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Biomedical subjects

T C Merigan

Publications and source records attributed to T C Merigan.

At least 145 records · Page 8Linked to original sources
PubMed1989

Pharmacokinetics of rifabutin.

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.

AIDS-Related Complex↗
PubMed1989

Antigen-presenting liposomes are effective in treatment of recurrent herpes simplex virus genitalis in guinea pigs.

The therapeutic and immunologic effects of a liposome preparation containing both a macrophage activator, muramyl-tripeptide-phosphatidylethanolamine, and a recombinant antigen, glycoprotein D of herpes simplex virus type 1, have been investigated. This preparation was tested in vitro for the ability to stimulate peripheral blood lymphocytes and in vivo for the control of recurrent herpes genitalis in guinea pigs. Our results show that the liposome-antigen-adjuvant preparation is capable of enhancing antigen-specific lymphocyte stimulation, which may be related to the observed 75% suppression of the frequency and severity of reactivation of recurrent herpes simplex virus type 2 genitalis compared with that of placebo controls.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Synergistic antitumor activity with IFN and monoclonal anti-idiotype for murine B cell lymphoma. Mechanism of action.

Combination therapy with syngeneic anti-idiotype antibody and human hybrid rIFN-alpha A/D synergistically increase survival in C3H/HeN mice challenged with a lethal dose of tumor cells. C3H/HeJ mice, which have previously been described to be LPS hyporesponsive and have a defect in Fc gamma R function, did not respond to anti-idiotype therapy as well as C3H/HeN normal mice. This defect was completely corrected in animals treated simultaneously with IFN. Anti-idiotype mAb that was cleaved into F(ab')2 fragments no longer had any antitumor activity alone and could not be enhanced by IFN therapy. These results suggest that antibody is functioning through Fc gamma R-bearing effector cells that are enhanced by IFN therapy. Synergy between IFN and anti-idiotype mAb was maintained in nude mice lacking classical T cells but was reduced in C3H beige mice lacking classical NK/killer cells. IFN did not increase idiotype expression on the tumor cells but did increase H-2 expression. Although we have previously shown that rIFN-alpha A/D can directly kill 38C13 in vitro, an IFN-resistant subclone derived from 38C13, SIR-1, was equally or more responsive to human rIFN-alpha A/D in vivo and had a synergistic antitumor response to combination IFN and anti-idiotype therapy, indicating that IFN acts primarily through host mediated effects rather than direct effects.

Animals↗
PubMed1988

Comparison of combinations of interferons with tumor specific and nonspecific monoclonal antibodies as therapy for murine B- and T-cell lymphomas.

Two murine models, C3H 38C13 B-cell lymphoma and AKR SL2 T-cell lymphoma were used to determine the efficacy of three different interferon preparations, recombinant human hybrid interferon-alpha A/D, recombinant murine interferon (rMIFN)-gamma, and natural MIFN-alpha/beta (greater than or equal to 85% beta), alone and in combination with tumor specific and nonspecific monoclonal antibody therapy. All three interferon preparations have direct in vitro antigrowth activity for 38C13 and SL2. All three interferons have direct antitumor activity in vivo for 38C13 lymphoma at high doses; however, none of these interferons has independent antitumor activity for SL2 in vivo. These data indicate that there is no relationship between in vitro growth cytostasis/cytolysis and in vivo antitumor response. All three interferon preparations will potentiate both tumor specific and nonspecific monoclonal antibody therapy. Natural MIFN-alpha/beta and recombinant human hybrid interferon-alpha A/D, which should share a common cell surface receptor, had similar antitumor activity in both models. Combining recombinant human hybrid interferon-alpha A/D and rMIFN-gamma therapy was not additive for 38C13 lymphoma and a three-way combination with antiidiotype was not significantly more effective than combination therapy with one interferon type. In general, rMIFN-gamma was more effective in in vivo combination therapy against the s.c. T-cell lymphoma than against the i.p. B-cell lymphoma and was more synergistic with anti-Thy1.1 than with antiidiotype.

Animals↗
PubMed1988

Syngeneic monoclonal anti-idiotype antibodies that bear the internal image of a human cytomegalovirus neutralization epitope.

Two glycoproteins have been identified on human CMV that induce neutralizing antibody; an 86,000-Da glycoprotein and a 130,000-, 92,000-, and 50,000-Da glycoprotein coimmunoprecipitating complex that appears to be the gB homologue of HSV. We have produced syngeneic monoclonal anti-Id antibodies (mAb2) of the IgM isotype to a CMV-neutralizing monoclonal antibody (mAb1) that is known to bind to the 86,000-Da glycoprotein on the virion envelope. These mAb2 bear the internal image of the original viral antigen as shown by their ability to 1) recognize an interspecies idiotype in CMV-positive human antisera, 2) block mAb1 binding to CMV antigen, and 3) block CMV neutralization by mAb1 in vitro. Immunization of mice with both of these affinity chromatography-purified mAb2 stimulated the production of anti-anti-Id monoclonal antibodies (which we termed mAb3), which bound to the mAb2 by ELISA and neutralized CMV infectivity.

Animals↗
PubMed1988

Recombinant interleukin 2 as an adjuvant for vaccine-induced protection. Immunization of guinea pigs with herpes simplex virus subunit vaccines.

We determined that recombinant interleukin 2 (rIL-2) administered in conjunction with herpes simplex virus (HSV) crude extract or recombinant glycoprotein D subunit vaccine enhances the protective effect of either antigen preparation against HSV type 2 genital infection in guinea pigs. Animals that received the vaccine accompanied by rIL-2 had an incidence of infection, assessed by detection of clinical lesions and/or viral shedding, that varied between 0 and 43% significantly lower than the incidence of 63 to 100% in guinea pigs submitted to the same immunization schedule without rIL-2. Animals that escaped acute infection failed to develop recurrent disease. In addition, severity of acute infection was decreased by rIL-2 co-administration as well as by increasing the number of vaccine doses. We also studied the immune response of the guinea pigs to vaccination and the mechanism of protection. Both enzyme-linked immunosorbent assay titers of antibodies to HSV type 2 and specific antigen stimulation of lymphocytes measured by proliferation and interferon production did not significantly differ among the immunization groups. However, specific cellular cytotoxicity was enhanced by rIL-2 co-administration and was positively correlated with protection. This suggests that rIL-2 may become an important adjuvant in active immunization programs using subunit vaccines, particularly against diseases in which cellular cytotoxicity is a major defense mechanism.

Adjuvants, Immunologic↗
PubMed1988

Human cytomegalovirus strain Towne glycoprotein B is processed by proteolytic cleavage.

The gene encoding glycoprotein B of human cytomegalovirus (CMV) strain Towne was cloned, sequenced, and expressed in order to study potential targets for viral neutralization. Secondary structure analysis of the 907 amino acid protein predicted a 24 amino acid N-terminal signal sequence and a potential transmembrane region composed of two domains, 34 and 21 amino acids. The CMV (Towne) gB gene had a 94% nucleotide similarity and a 95% amino acid similarity to the CMV (AD169) gB gene [as described by M.P. Cranage et al. (1986, EMBO J. 5, 3057-3063)]. Transcriptional analysis of the CMV (Towne) gB coding strand revealed that the gB message (3.9 kb), was transcribed from this region as early as 4 hr postinfection, and well in advance of gB protein synthesis. Full-length and truncated versions of the gB gene were expressed in COS cells using expression vectors where transcription was driven by the SV40 early promoter or the CMV major immediate early promoter. Expression was detected by immunofluorescence and ELISA using the virus neutralizing murine monoclonal antibody 15D8 (L. Rasmussen, J. Mullenax, R. Nelson, and T.C. Merigan, 1985, J. Virol. 55, 274-280). This antibody had been shown previously to recognize a 55-kDa CMV virion protein and a related 130-kDa intracellular precursor. Amino acid sequence analysis of the N-terminus of the 55-kDa viral glycoprotein (gp55) showed that gp55 is derived from gB (gp130) by proteolytic cleavage and represents the C-terminal region of gp130. The truncated version of gB expressed in COS and CHO cells was also processed by proteolytic cleavage as demonstrated by Western blotting. Our study localizes the epitope recognized by 15D8 to within a 186 amino acid fragment of the gp55 protein. These results indicate that CMV gB is a target for neutralization and establishes gp55 as a candidate component for use in a subunit vaccine.

Amino Acid Sequence↗
PubMed1988

Characterization of two different human cytomegalovirus glycoproteins which are targets for virus neutralizing antibody.

In previous studies we have identified two viral polypeptides detected by murine monoclonal antibodies which neutralize the infectivity of human cytomegalovirus (CMV) AD169. One is an 86,000-Da polypeptide (p86) and the second is a complex of two major coimmunoprecipitating polypeptides of 130,000 and 55,000 Da (p130/55). In this study we have shown that the two viral polypeptides are immunologically unrelated and have distinct peptide cleavage patterns. We have characterized these polypeptides as glycoproteins and studied their biosynthesis in human embryonic lung cells. The oligosaccharides found on both the p86 and the p130/55 were characterized by endoglycosidase digestion as N-linked high-mannose carbohydrates. Inhibitors of glycosylation were used to further characterize the oligosaccharides. Tunicamycin, which inhibits the biosynthesis of N-linked oligosaccharides on the endoplasmic reticulum, inhibited both the infectivity and biosynthesis of the p86 and p130/55. The underglycosylated forms in tunicamycin-treated cultures could be detected only under conditions of pulse-labeling with L-[35S]methionine. Monensin, which inhibits the modification of glycoproteins from simple to complex forms in the Golgi, reduced viral infectivity at concentrations which had no effect on viral protein synthesis, but did not alter the apparent molecular weight of either the p86 or the p130/55. The oligosaccharides were critical for the in vitro immunologic reactivity of the p86 in immunoblots. However, endoglycosidase F-treated p86 was comparable to the native form in inducing virus neutralizing antibody in guinea pigs. Endoglycosidase F-treated p130/55 retained its ability to bind antibody in Western blots.

Antibodies, Monoclonal↗
PubMed1988

Recombinant HIV structural proteins detect specific cellular immunity in vitro in infected individuals.

Peripheral blood mononuclear cell (PBMC) cultures were established from patients with antibody to human immunodeficiency virus (HIV). Asymptomatically infected patients [5 of 19] had significant lymphocyte transformation responses induced in culture by a purified, recombinant envelope glycoprotein (rgp120) from the virus. A few (4 of 55) subjects with AIDS related complex (ARC) and no subjects with AIDS (0 of 29) had proliferative responses to this protein. These responses correlated directly with circulating levels of helper/inducer lymphocytes (p less than .01) and indirectly with virus antigen in blood (p = .04). Also, these responses occurred significantly less frequently than responses to herpes simplex virus (HSV) or cytomegalovirus (CMV) antigens in seropositive ARC patients (p less than .005). These data indicate that the frequency of immune cellular responses to rgp120 decline in association with disease progression, and become undetectable in frank AIDS. As rgp120-induced proliferation was not observed in cells from 15 seronegative immunocompetent subjects, this response appears immune specific. Immune T-lymphocyte-mediated responses to this HIV envelope glycoprotein may allow the prediction of future clinical events and may be useful in monitoring immune-enhancing therapy in patients with ARC and AIDS.

AIDS-Related Complex↗
PubMed1988

Topical interferon for treating condyloma acuminata in women.

We conducted a randomized, double-blind, placebo-controlled trial of two forms of topical interferon therapy for condyloma acuminata in women. Gel containing 10(6) IU of leukocyte interferon/g, with or without nonoxynol-9, was compared with treatment with gel base alone. Eighty-nine patients applied the gel three times a day for four weeks and were studied for at least 16 w. Side effects were generally mild and limited to the site of application for all three drugs. Although a transient, statistically significant therapeutic effect was noted early in the course of treatment with both interferon gels as compared with placebo, this effect was lost by the end of the follow-up period, possibly because of a generally high response rate in patients receiving placebo. Hence, there was no overall difference in the number of patients with a partial or complete response to any of the agents by the end of therapy or by the end of the study.

Administration, Topical↗
PubMed1987

Assessment of the antigenic response in humans to a recombinant mutant interferon beta.

Cancer patients were given a recombinant mutant interferon beta by alternating IM and IV injections with weekly escalation of doses from 0.1 to 400 million U. Antibodies specific to the interferon of the IgG class were detected in 24 of 30 patients using an indirect enzyme-linked immunosorbent assay. Serum from only 1 of the 30 patients had detectable ability to neutralize interferon biological activity. The in vivo interferon serum level, assayed as antiviral activity immediately after IV injection, was not lower than levels seen in the absence of antibodies. Antibodies did not alter the kinetics of clearance of interferon from the serum after IV administration. Antibody levels progressively decreased when interferon administration was discontinued. In most patients antibody levels decreased during a maintenance period when interferon was being administered only by the IV route. In a subsequent trial interferon was given IV, and antibody developed in only 2 of 36 patients. In contrast, in a trial in which interferon was given IM, 20 of 25 patients developed antibody. No antibody-related clinical sequelae could be detected in any of these patients.

Antibody Formation↗
PubMed1987

Is recombinant interleukin-2 the best way to deliver interferon-gamma in human disease?

Studies in man have suggested that interferon-gamma (IFN-gamma)-producing T cells are important in herpes simplex disease recurrences. These have led to the use of interleukin-2 (IL-2) in a guinea pig model of herpes simplex genital infection. Here, that lymphokine lessens the severity of acute and chronic herpes simplex disease and it also produces an adjuvant action on the protective effect of herpes simplex virus (HSV) subunit vaccines. A variety of potentially useful actions of IL-2 might underly these effects, including increased lymphokine release and enhanced cytotoxic actions of natural killer, lymphokine-activated killer cells, or histocompatibility antigen restricted T cells. IL-2 appears to be involved in the mobilization of IFN-gamma-producing T lymphocytes, which may mediate the enhancement of the previously mentioned immune functions. It seems appropriate to explore these effects of IL-2 in human viral disease. Since the systemic use of IFN-gamma is limited by side effects, IL-2 may be an important mechanism for physiologic delivery of IFN-gamma to local sites.

Adjuvants, Immunologic↗
PubMed1987

Beta interferon produced by keratinocytes in human cutaneous infection with herpes simplex virus.

beta Interferon (IFN) was demonstrated by specific, sequential antibody-neutralization assays of vesicle fluids from patients with recurrent skin lesions due to herpes simplex virus. To determine the origin of this antiviral activity, we cultured keratinocytes from normal facial skin and infected them with three strains of herpes simplex virus. Keratinocyte cultures then developed characteristic cytopathic changes, and antiviral activity was found in culture supernatant media. All such activity from these supernatants was neutralized with specific antiserum to IFN-beta but not with antiserum to IFN-alpha. No IFN-gamma was detectable by radioimmunoassay. Immunoperoxidase staining with antiserum to IFN-beta in five biopsy specimens from culture-proven, recurrent herpes simplex lesions showed positive staining of epidermal keratinocytes but not of dermal or infiltrating cells. Thus, the primary sources of IFN-beta in recurrent herpes lesion vesicles are the virus-infected keratinocytes.

Cells, Cultured↗