James O. Hoppe

The pharmacology and toxicology of mepivacaine, a new local anesthetic.

Abstract The local anesthetic activity, toxicity, and irritancy of mepivacaine HCl 1 (1-methyl-2′,6′-pipecoloxylidide hydrochloride) and a solution (solution B) containing 2.0% mepivacaine HCl and 1:20,000 levo-nordefrin (levo-2,4-dihydroxyphenyl-3-hydroxy-2-isopropylamine 2 ) have been studied by various methods. By the intracutaneous wheal test in guinea pigs mepivacaine HCl is 2.5 times more active than procaine HCl. The addition of levo-nordefrin produced a slight increase in the local anesthetic activity of the solution. Solution B was found as active as a solution of 2.0% lidocaine + epinephrine 1:100,000 by the same route of administration ( dilution test ). At the 2.0% concentration level in solutions containing epinephrine 1:100,000 the duration of mepivacaine intradermal anesthesia was approximately 25% longer than that produced by lidocaine. Mepivacaine HCl was found to be as active as cocaine HCl by topical application to the rabbit eye. The topical TAC 5 was 0.18%. At 2, 3, 4, and 8% concentrations, mepivacaine HCl injected intraspinally in rabbits produced anesthesia lasting from 17 to 115 minutes (urethral anesthesia). The degree of intraspinal irritancy appears to be somewhat lower than that of lidocaine. By intravenous injection the following LD 50 values for mepivacaine HCl in mice, rabbits, and guinea pigs were obtained: 32±2, 22±2, and 20±1.4 mg/kg, respectively. Mepivacaine is approximately twice as toxic as procaine HCl and 40% less toxic than lidocaine HCl in mice. The subcutaneous LD 50 values were: 260±22, 110±11, and 94±10 mg/kg for mice, rabbits, and guinea pigs, respectively. Solution B and a 3% solution of mepivacaine HCl without levo-nordefrin (solution A) were well tolerated by monkeys and rats when injected intramuscularly or intravenously in single daily doses eighteen times in 21 days. No significant changes were observed in the body weights, blood counts, urinalyses, or blood pressures of the medicated animals at the end of the medication period. No changes attributable to medication with mepivacaine were observed at the autopsies of the medicated animals. By the trypan blue test the threshold irritant concentration 4 of mepivacaine HCl was 3.3%. That of lidocaine HCl, which was tested in parallel, was 1.9%. Lidocaine HCl is therefore approximately 70% more irritant than mepivacaine HCl. Applied topically on the rabbit eye, mepivacaine HCl and lidocaine HCl were well tolerated in concentrations up to 20%. Solution A and solution B produced a slight, transient inflammatory reaction when injected intramuscularly into rabbits in 1.0-cc doses. No lesions at the injection sites were observed at 7 days after the injection. In summary, mepivacaine HCl, which is 2.5 times more active than procaine HCl is only 25% more irritating and is well tolerated locally as well as systemically on repeated subcutaneous or intramuscular administration.

X-ray contrast media for cardiovascular angiography.

The search for a means of visualizing the chambers of the heart and the blood vessels on x-ray film began almost simultaneously with the discovery of cholecystography and the development of intravenous urography. In 1923 Sicard and Forestierl injected a small amount of iodized poppyseed oil intravenously in the dog and observed fluoroscopically the flow of the radiopaque material into the right heart and out into the pulmonary arteries. Also in 1923, Berberich and Hirsch2 succeeded in visualizing the arteries and veins of the hand with the use of strontium

Observations on the use of the trypan blue and skin-twitch tests for measuring local tissue toxicity☆

Abstract An objective and reasonably quantitative test method for estimating sting reaction following intradermal injection of a chemical irritant in the dog by means of the skin-twitch reponse was described. The end point, designated as the threshold twitch concentration (TTC), was defined as that concentration, expressed in per cent, which produced no more than a mild skin-twitch response. The results obtained were compared with local tissue irritancy data as measured by the trypan blue test in the rabbit (TIC). The local tissue response to hypo- and hypertonicity and to change in the pH of normal saline was essentially the same by both test methods. Of the fourteen compounds studied, sting appeared to be closely associated with irritancy in nine. Among the remaining five compounds, the TIC was found to be from 5 to 2560 times as great as the TTC. The ratio TIC: TTC, for each of these compounds was as follows: meperidine HCl, 5; tyloxapol, 7.8; polyethylene glycol 600 monooleate, 7.8; theraleptique, 500; and histamine, 2560; this indicates that it is possible to separate a sting reaction from mild reversible tissue injury. A negative sting reaction to normal saline and strongly positive sting reactions to distilled water and isotonic solutions of Theraleptique were observed following intradermal injection in man. The local tissue response to quinine HCl, as measured by the trypan blue test, was found to be the same in the rabbit and the dog.

Absorption, Excretion, and Toxicity of Milibis (Bismuthoxy-p-N-glycolyl-arsanilate) Following Oral Administration

Summary Milibis is almost completely non-toxic when administered orally to rats. A dose of 10 g/kg/day for 18 of 21 days inhibited growth only slightly, and at this dose level the mortality was 20%; with smaller doses there was no inhibition of growth, and no mortality attributable to the drug. Absorption was studied in human subjects and rats, during and following repeated oral administration. Both species excreted in the urine at most 2 to 4% of the ingested As. Human subjects excreted no detectable Bi in the urine, but the rats excreted about 1% of the amount ingested. In the rats tissue concentrations of both As and Bi were negligible, as was the As concentration in blood.

Toxicity and physiological disposition of sodium p-N-glycolylarsanilate

Abstract The acute intravenous LD 50 of SNGA to mice has been established as 5850 ± 360 mg/kg, and the oral LD 50 as 22500 ± 1540 mg/kg, based on deaths within 24 hours. The acute ALD 50 for the cat is 1060 mg/kg. SNGA is only slightly absorbed from the digestive tract of the rat; urinary excretion is 5–10%, and fecal excretion is 90–95% of the dose, following oral administration. Following parenteral administration to cat or rat, the urinary excretion is about 75% of the dose (for the limited periods of observation used). Biliary excretion in the cat is only about 1% of the dose, following i.v. administration, and fecal excretion in the rat following i.p. administration is 3–7% of the dose. Some of the parenterally administered arsenical is retained in the blood of the rat. Following oral administration to man, the 72-hour urinary excretion was 3–5% of the dose, and fecal excretion was 89–96%. In one of three subjects more than 99% of the dose was excreted within 72 hours, and in the other two the total recovery exceeded 90%. There is no appreciable conversion of SNGA to arsanilic acid, in either man or rat.

The pathologist and toxicologist in the evaluation of the safety and methods of development of radiodiagnostic compounds.

In searching for new X-ray contrast media, the pharmacologist, the chemist, the toxicologist, and the pathologist must work closely together as a research team. The work of the pharmacologist and chemist is fairly well understood; the one screens the chemical compounds made and submitted by the other. The role of the toxicologist and the pathologist in this team is not well understood. Their primary functions are to help in the selection of the best compound and to establish its safety prior to clinical investigation. Their studies usually include toxicity experiments comparing the new X-ray contrast media with each other and with commercially available products. Detailed gross and histological examinations of the tissues of animals often indicate which contrast medium is superior, even though several of them may have been equally good in terms of visualization. In addition, the pathologist can contribute his knowledge of the anatomy and histology of the various species of animals used in this kind of research. The toxicologist can sometimes determine the best chemical compound by carefully distinguishing between pharmacodynamic reactions resulting from injections of large doses of the new contrast media in the same and in different species of animals. In the following report, experiments will be presented indicative of the part the toxicologist and pathologist play in developing new X-ray contrast media.