Antivenom

“ While sub-Saharan Africa faces a dramatic crisis in antivenom production and supply [110] , [111] , shortage of antivenom is not the most pressing issue in South Asia. Indeed, it is estimated that India produces around one million vials of antivenom each year [112] . Despite these large volumes of production, several challenges persist that prevent appropriate management of snake bite victims in South Asia. Poor access to often inadequately equipped and staffed medical centres in rural areas, high cost of treatment, and inadequate use of antivenoms are major concerns [113] , [114] . ”

“ It will be understood from what has been already stated, that a man weighing 60 kilogrammes, if bitten by a snake which injects, let us say, what would amount to 20 milligrammes of venom if collected in the dry state (the mean quantity that a 268 Naja is able to inoculate in a single bite) , would only require, in order to escape death, to receive the quantity of antivenomous serum sufficient to neutralise the portion of venom in excess of the amount that he could tolerate without dying. ”

“ Two or three drops, introduced into the marginal vein of the ear of a rabbit, cause death from asphyxia in from four to ten minutes. The heart continues to beat for a fairly long time after respiration has entirely ceased; the blood is not coagulated.
The toxicity of this venom is completely destroyed by heating it to 100° C., by chloride of lime, and by chloride of gold. Antivenomous serum prepared from horses vaccinated against cobra-venom has absolutely no effect upon it in vitro. ”

“ Antivenomous serum completely protects citrate- or chloridate-plasmas against the anticoagulant action of venoms. It is sufficient to mix 1⁄2 c.c. of 4 per cent. saline antivenomous serum with 1 c.c. of 4 per cent. saline plasma to ensure that the subsequent addition of 1 milligramme of Cobra-venom to this mixture remains without effect upon the coagulability of the latter. If, 196 after a contact of two hours or more, 2 c.c. of distilled water be added, coagulation is produced just as in saline plasma without venom. ”

“ Lachesis-venom, when heated to 70° C., no longer has any dissolving action on either gelatine or fibrin. Moreover, antivenomous serum furnished by horses vaccinated against heated venoms does not prevent proteolysis by non-heated venoms. On the other hand, the serum of animals vaccinated against Viperine-venoms, simply filtered by the Chamberland process and non-heated, affords perfect protection to gelatine and fibrin against the dissolving action of these venoms. ”

“ Moreover, the recent foundation of the Serum-Therapic Institutes of Bombay and Kasauli, Sydney, São-Paulo, and Philadelphia, to-day renders it very easy for each country to provide itself with antivenomous serum, either specific or polyvalent. Other institutes will doubtless be established for the purpose of extending the benefits of a method, the efficacy of which is sufficiently evident for its adoption to be incumbent upon all those who are concerned with safeguarding human existence. ”

“ Neurotoxin being the essentially active substance in venoms, and that to which the dangerous properties of poisonous snakes, as regards man and domestic animals, are especially due, it is the effects of this that it is most necessary to prevent. Consequently, 251 the first quality that an antivenomous serum ought to exhibit, in order to be capable of being used in the therapeutics of poisoning, is the possession of an antineurotoxic power as high as possible. ”

“ To each tube 2 drops of defibrinated horse-blood are added, and the tubes are placed in the stove at a temperature of 35° C.
In tubes 1 and 6, which contain fresh rat-serum alone, and fresh serum + antivenomous serum, hæmolysis appears in a few minutes. 210 In tube 4, which received venom alone, hæmolysis is also produced in one hour. It is not produced at all in tubes 2 and 3, which received the neutral mixture of fresh serum and venom, proving that the hæmolytic alexin has been fixed by the venom. The latter, therefore, here plays the part of a true fixator or amboceptor. ”

“ When it is desired to procure large quantities of venom, as is indispensable in laboratories where antivenomous serum is prepared, the endeavour must be made to keep the snakes alive for the longest possible time. It then becomes necessary to resort 157 to artificial feeding in the manner previously described (see p. 17) , for they very often refuse to feed themselves.
Fig. 87.—Chloroforming a Cobra in order to Collect Venom, at the French Settlement of Pondicherry, in India (Stage II.) .
Except when a snake is moulting, the venom can be extracted from its glands about every fortnight ”

“ This method is, however, contraindicated for viper and cobra bites as it may increase local tissue damage [93] , [96] and may contribute to delaying transport of the victim to a treatment centre.
Antivenoms
Immunotherapy is the only specific treatment for snake bite envenoming. Antivenoms are produced by fractionation of plasma obtained from immunized animals, usually horses [97] . They can be either monovalent or polyvalent, depending on the number of species (single or multiple, respectively) whose venoms are used for immunization. ”

“ Laboratories for preparation of antivenomous serum, 248, 252. de Lacerda, on diastatic actions of venoms, 212. “ Elaps, 108. “ harmless ingestion of venom exceeding lethal dose, 214. 387 Lacertidæ, 321. Lachesis, 51, 109, 111. “ bite of, clinical symptoms, 169. “““ primarily local, violent, 169. “ classification of species, 52. “ venom of, absorption by digestive system, cause of acute inflammation of gastric mucous membrane, 180. ““ rich in kinase, 204. “ alternatus, 115. “ ammodytoides, 117. “ anamallensis, 56. “ atrox (grage) , immunity from bite of, 238. ““ (labaria) , 114. ”

“ Moudon, of Konakry, French Guinea.
“On December 9, 1898, a Foulah woman, eight months pregnant, was collecting wood when she was bitten in the heel, behind the internal malleolus of the right foot, by a snake which, from the description given, must have been a Horned Viper. When I saw her, four hours after the accident, the whole of the lower leg was swollen and painful. The swelling extended to the groin, and the patient complained of vertigo and nausea. I immediately gave her an injection of 10 c.c. of antivenomous serum in the right flank, followed by a second injection at 10 p.m. ”

“ The animal withstood the injection, but I am inclined to think that this is not a case of true immunity; it is probable that the pig owes its resistance to venom to the fact that its skin is lined with an enormous layer of adipose tissue, which is but very slightly vascular, and in which absorption takes place very slowly. This opinion is corroborated by my discovery that the serum of this animal is entirely destitute of any antitoxic substance. I mixed a dose of Cobra-venom, lethal for the rabbit, with 3·5 and 8 c.c. ”

“ In the case of young animals, venom is not modified by the digestive juices, and a portion of it is absorbed by the mucous membrane of the intestine. When the dose ingested is suitably reduced they withstand it, and when these ingestions are repeated every second or third day during the first weeks of life, the animals become perfectly vaccinated against doses certainly lethal for controls of the same age and weight. But it is always difficult to push the vaccination far enough for the serum to acquire antitoxic properties, and I have never been able to prove the appearance of the latter. ”

“ After a few hours everything returns to its normal condition, and if the injection of a lethal dose of venom is repeated several times, at intervals of a few days, it is not long before antitoxic substances are found to appear in the serum.
When the dose of venom injected is sufficient to cause death, we observe, a very few moments after the injection, a lowering of temperature and a hypoleucocytosis, which is the more pronounced in proportion to the nearness of the dose of venom to the minimal lethal dose. With very strong doses the hypoleucocytosis has not time to manifest itself. ”

“ We have seen that although most animals fall an easy prey to serpent venom, yet there are a few notable exceptions, amongst which may be mentioned hedgehogs, swine, and the mongoose. Now the very natural question arises why, if these animals are already in such a high degree immune from this poison, should not they be employed to furnish forth protective serum, instead of laboriously training up susceptible animals to become artificially immune and supply this venom anti-toxin? ”

“ The rapidity with which it acts is indeed one of the most astonishing properties of this particular anti-toxin. Thus if two cubic centimetres of anti-venomous serum be inoculated into the marginal vein of a rabbit's ear, it at once confers upon the latter complete immunity from snake poison. Immediately after the injection of the serum, venom sufficient to destroy an ordinary rabbit in a quarter of an hour may be injected with impunity into the vein of the other ear. ”

“ I inquired of the savant.
"Surely," he replied. "It neutralizes one of the two elements in the venom, the nervous poison, thus enabling the individual to devote all his vitality to overcoming the irritant poison. It is the nervous poison that is the chief death-dealing agent, producing paralysis of the heart and respiration. We advise all travelers to carry the protective serum if they are likely to be exposed to snake bites."
Kennedy picked up the tube containing the solution made from the towel spots. "This antivenin was your product, doctor?" ”

“ Fraser calls his immunised blood-serum, follows the poison into the system, even after the fatal symptoms have begun to show themselves, and arrests them at once. So the Anglo-Indian may throw away his ammonia phial and, arming himself with another of anti-venene and a hypodermic syringe, feel that he is safe against an accident which will never happen. As for the man who is not nervous, he will speak of the new antidote, and think of it as most interesting and valuable, and go on his way as before with no expectation of ever being bitten by a venomous snake. ”

“ After this I was not long in pushing the vaccination of a few horses until I made them resist, in a single injection, 2 grammes of dry cobra-venom, a dose about eighty times lethal; for I was able to satisfy myself that about 0·025 gramme of cobra-venom was sufficient to kill fresh horses in from twelve to twenty-four hours.
The immunisation of horses to this very high degree of tolerance of venom is not obtained without difficulties; many animals succumb 245 in course of treatment from endocarditis or acute nephritis ”

“ When inoculated into frogs it produces œdema and hæmorrhage; if injected into warm-blooded animals it causes necrosis. In sufficiently strong doses it kills by arresting respiration. Its effects strongly resemble those produced by Viperine venoms. This venom, if attenuated by being heated at 50° C. and injected into mammals, vaccinates them and leads to the formation in their blood of antitoxic substances, which are capable of preventing intoxication by salamander-venom, and, curiously enough, also confer immunity against viper-venom and the serum of the common snake. ”

“ Moreover, venom acts not only upon microbes of the same kind, but also on very different species which are not affected by rat-serum, especially upon B. pestis, for which, on the contrary, this serum, when fresh, proves a favourable culture medium. The bacteriolytic power of Cobra-venom therefore constitutes a special property of venom.
“In their work on the cytolysins of venom, S. Flexner and Noguchi have shown that animal cells, when heated to 55° C. and rendered inactive, do not undergo complete dissolution under the influence of venoms which destroy the fresh cells. ”

“ By experiments in vitro Calmette studied the influence of heat and chemical agents on these venoms; and, working by various methods, was able to immunize animals:—
“I have got to immunizing rabbits against doses of venom that are truly colossal. I have several, vaccinated more than a year ago, that take without the least discomfort so much as forty milligrammes of venom of Naja tripudians at once. Five drops of serum from these rabbits wholly neutralize in vitro the toxicity of one milligramme of Naja venom. ”

“ This rapid diffusion of the venom helps to explain the difficulty which is experienced in arresting the course of the poison by local treatment, for its passage is too rapid to permit of its being overtaken by superficial measures of even the most stringent character. But Calmette points out that local precautions are not to be neglected, for although they cannot nullify the action of the venom, they undoubtedly do delay its progress, and thus create a longer interval or respite, during which an opportunity is afforded for administering the anti-toxin. ”

“ We have seen that these animals can ingest without inconvenience doses of venom 600 times greater than the lethal dose, and that, if we cause these ingestions to be repeated several times, contrary to the assertion of Fraser66 (of 215 Edinburgh) , we never succeed in obtaining immunity to the subcutaneous injection of a simple lethal dose, and no antitoxin is formed in the blood. ”

“ Underneath all this storm and stress of the fever paroxysm, nature is quietly at work elaborating her antidote. In some marvelous fashion, which we do not even yet fully understand, the cells of the body are producing in ever-increasing quantities an anti-body, or antitoxin, which will unite with the toxin or poison produced by the hostile germs and render it entirely harmless. By a curious paradox of the process, it does not kill the germs themselves. It may not even stop their further multiplication. Indeed, it utilizes part of their products in the formation of the antitoxin ”