Interesting study
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2444737/pdf/brmedj07145-0008.pdf
THE USE OF 2: 4-DINITROPHENOL AS A METABOLIC STIMULANT BY D. M. DUNLOP, B.A., M.D., F.R.C.P.ED.* (From the Clinical Laboratory, Royal Infirmary, Edinburgh) It has been known since 1885' that nitrated naphthols can stimulate metabolism, and during the war attention was called to their toxic effects owing to the incidence of poisoning among workers in munition factories. A review of these effects was made by Perkins,2 and they were more recently commented on by the Council of Pharmacy and Chemistry of the American Medical Association.3 Only incomplete investigations of the pharmacological action of such compounds were, however, made till 1928, when Heymans4- and his co-workers revived interest in the subject by a series of publications which showed that certain nitrophenols are powerful stimulators of metabolism, causing a greatly increased oxygen consumption. When a considerable dose is taken the endogenous heat production may be so stimulated as to cause a rise of temperature, and death from a lethal dose occurs during a hyperpyrexia. The lethal dose of dinitrophenol for rats has been shown by Anderson, Reed, and Emerson5 to lie between 30 and 50 mg. per kilo of body weight, but doses as small as 5 mg. per kilo of body weight may produce pyrexia in man, and it has been stated that the margin between the febrile and fatal dose is narrow. During the last two years Magne, Mayer, and Plantefol, and Cutting and Tainter, have published reports on the main pharmacological actions of dinitrophenol. All these workers are agreed that the action of the drug in stimulating the metabolic rate is peripheral, due to an increased oxygen consumption in the tissues, and is independent of nervous and glandular action. In considering the source of the fuel for the increased metabolism they are also agreed that the body proteins are not broken down to any appreciable extent. The French workers, however, observing in the experimental animal under the influence of dinitrophenol a marked decrease of the carbohydrate content of the body, particularly in respect of the liver glycogen, and a corresponding rise in the blood sugar, argued that the excess metabolism was mostly at the expense of carbohydrate. The experimental and clin-cal studies of Cutting and Tainter, on the other hand, failed to reveal any difference between the excess metabolismn due to dinitrophenol and that occurring normally. The latter workers, using this drug in doses of 3 to 5 mg. per kilo of body weight, have recommended its use in the treatment of obesity, and have recently published encouraging results from extended clinical trials in which an average daily oral dose of 0.3 gram (5 grains) of tho drug was administered to 113 consecutive cases of obesity without drastic dietetic restrictions. No severe cumulative or toxic effects were produced, though most of the patients noticed a sense of increased warmth and increased sweating, while in 7 per cent. of them a skin rash occurred, and in 5.3 per cent. there was a loss of taste. These side actions cleared up quickly, without sequelae, on discontinuing the medication. Anderson, Reed, and Emerson5 have also treated fourteen cases of obesity, using similar doses of the drug, and obtained some slight loss in weight without much dietetic restriction. In one patient, however, they obtained a serious allergic skin and joint reaction. This patient suffered from chronic articular rheumatism, and it is suggested that individuals suffering from this complaint have a lessened resistance to the agent. Indeed, Perkins,2 in his review of the poisonous effects of dinitrophenol on * In receipt of part-time grant from the MIedical Research Council.
munition workers, reported that cases of chronic rheumatism, alcoholic addiction, diabetes mellitus, tuberculosis, and renal and hepatic insufficiency were particularly sensitive to it. In addition to dinitrophenol, a related compound, dinitro-o-cresol, has been reported on by Dodds and his co-workers.,8 They claim it to be considerably more active than dinitrophenol, and stress, as other workers have done in the case of dinitrophenol, that neither the pulse rate nor the blood pressure is raised in any way proportionately to the height of the metabolism. Dodds further states that toxic symptoins are occasioned by dinitro-o-cresol when the metabolic rate is raised by its means to over 50 per cent. above the patient's normal. He mentions particularly sweating, lethargy, headache, loss of appetite, and a greenish-yellow tinge in the conjunctivae. This latter syrnptom has also been noted by Tainter, using dinitrophenol, but neither worker discovered any excess bile pigments to be present in the blood of such cases; and it must also be remembered that the drugs themselves are dyes producing much the same colour as bile pigments. The fact that drugs of this type have specific powerful effects in raising metabolism, without at the same time causing tachycardia, combined with their cheapness and availability, might strongly recommend them as superior to other metabolic stimulants in general therapeutic use. On the other hand, Doddss has suggested that in spite of their effects on metabolism such drugs do not act as a substitute for thyroid in hypothyroid states, except in so far as they may reduce excess body weight. Further, it hL's yet to be demonstrated that they are as safe anl efficient for weight reduction in human beings as other methods in common use. It may indeed be argued that so many toxic reactions have been produced in the relatively small number of cases treated that the use of such compounds is not as yet clinically justifiable on a large scale, and that their popularization as weight reducers might well be disastrous. It is therefore of importance that careful pharmacological investigations and cautious clinical trials of these new and powerful products should be made before their widespread application is undertaken.
