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Biological Study of Dinitro Drugs in Humans
By Dr. Jacques Bell
Bell, Jacques. 1939. Etude biologique des produits dinitres chez l'homme.
Medecine. 19:749-54.
Translation © 1996 Robert Ames
There is a fundamental difference between biological experimentation with
dinitrophenol in humans and what was done in the laboratories of
physiologists. These last are essentially interested in hyperthermia (Andre
Mayer, Leon Binet, etc.). Yet, in medicine, the doses of dinitrophenol
employed do not determine any elevation of temperature. The physiological
effects, observed in these conditions, differ considerably from those made
by the experimenter. It is thus for example that the animal in hyperthermia
presents a polypnoea [rapid, shallow breathing], a hyperglycemia, a
hypoglobulinemia that one does not observe with therapeutic doses; it is
because experimental hyperthermia is essentially a combustion of
carbohydrates, while therapeutic hypermetabolism is mainly a combustion of
lipids, as is shown by the lowering of respiratory quotient.
One shouldn't be surprised at these differences. The clinician uses
strychnine as a tonic; the experimenter employs it to cause convulsions. The
clinician uses adrenaline, at titrated doses, to produce a manageable
hypertension; the physiologist, with massive doses causes acute edema of the
lung.
Yet, to base the clinical use of adrenaline or of strychnine on acute edema
of the lung or experimental convulsions, constitutes an obvious error. It is
the same for dinitrophenol.
In France, besides, one uses almost exclusively dinitrophenyl-lysidine,
which, according to the same terms of the study made by Professor Pouchet,
"is easy to purify by crystallization, to easily modify the first of its
components from the point of view of toxicity, dissolves easily in water,
and, by addition of the methylglyoxalidine (lysidine) group, favors
energetically the elimination of waste."
After Professor Pouchet, we have, in our thesis [1], demonstrated the
superiority of this last product; in what follows, it is by comparison with
him that we will study the biology of the dinitro drugs.
We shall see, in order:
I. Their action on the basal metabolism,
II. Their visceral action,
III. Their nutritional action.
I. ACTION ON BASAL METABOLISM
After the experimental research of Magne, Mayer and Plantefol, in animals,
the experiments of Cutting and Tainter has confirmed, in humans, that
dinitrophenol is a drug which strongly increases the metabolism,
exaggerating the oxidation process of the organism by direct action on the
cellular metabolism. These authors have observed a rise of close to 20%
after one hour, being able to attain 70% in ten hours and a tendency to
return to normal at 24 hours if the administration of the medicine is not
continued.
This increase is not due to a sympathetic deregulation. The dinitro
treatment respects the autonomic nervous system, in an inverse way from
thyroxine, which, at slimming doses, determines rapidly some tremors,
insomnia, and a mental instability of the type "basedowien." [a thyroid
illness where one secretes too much thyroid hormones]
In the thyroid illnesses, or the thyroid treatments, there is an inverse
connection between the level of the basal metabolism and that of blood
cholesterol, this being as much lower as the metabolism is higher. One
doesn't observe similar phenomena in the course of dinitro treatment.
This fact indicates that the changes caused in the blood cholesterol in the
course of thyroid treatment are directly linked with the thyroid medication
and not at all to do with the elevation of the metabolism which is
responsible for the reduction of obesity. Dinitrophenol has almost no action
on the blood cholesterol. (Grant and Schube).
An attentive exploration of the nutritional changes in the course of dinitro
treatment, in the cases of five obese women, has shown the following facts:
1. The administration of dinitrophenol, at a dose of 3.5 mg per kilo,
increases the total production of heat by about 40%, from the 3rd or 4th
day.
2. This increase of the metabolism is due mostly to an increase in the
combustion of the fat and a little to combustion of carbohydrates.
3. Dinitrophenol does not attack cell tissue albumin and does not determine
the fat loss to the expense of the muscles, contrary to thyroxine.
II. VISCERAL ACTION
Dinitro treatment respects the liver, the kidneys, the cardio-vascular
system and the blood.
This innocuity for the principal visceral functions is without doubt one of
the main reasons for the distribution of this therapy.
Tainter, Stockton and Cutting have reported a series of cases in which one
had measured the plasma bile index and determined the test of Van de Bergh.
Their analyses demonstrate, beyond a doubt, that the liver does not suffer
any damage in the course of dinitro treatment.
Experimental studies on animals do not show toxic effects of dinitrophenol
on the kidney (Taitner, Cutting, Wood and Proescher).
Anatomical-pathological examinations of animals, even those which died from
a massive dose of dinitrophenol, do not reveal any important anatomical
changes, except a small degree of cytolysis. Clinical documents are not
abundant, but, on the whole, do not seem to demonstrate that dinitrophenol
is toxic for the kidneys.
As T.L. Schulte and M.L. Tainter wrote, "it doesn't seem that dinitrophenol
at usual clinical doses is likely to harm the kidneys."
Dinitrophenol is remarkable for its absence of effect on the cardio-vascular
system. Even when the basal metabolism is found elevated to significant
levels, there is no change in the rhythm of the pulse (Rosenblum).
On this point, dinitrophenol differs from all the other metabolic
accelerants known. It is an observation that all the clinicians, today, have
had occasion to make.
All the clinicians know that, contrary to thyroxine, dinitrophenol is
absolutely devoid of toxicity for the heart.
The research of Professor Loeper and of his students has demonstrated the
physiological and clinical importance of myocardiac glycogen. Extensive
studies by P.N. Taussig have shown that dinitrophenol does not reduce
cardiac glycogen at all and that, on this point, it differs completely from
thyroxine.
III. ACTION ON NUTRITION
The influence of dinitro therapy on nutrition has been the object of a very
important clinical study.
"One does not observe variations in the elimination of chlorine; eliminated
phosphorus varies sometimes more, sometimes less, the elimination of sulphur
increases slightly, especially in the form of sulphur conjugates, urines
show a small increase of total nitrogen and of urea." (Prof. Pouchet).
It is a well known fact that the administration of thyroid extract or
hyperthyroidism is accompanied by an increased secretion of calcium and of
phosphorus. This calcium and phosphorus in the urine are not due to the
acceleration of metabolism, as one does not observe these facts either
during fever, nor in the course of leukemias which raise the metabolism
(J.C. Aub, N.B. Bauer, C.I. Heath, Alright, Bauer and Aub).
Thyroxine reduces bone density.
With dinitrophenol, nothing of the sort is observed. The experiments of
Clarence L. Robbins show that dinitrophenol, in spite of the elevation of
the metabolism that it produces, does not cause any increase of the loss of
calcium or of phosphorus. An increase of 37% in the basal metabolism, caused
by the ingestion of dinitrophenol, does not lead to modification in the
excretion of these elements.
In normal individuals, when one administers dinitrophenol during a short
period, it produces a small elevation of reduced substances in the blood
after fasting (although one would not be able to call this hyperglycemia).
When one administers the medication over a longer period, this phenomenon is
not produced and there is a marked elevation of the tolerance to
carbohydrates.
In diabetics, following treatments of short duration, the results are
variable, the tolerance to glucose being as often increased as it is
decreased, with parallel changes in the fasting blood sugar level. But, in
prolonging the administration of the medication, one observes an increase of
the tolerance of carbohydrates. Anyway, in basing himself on the study of 32
cases of diabetes, Simkins concludes that dinitrophenol is not toxic for
diabetics. He remarks that this observation goes counter to some assertions
that have been a little prematurely advanced.
Dinitrophenyl-lysidine at therapeutic doses therefore has an action on the
organism which is completely physiological. This action has been
demonstrated in obesity where it has been compared to the actions of thyroid
medication and physical exercise.
The existence of obesities of glandular origin, especially by thyroid
insufficiency, has resulted in the use of thyroxine in numerous subjects.
"This wasn't without inconveniences, sometimes grave, characterized
especially by cardiac and nervous troubles; the effective dose of thyroxine
is, in fact, very close to the toxic dose. Further, we has frequently seen
these accidents persisting after the administration even of a single dose,
which leads to the impossibility of stopping them immediately by a simple
suspension of the medication. Yet, from the point of view of its specific
action on the basal metabolism, dinitrophenol offers this precious advantage
that the cessation of its use at the slightest appearance of signs
indicating an imminence of intoxication results immediately in the arrest of
those symptoms." (Professor Pouchet).
Finally, thyroxine causes a nitrogen malnutrition: it burns the muscle and
fatigues the heart. Dinitrophenol-lysidine, to the contrary, causes a
lipid-glycemic loss: it is the elimination of reserve materials without
attacking visceral and muscle tissue.
As for physical exercise, it seems to act exactly like dinitro therapy.
Marcowitz, in his communication to the Academy of Medicine of Toronto on
October 9, 1934, based on 90 cases of obesity, having followed this
treatment during a period of 16 months, concludes that its action may be
succinctly described in saying that the effects on the organism are similar
to those of physical exercises.
The fact is besides established by physiologists, since dinitrophenol raises
thermogenesis and not the metabolic quotient.
All the clinicians know actually that dinitro medication is irreplaceable in
cases of monstrous obesities which prevent all exercise. It can be used in
the obese for whom occupations, life style or cardiac troubles do not permit
physical exercises. It is indispensible for the grossly obese in cases of
abdominal operations and immobilization due to illness (inflammation of
fallopian tubes, appendicitis, etc.) for which there is an urgency to obtain
a reduction of subcutaneous fat.
But this clinical use has not been able to be extended other than when the
experimental research pursued on humans, with a dinitro drug free from
impurities, has been able to demonstrate the biological effects of it in a
very precise way.
1. La Therapeutique dinitree (J.-B. Bailliere et Fils, editeurs, 1937).
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Concerning Two Cases of Cataract Caused by Dinitrophenol
By Jean Sedan (Marseille)
Sedan, Jean. 1939. A propos de deux cas de cataracte par phenols dinitres.
Annales d'Oculistes. 176:191.
Translation © 1996 Robert Ames
The implementation of the treatment for obesity by dinitrophenol dates only
from 1933, the year when it was suddenly and rapidly put in the limelight by
the work of the Americans Tainter, Mehrtens and Cutting.
These authors have established that the ingestion of dinitrophenol
accelerates metabolism, causing a marked elevation in temperature. It seemed
that dinitrophenol was a specially effective treatment for obesity. In 1936,
Horner estimated that in the first 15 months following the appearance of the
medication in the market, one hundred thousand persons used it to lose
weight.
Incidents and accidents multiplied and appeared sufficiently serious that
the American Medical Association warned the public against the dangers of
unsupervised treatment.
Here we discuss only the case of cataracts, which Horner had said that it
occurs in one case in 1000 treatments. At the end of this report we will
note the principle bibliographic references concerning the American
literature devoted to the subject and which is of a great value, but we wish
to emphasize how the European work and especially French are on the other
hand still rare and even exceptional.
One can say that it is by the work of Onfray and Gilbert Dreyfus presented
to the Congress of the S.F.O. [Societe Francaise des Oculistes?] in 1937
that French opthamologists had their attention drawn to the subject. This
remarkably precise work is enriched by two observations of which one is due
to Doctor A. Gallois, of Besancon. We frequently reference this, for it
contains in addition to minutely observed details, important
physio-pathogenic considerations and a complete history of the subject.
Apart from this work, we should also to point out the observations of Van de
Hoeve and Polak-Daniels published in Holland in 1936, as well as the French
summaries and reviews of Halbron on cataracts and of Laignel-Lavastine on
dinitrophenol intoxication.
Finally, we emphasize the interest of the work of Vogt on the cataracts
caused by dinitrophenol in Switzerland and of G. Ciotola of those caused by
alphadinitrophenol in Italy, both published in 1937. The same year, Stein
and Crevecoeur pointed out that in their opinion this affectation was, when
all is said and done, quite rare if one thinks of the enormous dissemination
of dinitro treatment. This was also the opinion of Andre Mayer, based on the
fact that despite the considerable number of intoxications by dintrophenol
observed in munitions factories, no cases of cataracts have been noted.
Finally, in 1938, Carlotti and Rivoire de Nice presented a case of cataract
by dintrophenyl-lysidine which developed "with almost lightning-like
rapidity."
* * *
It was possible for us to observe two very demonstrative cases. In one there
was an arrest of development of opacity after the patient stopped taking
dinitrophenol, which is more than a rarity, a real exception in the
pathological history of dinitrophenol cataracts.
OBSERVATION I. -- Mme. K... Lea, 32 years old presented herself to me in
December 1937 with a marked lowering of the vision of both eyes, which began
a few weeks earlier, developing extremely fast and was all the more
disturbing since she works at a very visual profession in the editing of a
newspaper and as she is especially partial to this pleasant and remunerative
position. I noticed a beginning of bilateral cataract appearing striated and
fleecy which is found almost constantly in the description of toxic lens
opacities of this kind. The opacity is situated mainly at the level of the
equator of the lens, but also involves the posterior part of the central
mass. The vision is only 4/10 in the right and 5/10 in the left, these two
acuities correctable to 7/10 O.D.G. -- 2.50.
Mme K... thus learned that she was rapidly becoming myopic.
The most minute research were done in view of identifying a possible cause
of this bilateral cataract. All the blood and urine tests were negative.
Very complete clinical examinations by Doctor P..., referring physician,
point to the same conclusion that it is impossible to relieve Mmme. K...'s
pathological process at all.
It is then that I thought of asking her about the possibility of a
dinitrophenol anti-obesity treatment, even though the corpulence of my
client did not seem excessive. She told me then of having taken two pills
each day of 0.30 grams of dinitrophenol in series of ten days with a rest of
15 days, for the past year and a half.
She had, without the least dietary restriction, lost 19 kilograms out of 87
[42 pounds out of 191]. It was at that point that she began complaining
about her vision.
I wasn't aware of the topic at that time except by the short summaries of
American works, but I didn't hesitate to warn her against what I considered
to be the real origin of her sickness.
Very anxious about her state, she was easily convinced and stopped that
therapy suddenly and definitively.
I had the opportunity to see her in March, July and October 1938 and I
noticed with great interest the complete arrest in the development of these
catacts, which accompanied in very precise fashion the progressive and total
disappearance of myopia to the extent that although it was possible to note
an appreciable modification in the lens opacities, the visual acuity was
spontaneously returned to 7/10 (uncorrected) at the end of October 1938.
We add that Mme. K..., doubly happy, very far from regaining weight in spite
of the renunciation of dinitrophenol, had lost another 5 kilos by a very
strict nutritional discipline complemented with rigorous gymnastic practices
and the introduction into her life of a new intoxification, certainly less
dangerous than the preceeding -- tea.
In this case, the role played by the toxin in the opacification of the lens
seems to us demonstrated in an almost experimental fashion by the
disappearance of the myopia at the moment of the cessation of the
intoxification and even more by the incontestable and enduring stabilization
of the state of opacities that maintained itself for six months. In
contrast, the development was very sudden in a month before the application
of this measure. It is presumed that only the precocity of the requested
medical consultation and of the medical diagnostic given, has permitted a
stop in the development of this toxic cataract -- a completely unusual
phenomenon.
We emphasize that the treatment had included plainly excessive doses and
that however the opacification only appeared late in the treatment. On this
topic remember that in the discussion which followed the expose made to the
S.F.O. in 1937 by MM. Onfray and Gilbert Dreyfus-Arruga, who had occasion to
observe and operate in America [illegible] ... don't generally appear except
at the end of many months and even sometimes six to twelve months after the
cessation of treatment. These late-developing cataracts are almost always
bilateral.
OBSERVATION II.
[Not included. Summary: A 32 year old woman weighing 90 kg. (198 pounds)
began taking dinitrophenol on February 1st, 1937. She began with 9 to 10
pills daily, each being 30 mg. of DNP. After a week she increased the dose
to 12 pills / day (360 mg.). At this dosage she lost 800 grams per week, or
10 kg. (22 pounds) in three months, without changing her diet. She stopped
taking DNP for four months and then began again. So she took 32.4 grams of
DNP in the first 90 days and the same amount in the second course. American
reports indicated that cataracts had resulted from doses as small as 100 mg.
per day for a total of 40 grams.
On June 10th 1938, after several days in a very sunny seaside resort, the
patient began to lose vision in her left eye, and on July 12th, the other
eye was affected. By August 1st she was unable to see to drive. By September
she was blind.
Fortunately, surgery produced favorable results.]
It is necessary, indeed, to publicize cases in order to attract the
attention of physicians and of the French public to the danger of
intoxification by dinitrophenol. The fact that we have been able to
stabilize, if not make regress one cataract of this class by stopping all
toxic ingestion is but another reason which compels us to make it known.
These arguments and our observations are so needed to challenge the
imagination and influence young women against harmful weight loss techniques
that the work appears discouraging.
Indeed, in ending, we repeat the unlikely remark that our second patient
made to us upon taking leave following the success of her first operation:
"And now, Doctor, do not oppose my taking of dinitrophenol since I no longer
risk having cataracts."
References
· ALLEN and BENSON. -- Late development of cataracts following use of
dinitrophenol about a year before. JAMA, 1935, V, 105, p. 795.
· BARKAN, BORLEY, FINE and BETTMAN. -- Operative results in cataracts
coincident with dinitrophenol therapy. Cal W. Med. 1936, XXXXIV, p. 360.
· BENCE, JONES. -- On the rate of passage of crystalloids into and out of
the vascular and non-vascular textures of the body. Pr. R. Soc., 1863,
London, 14, 400.
· BOARDMAN. -- Rapidly developing cataracts after dinitrophenol. JAMA, 1935,
CV, p. 108.
· CAMERON, cited by HORNER. -- Arch. of opth. 1936, XVI, p. 452.
· CARLOTTI and RIVOIRE. -- Sur un cas de cataracte per le
Dinitrophenyllyside. Rev. O.N.O., Nov. 1938, p. 622-624.
· CAZENEUVE and LEPINE. -- Sur les effets produits par l'ingestion et
l'injection intraveineuse de trois colorants jaunes derives de la houille.
C.R. Ac. Sc. de Paris, 1885, CI, p. 1, 167.
· CIOTOLA (G.). -- Cataracte par alpha-dinitrophenol. Boll. d'Oc., 16, 1937,
p. 531.
· COGAN D. and COGAN F. -- Dinitrophenol cataract. JAMA, 1935, CV, p. 794.
· CUTTING, MEHRTENS, TAINTER. -- Dinitrophenol, not acceptable for N.N.R.
JAMA. 1935, CV, p. 31. (Important bibliography on the subject).
· DALLY. -- Du nouveau sur le dinitrophenol. Concours Med. 1935, L, p. 3,
491.
· EBSTEIN and ROSENBLUM. -- Peripheral neuritis and abortion following
dinitrophenol therapy. J. Lab. an Clin. Med. 1935, XX, p. 1, 118.
· GIBBS-Reichert. -- Am. Chem. J., 1891, XIII, p. 289.
· GUTZEIT (R.). -- Cure d'obesite et cataracte. Munch. med. Wschr., 2, 1937,
p. I.724.
· HALBRON. -- Les cataractes apres emploi therapeutique du dinitrophenol.
Sem. des Hopitaux de Paris, XII, 1937, p. 329.
· HORNER, JONES, BOARDMAN. -- Cataracts following the use of dinitro. JAMA,
1935, CV, p. 108.
· HORNER. -- Cataracts after dinitrophenol. Ar. of Opth. 1936, XVI, p.
446-461.
· HORNER (W.-D.). -- Cataracts following dinitrophenol treatment for
obesity. Transact. of the opth. sect. of the Amer. Med. Ass., 1936.
· KNISKERN. -- Cataract following dinitrophenol. JAMA, 1935, CV, p. 794.
· KOCH-LEE and TAINTER. -- Dinitrophenol on liver function. Calif. and W.
Med., 1935, XXXXIII, p. 337.
· LAIGNEL-LAVASTINE. -- Soc. Med. des Hopit. de Paris, 1937.
· LAZAR. -- Cataract following dinitrophenol. JAMA, 1935, CV, p. 794.
· LEUTSKER. -- Instance of circulatory collapse attributed to dinitrophenol.
U.S. Nav. Med. Bull., 1935, XXXIII, p. 394.
· MAC BRYDE-TAUSIG. -- Functional changes in liver, heart and muscles loss
of dextrose tolerance resulting from dinitrophenol. JAMA, 1935, CV, p. 13.
· MAGNE, MAYER, PLANTEFOL, et al. -- Etude sur l'action du dinitrophenol.
An. de Physiol., 1932, CV, p. 12.
· NADLER. -- Peripheral neuritis caused by prolonged use of dinitrophenol.
JAMA, 1935, p. 12.
· ONFRAY and GILBERT DREYFUS. -- Bull. et Memoires S.F.O., 1937, (I, pp.
114-12.
· ONETO-GALINO-NATALE. -- Developpement de cataracte aux deux yeux,
consequence d'un traitment au dinitrophenol pour amaigrissement. Soc.
Argentin. of., 24 Oct. 1937.
· PERKINS. -- A study of munitions intoxication in France. Pub. Health Rep.,
1919, XXXIV, p. 2, 335.
· RODIN. -- Cataracts following the use of dinitrophenol. Calif. West Med.
44.4, 1936, p. 3.
· SCHUTES. -- Dinitrophenol. Am. J. Opth., 1935, 18, p. 752.
· SPAETH (E.-B.). -- Cataractes dues au dinitrophenol avec symptomes de
tetanie. Am. J. Opth., Apr. 1936, p. 320-323.
· STEIN and CREVECOEUR. -- Semaine des Hopitaux de Paris, 15 Dec. 1937.
· TAINTER, CUTTING and STOCKTON. -- Use of dinitrophenol in nutritional
disorders. Am. J. Pub. Health., 1934, XXIV, p. 1045.
· VAN DER HOEVE and POLAK-DANIELS. -- Cataracte et dinitrophenol. Nederl.
Tijdsch. V. Genessk., I, 1936, no. 2, p. 126.
· VOGT (A.). -- La Cataracte par dinitrophenol en Suisse. Schweiz. Med.
Wocst., 76-37, 11 Sep. 1937, p. 873.
· WHALMAN. -- Dinitrophenol cataract. Am. J. O., Oct. 1936, XIX, p. 885.
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