Biomedical subjects
Publications and source records attributed to E R Kern.
Treatment of a cytomegalovirus infection of mice with exogenous murine interferon did not alter final mortality or mean day of death. Pretreatment with two interferon inducers significantly reduced mortality, but treatment initiated after infection was not effective.
Extracts of two species of marine algae, Constantinea simplex and Farlowia mollis, were tested for antiviral activity in tissue culture and in experimental infections of mice. Treatment of confluent mouse embryo fibroblast cell monolayers with either compound before viral inoculation was effective in inhibiting the replication of herpes simplex virus type 1 and type 2, vaccinia virus, and vesicular stomatitis virus, but not encephalomyocarditis virus, Semliki Forest virus, or murine cytomegalovirus. Prophylactic administration of these extracts was effective in reducing final mortality or prolonging the mean day of death of animals inoculated by the intraperitoneal, intracerebral, or intranasal routes with herpes simplex virus type 2. When therapy was initiated after viral inoculation or at a site other than that of viral inoculation, no significant effect on mortality or on mean day of death was observed. Neither preparation was effective in mice inoculated intraperitoneally with encephalomyocarditis virus, Semliki Forest virus, or murine cytomegalovirus or in animals infected intravaginally with herpes simplex virus type 2. The prophylactic but not therapeutic antiviral activity of these preparations seriously limits their potential use in human herpes simplex virus infections.
Phosphonoformate (PF) at a concentration of 5 to 10 mug/ml inhibited the growth of type 1 strains of herpes simplex virus (HSV) in tissue culture, whereas 20 to 30 mug/ml was required for inhibition of type 2 strains and about 50 mug/ml was required for murine cytomegalovirus. In mice inoculated intraperitoneally or intracerebrally with HSV or intraperitoneally with murine cytomegalovirus, treatment with 250 to 400 mg of PF per kg twice daily for 5 days had only minimal effectiveness. When mice were inoculated intravaginally (i.vg.) with HSV type 2 and treated i.vg. with 10% PF beginning 3 h after viral inoculation, treatment was effective in completely inhibiting viral replication in the genital tract. If i.vg. therapy was initiated 24 h after infection, when the mice had a mean virus titer of 10(5) plaque-forming units in vaginal secretions, a significant reduction in the mean virus titer was observed on days 3, 5, and 7 after infection as compared with control animals. In guinea pigs treated i.vg. with 10% PF beginning 6 h after i.vg. inoculation with HSV type 2 there was also complete inhibition of viral replication in the genital tract, and no extenal lesions developed. When therapy was initiated 24 h after infection there was a 4 to 5-log decrease in viral titers on days 3, 5, and 7 of the infection and a slight delay in the development of external lesions.
Interferon was used to treat C57BL/6 female mice inoculated with a continuous line of murine osteogenic sarcoma cells. A short 7-day course of 30,000--60,000 U/day of tpe I interferon either completely inhibited or delayed the appearance of tumors in experimental animals. The therapeutic efficacy of type I interferon was compared with murine serum that contained type II interferon as well as other lymphokine activity. Tumor development was strikingly inhibited in animals treated for 7 days with serum containing only 600 U of type II interferon. Inhibition of tumor development was thus achieved with 100-fold less interferon than that required with type I preparation.
Murine interferon inhibited the growth of a continuous line of osteogenic sarcoma cells in tissue culture. Inhibition of tumor cell growth was documented by decreased clone formation in liquid medium, decreased tumor cell counts in monolayer cultures, suppression of colony formation in semi-solid agar, and decreased uptake of 3H-thymidine by the osteogenic sarcoma cells in culture. The capacity of anti-interferon antibody to block the tumor cell growth inhibitory activity of the interferon preparation suggested that interferon itself is the biologically active component of the interferon preparations. In vivo, a 7-day course of 30,000-60,000 units/day of type I interferon prepared in cell cultures either completely inhibited or delayed the appearance of tumors in experimental animals inoculated with osteogenic sarcoma cells by the sc route. The therapeutic efficacy of a preparation of murine sera containing type II interferon as well as other lymphokine activity was compared with the type I interferon preparation. Animals treated with 600 units of type II interferon were protected against tumor development as effectively as with 60,000 units/day of type I.
An aqueous-ether extract of Brucella abortus, Bru-Pel, enhanced resistance of mice to a transplantable osteogenic sarcoma (OGS). The results presented in this report suggest that Bru-Pel is an effective immunomodulator and that one mechanism through which it enhances host resistance is activation of phagocytic cells of the reticuloendothelial system. Peritoneal macrophages from mice inoculated with Bru-Pel 14 days previously were cytotoxic for OGS cells in vitro, limited the multiplication of vaccinia virus in cell cultures, and demonstrated increased chemiluminescence during phagocytosis. Furthermore, Bru-Pel enhanced host resistance to Listeria monocytogenes, in addition to viral infections and a transplantable tumor. These results support the hypothesis that Bru-Pel shares a number of characteristics with other recognized immunomodulating agents and suggest that further studies are warranted to better define the potential of Bru-Pel for immunotherapeutic regimens in man.
We performed daily examination of 80 patients with recurrent herpes simplex labialis to define the course of the disease and to identify quantitative and objective measurements for use in monitoring the efficacy of antiviral chemotherapy. Pain, lesion size, mean virus titers from lesion swabs (10(5) plaque-forming units [PFU]) and frequency of virus-positive lesions (89 per cent) were maximal during the first 24 hours and decreased thereafter. Lesion punch-biopsy virus titers increased from a mean of less than 10(1) PFU in the prodromal and erythema stages to a mean of 10(4.7) in the vesicle stage. MEasurements potentially useful in monitoring antiviral efficacy include: time to loss of crust, time to complete healing, intensity and duration of lesion pain, area defined by lesion virus titer and duration of lesion virus excretion, and maximum lesion virus titer after the first visit. Early application of topical antiviral therapy should theoretically be able to alter the course of this disease.
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Mice infected with encephalomyocarditis virus, Semliki Forest virus, influenza A2 virus, Herpesvirus hominis type 2, or murine cytomegalovirus developed a state of hyporeactivity to interferon induction. In general, the capacity of infected animals to produce interferon in response to inducers became progressively impaired during the course of infection. The severity and time of onset of hyporeactivity, however, were dependent upon the inducer and the nature of the viral infection. During viral infections associated with generalized hyporesponsiveness, a factor that could inhibit interferon production by murine cells in culture was identified in the serum. This serum hyporeactive factor may have mediated the development of hyporeactivity in vivo. Hyporeactivity of the host's interferon response was associated with progression of viral infection and may be partially responsible for the limited effectiveness of interferon inducers in the modification of viral infections, when administered after onset of symptoms.
Genital infection of mice with Herpesvirus hominis type 2 provides an experimental model for screening potential antiviral chemotherapeutic agents before clinical trials in humans. Intravaginal treatment with phosphonoacetic acid (at a dose of 500 mg/kg in saline or as a 5% cream) initiated 3 hr after inoculation with H. hominis type 2 completely inhibited viral replication in the genital tract and prevented subsequent mortality. Although therapy initiated 24-72 hr after infection significantly reduced titers of virus in vaginal secretions from three- to 100-fold, most mice eventually died of encephalitis. Topical treatment with either adenine arabinoside or adenine arabinoside 5'-monophosphate at a dose of 500 mg/kg in saline or as a 10% cream failed to alter viral replication in the genital tract or to protect the mice from death due to encephalitis. Treatment by the intraperitoneal route with any of these three agents had no effect on local viral replication or final mortality.
Resistance to a representative group of experimental virual infections in mice was significantly enhanced by nonspecific modulation of host defense mechanisms. Corynebacterium acnes, Corynebacterium parvum, and bacille Calmette-Guérin were effective in enhancing host resistance. Animals treated seven to 10 days before inoculation of virus were protected against a lethal infection with Herpesvirus hominis type 2, encephalomyocarditis virus, murine cytomegalovirus, or Semliki Forest virus. The protection of experimental animals against encephalomyocarditis virus infection intitiated by either the intraperitoneal or the respiratory route indicated that C. acnes exerted a systemic, rather than local, effect. A maturation process was required for host defense mechanisms stimulated by C. acnes, as indicated by the failure to enhance resistance in suckling animals. Involvement of cells of the lymphoreticular system was demonstrated by transfer of enhanced resistance against H. hominis type 2 to recipient animals with peritoneal exudate cells harvested from mice pretreated with C. acnes. Finally, these same cells inhibited the progression of herpetic infection in tissue culture. The data suggest that immunomodulation, possibly through activation of macrophages, may offer a method for enhancement of host resistance to viral infections.
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The studies reviewed here are encouraging in that HSV is moderately sensitive to the action of interferon and that infections in experimental animals clearly may be altered by exogenous interferon and interferon inducers. On the other hand it is apparent that the potential of this approach to treatment of herpesvirus infections is limited by the levels of interferon that can be passively administered or induced, the development of hyporeactivity which prevents maintaining high levels of interferon in infected animals after inoculation of inducers, and the failure to alter the course of HSV infection once the virus is established in target organs.
Both murine and human strains of cytomegalovirus were shown to be sensitive to the antiviral effects of adenine arabinoside and phosphonoacetic acid in tissue culture. In mice with lethal cytomegalovirus infections, treatment with adenine arabinoside (either 500 mg/kg intraperitoneally once daily or 250 mg/kg intraperitoneally twice daily for seven days) failed to reduce the mortality rate or to decrease the mean number of days until death. In contrast, treatment with the same dosage regimen of phosphonoacetic acid significantly reduced the mortality rate and decreased the mean number of days until death even when therapy was delayed for 24 hr. Although early treatment with phosphonoacetic acid resulted in a marked reduction in viral titers in the brains and lungs of infected mice, the major reason for efficacy appeared to be complete inhibition of viral replication in the liver. The observation that titers of complement-requiring neutralizing antibody were significantly lower in treated animals than in untreated controls is further evidence of successful therapy. Treatment of a nonlethal cytomegalovirus infection with phosphonoacetic acid beginning 48 hr after viral challenge resulted in elimination of clinical signs of illness and reduction in viral titers in tissues. These results indicate that phosphonoacetic acid is successful in the treatment of murine infections with cytomegalovirus; they suggest that this drug should be considered for potential use in serious cytomegalovirus infections in humans.
The effect of treatment with exogenous interferon was compared with two interferon inducers, polyinosinic acid-polycytidylic acid [poly(I:C)] and [poly(I:C)]-poly-l-lysine complex (P-L-L complex), in two model encephalomyocarditis virus infections of mice. Although both inducers stimulated the production of interferon, the peak serum levels induced by P-L-L complex were five- to eightfold greater than those induced with poly(I:C). When encephalomyocarditis virus was inoculated by either the intraperitoneal or the intranasal route, interferon and both of the inducers protected mice against mortality and prolonged the mean day of death when the compounds were given prior to or immediately after viral challenge. In general, treatment with interferon was not as successful as treatment with poly(I:C) or P-L-L complex. In these infections, P-L-L complex appeared to be the most effective agent in that successful treatment resulted when drug therapy was initiated as late as 48 h after virus inoculation. An examination of the effect of treatment on the pathogenesis of the infection indicated that protection was associated with the prevention of viremia and subsequent seeding of target organs, particularly the central nervous system.
Oral administration of BL-3849A to adult mice resulted in peak serum interferon titers of 4,000 units from 15 to 30 h after administration, with detectable levels persisting until 48 h. After intraperitoneal (i.p.) inoculation, peak serum interferon titers of 1,000 to 3,000 units were noted between 9 and 18 h. Multiple injections of the inducer by either route resulted in a marked decrease in the interferon response with each successive dose. In mice infected intranasally with the Rochester mouse virus strain of encephalomyocarditis virus, oral treatment with BL-3849A reduced mortality when initiated either 18 h before or 1 h after infection. In contrast, administration of drug by the i.p. route decreased mortality only if begun before infection. In mice inoculated i.p. with encephalomyocarditis virus, treatment by both the oral and the i.p. route decreased the mortality whether initiated 18 h before or 1 h after infection. Treatment by the oral, but not the i.p., route reduced mortality of mice inoculated i.p. with Semliki forest virus or Herpesvirus hominis type 2. BL-3849A appeared to be as effective as tilorone hydrochloride, but less effective than polyriboinosinic-polyribocytidylic acid, in the treatment of these viral infections of mice.
Murine cytomegalovirus was inhibited by 0.6 to 1.2 mug of cytosine arabinoside per ml and by 0.3 to 0.6 mug of 5-iodo-2'-deoxyuridine in mouse embryo fibroblast cells. Human cytomegalovirus was inhibited by similar concentrations of the two drugs in WI-38 cells. Intraperitoneal inoculation of suckling mice with 10(4.5) plaque-forming units of murine cytomegalovirus provides a model for disseminated human cytomegalovirus infection in human newborn infants and is characterized by a widespread infection involving the liver, spleen, lung, kidney, and brain with a 70 to 90% mortality in 7 to 9 days. Treatment with 12.5 mg of cytosine arabinoside per kg or 25 mg of 5-iodo-2'-deoxyuridine per kg twice daily for 8 days had no effect on final mortality or the pathogenesis of the infection with the exception of reduced viral titers in the spleen of 5-iodo-2'-deoxyuridine-treated animals. These data indicate that neither cytosine arabinoside nor 5-iodo-2'-deoxyuridine are effective in the treatment of murine cytomegalovirus infections in suckling mice and suggest that they may be of limited value in the treatment of severe cytomegalovirus infections in human neonates.
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