Clinical Studies Employing Interferon Inducers in Man and Animals *

Merigan, Thomas C.; Clercq, Erik De; Finkelatein, M. S.; Clever, Linda Hawes; Walker, Stewart; Waddell, Dorothy

doi:10.1111/j.1749-6632.1970.tb53468.x

Cited by 24 publications

(11 citation statements)

References 25 publications

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“…These findings suggest that the amount of IFN in the lung has an important role in the defense against influenza virus infection in mice. Similar results showing that the amounts of IFN in virus propagating tissues, but not in circulating IFN titers correlate to the resistance to viral diseases have been reported with pyran and poly I:C on mengovirus infected mice (Merigan et al 1970) and with tilorone hydrochloride on MM virus infected mice (Giron et al 1972).…”

Section: Discussionsupporting

confidence: 71%

Antiviral effect of interferon on influenza virus infection in mice.

Saito¹,

Suzuki²,

Ishida³

1983

Tohoku J. Exp. Med.

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The antiviral effect of highly purified mouse interferon (IFN) was studied on influenza virus infection in mice, by changing the routes of administration. By repeated intravenous (iv.) administrations of IFN, no antiviral effect was observed. However, IFN was effective when the infected mice received either intraperitoneal (i.p.) or intranasal (in.) administrations. While all of the untreated mice died within 10 days after infection, 20% of the i.p. treated mice and 67% of the i.n. treated mice survived more than 30 days. To explain these different effects after administration by different routes, the distribution of given IFN in mouse organs was examined. Fifteen min after i.v. injection, only a low-titered IFN was detected in the serum, lung, spleen and liver of the mice and soon disappeared. However, a relatively high-titered IFN was detected 30 min after i.p, administration in the lung and serum. After i.n. administration, high-titered IFN was detected in the lung within 15 min after administration and continued for 90 min. Thus the findings demonstrated that the maintenance of a detectable amount of IFN in mice organs is dependent on the route of administration, and the higher the titer of IFN in the lung, the higher the protective effect of IFN against influenza virus infection, mouse interferon; anti-influenza effect; distribution Distribution and metabolism of IFN in animals were well reviewed by Ho and Armstrong (1975). The clearance of IFN given to animals and man was also documented by Cantell et al. (1974), Cantell andPyhala (1976) and other workers (Gresser et al. 1967;Nuwer et al. 1972;Pyhala and Cantell 1974;Edy et al. 1976). Their results may be summarized as follows : (i) In the blood, IFN has an extremely rapid half-life (about 20 min), hence it is difficult to maintain elevated serum concentrations. (ii) IFN in the blood slowly decreases after repeated i.v. injections of IFN. (iii) IFN activity has been detected in the blood for more than 5 hr after i.p. administration. However, the relationship between the effect of IFN on viral infections and the distribution of IFN in the organs of these animals has never been fully investigated.Only Finter (1967) described the fact that, although intramuscular (i.m.) or i.v. injections of IFN were not effective against aerosolized influenza virus infection in mice, levels of IFN sufficient to protect against Semilki forest virus infection were obtained from the blood after those injections. On the other hand, nose-dropped IFN was found to be effective against

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Section: Discussionsupporting

confidence: 71%

Antiviral effect of interferon on influenza virus infection in mice.

Saito¹,

Suzuki²,

Ishida³

1983

Tohoku J. Exp. Med.

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“…Thus, lower doses of tilorone, which do not induce detectable amounts of circulating interferon, were effective. (7) presented data which show a lack of correlation between the amounts of circulating interferon induced by pyran and polyinosinic-polycytidylic acid and the degree of protection by these agents against mengovirus infection in mice. These reports, together with the present study, imply that determination of circulating interferon titers is of limited value in assessing the potential of a substance as an antiviral agent.…”

mentioning

confidence: 99%

Tilorone Hydrochloride: Lack of Correlation Between Interferon Induction and Viral Protection

Giron¹,

Schmidt²,

Pindak³

1972

Antimicrob Agents Chemother

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The protection of mice against MM virus infection and the induction of circulating interferon by tilorone hydrochloride were determined. Whereas protection was evident with doses of 0.15 and 1.5 mg/kg, interferon was not detected with doses lower than 150 mg/kg. Protection was apparently not dependent on interferon induction.Tilorone hydrochloride, the orange, watersoluble dihydrochloride salt of 2,7-bis[2-(diethylamino) ethoxy] fluoren-9-one, is a broadspectrum antiviral agent (5). In mice, it is effective against Semliki Forest virus by the oral, subcutaneous, and intraperitoneal treatment routes. It has also been shown to be effective against intranasal infection by vesicular stomatis virus (VSV; 2). Its mode of action is presumably interferon stimulation (2, 6). We have investigated the protection elicited by different doses of tilorone given intraperitoneally against MM virus infection in mice. At the same time, the amount of circulating interferon induced by each dose of tilorone was determined.Female Swiss Webster mice weighing about 14 g were treated intraperitoneally with different doses of tilorone diluted in Hanks balanced salt solution. Ten mice from each group were bled at 6, 12, and 24 hr after the administration of tilorone. The blood was pooled, and the plasma was collected and assayed for interferon activity. At 24 hr after the injection of tilorone, the mice remaining in each group were challenged intraperitoneatly with about 100 plaque-forming units of MM virus (2 LD50). Deaths were recorded daily for 20 days. The results (Table 1) show that, in terms of mortality and mean survival time, a tilorone dose of 7.5 mg/kg was sufficient to protect mice. They also suggest that doses as low as 0.15 and 1.5 mg/kg can have a protective effect, although at these doses the results were variable. Circulating interferon, however, was not detected with tilorone doses of less than 150 mg/kg. As these data show, in our system there was no correlation between the protection of mice against MM virus infection and the amount of circulating interferon induced by tilorone.These results are not in agreement with those of De Clercq and Merigan (2), who reported that the degree of protection of mice against intranasal infection with VSV was directly related to the titers of interferon induced by different doses of tilorone. Their interferon titers in response to tilorone were much higher than those in the present study. Since the 50% reduction in plaque count as a method for assay of interferon is more sensitive when MM virus is the challenge agent than when VSV is used (1), we must conclude that the differences in interferon titers in the two studies are real. This discrepancy could be due to a genotypic difference in the animals.

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“…162,163 The later 1970s saw the evolution of other forms of melanoma vaccination, including the use of oncolysates prepared from surgically excised autologous melanoma infected with the Newcastle disease virus or vaccinia virus. 164,165 By that time, it had been reported that this and other viruses could induce the production of interferon, 166 so the stage was set for the advent of interferon in melanoma therapy. In Cancer in 1983, Retsas et al reported a single response among 17 pretreated melanoma patients receiving human lymphoblastoid interferon, 167 and the next year Creagan et al reported a 31-patient trial of highdose recombinant interferon-a, given intramuscularly 3 times weekly, with 7 objective responses but substantial toxicity, predominantly constitutional.…”

Section: Immunologic Therapies In Melanomamentioning

confidence: 99%