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Biomedical subjects

R A Burger

Publications and source records attributed to R A Burger.

13 recordsLinked to original sources
PubMed1992

Suppression of murine retroviral disease by 2',3'-didehydro-2',3'-dideoxythymidine (D4T).

The thymidine analog, 2',3'-didehydro-2',3'-dideoxythymidine (D4T), and 3'-azido-3'-deoxythymidine (AZT) were evaluated for activity against Friend virus complex (FV) in Mus dunni cells using a focal immunoenzyme assay. The 50% effective doses were, respectively, 1.2 and 0.1 microM for the two compounds; the 50% cytotoxic doses using trypan blue dye exclusion were 25.4 and > 100 microM. Four FV inhibition experiments with D4T were run in F1 hybrid mice containing the Rfv-3r/s genotype. This mouse strain allows the study of treatment effects on development of specific neutralizing antibodies and on splenomegaly, splenic and plasma virus titers, and splenic viral RNA. In the first experiment, D4T was given by oral gavage (p.o.) three times daily (t.i.d.) for 14 days beginning 4 h post-virus inoculation. All dosages used (187.5, 375, 750 mg/kg/day) significantly inhibited all viral parameters. Other experiments used D4T p.o. twice daily, with dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day or four times daily with a dose of 375 mg/kg/day. No significant disease inhibition was seen using the twice daily treatment schedule, but efficacy was apparent using the four times daily treatment. The final experiment repeated the initial study, extending the t.i.d. treatments to 25 days and using dosages of 46.9, 93.8, 187.5 and 375 mg/kg/day. All but the lowest dose reduced each virus parameter. None of the D4T treatment regimens caused death in toxicity controls, although moderate host weight loss or less weight gain was seen, and variable hematocrit decreases occurred, particularly in mice receiving the highest drug dosage. Inhibition of natural killer (NK) cell activity also was seen in these same animals, but in infected mice, FV-induced decrease in NK cell activity was prevented by D4T treatment. Virus-specific neutralizing antibodies developed in all infected, treated animals. These data indicate D4T has potential as a possible candidate for anti-human immunodeficiency virus evaluations in the clinic.

Animals↗
PubMed1992

Elucidation of mode of retroviral-inhibitory effects of imexon through use of immune competent and severe combined immune deficiency (SCID) mice.

Mice infected with various tumor retroviruses have been used as models for evaluating therapeutic substances for the treatment of some cancers, and more recently, for human immunodeficiency virus (HIV) infection, the causative agent of acquired immune deficiency syndrome (AIDS). Consequently, there is a need to determine the ability of biological response modifiers (BRMs) to specifically reduce virus-infected cells, as compared to their non-specific anti-proliferative effects. To address this need, a BRM, imexon, was evaluated in this study using three strains of mice having different Friend virus (FV)-specific immunological capabilities. The first strain, (B10.A x A/WySn)F1, was genetically capable of producing FV-specific neutralization and cytotoxic antibodies, the second, Balb/c, was not, and the third, SCID mice, lacked functional T and B cell immunity. Imexon treatment reduced virally-induced splenomegaly in all 3 strains; however, the concentration of splenic viral infectious centers (IC) were not affected. Since imexon was efficacious in reducing splenomegaly in SCID mice, the mode of action was concluded to not require functional T or B cell immunity. The observation that imexon did not affect splenic IC titers also suggested that imexon did not specifically eliminate virally infected cells, but may have functioned by other mechanisms. This study also demonstrated the use of various mouse strains as a strategy for delineating the modes of action of BRMs against murine retroviral infections.

Animals↗
PubMed1992

Murine retroviral disease-enhancing effects of a pyrimidinone immunomodulator.

(B10.A x A/WySn)F1 mice, infected with the Friend virus (FV) complex, were used as a predictive therapeutic model for AIDS. These infected mice exhibit many of the viral and immunologic manifestations of AIDS. Bropirimine (2-amino-5-bromo-6-phenyl-4[3H]pyrimidinone, ABPP) is an immunomodulating compound which has been shown to inhibit other viral infections. Oral (per os treatment) dosages of ABPP ranging from 50 to 400 mg/kg/day for 3 days resulted in increased numbers of infectious centers in the infected mice and increased splenomegaly and percentage of Ig+ (B cells) in spleens of infected and uninfected mice. Decreased percentages of total Thy-1.2+ (total T) cells and L3T4+ (T-helper) cells were seen in both uninfected and infected mice and a slightly decreased percentage of Ly-2+ (T-suppressor/cytotoxic) cells was observed in spleens of the infected mice. No effect on Ly2+ cells in spleens of uninfected mice was found. Intraperitoneal injection, single or multiple, of 20-200 mg/kg ABPP prior to FV injection resulted in increased spleen weights but had no effect on numbers of infectious centers in the spleens or on FV antibody titers in the plasma. Intraperitoneal treatment of uninfected mice with ABPP resulted in slight or no changes in percentages of Thy-1.2+, L3T4+ and Ly-2+ cells. Mice receiving multiple exposures of ABPP had an increase in percentage of splenic B cells and a depressed response to the T cell mitogen PHA. Treatment with ABPP induced the production of interferon (IFN); however, a state of hyporesponsive IFN production was seen following multiple administrations of ABPP. These data suggest that the immunomodulator ABPP may have an enhancing effect on this retroviral disease.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Effect of triacontanol on numbers and functions of cells involved in inflammatory responses.

A preparation of a triacontanol-containing compound was studied for its effect on cells involved in the inflammatory response. C57BL/6 mice were injected intraperitoneally with various concentrations of this compound and investigated for total body weight, wet weight of thymus tissue, number of thymus cells and splenocytes, interleukin 1 production of spleen monocytes, and response of splenocytes to the T cell mitogen, phytohemagglutinin. Mice treated with the triacontanol preparation exhibited decreased total body weight, 24% reduction in thymus weights, 39% decrease in the number of thymus cells, and 21% depression in total splenocytes. Splenic monocytes of these animals produced a significantly reduced amount of interleukin 1 and splenocytes had a significantly depressed response to phytohemagglutinin. It is concluded that triacontanol has an inhibitory effect on at least some of the cells responsible for inflammation.

Animals↗
PubMed1991

Effect of human, recombinant interleukin 2 on Punta Toro virus infections in C57BL/6 mice.

The effect of human recombinant interleukin-2 (rIL-2) on Punta Toro virus (PTV) infection was investigated in C57BL/6 mice. Immunologic and viral parameters were assessed after mice were treated i.p. with rIL-2 for 5 days. Treatment of mice with 25000 and 12500 units/mouse of rIL-2 resulted in significant inhibition of the disease as indicated by increases in survival of mice as well as decreases in liver and serum virus titers. Serum glutamic oxalic acid and pyruvic acid transaminase levels were also lowered indicating reduced liver damage. Murine IL-2 production returned to normal or above-normal levels in rIL-2 treated mice. Natural killer cell activity was also moderately stimulated by rIL-2 treatment. Significant amounts of interferon were not detected in the sera of treated mice. Weight gain and survival rates were similar for both toxicity and normal controls indicating that rIL-2 treatments had no toxic effect.

Animals↗
PubMed1991

Effect of imexon treatment on Friend virus complex infection using genetically defined mice as a model for HIV-1 infection.

Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one) was moderately effective in the treatment of a retroviral infection in a genetically defined murine model. The animal model consisted of a Friend virus complex (FV) infection in a hybrid mouse strain, (B10.A x A/WySn)F1, which has similarities with acquired immune deficiency syndrome (AIDS). Intraperitoneal imexon initiated 1 or 3 days after FV inoculation and continued through 13 days after inoculation significantly reduced splenomegaly, splenic cell-free virus titers and viral RNA. Viral infectious centers/10(6) splenocytes and FV titers in the plasma were reduced, though not to a statistically significant level. The effect of imexon on survival was not statistically significant which suggested that the antiviral effects were only transiently effective. Phytohemagglutinin-induced blastogenesis and percent of total T cells, T helper cells and T suppressor/cytotoxic cells in the spleens were increased, and the percentage of B cells decreased by imexon treatment of both FV-infected and uninfected mice. The splenic natural killer cell activity and interleukin-1 production were not markedly affected. Virus specific neutralizing antibody developed in both imexon- and placebo-treated FV-infected mice, although titers were lower in the imexon-treated animals.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Progressive murine cytomegalovirus disease after termination of ganciclovir therapy in mice immunosuppressed by cyclophosphamide treatment.

Treatment of mice with cyclophosphamide causes immunosuppression and an enhancement of murine cytomegalovirus infection. In chemotherapy experiments, animals received cyclophosphamide (100 mg/kg by intraperitoneal [ip] injection) every 3-4 days starting 1 day before viral challenge. Once-daily ip treatments with ganciclovir (12.5, 25, and 50 mg/kg) for 5 or 10 days starting 24 h after viral challenge delayed but did not prevent death. In each case the animals died 8-12 days after the last dose of drug was given. Murine cytomegalovirus titers in tissues were suppressed during ganciclovir treatments but rose with discontinuation of therapy. Concanavalin A (T cell blastogenic) responses and, to a lesser extent, lipopolysaccharide (B cell blastogenic) responses were increased in ganciclovir-treated mice compared with the placebo group. Because of the progressive nature of the infection after termination of drug treatment, this model mimics the situation encountered in AIDS patients. The cyclophosphamide model will be useful to study drug treatment regimens.

Animals↗
PubMed1991

Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice.

The nucleotide analog 7-deazaguanosine has not previously been reported to possess biological (antiviral or antitumor) properties in cell culture or in vivo. Up to 10(5) U of interferon per ml was detected in mouse sera 1 to 4 h following oral (200-mg/kg of body weight) and intraperitoneal (50-mg/kg) doses of the compound. 7-Deazaguanosine also caused significant activation of natural killer and phagocytic cells but did not augment T- and B-cell blastogenesis. Intraperitoneal treatments of 50, 100, and 200 mg/kg/day administered 24 and 18 h before virus inoculation were highly protective in mice inoculated with lethal doses of Semliki Forest or San Angelo viruses. Less but still significant survivor increases were evident in treated mice infected with banzi or encephalomyocarditis viruses. In most cases, the degree of antiviral activity was similar to that exhibited by the biological response modifier 7-thia-8-oxoguanosine. 7-Thia-8-oxoguanosine was more potent than 7-deazaguanosine against encephalomyocarditis virus in mice, however. Oral efficacy was achieved with 7-deazaguanosine treatments of greater than or equal to 100 mg/kg against all virus infections, whereas 7-thia-8-oxoguanosine is reported to be devoid of oral activity in rodents. Thus, 7-deazaguanosine represents the first reported orally active nucleoside biological response modifier exhibiting broad-spectrum antiviral activity against particular types of RNA viruses.

Adjuvants, Immunologic↗
PubMed1990

CD4+ helper T cell depression in autism.

CD4+ (helper) T cells are a heterogenous population of lymphocytes including at least two distinct subpopulations. To investigate the possibility that immune abnormalities in some subjects with autism may involve abnormal distributions of CD4+ and/or CD8+ cells, (suppressor) T cells, peripheral blood lymphocytes of 25 autistic subjects were characterized with monoclonal antibodies and flow cytometry. The autistic subjects had a significantly lower percentage and number of CD4+ cells, a lower number of T cells (CD2+ cells) and B cells (CD20+ cells), and a lower percentage and number of total lymphocytes than siblings and normal subjects. The level of blood values for female subjects appeared lower than those for males as compared to normal subjects of the same sex. These results suggest that a decrease in CD4+ cells is associated with autism.

Adolescent↗
PubMed1990

Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism.

CD4+ cells are a heterogenous population of lymphocytes including at least two distinct subpopulations: CD45RA+ cells, inducers of suppressor T cells and CDw29+ cells, inducers of helper function for antibody production. To investigate the possibility that immune abnormalities in autism may involve abnormal distribution of these helper subpopulations, monoclonal antibodies were used in flow cytometric analysis to characterize peripheral blood lymphocytes of 36 subjects with autism. The autistic subjects as compared to a group of 35 healthy age-matched subjects had a significantly reduced number of lymphocytes, a decreased number of CD2+ T cells and reduced numbers of CD4+ and CD4+CD45RA+ lymphocytes. The numbers of B (CD20+) cells, suppressor T (CD8+) cells, inducers of helper function (CD4+CDw29+) and natural killer (CD56+) cells were not altered in the autistic subjects. Our results suggest that an alteration in the suppressor-inducer T-cell subset is associated with autism.

Adolescent↗
PubMed1990

Effects of zidovudine on Friend virus complex infection in Rfv-3r/s genotype-containing mice used as a model for HIV infection.

Infection with the Friend virus complex (FV) in (B10.A x A/WySn)F1 mice containing the Rfv-3r/s genotype results in several disease manifestations analogous to those seen in patients with acquired immune deficiency syndrome, predominantly high levels of specific antibody and low levels of infectious virus with eventual retroviral disease-induced death of the host. Other immunologic manifestations of FV infection in this murine host included inhibition of percent total T, T-helper, and T-suppressor/cytotoxic cells of total splenic lymphocytes and phytohemagglutinin-induced response of spleen cells. Interleukin-1 production was not affected but the numbers of splenic B cells were increased by the infection. 3'-Azido-3'-deoxythymidine (zidovudine, AZT) administered (a) intraperitoneally three times daily for 24 days beginning 4 h after virus inoculation in doses of 60 to 480 mg/kg/day, (b) in drinking water for 22 days beginning 4 h after virus inoculation in doses of 22 to 216 mg/kg/day, or (c) in drinking water for 29 days beginning 6 days after virus inoculation in doses of 22 to 216 mg/kg/day markedly inhibited FV-induced disease. In the mice receiving early-initiated AZT therapy, FV-induced splenomegaly and hematocrit values were inhibited and infectious centers in the spleen and FV titers in the plasma were reduced to below detectable levels at the higher AZT dosage levels. The percent of total T cells in splenic lymphocytes was increased in the infected, AZT-treated mice. In the intraperitoneal experiment, FV disease-induced death was prevented by treatment with all doses of AZT. Neutralizing antibody to FV was significantly reduced in all AZT-treated groups. Toxicologic manifestations of these AZT treatments included splenic enlargement and reduced hematocrit, although all treated, uninfected mice survived the treatments, gained weight, and displayed no significant effects on enumeration of T and B cells.

Animals↗
PubMed1987

Urology.

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Humans↗