and thus were able to reduce weight. A n u m b e r of pat ients lost weight while on the placebos. This fact does not in- validate the weight loss on the drugs themselves, as recent correspon- dence tends to suppor t the view that placebos in themselves have a decided therapeut ic action. (Findley. T M ) The effect on appet i te and on mood is shown in Tables I and I I respect ively

TABLE I.

Effect of Drugs on Appetite.

Cafilon Placebo C. Ritalin Placebo R.

Drug

° . .

° . .

. , .

. o .

o . °

, . .

Appetite Decrease

20 7 7 5

Appetite Increase or Unchanged.

5 18 18 20

TABLE II.

Effect of Drugs on Mood.

Cafilon Paeebo C. Ritalin Placebo R.

Drug

. . o

. ° . . . ° ° . .

Improved or Elated

12 6

16 4

No change or Depressed.

13 19 9

21

I t can be seen (Table I) tha~ Cafilon had the grea ter appeti te-depressant action. Many pat ients s tated they had no desire for food in the evenings while on CafiIon, and with la rger doses a more marked effect should be seen. Only seven pat ients noted a reduction of appet i te while taking Ritalin, which suppor ts the claim of the manufac tu re r tha t the Rital in has no appet i te-depressant action. In fact, several pa t ien ts claimed to be quite hung ry on Ritalin.

I t will be noted (Table I I ) that both drugs had a mood-elevating action. F rom our experience with the group we should say that Rital in was the more poten t of the two in this respect. Several pat ients who were depressed and tearful , re turned a f t e r one week on Ri~alin grea t ly improved and said they were full of energy. One female claimed tha t a f t e r Rital in she could not find enough housework to occupy her tha t morning.

A few side-effects were noted with Ritalin, none with Carl]on. No pat ient repor ted any dis turbance of sleep on either drug, and a few volunteered they were sleeping much bet ter since commencing the i r tablets. Three pat ients noted intolerable side-effects while taking Ritalin, viz., nervousness, i rr i tabi l i ty, palpi ta t ions and a sense of anxiety. All these cleared rap id ly when the d rug was discontinued.

CLINICAL TRIAL OF CAFILON AND R I T A L I N 399

D i s c u s s i e , n .

The field of therapeutics has been marked in recent years by the introduction of a number of drugs which affect mood--both tranquillizers a n d psycho-analeptics. Sargent 22 gives an up-to-date review of the fo rmer and included bromides, barbiturates, chlorpromazine and reserpine ; he has also introduced a new compound " Frenquel ". To this list we may add Meprobamate- - (" Equani l " and " Milltown " ) - - a n d Benac- tyzine products (Suavitil). None of these compounds other than Reserpine appears to have any direct action on appetite. Moore and Martin, 19 when t reat ing a group of schizophrenics with Reserpine, noted an initial increase in appeti te with a decrease later on when the side- effects of the drug became marked.

A number of psycho-analeptics are available; of these the amphetamines are the oldest and most widely known. Their depressant action on appetite is well recognised. Begg and Reid 3 report on a clinical tr ial o f " Meratran ", and state that it is of value in reactive depressions; but, unlike the amphetamines, Meratran caused little disturbance of sleep or appetite. Cafilon and Ritalin are both psycho-analeptics, and of the two Ritalin appears the more potent in respect to, " pepping-up " action. Ritalin does not appear to have any appetite-depressant action. Cafilon, on the other hand, can only be regarded as a mild psycho- analeptic, but it has a marked appetite-depressant effect. A review of the available l i terature suggests tha t Ritalin is a fa i r ly potent stimulant. We would agree with this. In selection of patients fo r Ritalin, caution is needed to exclude those with any suggestion of an agitated depression, as there is a real danger of accentuating their agitation. The absence o f an appetite-depressant effect is a valuable p roper ty when treat ing underweight depressed patients.

As regards Cafilon, its psycho-analeptic action is so mild at the dosage studied that we should hesitate to use it for the purpose alone. I t would appear to be a potent appetite-depressant, possibly with a central site of action : f rom our experience we should say that Cafilon is a more potent appetite-depressant than are the amphetamines. In our opinion Cafilon will prove useful in patients who should reduce weight. As it has no effect on blood pressure it may be used in hypertensive and cardiac patients. Unlike the amphetamines, there appears to be no habituation with Cafilon but, quite clearly, it is too ear ly to be certain of this point. When obese patients commence reducing diets many of them are miserable and depressed; Cafilon, with its mild psycho- unaleptic action in addition to its appeti te depressant effect, will prove useful to such patients. Larger doses of Cafilon than we used in the tr ial should have a more marked effect in depressing appetite. Fu r the r recent experience has led us to prescribe doses of ]00-200 rags. twice daily. I t is wiser to commence with 50 mgs. and build up to 200 rags. over a couple of weeks.

We may be reasonably certain that obesity will remain the problem it is today. We must explain to our patients the dangers of obesity and the advantages to be gained by weight reduction. In addition to diets and drugs a sympathetic approach is very necessary, as these patients are often in need of our guidance and instructions. Continuity of treatment is most essential. We must continue to encourage our patients,

400 IRISH JOURNAL OF MEDICAL SCIENCE

though we find it irksome and trying at times. The numerous drugs available should be used generously, especially when commencing a reducing programme. Of the many drugs now ~o hand we consider that Cafilon will prove a useful addition for which a place exists at present.

S u m m a r y .

The problems of obesity and the importance of weight reduction are considered.

Methods currently used to reduce weight--both diets and drugs--are reviewed.

The drugs affecting mood are referred to and ~heir known effects on appetite discussed.

Two newer compounds--" Cafilon " and " Ritalin "--were used and the results of a clinical trial are reported. They are psyeho-analeptics, and Ritalin is the more potent of the two. Cafilon, however, has a marked appetite-depressan~ action.

The place of Cafilon in weight reduction programmes is discussed. The importance of persisting with dietary therapy for obese subjects

is stressed.

Acknowledgments.

We should like to thank Miss M. O'Shaughnessy, dietician, St. Vincent 's l~ospital for her help with diets and in the follow-up of patients. We wish to thank Messrs. Ciba Ltd. for supplies of l~italin and Placebo, and Messrs. l~avensberg, Constance for supplies of Cafilon and t)laeebo.

We are much obliged to Professor E. J. Conway F.I~.S. and Mr. I-~udson for statistical advice. We are also obliged to the pharmacists, Misses Lawn and Murphy and to Mr. I~. Carrick, for the illustrations.

References.

1. Armstrong, D. et al. (1951). J . A . M . A . , [47 1007. 2. ]3alg, K. ]~. and Frohlich, G. (1956). Die Medizinische. (in print). 3. Begg W. and Reid A. (1956). B . M . J . , i, 946. 4. Berncike, K. I~. (1954). Med. Klinik, 49, 478. 5. Burger, G. (1956). Therapie d. Gegnwart, 95, 81. 6. Conference on Therapy (1952). Am. J. Med., 13, 478. 7. Drassdo A. and Schmidt M. (1954). Med. Monatschr., 8, 306. 8. Ferguson, J. T. (1955). Ann. N . Y . Acad. Sci., 61 (1), 101, P. 316~ 9. Ferguson et Yunder Burk (1956). J . A . M . A . , 160, 259.

10. Findley, T. (1953). Med. Clinics Nth. America, 37, 6. 11. Geller, W. (1955). Die Mcdizinisvhe, 16, 606. 12. ]:~aaf, E. (1956). Med. Klin., 51. 13. I-~arris, S. C- (1955). Ann. N Y Acad. Scg., 63 (1) 121. 14. ]:Iengen and Siemer, YI. (1955). Arzneimlttelforseh, 5, 256. 15. I-Iengen, O. (1956). Private Communication. 16. Koenig, P. (1955). Aerzt. Praxis, 7, 11. 17. Masaki, T. (1956). W.I-I.O. Techn. J~ep., Sr. 102. St. 18. ]Yleier, 1~. et al. (1954). Verb. Dtsch. Ge8. f. Inn. Med., 60th Co~lgresa. P. 316. 19. Moore, J. ~ . P. and Martin, E. A. (1957). B . M . J . , i. 20. Me ,a i r , J. D. (1955). Am. Praet. Digest of Treat., 6, 11. 21. l~ostalski, M. (1954). Medizinsche, ~o. 33/~34 111. 22. Sargent, Win. (1956). B . M . J . , i, 939. 23. Stier, C. (1955). Therap. d. Gegenwart, 94, 92. 24. Suds, J. (1956). Private Communication. 25. Thoma, O. and Wick, I-I. (1954). Arch. Exp. Path. u. Pharmakol., 222', 540.

clinical trial of cafilon and ritalin in the treatment of obesity

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