Raymond N. Bieter

Applied pharmacology of local anesthetics

Abstract The intelligent and safe use of local anesthetics requires a thorough knowledge of their pharmacological actions, the potentiation of these actions, their toxicity, and the prevention and control of toxic reactions, by anesthetists and surgeons. This involves more than a superficial knowledge of these drugs.

METHADONE IN INTERNAL MEDICINE

HE release of methadone (10820) by the Food and Drug AdminisT tration about a year ago opened a new and interesting chapter on the action and uses of analgesics, particularly of the morphine type. Since then, other derivatives have been made available for experimental study. It is the hope that investigators will be able to discover the drugs of maximum use with the minimum untoward reactions, for routine or special uses. It appears at present that rather extensive clinical trials will be necessary to find the answers to these questions. Among the available reports on the clinical usefulness of methadone in internal medicine are those of Scott, Kohlstaedt, and Chen,l Kirchhof and David? Ishmael and Stacy: Bercelt and Troxil.6 All of these investigators found methadone to be a powerful analgesic. Milligram for milligram, it is probably more active than morphine. In most clinical investigations, a small number of patients have been studied in which bothmethadone and morphine or another opium alkaloid have been used. A considerable number of patients have shown a preference for methadone over morphine, meperidine and codeine. Reversed preferences have also been observed. Whether there exists a striking preference for any one of these drugs is still not proven. Likewise, some patients have been observed in whom one or more of the above analgesics have failed. In these instances, methadone has not always been the least active drug. And again, certain patients who have been unable to tolerate morphine have taken methadone and have shown satisfactory analgesia with no side effects. Therefore, methadone, as an analgesic, cannot be dismissed lightly. In the overall picture presented by these investigators, complete relief of pain was obtained in 50 to 70 per cent of patients, moderate relief in an additional 20 to 30 per cent, and failures in from 8 to 20 per cent. If one selects the patients in “general medicine” to whom the drug was given from the reports of Scott et al., and Troxil, one finds that moderate to complete reliefwas obtained in over 90 per cent patients. On the other hand, Batterman‘j reported in 180 patients that control of pain by oral administration was produced in only 40 per cent of trials, and by parenteral injection in 76 per cent of trials. Inasmuch as no description of the type of patient was included and no data given as to whether control of pain was moderate and/or complete, these results cannot be adequately evaluated.

Temperature Reactions in Mice Infected with Pneumococci.

Summary The body temperature of mice is markedly influenced by the surrounding temperature. Pneumococcic infections in mice are associated with a marked drop in temperature. Infected mice held at incubator temperature succumb more rapidly than those at room temperature. Incubator temperature promotes the infective processes in mice more than the protective action of sulfanilamide.

Excretion of Phenol Red by the Aglomerular Kidney.

Summary When phenol red is injected intramuscularly into toadfish in doses of 0.01, 0.02, 0.04, 0.08 and 0.16 mg. per kg. of body weight, the % elimination from these doses is 47, 23.5, 13.9, 7.3 and 3.5, respectively. Based on body weight of the fish, this elimination amounts to 0.0047, 0.0047, 0.0054, 0.0057 and 0.0056 mg. per kg. Through this series, increasing the injected dose up to 16 times, increases the mg. per kg. elimination by not more than one-fifth. In other words the excretion remains practically constant.

CHEMOTHERAPEUTIC ACTIVITY OF CYANINES AND RELATED COMPOUNDS IN FILARIASIS IN THE COTTON RAT

A group of more than sixty cyanine dyes and related compounds has been studiedla for chemotherapeutic activity against the naturally acquired Litomosoides carinii infestation in the wild cotton rat as part of a coordinated research program on filariasis under the auspices of thc Office of Scientific Research and Development. A similar study with a group of pyrryl, pyrimidyl and related cyanines was carried out simultaneously by Dr. A. D. Welch and his associate^^-^ at Western Reserve University. Care of the animals and administration of drugs was greatly facilitated by the use of special cages, holders, and feed cups designed by one of the authors (J. T. Litchfield, Jr.). The cages were made of a heavy wire mesh, were oblong in shape and of a size suitable for housing the rats individually. One end of the cage was designed as consisting of flanged sheet metal into which fitted a sliding door and to which either the holder or feed cup could be attached (FIGURE 1 ) . The holders were equipped with sliding doors at both ends and had a curved piece of metal extending most of the length inside the top, which was attached by springs to a metal bar outside the holder. With the holder in hand, slight pressure from the palm could be exerted on the bar, thus pressing the abdomen of the rat gently against the wire mesh bottom of the holder, through which intraperitoneal injections were then made. For drug diet administration, feed cups were attached to the metal flanges on the outside of the cages, thus allowing easy removal for daily filling and weighing. . Tests for chemotherapeutic activity were made in uivo against the adult filaria. Administration was usually by intraperitoneal injection every eight hours for eighteen doses with autopsy on the eighth day. The filaria were removed at autopsy, placed in a modified Sim’s solution and examined for motility for 24 hours. The minimum curative dose was taken to be that dose of drug which killed 50 per cent or more of the adult filaria. Therapeutic indices were determined as the ratio of the maximum tolerated dose (M.T.D.) to the minimum curative dose (M.C.D.) based

Inhibitory Action of Peptone on Sulfapyridine Adsorption.

The bacteriostatic effect of sulfapyridin on the pneumococcus in vitro and the inhibitory action of peptone have been shown previously. 1 The findings compare with those reported by Lockwood, 2 who studied the effect of sulfanilamide on the streptococcus under similar conditions. The effect of peptone in preventing drug-action suggested the possibility of an interference in adsorption of the drug. To test this, a study was made of the adsorption of sulfapyridine by activated carbon particles. Varying amounts of activated carbon were added to solutions containing 10 mg of sulfapyridine and 0.85 g of sodium chloride per 100 cc. After allowing the reaction to take place for 15 minutes, the carbon was removed by filtration, and the filtrate was tested for the presence of the drug by the method described by Marshall. 3 Adsorption was found to occur, as shown in Fig. 1 (solid line). If 1% peptone (Parke-Davis) is added to the solution containing the drug, and adsorption by carbon allowed to take place, the removal of the drug is retarded. This is shown in Fig. 1 by the broken line. That this adsorption is selective is illustrated by the following experiment: 2 cc of a 1:1000 solution of sulfapyridine were added to 8 cc of saline, and adsorbed with 20 mg of carbon. After 15 minutes, the mixture was divided into 2 parts; to one, 5 cc of 0.85% saline was added, and to the other 0.85% saline containing 1% peptone. These were allowed to stand for another 15 minutes, when they were filtered and tested for sulfapyridine. The portion to which saline had been added showed adsorption of 73% of the drug, as compared with a removal of 55% in the portion to which peptone had been added. This suggests that peptone is able to displace the drug from the surface of the carbon particles.

Further observations on relation of glomerular function to phenolsulphonephthalein excretion in frog's kidney.

Summary When a dye solution is run into the frogs kidney in such a way that, in the lower portion of the kidney, it runs into tubular capillaries and into a large number of glomerular capillaries, while in the upper portion of the kidney it runs into tubular capillaries, and into only a few glomerular capillaries, the amount of dye excreted follows the number of active glomeruli receiving dye solution, although both halves of the kidney are producing urine.

Protective Action of Sulfapyridine in Rabbits Infected with Pneumococci.

Most of the studies on the protective action of sulfanilamide and sulfapyridine on streptococcic and pneumococcic infections have been made on white mice. In the work here reported rabbits were used as the experimental animals. Intracutaneous inoculations were made in order to permit the observation of differences in the local lesions occurring in the treated and the control groups. Rabbits weighing approximately 2 kilos were given 0.3 cc of a 1-100 dilution of an 8-hour culture of a Type II pneumococcus. The strain used had been transferred alternately through mice and veal broth for more than a year. Intraperitoneal injections of 0.2 cc into mice, in dilutions of 1:10,000,000, kills 50% of the animals. Sulfapyridine, 2-(sulfanilamide)-pyridine, was administered orally by suspending in 10% acacia and permitting the suspension to trickle down the throat from a large syringe. The treated animals were given 0.5 g one hour before inoculation, 0.5 g 3 hours after inoculation, and 0.5 g every 12 hours thereafter for a total of 5 g. In addition to the difference in mortality, there was observed a marked difference in the lesions produced in the treated and control animals. Rhoads and Goodner 1 have reported oedema and a spread of the cutaneous lesion by gravity in rabbits inoculated endermally with pneumococci. These results were evident in our control group. The treated animals showed little or no oedema, and probably because of this, showed little or no spread by gravity. That an infection was present in the skin was evidenced by the area of inflammation in the skin of treated animals. The above authors have also stated that in occasional animals they find signs of hemorrhage in the skin. In the lesions of our control series there were extensive hemorrhages, caused either by the virulence of our strain or by the age of the culture.

Active Immunity to Pneumococci in Rabbits Protected by Sulfapyridine.

The results of experiments on the protection of rabbits, infected with pneumococci, by oral administration of sulfapyridine have been reported previously. 1 The purpose of this communication is to present data obtained in the study of the immunity in animals that had recovered from the infection produced under such circumstances. Rabbits weighing approximately 2 kilos were inoculated intracutaneously with 0.3 cc of a 1/100 dilution of an 8-hour culture of a pneumococcus type II. The inoculum contained an average of 300,000 organisms as determined by plate-count. The virulence of the organism is such that an average of 1.5 organisms are necessary to cause an infection in 66% of a statistically sized group of mice weighing 20 g. This we have taken to be our minimal lethal dose. Its virulence for rabbits is such that 0.3 cc of a 1/1000 dilution of the original culture, containing 30,000 organisms, will kill all of the rabbits inoculated. The drug-treated animals were given sulfapyridine orally in a 10% acacia suspension. Each animal received a total of 5 g of the drug, 0.5 g 1 hour before infection, 0.5 g 3 hours after the initial dose, and 0.5 g every 12 hours thereafter until the full dosage was administered. Daily record was made of the temperature, and the size and nature of the skin-lesion. Rabbits recovering from the primary infection were reinoculated intracutaneously in the same general areas as previously, but not at the site of the original lesion if a scar had persisted. Only normal areas of the skin were used for reinoculation. Type-specific Immunity. Twelve rabbits reinoculated intracutaneously with 0.3 cc of the whole 8-hour culture of the homologous type II pneumococcus 30 days after the original infection, showed no rise in temperature, and no local reaction around the point of inoculation.

Protective Action of Sulfapyridine Against Type II Pneumococcal Infections in Mice.

Summary With subcutaneous inoculations of 4000 to 8000 average lethal doses of a Type II pneumococcus in mice, the survival rates at both 30 and 60 days were (1) with 0.5% sulfapyridine in the food, 44%, and (2) with 1.0% sulfapyridine in the food, 63.4%. It is believed that the slight variations in drug-intake from day to day are more than counterbalanced by a more or less continuous drug-absorption from ingested food plus drug.