Biomedical subjects
T C Merigan
Publications and source records attributed to T C Merigan.
Human leukocyte interferon for the treatment of varicella in children with cancer.
Human leukocyte interferon was evaluated as a treatment for varicella in a randomized double-blind, placebo-controlled study carried out in two phases. A total of 44 children being treated for cancer were enrolled within 72 hours of the appearance of the exanthem. The mean number of days of new lesion formation was 3.8 +/- 1.89 (+/- S.D.) in the interferon recipients and 5.3 +/- 2.56 in the placebo recipients (P less than 0.05). Eighty-one per cent of the interferon recipients had had no new lesions for 24 hours by Day 7, as compared with 56 per cent of the placebo recipients (P less than 0.025). In the second, higher-dose phase of the study 92 per cent of the interferon recipients had had no new lesions for 24 hours by Day 6, as compared with 45 per cent of the placebo recipients (P less than 0.025). Three of 21 placebo recipients died of progressive varicella. Two of the 23 interferon recipients died two to three weeks after the onset of varicella; viral cultures were negative in one of these patients, and the second had recurrent viremia at the end of the treatment period. Among the survivors, treatment with interferon reduced the number of patients who had life-threatening dissemination (none of 21 vs. three of 18; P = 0.053). We conclude that interferon had an antiviral effect against varicella virus in immunocompromised patients.
Clinical and immunologic effects of recombinant leukocyte A interferon in eight patients with advanced cancer.
The clinical and immunologic effects of a biosynthetic human leukocyte interferon, recombinant leukocyte A interferon (IFL-rA), are reported in eight patients with advanced cancer. Single escalating doses from 3 X 10(6) units to 198 X 10(6) units were given by intramuscular injection in a phase I study. Major toxic effects included pyrexia, fatigue, myalgia, and headache. Data on the effects of IFL-rA on lymphocyte subpopulations and peripheral blood mononuclear-cell surface beta 2-microglobulin are presented. Four of eight patients had objective tumor regression, indicating that further investigation of this biologically active material is warranted.
Cytomegalovirus infection in heart transplant recipients: preliminary results of a controlled trial of intravenous gamma globulin.
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Use of intravenous immune globulin in patients receiving bone marrow transplants.
Patients undergoing bone marrow transplantation for acute leukemia or aplastic are a great risk for the development of interstitial pneumonia associated with the cytomegalovirus (CMV). Passive immunization with a CMV immune plasma has been found to be effective for the prevention of interstitial pneumonia after marrow transplantation. Because of the limited availability of high-titered CMV plasma, we studied the kinetics of CMV antibody in bone marrow transplant patients receiving immune globulin intravenous, 5%, in 10% maltose (IGIV). Several lots of IGIV had CMV radioimmunoassay (RIA) antibody titers (1:30,000) comparable to the CMV antibody titers in the CMV immune plasma. A single infusion of 20 cc/kg of IGIV produced a mean peak CMV RIA antibody titer of 1:9,500. This titer fell to 1:1,000 after seven days. These antibody titers were approximately two-to three-fold lower than the CMV RIA antibody titers achieved after a 10 cc/kg dose of the CMV immune plasma. Administration of IGIV at doses lower than 20 cc/kg produced correspondingly lesser increases in the CMV antibody titers of recipients. At all doses, IGIV was well tolerated and caused no significant biochemical abnormalities. Some patients experienced mild elevation of their serum glucose levels and asymptomatic glycosuria. We are presently evaluating the efficacy of IGIV (20 cc/kg given once every week) for the modification of CMV infection and prevention of interstitial pneumonia after bone marrow transplantation in a randomized, controlled study. The effects of IGIV on the incidence and outcome of bacterial, fungal, and other viral infections are also being analyzed.
Specific cell-mediated immunity and infections with herpes viruses in cardiac transplant recipients.
Immune responses and infections with herpes viruses were studied prospectively in 36 cardiac transplant recipients. Specific lymphocyte transformation and interferon production in response to viral antigens, viral culture results, antibody levels, responses to phytohemagglutinin, and T-cell numbers were determined. Responses to phytohemagglutinin and T-cell numbers were depressed for six to 12 weeks. Cytomegalovirus infection occurred in 100 percent of seropositive patients and in 62 percent of seronegative patients. Primary infection was more frequently symptomatic. Heart implantation from a seropositive patient wwas significantly correlated with subsequent infection in seronegative patients. Depression of transformation in response to cytomegalovirus correlated with prolonged shedding. Herpes simplex infection occurred in 95 percent of seropositive patients but decreased after 12 weeks. Asymptomatic shedding was rare, and primary infection did not occur. Return of transformation in response to herpes simplex was associated with decreased infection. Herpes zoster occurred in 22 percent during the first year, and transformation responses to varicella-zoster returned thereafter. Depression of interferon production in response to viruses did not correlate with infection as well as did lymphocyte transformation.
Interferon increases HLA synthesis in melanoma cells: interferon-resistant and -sensitive cell lines.
We report that human leukocyte interferon preparations increase the expression of beta 2-microglobulin by 100-200% on the surface of normal fibroblast and melanoma cell lines sensitive to interferon. This increase in expression can be correlated with an increase in HLA synthesis as measured by incorporation of [35S]methionine in these antigens. This enhanced HLA synthesis, which is 5- to 17-fold, is time dependent and dose related. Synchronized cells in the G0/G1 phase of the cell cycle appear to be more sensitive to this interferon action. Neither an increase in surface expression nor in HLA synthesis is observed in a melanoma cell line resistant to the antiviral and antigrowth effects of interferon. Furthermore, there appears to be a stronger correlation between this increased HLA synthesis and the antiviral function than between it and the antiproliferative action of interferon.
Effects of interferon-alpha on human warts.
Two patients with extensive warts which were stable for two years or more were treated with human interferon-alpha to assess the ability of interferon to affect this benign tumor of viral etiology. Intramuscular administration of 96.6 and 135 million units over 12-15 weeks produced softening and decreased scaling of each patient's warts. Double blind, placebo-controlled intralesional injections resulted in progressive disappearance of interferon treated warts. A dose response relationship was shown in eight warts. The minimum effective dose was 1.2 x 10(6) units injected over 15.5 weeks.
Virus-specific IgG and IgM antibodies in normal and immunocompromised subjects infected with cytomegalovirus.
Levels of IgG and IgM antibodies t human cytomegalovirus (CMV) were measured using a solid-phase radioimmunoassay. Individuals positive by complement-fixation test consistently had detectable IgG titers by radioimmunoassay, but no quantitative relationship was apparent. An elevated IgM titer was considered specific for CMV infection because sera from individuals with other herpesvirus infections did not cross-react. In patients with mononucleosis, elevated titers of IgM antibody to CMV correlated (P less than 0.001) with active infection and were highest during viremia. Titers of IgG antibody to CMV during and after symptomatic infection were similar to those of asymptomatic positive individuals. Increases in CMV-specific IGM were observed in both primary and reactivated infections in cardiac transplant recipients. In a small group of cardiac transplant recipients with recurrent symptomatic disease, IgM titers were low at the time of viruria and did not increase with CMV tissue involvement, a result which suggests that quantitative deficiencies in IgM may be related to the severity of CMV infections.
Infectious Diseases Society of America. Trials of interferon therapy for multiple sclerosis.
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Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination.
In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.
Alpha interferon administration to infants with congenital rubella.
Three infants with congenital rubella syndrome were given human leukocyte (alpha) interferon at doses of 2 x 10(5) to 7 X 10(5) U/kg per day for 10 days. A transient decrease in pharyngeal virus excretion was observed with treatment. No significant side effects were associated with the administration of human leukocyte interferon to these infants.
Inactivation of S-adenosylhomocysteine hydrolase during adenine arabinoside therapy.
To assess for possible inhibition of cellular transmethylation during adenine arabinoside (ara-A) therapy, S-adenosylhomocysteine hydrolase activity was analyzed in 10 patients with chronic hepatitis B virus infection. In six patients receiving ara-A, enzyme activity was suppressed to 0-2% of control erythrocyte enzyme activity. This decrease in enzyme activity was evident within 4 h of starting the drug infusion and continued for 7 d after cessation of therapy. S-adenosylhomocysteine hydrolase activity of peripheral mononuclear cells was also measured in two patients receiving ara-A. Suppression to as low as 3.5% of pretreatment levels was found; however, marked fluctuations with partial return of enzyme activity during therapy was also observed in mononuclear cells. Inhibition of an enzyme involved in transmethylation reactions was observed in patients during ara-A therapy. This could contribute to the side effects and antiviral properties of ara-A.
UCLA conference. Interferon: immunobiology and clinical significance.
Interferons are proteins elaborated by infected cells that protect noninfected cells from viral infection. These proteins produce a temporary "antiviral state" by altering nucleotide metabolism and cytoplasmic enzyme induction. Interferons appear early after viral infection locally and systematically to limit spread of viral infection; they also affect cell differentiation, growth, surface, antigen expression, morphologic findings, and immunoregulation. Several human disorders have diminished interferon production. Newborns have normal interferon alpha but deficient interferon gamma production. Infants with congenital infections may also have defects in interferon production. Immunosuppressed patients receiving transplants (marrow, heart, of kidney) have diminished interferon production, particularly immediately after transplant. Deficiencies of interferon have also been noted in Down's syndrome, cellular immunodeficiencies, uremia, malnutrition, and hematopoietic malignancy. Leukocyte interferon has been of therapeutic value in herpes zoster infections, in patients with cancer, and in patients with hepatitis B infection. Interferon has not been proved to help children with congenital cytomegalovirus or rubella. Interferon can shrink lymphoid tumors, particularly non-Hodgkin's lymphoma.
Cytomegalovirus immune plasma in bone marrow transplant recipients.
The effects of passive immunization on cytomegalovirus infection and interstitial pneumonia in marrow transplants were evaluated in a randomized, controlled trial. Twenty-four patients received cytomegalovirus immune plasma before and after transplantation, and 24 patients were controls. Although the incidence of cytomegalovirus infection was similar in the control and plasma groups, symptomatic infection (12 of 24 versus five of 24, p = 0.07) and interstitial pneumonia (11 of 24 versus five of 24, p = 0.12) occurred less frequently in the group receiving plasma. Cytomegalovirus infection occurred in 11 of 13 recipients of leukocyte transfusions and in 16 of 35 patients not given leukocyte transfusions (p = 0.02). Among patients not given leukocyte transfusions, the incidence of cytomegalovirus infection was similar in the control and plasma groups, but symptomatic infection (eight of 18 versus one of 17, p = 0.03) and interstitial pneumonia (nine of 18 versus one of 17, p = 0.01) were significantly less in the group receiving plasma. These results suggest that passive immunization modifies cytomegalovirus infection in humans and prevents interstitial pneumonia in marrow transplants especially when leukocyte transfusions are not used.
Advances in interferon research - Medical Staff Conference.
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Therapeutic approaches to chronic hepatitis B.
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Systemic antivirals for therapy of herpesvirus diseases.
Several chemicals and interferons have been utilized in the prophylaxis and the treatment of a number of human herpesvirus infections. For example, adenine arabinoside as well as acyclovir and human leukocyte interferon appear active against acute varicella zoster and herpes simplex infections in controlled trials. Some of these agents have transient in vivo actions against CMV and EBV as well. Further open trial work with these 2 viruses appears necessary to improve dose regimens or to employ combination therapy or study new derivatives or agents before controlled trials are warranted. Recombinant DNA methodology is currently providing much greater yields of pure interferon for such uses. Recent successes in eradicating chronic hepatitis B virus infection suggest that it is even possible in the future that persistent herpesviruses in the CNS or lymphoreticular systems may be amenable to long-term therapy. As hyperimmune globulin appears to diminish the severity of CMV disease, it is also possible that human monoclonal antibodies may provide a useful approach for immunoprophylaxis as therapy.