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Evaluation of Phenylmethyl Oxadiazole (PMO) as a Tobacco Additive . Historical Evaluation of the compound known as Oxolamine Citrate by Dalhamn and coworkers as a possible antitussive agent, led to the discovery that this compound seemed to counteract or decrease the ciliastatic effect of cigarette smoke when tested in vivo in cats. Initial tests using the smoke from cigarettes made from tobacco treated with Oxolamine Citrate confirmed the earlier observations and led us to investigate compounds with structural features-similar to those characteristic of the Oxolamine Salt. - - The first-such compound tested was 3-phenyl-5-vinyl-1,2,4- oxadiazole (PVO) which was_synthesized in our laboratory. This compound retained the substituted oxadiazole ring system found in Oxolamine, and was identical to one of the degradation products of Oxolamine isolated from smoke. Furthermore, it did not contain the diethylamine group which is a known bladder irritant, and, therefore, an undesirable by-product in the smoke. Cilia toxicity tests carried out by Dalhamn on polymerized into an unusable, rubbery mass. In`sfurther pursuit PVO-treated cigarettes indicated that this compound was more effective than Oxolamine Citrate. The chief disadvantage of PVO was-its difficulty of synthesis, in that it very easily of a usable compound having the pertinent structure similarities to Oxolamine Citrate and PVO, we synthesized several materials '' having a 1,2,4-oxadiazole ring substituted at the three-position,p' ., with phenyl, and at the five-position with an alkyl group. The.`, .,...,. , ,p.. simplest member or this series was the 5-methY1 com .,. ..._ . pound ; to ..tha~.of "PVO:. :.Testincr 'of ciaarettes with va,-tr„Q ' - ~ - 4 . : t,<_; . . ,. :,~ q ~~ ~G j "_ s * ~ t I - :wx .' PMO-treated cigarettes by Dalhamn indicated an effect ec;u•a1~L - l namely;':1-3-phenyl-5-methyl-1,2,4-oxadiazole (PMO). Testing o ...r.~ Z-WL.'T:'is.L"~." . ~~ 7 Srr.l:Y.,LLa ~sl. S7Ptt 1,

PMO addition is presently underway, in an attempt to establish the minimum effective level and the dose response relationship. Preliminary experiments were carried out with mice to determine the acute toxicity of PMO. The compound was administered by intraperitonealy injection in ethanol solution, and it was found to have an acute toxicity of the same order as that reported for aspirin. Chronic smoke exposure studies with guinea pigs, using PMO-treated and-untreated cigarettes are currently underway under the direction of Doctor Rylander. As mentioned above, several other related compounds, differing only in the alkyl constituent at the five-position have been synthesized. None of these, however, have been- evaluated for their effect on the ciliatoxicity of cigarette smoke. - II. Proposed Future Work - - Before commercial feasibility of PMO can be ascertained,- further testing and evaluation required. in several areaB will be A. Confirmation of Cilia Data - ' The data obtained b Doctor Dalhamn should b y e confirmed by another independent laboratory. The test system used may be the same as that devised by Dalhamn or a suitable alternate, which we are not at present in a position to suggest. The time .required for completion of this work should,not exceed two months from its time of initiation. cute Toxicity Studies - - - Studies designed to determine the acute toxicity ;of PMO should be carried out in a manner_similar to ;-that recommended by the Federal Drug Administration '~ of administration of the compound, including oral, ;:',for new drugs. It is anticipated that several methods V" subcutaneous injection and possibly aerosol T !. nhalation,-would be used on at least two animal species. ~~ ~ 4, The details would,^ of course, need ~to~f~e~ r worked out=~ai~ the "consulting ' labora~ory before` a ~ '' : ~ ' ~ i ! r.~.: ~. 1 ,y,j,;~s -r ~ti.~ . ~. s> . c, * t 1 t~c,,F~~timat~o_iime~and~gost~~uld~'~e~a~ Y

01 C. Chronic Toxicity Studies Chronic toxicity studies on PMO would be conducted using the same animals and-administration methods used for the acute studies at dose levels - in the subacute range. These studies should be carried out in a manner similar to that recommended by the FDA for new drugs. D. Smoke Inhalation Studies - - The effects of chronic smoke inhalation from treated and untreated cigarettes should be conducted using at least two animal species. The dose levels used should be as large as practical, considering the toxic effects of the control sample, and should be continued long enough to cause some positive effect. At the end of the experiment, the animals should be sacrificed and examined histologically for vital organ abnormalities which might be attributable to the PMO treatment. One might well expect these studies to require 1-2 years to complete. E. Smoke Composition Studies Concurrently with the above experiments, we would undertake a program to isolate, identify and measure=the products in the smoke arising from-the PMO additive. The possibility of biological studies concerned with these products cannot be overlooked, particularly if_such data on the individual compounds identified are not already available. No mpre than three months should be required for this chemical work. . PMO Svnthesis- - Possible synthetic routes to obtain PMO should - be investigated with an eye toward the best large scale production method. Consideration must be ` given to the question of the cost of PMO in production . . . . . L.. quantities and of whether we as a company would under- " " * s take its production or contract with a chemical firm ~`. ' J, 'for our requirements. About three months should be l w o t~' a l ed f o r .this stud eti~7~t~+i~~11_a .rl~dPSfli~.;X _ V ,s ~ . -... .. ~ • ~1 II. Proposed Future Work (Cont'd.) - B. Acute Toxicity Studies (Cont'd.) A-time_period of three months would seem to be a reasonable guess for completion of this study. :1i