Document ExOg4myDRnjQa32mpb18YYJ0n

July 31* 196 Dr. J. M. Raegsegger Lederle Laboratories Division American Gyanamid Company Pearl River, lew York Dear Jim: I hope yob will forgive the tardiness of my reply to your letter of June 12th, I 'j/e been swamped, and only now, in preparation for a vacation, have I had a chance - or rather manufactured the chance - to take care of letters that w^re not virgent, Fairly recently trie therapy of metallic poisoning, lead in particular, has been shifted vigorously in the direction of the chelating agent ethylenetdiaminetetraacetic acid (EDTA) administered in the form of its disodium* calc ijum salt principally. It might be difficult to draw much attention to thioctic acid at present, In view of the largely justified enthusiasm fori this agent. However, there are people who are interested In developing new means for the therapy of the heavy metals, and certainly anything t h a t .offers hope for a prompt benefit in the treatment of the more severe forms of these diseases will receive attention. The paragraph In Professor Donatelli's discussion sounds a bit glib and overenthusiastic, particularly in relation to the therapy of mercury and arsenic poisoning, and I .should like to see some of the evidence on which hi3 statements are based* iloreoverj I 'd like to have some idea of the rationale In the use of the compound :n heavy metal poisoning. If you would be good enough to tell me more atbout this, I 'd be glad to put you in touch with some people who could take a look at it. We have a very serious problem of fatal and permanently disabllng load Intoxication in children, and I would havo no trouble here itn trying out a material that could offer real promise. The so-called prophylaxis of load poisoning in industry, in my opinion, is not only unnecessary for the solution of the problem, but worse - it tends to hinder the progress of sound industrial hygiene. The same, In a general way, istrue of the other heavy metals as industrial hazards. The way to prevent such poisoning Is not therapeutic but preventive in the sense of the limitation of exposure. The latter can N6269 Ru e gs e gge r - (2 ) - July 3 1 , 1956 be dons, and jis being done, -where there is a v/ill to do it. Palliative treatment only delays the day \f/hen it will be done generally and effective* ly. I am not objecting here to the medical treatment of people who are ill. I am objecting, strenuously, however, to the medical pandering to the ignorance or social carelessness of industrial management. Let me know something about the possible or probable usefulness of thioctic acid, and 1*11 see what I can do about it. It is good to hear from you again. I shall look forward to doing so again. Ii} would be nice to see you also. With kindest regards, Sincerely yours, RAK:vr Robert , nchoe, L?.D. LEDERLE LABORATORIES DIVISION PEARl RIVER, NEW YORK . CARLE ADDRESS: LEDLAS TELEPHONE: PEARL RIVER 5 - 5 0 0 0 June 12, 1956 Dr. Robert A. Kehoe, Kettering Laboratories University of Cincinnati College of Medicine, Cincinnati Ohio Dear Bob: Two .onths ago I intended to call you in your office when I ras in * Cinci rinati but my plans in Cincinnati were rudely changed. For sometime we have been conducting some investigations with a synthetic compound variously ceiled thioctic acid, lipoic acid or protogen. While it was postulated by the chemists that it might belor.g to the; Vitamin B group of compounds, its real role in human nutrition has never been ascertained. There has been an inkling in some clinical; studies originating in Germany as well as in the United States, that it might be effective in treating pa-tients with hepatic coma. As you will see from the enclosed translations, the Italians haveheld a symposium in Naples regarding the clinical usefulness of this compounds I am writing to you particularly in regard to the possible use of thioctic acid; in the treatment of heavy metal poisoning. If you know of clinics orj Industrial hospitals which might be in a position to use this material I shall be very happy to have you refer such places to me. Inasmuch as the compound is fully absorbed when given by mouth it is cdnceivable too that this might serve as an effective prophylaxis for people who have a high exposure to intoxication by lead and other heavy metals.: At any rate, I shall appreciate your ideas in this regard. With best wishes to you and my many friends around Cincinnati, Sincerely yours i JMR:c1 Enc RESEARCH DIVISION, American Cyanamid Company i / t --- J\M. Euegsegger, M.D. Clinical Research Section N6269.01 SUMMARIES OF SIS PAPERS (Thioctic Acid Symposium, Naples Italy, November 28-30, 1955) 1.' Professor Calvin - The Participation of Thioctic Acid in Photosynthesis. As a C-S-S,-C-system thioctic acid is actively involved In photosynthesis and also partieiipates in the porphyrin synthesis. The addition of thioctic acid causes the increase of 0- by more then 50$. Thioctic acid, however, is probably not an active reactive fora of the plant and animal organisms. Dr. Braude - Dr. Braude developed his own synthesis of thioctic acid In England which differs from the Re ed synthesis by the position of the sulfur atoms. Also this synthesis stl! ,1 requires 5 steps of development. He obtained a yield of aporoxilately 30$ Production of thioctic acid is planned to start in England according to the synthesis by Braude. 3. Professor Donatelli. Naples - Pharmacological Studies on Thioctic Acid, Thioctic a cid occurs in all organs with the exception of the thyroid gland, Many organ systems can be activated by thioctic acid* A chemical deaonstra- tiori was a aborated ^hich, however, still lacks sufficient precision. Pharaaeologfeal tudies were carried out in cooperation with professor Pontecorvo. Thioctic apid has a certain bacteriostatic effect on a number of bacteria. In plants, Ismail doses of thioctic acid stimulate growth of roots} high doses, however, h a.ve a depressive effect. Therefore, it Is believed that large doses of thioetib acid have an effect on tumors* Trials have been made on the following an,iinihlss araeba, guinea pigs, nice, rats, pigeons, rabbits. Mercuric chloride poisoning-as well as arsenic poisoning can be influenced better by thioctic acid than by BAL. It has also a beneficial influence on cyanide poisoning* Alloxan-diabetes can be prevented by thioctic acid In experimental dogs. Lead poisoning responds to this therapy. Moreover, all substances promoting actylisation processes in the body can be inhibited by thioctic acid* Carbon tetrachloride poisoning (CCl^) can be prevented with thioctic acid. Thioctic acid has no influence on arterial blood pressure. Respiration can be stimulated up to a dosage one hundred times the quantities given,to htjmans.. It is still doubtful, whether thioctic acid, has; an effect on the neurovegetative system. There is an increased, motility of the intestines by thioctic acid. In animal experiments increased diuresis and biliary excre tion are observed. In acute hepatitis the icterus disappears more promptly with the aid of thiootic acid than without it. The kidneys and the liver have the highest thioctic acid content as compared to other organs. It is excreted by the kidneys. : A. Professor Laritaa. Sardinia - Pathological Physiology of Thioctic Acid. Animals are able to synthesize thioctic acid. The range of application is much wider then supposed until now. Trials at the Pathological Institute in Messina with thioctic acid revealed that this substance is in a position to prevent fatty liver. The blood cboleeterine values as such are not being changed. The relation of ehoiesterine to cholesterinestsr, however, is being f 0042337 - 2- influenced. A combination of thioctic acid with cocarboxyiase is less effec- tiV8 than thioctic acid alone* There is a certain interrelation to body-own hormones like the antidiuretic hormone (ABE), cortisone mid ACTH. The daily optimal dosage is stated to be 10 - 20 mg,; injection of quantities up to 60 mg., however, is also possible. '' i _ 5* Professor Colarusso. Maples -- Clinical Trials with Thioctic Acid. The widest field of application for thioctic acid are hepatopathieg from hepatitis to cirrhosis of the liver. In.cardiac patients diuresis is favor ably influenced. Surprising results were seen following infusions of 20 to 40 ag. of thioctic acid dissolved in isotonic sodium chloride solution given over a period of 5 to 6 hours* Until now 28 hepatic cases were treated with the Italian drag, among them 10 eirrhoses of the liver. All toxieo-dyspeptic symptoms subsided. B y improving the function of the liver parenchyma the symptomatology of the diseases is favorably influenced. Due to the diuretic effect, ascites and edemas are being eliminated. The icterus disappears. .Fur thermore, cardiac and pulmonary congestions respond well and the effect of strophantine is being improved. A certain cytostatic effect in leukemias could be seen following high doses. The leukocyte counts dropped from 39,000 to 9,000* Thioctic acid has an antitoxic action and is a liver protection factor, . 6* Dr. Rausch - Clinical Activity of Thioctic Acid. In a survey Dr. Rausch reported on his experiences so far obtained. We shall receive a; copy of his manuscript. He also made statements on a control trialwith placebos which is now being carried out* It has been revealed by these trials that there is a significant difference in.the effect of thioctic acid and physiological sodium chloride solution. The blood count of the patients is favorably influenced by small doses. Leukocyte and thrombocyte counts increase* Following points were considered in the discussion; Thioctic acid leads to a decrease of the blood glucose via an effect on pyruvic acid and lactic acid* There is no influence on the functional test-of the liver. Trials'on the pyruvic acid metabolism revealed an initial increase end subse quent drop of the pyruvic acid values in the blood. The effect of high doses on leukemia persists for about 2 to 3 weeks. Xf Jt'.'A