BAL

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a new product in :he treatment of BAL,arsenic and mercury pOlsonmg has become

NEW ANTIDOTAL TREATMENT FOR , ARSENIC POISONING NOW READILY A V AILABLEJ ' EVIDENCE INDICATES USE OF DRUG MAY HELP REDUCE TOXIC EFFECT OF OTHER METALS

available for civilian medical use. * , Discovery of the anti-arsenical properties of BAL was hailed as one of the outstanding wartime achievements in the field of chemical warfare. The first report , on this important drug came from Prof. R . A. ' Peters of Oxford University and his co-workers, who discovered the therapeutic value of BAL. As ments led directly to further studies in animals of the name BAL (British anti-lewisite) sugges,ts, the toxicity and therapeutic effects of ~AL in the drug was intended as an antidote for local and various vehicles and by, various methods of ad- , systemic toxic ,effects Qf certain arsenical war ministration. A detailed investigation of dosage gases. Chemically, it is 2,3-dimercaptopropanol. was also undertaken, at first on animals and later Early work showed that experimental animals on human volunteers. " usually died within twenty-four hours following From the information assembled in this way application oflethal amountsoflewisheto theskin, formulas were develop~d for topical applicatio~ but 'that they almost invariably recovered when as well as for a solution to be injected intramusBAL was applied to the treated area within two cularly. BAL is not an innocuous drug, bu! . hours. Information on the chemistry, method of fortunately dilutions that are therapeutically , preparation and basic biochemical char~cteristics effective may be used with no lasting ill effects. of BAL was transmitted to the United States ,During the war, preparations were mad~ for early in the war through the British government, topical application tp the eyes and skin to overand a supply of BAL itself was received in this come local reactions in case poisonous arsenical . country late in 1941. gases were used. But of chief interest to civilians An intensive study of the drug and its properis the solution used by injection in cases 'of systies was at once undertaken by various govemtemic poisoning. ment\ agencies. The United States Army and The most effective solution for injection, de~ Navy, the Office of Scientific Research and Devdoped by Dr. Harry Eagle of the U. S. Public velopment, the National Research Council and He'a lth Service and his collaborators, proved to be the Federal Security Agency all cooperated in the a 10% solution of BAL in peanut oil containing 20 program. At the same time further studies were % benzyl benzoate. This solution was first tested being made in Great Britain and in Canada. on animals, then on ,human subjects, and was fiMany related compounds were prepared and nally given a clinical trial. t~sted, but of the whole series BAL gave the most Since toxic reactions are occasionally observed favorable results. in patients receiving arsenotherapy for syphilis, Because of its great importance to the armed , a carefully st.lpervised study of these cases was f0rces ' BAL and the preparations made from it made. As a result more than 200 case histories of were produced under "secret" classific~tion. All various types of arseni~al poisoning treated with data relating to the drug, its uses and method of BAL were assembled. Most of the toxic reactions preparation were guarded w~th the greatest care. treated consisted of arsenical dermatitis or hemorThis information is now becoming available, and rhagic encephalitis occurring as a result of treatonly in the past few months have ampuls been rements' for syphilis. Only seriously ill patients leased for civilian medical use. were treated with BAL at first and they, of course, The development ' of BAL began with the obreceived the usual supportive treatment. In servation that the drug, applied as a solution or spite of the difficulties of making an exact estiointme~t, counteracted local 'a nd to a considerable mate 6f the value of a drug under such conditions, extent , systemic effects of applications of toxic the data obtai~ed supported the results secured \ arsenical compounds to t4e skin. These experion animals. i * Supplied by Hynson, Westcott & Dunning; Inc., Charles After the therapeutic value of BAL became esaild Chase Sts., Baltimore 1, Md. ,

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J OU~,AL OF THE 'AME,RICAN PHARMACEUTICAL ASSOCIATION

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tablished, the Hynson, Westc~tt & Dunning laboratory' was reqllested to cooperate in'developing the ampul product. Because of drgent need f~ the drug, manufacturing .was updertaken while the new plant was being organized. Meanwhile, work on animals indicates that BAL' also niay be of use in treating poisoning by other m~tals such as cadmium, zinc and mercury. Although its value in' 'poisoning due to metals other than arsenic is l1:ot yet definite, a recent report by the Council on Pharmacy and Chemistry of the American Medical Association stated that BAL had been used with promising results in mercury poisoning [J. Am. Med. Assoc., 131: 824, 1946]. It should be emphasized, however, that successful treatment of arsenic and mercury poisoning depends on beginning the course of injections at the earliest possible moment, use of adequate dosage, and the proper supportive meas'ures. The possible value of BAL in gold poisoning is also under investigation. ' As to the mechanism of action of BAL, wartime studies showed that arsenic and mercury combine with certain cheniical groupings in the / body cells (specifically the -SH groups) and prevent their proper functioning. BAL has a greater chemical affinity than the cells for the heavy metals and apparently removes the metal from the cell by forming a metal-BAL compound. The

effect ' of this is that arsenic, for example, is renlOved from the cel1s, forms a stable combination with BAL and is rapidly eliminated from the body. It has been shown,that the arsenic content of the urine in these cases rises rapidly after administration of BAL. • BAL is unstable in aqueous solution and must be administered intramuscularly in oil solution. Benzyl benzoate is added because the ,d rug is more soluble in the mixture than in peanut oil alone. The recommended dose per injection is adjusted to body weight on the basis of 2.5 mg. per Kg~, or 0.025 cc. of the solution per Kg. In a ma~ weighing 165 pounds the unit dose per injection is 1.8 cc. This dose is repeated at four-hour intervals for a total of4 to 6 injections on each of the first two days. The dosage may then be reduced to '2 injections daily for a total of ten days or until the patient recovers completely. Larger doses of BAL seem necessary in cases of mercury poisoning. An initial dose of 5 mg. per Kg. is followed in one or two hours by a dose of , 2.5 mg. per Kg. The smaller dose is repeated two to four hours later and in severe cases a third 2.5 mg. per Kg. dose is given within the .first twelve hours of therapy. Two 2.5 mg. per Kg. doses may be given on the second day and one on the third.

PHYSOSTIGMINE FOR RHEUMATOID ARTHRITIS salicylate has been put t9 a new Puse by three physicians who find that it is effec-

for better patient cooperation. . .. It is because ()f this and for reasons aforementioned that we \ ' tive in relie~g muscle spasms and some of the have substituted physostigmine for neostigmine , in all our studies. As will be noted, physostig, , pain in rheumatoid arthritis. Drs. Abraham Cohen, ~hilip Trommer and mine bears out our original premise in respect to Joel Goldman (J.Am. Med.Assoc., 130:265, 1946) clinical improvement. I t relieves muscle spasm reject their previous recommendation of neo- . and therefore relieves pain in many instances. stigmine, a drug successfully 'used in treating The relief is common to a large portion of cases muscl~ spasm in poliomyelitis. Physostigmine , and is frequently encountered within fifteen to was selected for study because it is closely related thirty minutes after inje~on." in action to theformerarug. ' The usual procedure was to give 0.6 mg. each of The authors conducted their study in the physostigmine and atropine sulfate simultanespecial arthritis wards of the Philadelphia General ously. If no relaxation of muscle was obtainable Hospital. From the4' observations they conclude with this dose, physostigmine was increased to 1.2 that physostigmine is successful in giving immedi- mg. The atropine eliminates unpleasant paraate relief from musc~e spasms and for preventing sympathetic side effects of physostigmine. The deformities and, moreover, it is an inexpensive dosage of either atropine or physostigmine was form of treatment. carefuily adjusted depending on the reaction. William Levin, chief pharmacist atPhiladelIn addition the authors found that there were fewer undesirable reactions with physostigmine phia General Hospital, is credited by the physithan with neostigtnine~ , They say: "The lesser cians with assistance in the early part of the ex, frequency of complaints with physostigmine made periments. HYSOSTIGMINE

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