Use of poly I poly C in the prophylaxis and treatment of acute viral infections

696 DISCUSSION PAPERS-SESSION VI studies in the high-risk group since in these individuals the disease may be more severe and complications are more likely to occur. In this regard, one must consider the toxicity of amantadine hydrochloride. In our studies and in those reported at this Conference, toxicity from amantadine was minimal to absent. I think that sufficient evidence is now available to say that toxicity is not the primary reason for limiting the use of amantadine for control of influenza. However, the risk of toxicity with diffe- rent age-groups and various chronic disease states is not clear. More pharmacological data are needed for such individuals. and these data could be col- lected in combination with the therapeutic trials just proposed. While antiviral therapy for influenza is desirable, chemoprophylaxis remains the major consideration of the proposed antiviral agents for influenza. The ability of amantadine to prevent infection with type A2 strains if given prior to exposure is established. Smorodincev c in extensive trials and Galbraith et al. d9 in detailed studies have provided data indicating that in open-community field trials amantadine is an effective prophylactic for A2 influenza. However, as with the current vaccines, the prophylactic effect is less than optimal. This finding, in combination with the observation that the prophylactic effect was better in those individuals c Unpublished. d See paper by A. W. Galbraith et al. on page 677 of this issue. with some pre-existing antibody, caused these investigators to suggest that a combination of influenza vaccine and amantadine might produce optimal protection. Obviously, since neither method of prophylaxis alone appears ideal, the combination should be tested. This investigation deserves high priority in prospective studies with amantadine. In addition, it should be noted that Solov'eve suggested that a combination of interferon and amantadine might produce optimal prophylaxis. At the present time amantadine has a limited but definite place in prophylaxis for human influenza. I believe that it should be recommended for ad- ministration to non-vaccinated individuals in the high-risk group when influenza A2 is identified in the community, a situation that occurred in extensive areas of the USA and other parts of the world in 1968-69. In addition, however, careful monitoring for toxicity should be performed and the drug dis- continued if toxicity occurs. Exceptions to this general recommendation are defined by the dis- tributor. In summary, I believe it possible that in the future an important role for antiviral com- pounds in influenza will be defined. Evaluation of available and emerging antiviral agents should continue because of the possibility that they may provide an important link in producing safe, effective, and optimal prophylaxis of human in- fluenza. e See paper by V. D. Solov'ev on page 683 of this issue. Use of Poly I poly C in the Prophylaxis and Treatment of Acute Viral Infections by M. R. HILLEMAN a Extensive investigations have been carried out in animal models in our laboratory to assess the potential usefulness in the prophylaxis and treatment of acute viral infections of poly I-poly C (poly- riboinosinic: polyribocytidylic acid complex; poly I: C; rlnrCn; rI: rC). a Merck Institute for Therapeutic Research, West Point, Pa., USA. The accompanying table presents an interpretative summary of tests in various animal models. The drug was given in a single dose, 3 hours prior to severe viral challenge. Various route combinations were employed and the test results are expressed in terms of findings (death, except for vaccinial tail lesions) 7-21 days after challenge. Strong activity was found against PVM, Columbia SK, vaccinia, and para- influenza viruses. Weak activity was found against 2426B POLY I'POLY C IN PROPHYLAXIS AND TREATMENT OF ACUTE VIRAL INFECTIONS SUMMARY OF OPTIMAL EFFECT OF POLY I-POLY C ON VIRAL INFECTIONS IN MICE AND CHICKS Test virus Appraisal Route of Kind Route poly I-poly C activity PVM I ntranasal I ntranasal Excellent Columbia SK Intranasal Intranasal Very good Columbia SK Intranasal Intraperitoneal Very good Columbia SK Subcutaneous Intraperitoneal Very good Vacci n ia Intravenous I ntraperitoneal Very good Intravenous Subcutaneous Very good Para- influenza-1 (Sendai) Intranasal Intranasal Good Rabies I ntraplantar ntraperitoneal Weak Rabies I ntracerebral Intraperitoneal Weak Influenza A Intranasal Intranasal None Influenza A2 I ntranasal I ntranasal None Influenza B I ntranasal I ntranasal Weak Yellow fever Intracranial Intraperitoneal None influenza B and rabies viruses, and no activity was shown against influenza A, A2 or yellow fever viruses. The challenge was always quite severe, in no way resembling that for the natural infection. In the influenza system, for instance, 10 LD50-30 LD50 of virus were given and the findings were expressed in terms of survival 14 days later. It was of special interest that in most systems the drug and virus could be given by different routes and still display activity. The important matter is whether poly I -poly C will be useful in man. It is especially encouraging, from the respiratory disease standpoint, that the drug was highly effective when given nasally. In the PVM system, the drug effect lasted for about 7 days and was highly therapeutic, even when given 3 days after virus. One problem with poly I *poly C is its toxicity: this was not seen in the antiviral models but was evident in the routine safety assessments (toxicology), especially in the histopathological findings in mice, rats, and dogs. The most significant toxicological changes noted appeared to have a vascular, hepatic or haematological basis. Pathological findings in dogs included necrotic changes in several organs, especially the liver, bone-marrow, bone and spleen. Monkeys were less reactive than the other animal species. Early clinical tests in man have shown manifestations which appear to be due to toxicity but it is too early to assess their importance. It seems clear that the toxicity of poly I * poly C will limit its application. It is as yet impossible to assess the potential usefulness in man since neither the toxic dose nor the active dose has been established. It appears likely, however, that a satisfactory toxic- ity: activity ratio will be found for certain kinds of infection, especially since the drug is highly active when given nasally in animals and since relatively small doses are required by this route. Attempts to improve the toxicity: activity ratio by molecule manipulation are already in progress. 697