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As part of the necessary pharmacological evaluation of a new drug1before it should be tried even in controlled clinical experimentation, its rate of absorption (if given by mouth) and excretion should be studied. If possible this should be done on normal human volunteers in order that any deleterious effects may be noted to be guarded against when used in patients. Especially is this procedure important in order to judge the danger of cumulative effect before venturing to employ arsenical compounds on repeated administration in human therapy.Except for the bare statement that 3-acetylamino-4-hydroxy-phenylarsonic acid (acetarsone N.N.R. or “stovarsol”) is excreted in the urine after oral administration,2we have not been able to find any information regarding its absorption or excretion, in spite of the fact that it has considerable toxicity3and has been widely exploited in human therapy with some incidence of poisoning.†The present-study was undertaken to supply this deficiency in part. Since our laboratory investigation of a considerable number of arsenical compounds revealed several which would seem on experimental evidence to be superior to acetarsone in treating amebiasis, we decided to include in this study the one upon which we had the most satisfactory data. This was 4-carbaminophenylarsonic acid,‡previously shown on comparison with acetarsone to have a lower toxicity on oral administration, but more amebacidal action in vitro, and with a calculated therapeutic index about 8 times as great.4Excretion in the urine is evidence of absorption from the gut following oral administration. The rate of excretion (assuming all the arsenic to be excreted that is absorbed) then would be, for these compounds, an index of the rate of alimentary absorption, and might give some indication of the degree of systemic action to be expected.

From a general consideration of the chemo-pharmacological properties of di-ethyl ether and ethylene, especially in regard to their marked anesthetic power and relatively low toxicity, it seemed possible to predict that compounds combining the chemical characteristics of each would be interesting general anesthetic agents. This prediction might be made more specific by further reference to the theory of the relationship between chemical constitution and pharmacological action. In certain homologous series of absorbable aliphatic compounds (as the monohydric alcohols) toxicity increases (without a comparable increase in desiredactivity), in proportion to the number of carbon atoms in the straight carbon chain. Also related to chemical structure in such a series are certain anesthetically important physical properties, such as boiling points. So, one might venture to anticipate that the higher members of our proposed homologous series of unsaturated ethers would not be found as satisfactory inhalation anesthetic substances as the lower members of the series, because of too high boiling points and too great toxicity.Through the kindness of Professor Sigmund Fraenkel of Vienna, we obtained vinyl-ethyl ether, allyl-ethyl ether, and di-allyl ether, and through the courtesy of Professor Lauder Jones of Princeton, we secured from Doctor Randolph Major di-vinyl ether, vinyl-ethyl ether, and isopropenyl-ethyl ether. These agents are all volatile colorless liquids with odors varying from the rather pleasant aromatic vapor of di-vinyl ether to the pungent irritation of the allyl compounds. Unfortunately only small quantities of these substances could be supplied (none in excess of 12 cc), so that only tentative determinations could be made of their partition coefficients and of their action on inhalation in mice.

In 8 subjects on which 16 experiments were carried out a slight depression of oxygen consumption was noted following subcutaneous injections of therapeutic doses of emetine hydrochloride. Respiration was increased when affected. Changes in pulse rate were inconstant. A definite fall in blood pressure was noted in 2 instances when 455 to 520 mgm. were given over a 10-day period.

In studying the effects of drugs on basal metabolism, Boothby and Rowntree1reported two experiments with codeine in which they found 3% and 8% depression respectively of the basal metabolic rate one hour following the administration of a therapeutic dose of codeine (0.03 gm.). Investigating the effect of pre-anesthetic medicants on functional activity in normal humans, we found that morphine in oral doses ranging from 0.1 to 0.5 mgm. per kilo generally depresses within an hour the basal metabolic rate and tactile discrimination,2while pulse rate, interestingly, is increased but respiration is unaffected. In a similar study of the barbituric acid hypnotics we noted3a definite depression of oxygen consumption and tactile discrimination with the oral use of therapeutic doses of sodium di-ethyl barbiturate and of some of its common derivatives. Iso-amyl ethyl barbiturate and phenyl ethyl barbituric acid in ordinary doses, however, both increase the basal metabolic rate, but decrease the tactile discrimination. Codeine was next studied from the same aspect and the results of 10 experiments on 8 normal human subjects are reported here.The determinations of oxygen consumption were made by the closed method with the Sanborn “graphic” apparatus and the Sanborn averages were used for estimating the basal metabolic rate. The subjects were trained healthy adults and the usual precautions were observed in making determinations. Codeine phosphate, in doses ranging from 0.2 to 1.0 mgm. per kilo, was dissolved in water and administered by mouth. The “normal” basal metabolic rate was estimated before administration of the drug and subsequent tests were carried out at 20, 40, and 75 minutes after the drug was given. Pulse rate and blood pressure determinations and tactile discrimination tests were made before and after the drug was given, while the respiratory rate was obtained from the “graphic” record.