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

Giron, David; Schmidt, Jerome P.; Pindak, Frank F.

doi:10.1128/aac.1.1.78

Cited by 23 publications

(10 citation statements)

References 5 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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“…2). However, the presence of tilorone (10 ug/ml) did not affect significantly the rate of adsorption of the two virus preparations tested (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…Tilorone hydrochloride at a concentration of 10 ,ug/ml very efficiently inhibited herpes simplex virus growth in BSC1 cells when the virus is infected at a low multiplicity of infection. The adsorption of the virus was not affected by the drug, and the penetration of the deoxyribonucleic acid of the input virus into the cytoplasm and nuclei proceeded normally when tilorone hydrochloride was present.…”

mentioning

confidence: 99%

Inhibition of Herpesvirus Deoxyribonucleic Acid and Protein Synthesis by Tilorone Hydrochloride

Katz

Margalith

Winer

1976

Antimicrob Agents Chemother

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Tilorone hydrochloride at a concentration of 10 ,ug/ml very efficiently inhibited herpes simplex virus growth in BSC1 cells when the virus is infected at a low multiplicity of infection. The adsorption of the virus was not affected by the drug, and the penetration of the deoxyribonucleic acid of the input virus into the cytoplasm and nuclei proceeded normally when tilorone hydrochloride was present. However, newly synthesized viral deoxyribonucleic acid was not detectable under these conditions, there was a remarkable decrease in the rate of viral polypeptide synthesis, and virus particles were not formed. The inhibition of herpesvirus growth by tilorone hydrochloride was absolutely dependent on the presence of the drug in the cultures. Pretreatment of the cells with the drug did not result in resistance to herpesvirus infection after the removal of the drug.Tilorone hydrochloride, a dihydrochloride salt of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one (2), reduces infection of mice with Semliki Forest, vesicular stomatitis, encephalomyocarditis, mengo, influenza A and B, and herpes simplex viruses. It also inhibits tail lesions by nonlethal doses of vaccinia virus (6,14). It has been suggested that in vivo antiviral activity caused by tilorone results from induction of interferon (6,14,22). Tilorone also has antitumor activity (1,3,18,19) and reduces the deoxyribonucleic acid (DNA) polymerase activity associated with ribonucleic acid tumor viruses (5).Recently, we showed that tilorone hydrochloride (10 ,ug/ml) very efficiently inhibits the growth of herpes simplex virus type 1 in BSC1 cells (E. Katz, E. Margalith, and B. Winer, J. Gen. Virol., in press). Since no direct inactivation of virus infectivity was observed after incubation of virus suspension with the drug, an intracellular mechanism of antiviral action was suggested. The inhibition of herpesvirus growth was more effective when the multiplicity of infection was less than 1 and when the drug was added early in the course of infection.The aim of the present study was to examine the intracellular antiviral action of tilorone hydrochloride and to observe the synthesis of macromolecules of herpes simplex virus in BSC1 cells in the presence of the drug.MATERIALS AND METHODS Virus. Herpes simplex virus type 1 HF was obtained from ATCC. Virus stock was kept at 4 C.Cell cultures. BSC1 cells were grown in M199 supplemented with 10% inactivated calf serum in 60-mm plastic petri dishes (Nunc, Denmark). The dishes were incubated at 37 C in a humidified atmosphere supplied with 5% CO2. Infection procedure. Monolayers of BSC1 cells were infected with 0.3 ml of virus suspension at a multiplicity of infection of 0.5. After 1 h at 37 C the monolayers were washed with saline buffer, and 5 ml of M199 supplemented with 2% calf serum was added.Plaque assay. Monolayers of BSC1 cells were infected with 0.2 or 0.3 ml of virus dilution. After 1 h at 37 C, the cells were overlaid with Eagle medium containing 1% special Agar Noble (Difco Laboratories, Detroit, Mich.) and 5% inact...

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“…Giron et al (3) reported that protection of mice with tilorone hydrochloride against MM virus is apparently not dependent on interferon induction. In their studies, circulating interferon was not detected with i.p.…”

mentioning

confidence: 99%

“…Giron et al (3) concluded that determination of circulating interferon concentration is of limited value in assessing antiviral activity, since protection can be demonstrated without the simultaneous detection of interferon. In contrast, others report that protection of mice against intranasal infection with VSV is directly related to the concentrations of interferon induced by different doses of tilorone (1).…”

mentioning

confidence: 99%

Evaluation of Various Analogues of Tilorone Hydrochloride Against Venezuelan Equine Encephalitis Virus in Mice

Kuehne

Pannier

Stephen

1977

Antimicrob Agents Chemother

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The antiviral activity of tilorone hydrochloride and three of its analogues (11,002, 11,567, and 11,877) was assessed by oral and intraperitoneal (i.p.) administration to Venezuelan equine encephalitis (VEE) virus-infected mice. Significant increases in the percentage of survival ( P < 0.01) were apparent after oral administration of tilorone and analogue 11,877 at dosages of 250 and 500 mg/kg. Neither tilorone nor 11,877 increased percentage of survival when dosages of 31.25 to 500 mg/kg were given by the i.p. route. Orally administered analogue 11,002 was effective against 100 mouse intracranial median lethal doses (MICLD 50 ) of VEE virus at doses at 250 to 1,000 mg/kg; doses of 31.25 to 250 mg/kg given i.p. were effective against 10 MICLD 50 . Oral dosages of 250 to 1,000 mg of analogue 11,567 per kg were active against 100 MICLD 50 of virus. By the i.p. route, 250 mg of 11,567 per kg protected mice against 1,000 MICLD 50 , and a dose of 125 mg/kg protected against 100 MICLD 50 . Oral treatment of VEE infection with analogue 11,567 24 h after subcutaneous inoculation of VEE virus resulted in no significant increase in the percentage of survivors. All survivors of these studies were susceptible to rechallenge 21 days after the first inoculation of virus.

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

Cited by 23 publications

References 5 publications

Antiviral effect of interferon on influenza virus infection in mice.

Antiviral effect of interferon on influenza virus infection in mice.

Inhibition of Herpesvirus Deoxyribonucleic Acid and Protein Synthesis by Tilorone Hydrochloride

Evaluation of Various Analogues of Tilorone Hydrochloride Against Venezuelan Equine Encephalitis Virus in Mice

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