Method and material for detoxifying local anesthetics
United States Patent 2268915

Our invention refers generally to the detoxification of local anesthetics and more particularly to the detoxification of procaine derivatives and butyn sulfate with certain of the organic salts of calcium. It is a matter of importance to determine what materials must be added to local anesthetics...

Helene, Wastl
Reinhard, Beutner
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514/536, 514/578, 514/974
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Our invention refers generally to the detoxification of local anesthetics and more particularly to the detoxification of procaine derivatives and butyn sulfate with certain of the organic salts of calcium.

It is a matter of importance to determine what materials must be added to local anesthetics to cause a delay of absorption into the general circulation from the place of injection in order that the general toxic effect of the injected local anesthetics be diminished or eliminated. Such a point of view-of holding the anesthetic locally at the place of injection-has a definitely practical significance; and for that reason adrenaline is usually added routinely to local anesthetics.

In many cases such a procedure is satisfactory.

However, there are individuals in whom adrenaline induces inimical effects, since adrenaline is a highly toxic substance even in conjunction with a local anesthetic. Since it is difficult to determine in advance the undue sensitivity of such individuals, it becomes eminently desirable to discover materials to be added to local anesthetics for the purpose of delaying their absorption, whether it be done by increasing the density of the membranes or by establishing local vasoconstruction. Such materials, obviously, must' be harmless to the individual if they are to replace the adrenaline that accompanies the human use of local anesthetics.

Local anesthetics act on the central nervous system as a general poison when absorbed at a sufficiently rapid rate and with their elimination lagging behind at a certain rate. Convulsions and equilibrium disturbances are largely of a cortical origin. Therefore, one can determine, when studying the convulsions caused by toxic doses of local anesthetics in animals, those substances, mostly Ca salts, which lead to a lesser incidence or to a complete disappearance of the aforesaid toxic effects. Although we have observed the effectiveness of our means for detoxifying local anesthetics in animal studies, yet the same agencies in smaller dosage, are safely applicable, as attested by clinical experience, to humans by replacing adrenaline with the Ca salts. Incidentally, the measurement of the efficiency of the anti-convulsive actions of Ca salts has a certain significance in the choice of the Ca salts to be used in tetany treatment, whenever an emergency indicates a subcutaneous or intramuscular injection.

Aside from the local effects of such additions to a local anesthetic, one must take into consideration whether or not the Ca salts act anticonvulsively on the central nervous system after having been absorbed. The real site of the action of a drug is unknown, but it is an accepted thesis that every drug must combine with unknown substances (dominant receptors) at the site of the action and also -with secondary receptors apart from the site of the action. The site of the action may be more or less irritable and the dominant receptors may be more or less accessible to the drug. However, there is little known about the factors that influence the rate of the chemical destruction of the drug in the animal body, those that change the action of the drug by influencing its milieu and those that modify the distribution of the drug between the dominant and the secondary receptors. But if two drugs have the same dominant receptors, it is likely that one drug will be more easily absorbed Ij than the other, i. e., the recognized phenomenon of replacement becomes evident. Accordingly, detoxification of local anesthetics by the addition to them of other substances cannot be attributed solely to a single mechanism,,'as, for example, a knowledge of their local effects upon the site of injection. Combined local effects at the various sites of the action of a drug and a study of the detoxifying additions to it'in variable and largely unknown interchanges and relations contribute toward the making of a more comprehensive and factual picture.

In our research work, we first injected healthy guinea pigs intra-muscularly with a number of local anesthetics like butyn sulfate, procaine o HC1, procaine bicarbonate, and the like. The animals responded with uncoordinated movements, loss of equilibrium and a falling to their sides. Convulsions then set in, alternately tonic and tetanic in type. Frequently, there was observed a marked opisthotonus and ultimately there developed a profound and persistent prostration. However, recovery invariably followed, except in a few cases when the animals succumbed to respiratory failure when highly toxic doses had been administered.

The reaction of the drugs was observed as ended when the animals arose voluntarily, walked about or at least sat in their usual position. In border line cases, convulsions were provoked sooner by the attempts of the animals to move or by turning the animals over when initial shakings, twitchings and staggering indicated the oncoming of a positive reaction. Notwithstanding the fact taat a seven day period usually elapsed (in some cases, a ten to twelve day period) between injections into an animal, yet not infrequently there were observed cumulative effects in later injections, as evidenced by a higher Dercentual incidence of convulsions.

Furthermore, we had to take in consideration, on the general principle of biological variation, the variations in sensitiveness or resistance of the numerous test animals. Because of such variability factors, pertinent results could be achieved only by studying for every combination of a drug with added substances a large group of animals and by treating out data thus obtained in a statistical analysis of the number of times thas a positive reaction occurred after injection, of the type and the duration of the reaction, and of the percentual incidence in the different groups. In this way, average results and the range of variations were determined.

Individual reactions were distributed over a fairly wide range, but as Treva has demonstrated, irregular results disappear when a sufficiently large number of animals are tested.

In our investigation, over 3500 experiments were performed in the following categories: In groups 1 and 2, varying concentrations of procaine bicarbonate and butyn sulfate were administered alone into the guinea pigs.- Our results indicate that butyn is far more toxic than procaine and a smaller dosage must be used.

In the administration of butyn a dose of 50 mg. of butyn/kg. of body weight was found to be lethal and a dose of 25 mg./kg. was observed as sublethal.

Furthermore, it was observed that procaine bicarbonate is more effective than its hydro- 21 chloride in respect to the incidence of convulsions and to the intensity and the duration of reaction.

In groups 3 and 4, the aforesaid characteristics of procaine and butyn were confirmed by 3( experiments testing the time for the reflexdisappearance in frogs and for the corneal reflex-disappearance in rabbits.

In group 5, over a thousand experiments were performed in which various Ca salts were used 31 in conjunction with procaine HC1 in a dosage of 100 mg. procaine/1 kg. of weight. Among the Ca salts thus used were the salicylate, the chlor-acetate, the lactate, the iodide, the bromide, the chloride, the gluconate, the ortho- 41 iodoxy-benzoate and the levulinate. Our results disclose that the most effective anti-convulsant in this group is Ca salicylate and the least effective, Ca ortho-iodoxy-benzoate. Ca gluconate has almost as little effect as Ca ortho- 4 iodoxy-benzoate.

In group 6, many experiments were performed with the Ca salts in conjunction with procaine HC1 in a. dosage of 200 mg./kg. of weight. Our results indicate that the protective effect of the I Ca salts varies in the manner demonstrated by the experiments of group 5, in spite of the fact that the "double" dose of procaine is highly toxic and sublethal.

In group 7, CaC12 was added to butyn sulfate, although in higher concentrations insoluble CaSO4 is precipitated. Our results show that CaC12 exerts a definite protective action against convulsions. However, we obtained evidence to the effect that repeated injections lead to an increasingly higher incidence of convulsions.

In group 8, Ca gluconate and Ca lactate were studied in conjunction with butyn sulfate. As in the case of procaine HC1, the detoxifying effect of Ca gluconate on butyn is negligible; but the effect of Ca lactate is pronounced in even fairly low concentrations.

In group 9, the detoxifying effect of Ca levulinate on butyn sulfate was exhaustively studied with definitely positive results.

In group 10, the effects of other (than Ca) salts were studied alone and in conjunction with the Ca salts from the view point of their influence on the detoxification of procaine HC1. KC1 alone with procaine decreases somewhat the incidence of convulsions. When KOC was combined with Ca salts, the anti-convulsant effect became greater-but not so striking as was anticipated. MgC12 in conjunction with CaCI2 is far less effective than CaCl alone in decreasing the incidence of convulsions induced by procaine.

In group 11, we undertook experiments with adrenaline additions to procaine HC1 and the results demonstrated combinations very effective in decreasing the incidence of convulsions and the duration of the positive reaction.

In group 12, we studied the effects of additions of luminal and nembutal to procaine HC1 with comparatively negative results. In the case of nembutal, the procaine convulsions occur and disappear before the depressing effect of nembutal on the central nervous system is asserted.

In the aforesaid groups of experiments extensive material has been obtained for the purpose of presenting a comparative study of the Ca" salts in so far as their efficiency in detoxifying local anesthetics is of moment in clinical application. Various theories attempt to explain the effect of CaC12 on the toxicity of cocaine and Sprocaine. It has been suggested that the antagonism of cocaine and CaC12 depends on a change in the state of the lipoids, particularly lecithin which has an affinity foi cocaine and CaC12. Also, the conjecture has been offered Sthat substances having opposite effects on permeability can antagonize each other as do the alkaloids and salts. Furthermore, Ca has the effect of increasing colloid density and should induce, therefore, a decreased rate of absorption. But irrespective of the explanations for the mechanism of the changes produced in, the effects of procaine and butyn by the Ca salts, a number of the Ca salts must be eliminated from clinical use in subcutaneous, intra-muscular and in0 tra-spinal injections because of their locally irritating and necrotic reactions. Accordingly, the Ca halides are discarded along with Ca gluconate which has only a slightly effective,. anti-convulsive action. Among those Ca salts that can :5 be effectively used in clinical routine are the salicylate and the levulinate. Of these, Ca levulinate is to be recommended, first because it is very soluble in water, is readily sterilized, and is non-toxic and non-irritating locally in theraiO peutic doses. Ca lactate is likewise effective, although it is less soluble and stable than the levulinate.

The following table is signficant. We have selected procaine HC1 (100 mg./kg.) with the 55 addition of Ca salts of 9 mg. of the Ca to 1 kg. and have regarded the average percentage of convolutions occurring with Ca salicylate as unity.

Convulsion index 60 Ca salicylate---------------------------- 1 Ca chloracetate----------------------- 1.62 Ca levulinate ------------------------- 1.77 Ca lactate---------------------------- 3.87 Ca I 2 -------------------------------- 4.57 SCa Br2-------------------------------6.02 Ca gluconate-------------------------- 9.94 Ca C12-------------------------------- 6.79 Ca drtho-idoxy benzoate---------------- 12.05 70 The quantity of Ca levulinate corresponding to 9 mg. Ca/kg. is 60 mg./kg. If the concentration is increased to 150 mg./kg., then the 100 mg. of procaine/kg. are completely detoxified.

Butyn sulfate can likewise be studied. Select75 ing 25 mg. butyn/kg. with 18 mg. Ca/kg. and accepting the average value of incidence with Ca levulinate as unity the following comparative table results: Ca levulinate------------------------ 1 Ca lactate . ---------------------- 4.88 CaC12 -------------------------------- 11.24 Ca gluconate --------------------- 18.14 Throughout our many experiments involving the conjunction of Ca salts with local anesthetics as applicable to the incidence of convulsions in animals, we have come to these definite generalizations: 1. The duration of a positive reaction varies inversely as the concentration of the Ca salt addition.

2. The period between reactions varies directly as the concentration of the Ca salt addition.

It is to be understood that the aforesaid experimental disclosure is merely illustrative, and is not to be construed as restrictive of the scope nor of the spirit of our invention, which has been further defined by the following annexed claims. We claim: 1. A detoxified local anesthetic comprising a mixture containing a member selected from the group consisting of procaine and butyn and an organic calcium salt selected from the group consisting oflevulinate, lactate and salicylate.

2. A method for detoxifying a member selected from the group consisting of procaine and butyn for use as a local anesthetic, comprising the mixing of said member with an organic calcium salt selected from the group consisting of levulinate, lactate and salicylate prior to administration.