Human interferon: Pharmacokinetics and antiviral chemotherapy

Molec. AspectsMed. Vol. 5, pp. 197 to 207, 1982

0098-2997/82/030197-11505.50/0 Copyright © 1982 Pergamon Press Ltd.

Printed in Great Britain. All rights reserved.

H U M A N INTERFERON: PHARMACOKINETICS A N D ANTIVIRAL CHEMOTHERAPY George W. Jordan Section of Infectious and Immunologic Diseases, and Microbiology

Laboratories, School of Medicine, University of California, Davis, California 95616, U. S.A.

Contents i. 2. 3. 4.

Rationale for Antiviral Therapy with Interferon Pharmacokinetics Unwanted Effects Exogenous Interferon in Human Viral Diseases 4.1. Herpes Zoster in Immunosuppressed Patients 4.2. Hepatitis B Virus Infection 4.3. Cytomegalovirus Infection 4.4. Herpes Simplex Virus 4. 5 . Interferon in Local Virus Infections 5. Summary and Conclusions References

197 198 199 2OO 2OO 201 2O2 2O2 203 2O4 2O4

1. Rationale for Antiviral Therapy with Interferon Attempts to exploit the phenomenon of viral interference for clinical benefit have, in part, motivated research in several areas including attenuated virus strains, defective-interfering particles and the interferon system.

Interferon was

recognized early as a theoretically ideal therapeutic agent because of its activity against a large number of serologically unrelated viruses and its lack of toxicity in experimental animals.

Further support for the clinical potential of

interferon came from the discovery of circulating interferon in human systemic viral infections and its association with viral interference in man (Wheelock and Sibley, 1965; Petralli et al., 1965a,b).

The presence of interferon in the vesi-

cles of patients with Herpes zoster and the correlation of the appearance of vesicle fluid interferon and the cessation of virus dissemination in immunosuppresseal patients provided further evidence of a normal role of interferon as an antiviral defense in man (Armstrong et al. , 1970).

Strong evidence for a physiol-

ogic role for interferon was provided by the results of experiments in mice using

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anti-interferon serum.

By ablating the interferon system with anti-interferon

globulins, Gresser et ai.(1976 a,b) were able to show enhanced spread of several different viruses and higher mortality in infected animals.

This background

coupled with the availability of sufficient quantities of human leukocyte interferon led to the early clinical trials in human viral infections.

Antiviral

effects of exogenous interferon have been clearly shown in some of these studies as recently summarized by Galasso and Dunnick (1977), Dunniek and Galasso (1979) and Hirsch and Swartz (1980).

Concomitant with these events, other dimensions of the interferon system became known.

Foremost among these developments, from a therapeutic point of view, were

the discovery and characterization of different molecular species of human interferon and the recognition of the "non-antiviral" effects of the interferons, especially the immunoregulatory effects (Stewart, 1979; Baron et al., 1979). Interferon preparations have been shown to inhibit multiplication of normal and malignant cells in vitro and are effective inhibitors of animal tumors of both viral and non-viral origin.

Although the interferons have a variety of significant

effects on lymphocyte functions, the stimulation of natural killer cells and anti-body-dependent cell-mediated cytotoxicity may eventually be shown to depend physiologically on a hormone-like action of interferon in vivo.

Thus, the results

of clinical trials of interferon in viral and neoplastic diseases of humans may be determined not only by the direct effects of interferon on somatic target cells, but also by the regulatory effects of interferon on functioning immune cells.

2. Pharmacokinetics At this time, almost all of the interferon administered to humans has been prepared from human blood bank leukocytes (Cantell and Hirvonen, 1977, 1978). When given intramuscularly (i.m.) or by constant intravenous infusion, interferon levels about I00 units/ml can be maintained in the circulation for prolonged periods (Jordan et al., 1974; ~ o d i Maximum blood levels occur 4-8 h o ~

et al., 1975; Cantell and Pyhala, 1976). after i.m. injection in humans.

Repeated i.m.

injections at 12-24 hour intervals provide continuous levels of circulating interferon without evidence for accumulation.

The appesuzance of human leukocyte inter-

feron in the circulation of rabbits was similar to that of humans following i.m. or subcutaneous injection (Emodi et al., 1975b).

Because interferon is a protein,

uptake from the gut following oral administration would not be expected in adults, however, in weanling mice sufficient amounts can be absorbed to protect against a virus challenge (Sohofer et al., 1972).

Interferon applied to the nasal mueosa

of humans and chimpanzees is rapidly cleared by mucoeiliary action, however, after

Humanlntederon: Pharmacokineticsand AntiviralChemotherapy

199

application of high doses, residual interferon could be detected after one hour (Greenberg et al., 1977).

Although interferon can be detected readily in the circulation, penetration has been poor into other compartments such as the cerebrospinal fluid, eye, and brain (Merigan, 1977).

When injected rapidly into animals, circulating interferon

disappears with a tl/2 of less than 5 minutes.

This probably represents both

distribution as well as clearance because after steady state conditions are reached in man by constant infusion, a tl/2 of 2.8 hours could be determined (Jordan et al., 1974; Merigan, 1977).

Although interferon is inactivated by

dialyzable components of urine (Cesarie and Tilles, 1973), neither urinary, hepatic, or gastrointestinal elimination are responsible for clearance from the circulation.

The mechanisms resp6nsible for the clearance of interferon are not

known, but binding to tissue is a likely explanation.

There has been less clinical experience with human fibroblast interferon, however, entry into the circulation following i.m. injection has not been demonstrated (Edy et al., 1978).

3. Unwanted Effects Administration of early preparations of human leukocyte interferon was associated with fever beginning 2-6 hours after injection (Jordan et al., 1974; Strander et al., 1973a).

This response varied in intensity from patient to patient and

was usually not distressing. chills have occurred.

In some patients, nausea, vomiting malaise, and

In general, the more severe reactions were associated with

higher doses of the earlier, less pure, preparations (Merigan, 1977).

Hypotens-

ion occurred in one patient after the rapid injection of 4. 5 x 106 units intravenously (Strander et al., 1973b), however, hypotension has not been a problem when I0 to lO0-fold greater amounts are given by slow intravenous infusion or by intramuscular or subcutaneous injections (Jordan et al., 1974; Strander et al., 1973).

When human interferon preparations of different grades of purity were

tested for pyrogenicity in rabbits, pyrexia was not correlated with the purity of the preparation but rather with the amount of interferon activity present (Stewart, 1979).

Thus, it is possible that the interferon molecule itself is

pyrogenic or that it induces endogenous pyrogen when injected.

Experiance with

more highly purified material will be needed to resolve this question.

Suppression of the bone marrow has been observed.

Decreases in reticulocytes,

platelets, and granulocytes begin at 3-5 days after initiation of treatment

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(Merigan, 1977).

These effects are rapidly reversible upon cessation of treat-

ment and have not led to complications.

For unknown reasons, these effects have

been seen in patients with chronic hepatitis at lower interferon doses than in patients with varicella-zoster infection (Greenberg et al., 1976; Merigan et al., 1978).

In addition to the systemic effects, injection site tenderness and

erythema may occur with human leukocyte interferon.

Mild elevations of serum

transaminases have also been reported.

There has been less clinical experience with human fibroblast interferon~ however, fever, suppression of myeloid stem cells, and delayed type hypersensitivity reactions at the injection site have been seen with the less purified preparations (De Somer et al., 1977; Scott et al.~ 1977; Carter et al., 1979).

4. Exogenous Interferon in Human Viral Diseases ~.i.

Herpes Zoster in Immunosuppressed Patients

Herpes zoster is a common infection in immunosuppressed patients with various malignancies, especially lymphoma patients following irradiation and chemotherapy.

Although rarely fatal, disseminated zoster is often a serious and prolonged

complication in these patients.

Previous studies had shown that the appearance

of interferon in vesicle fluid correlated with recovery and that this response was delayed in patients with continued dissemination beyond the primary dermatome or in those who had prolonged disease due to the immunosuppressive effect of cytosine arabinoside (Armstrong et al., 1970; Stevens et al., 1973).

Varicella-

zoster virus is sensitive to human interferon in tissue culture, and, little, or no interferon has been found in the blood of patients with varicella-zoster infections.

With this background, a randomized, double-blind, placebo controlled

study of human interferon was conducted in 90 cancer patients with localized zoster (Herigan et al., 1978).

The doses employed ranged from 4.2 x 106 units/

kg/day to 5.1 x 105 units/kg/day resulting in peak serum interferon levels of from 52 to ~5~ units/ml.

The higher doses of interferon resulted in a limitation

of cutaneous spread within the primary dermatome with no distant dissemination occurring in patients receiving the highest doses. post-herpetic neuralgia were significantly reduced.

New vesicle formation and Most importantly, visceral

complications were less frequent in patients receiving interferon than in placebo treated controls.

In a similar, placebo controlled study, Emodi et al., (197~a,

1977) found less acute pain, a decrease in virus spread and an acceleration of hes/ing in patients treated with human leukocyte interferon.

In addition, they

demonstrated a decreased time of virus persistence in the vesicle fluid of

Human Interferon: Pharmacokinetics and Antiviral Chemotherapy treated patients.

201

Although fewer patients were studied, less visceral complicat-

ion occurred in children with varicella and an underlying malignancy when treated with human leukocyte interferon than in controls (Arvin et al., 1978).

The

unwanted effects of the human leukocyte interferon preparations used in these studies included fever, local reaction, and transient granulocytopenia, however, none of these effects were severe enough to limit therapy.

Taken together, these

early trials have clearly demonstrated the biological activity, in humans, of the semi-crude materials employed.

4.2.

Hepatitis B Virus Infection

Approximately 10% of persons infected with hepatitis B virus (HBV) become carriers and a smaller fraction will have chronic active hepatitis in association with the HBV carrier state.

The lack of an interferon response in HBV infection and the

persistence of virus markers in chronic infection provides an opportunity to determine the effects of interferon administration.

Human leukocyte interferon

produced a reproducible decline in circulating levels of HBV core antigen (HBcAg), DNA polymerase activity, and Dane particle associated DNA.

When treatment was

prolonged, decreases in HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) were observed as well (Greenberg et al., 1976).

Subsequently, several other open

studies with small numbers of patients have described decreases in virus markers following interTeron administration (Scott et al., 1977; Kingham et al., 1977; Weimar et al., 1979, 1980; Merigan et al., 1980; Weimar and Schellekens, 1980). At this time it appears that Dane particle associated DNA pelymerase is the HBV marker most sensitive to the effects of interferon.

Higher doses and prolonged

administration have been associated with greater frequency and duration of virus marker suppression, but effects on the clinical course or liver pathology of these patients have not been clearly demonstrated.

In the few patients treated with

human fibroblast interferon, decreases in serum transaminase (Weimar et al., 1979) and virus markers (Desmyter et al., 1976) have also been reported, although it is clear that fibroblast and leukocyte interferon preparations have important pharmacologic and biological differences that need further definition (Weimar et al., 1979).

In the case report by Dolen et al., (1979, the number of circula-

ting T lymphocytes increased to normal and a rosette-inhibitory factor disappeared in association with the loss of HBV markers following treatment with human fibroblast interferon suggesting that the effects of interferon treatment may, in part, be mediated by the immune system.

Only a few patients with fulminant hepatitis

have been treated with human interferon at this time and it is not possible to conclude that beneficial effects were obtained (Dumnick and Galasso, 1979).

202 4. 3 .

George W. Jordan Cytome~alovirus Infection

Although cytomegalovirus causes a common, asymptomatic infection in normal individuals, severe consequences may occur in congenitally acquired infection or in immunosuppressed patients such as transplant and bone marrow recipients. Human cytomegalovirus (CMV) is sensitive to the effects of interferon in vitro. Lymphocytes from immunosuppressed adults (Rytel and Balay, 1973) and children with symptomatic cytomegalic inclusion disease (Emodi and Just, 1974) produce less interferon than lymphocytes from either normal adults or from asymptomatic children excreting CMV, although the significance of these findings to the pathogenesis of the disease is unknown.

Human leukocyte interferon has been

given to a few infants with symptomatic CMV infection in uncontrolled studies. Viruria disappeared in some, but not all of the cases, however, beneficial effects on the disease process could not be determined.

Furthermore, the interferon

treated infants had a decrease in their rate of weight gain and some showed an increase in serum transaminases.

Hence, it appears that toxicity will limit the

use of higher doses in these infants (Arvin et al., 1976).

Human leukocyte interferon has been used to treat 8 patients with CMV pneumonia following bone marrow transplantation (Meyers et al., 1980).

Six of the 8

patients received from 3.2 x 103 to 6.4 x 103 units/kg/day and achieved peak serum levels of from 206 to 1.244 units. without evidence of benefit.

All patients died of CMV pneumonia

In a controlled trial of prophylactic human leuko-

cyte interferon administration (3 x 106 units twice weekly) in renal transplant patients, CMV viruria was delayed and CMV viremia was less frequent in the interferon treated patients (Cheesman et al., 1979).

The protective effect of inter-

feron against CMV viremia was most striking in patients not also receiving antithymocyte globulin, consistent with a role for immunologically mediated effects of interferon in addition to a direct antiviral action.

A similar trial of

human fibroblast interferon in renal transplant patients was difficult to interpret because circulating interferon activity was not obtained after intramuscular injection of fibroblast interferon and routine virus isolation was not attempted, however, no adverse effects on liver function, platelet or leukocyte counts, or acute rejection episodes were encountered (Weimar et al., 1978).

4.4.

Herpes Simplex Virus

The predictable reactivation of Herpes simplex virus (HSV) following surgery on the trigeminal-nerve root provided an opportunity to determine the effects of human leukocyte interferon given prophylactically.

In a placebo controlled study,

Human Interferon: Pharmacokinetics and Antiviral Chemotherapy

203

7 x i0 ~ units of interferon per day for 5 days beginning the day before operation significantly reduced the frequency of HSV reactivation as measured by positive throat culture or the presence of lesions (Pazin et al., 1979).

Also of interest

in this study was the use of dexamethasone, i0 mg being given before surgery and approximately 90 mg being given during the next 90 hours.

Interferon blunted the

steroid-induced increase in polymorphonuclear leukocytes and intensified the steroid-induced decline in lymphocytes.

Even though these patients did not have

underlying malignant diseases, the interferon-induced protection against HSV reactivation could be demonstrated in this setting of transient immunosuppression at least suggesting that the steroid-sensitive functions of the immune system were not involved in mediating these antiviral effects of interferon,

In contrast to these findings, interferon given prophylactically to renal transplant patients was not effective in preventing oral HSV excretion (Cheesman et al. 1979).

In addition, active HSV lesions appeared in a patient receiving from

14 x 106 to 28 x 106 units of interferon per day for metastatic carcinoma of the breast.

This patient had impaired cellular immunity as evidenced by absent

delayed hypersensitivity skin reactions and impaired phytohemagglutinin stimulated lymphocyte transformation (Khan and Hill, 1980).

4.5.

Interferon in Local Virus Infections

Historically, the first evidence that interferon was biologically active in humans came from the protection conferred by the injection of monkey kidney interferon one day prior to vaccinia virus challenge at the same site (Scientific Committee on Interferon, 1962).

More recently, human fibroblast interferon injected intra-

dermally, has been associated with a decrease in local vaccinia virus takes (Scott et al., 1978).

Because of the large number of antigenically distinct viral pathogens, human respiratory tract infections were logically considered appropriate targets for clinical applications of interferon.

In a placebo controlled study (Merigan et

al., 1973), human leukocyte interferon was effective in preventing symptoms and virus shedding in volunteers challenged with Bhinovirus type 4.

The interferon

treatment was begun one day prior to virus challenge and was continued for 3 days afterward; a total of 1.4 x 107 units in 39 applications of nasal spray were given. These large doses and repeated applications were probably necessary due to the rapid mucociliary clearance of locally applied interferon.

Other reports of the

use of interferon in infections of the respiratory tract are difficult to interpret due to the study design, to the lower doses of interferon employed, or to

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George W. Jordan

the lack of repeated applications to offset rapid mucociliary clearance (Dunnick and Calasso, 1979; Soloviev, 1969; Arnaoudova, 1976).

Several studies of leukocyte and fibroblast interferon treatment of HSV keratitis have been performed (Jones et al., 1976; Guerra et al., 1977; Sundmacher et al., 1978).

Taken together, it appears that interferon treatment is non-toxic in the

eye and may be beneficial in preventing recurrences and accelerating healing. Best results were obtained when interferon was used prophylactically or in early disease, and in conjunction with debridement.

5. Summary and Conclusions The results of human interferon trials, thus far, have been in accord with expectations based on animal studies.

The effects achieved in humans have been

dose-dependent, with best results obtained with early or prophylactic treatment. Activity in humans against a variety of antigenically distinct viruses (vaecinia, V-Z, HSV, CMV, HBV, rhinovirus) has been demonstrated.

Unwanted effects have

been minimal and have not seriously limited the trials that have been conducted.

The interferon preparations that have been used in these trials have been crude, probably about one percent interferon. are necessary.

Obviously, preparations of greater purity

Purity is essential in order to determine which effects, wanted

as well as unwanted, are due to the interferon molecule itself and not to other biologically active proteins which may also be present.

The mechanisms respons-

ible for the antiviral effects of interferon administration in vivo are of both theoretical and practical interest.

The results of clinical studies performed

to date suggest that in certain patients the antiviral effects of interferon may be mediated, in part, by its immunoregulatory properties.

On the other hand,

clinical studies of locally applied interferon have given results that must be regarded as due to the direct antiviral action of interferon on somatic target cells.

In future clinical trials in systemic diseases, it will be important to

observe host defense mechanisms of interferon action in vivo as well as for the presence of potentially detrimental side effects.

References Armstrong, R.W., Gurwith, M.J., Waddel, D., and Merigan, T.C., (1970). Cutaneous interferon production in patients with Hodgkin's Disease and other cancers infected with varicella or vacciniao New En61. J. Ned. 289.1182-1187. Arnaoudova, V. (1976). Treatment and prevention of acute respiratory virus infections in children with leukocytic interferon. (Abstract in English). Virolosie (Bucuresti) 27:83-88.

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Arvin, A.M., Fledman, S. and Merigan, T.C. (1978)o Human leukocyte interferon in the treatment of varicella in children with cancer; a preliminary controlled trial. Antimicrob. Asents Chemother. 13:605-607 Arvin, A.M., Yeager, A.S. and Merigan, T.C. (1976). Effect of leukocyte interferon on urinary excretion of cytomeglaovirus by infants. J. Infect. Dis. l>> (Suppl.):A2OS-A210. Baron, S., Blalock, J.Eo, Dianzani, R., Fleischmann, R., Georgiades, J., Johnson, H. and Stanton, J. (1979). Interferon: Antivirs-1 r immunoregulatory and anticellular activities. Ed. Proffit, pp.l-16. Cantell, K. and Hirvonen, S. (1977). Preparation of human leukocyte interferon for clinical use. Tex. Rep. Biol. Med. 35:138-144. Cantell, K. and Hirvonen, ~o (1978). Large-scale production of human leukocyte interferon containing lO U units per ml. J. ~en. Virol. 39:541-543. Cantell, K. and Pyhala, L. (1976). Pharmacokinetics of human leukocyte interferon. J. Infect. Dis. l>>:A6-A12. Carter, W.A., Dolen, J.G., Leong, S.S., Horoszewicz, J.S., Vladutiu, A.O., Leibowitz, A.I. and Nolan, J.P. (1979). Purified human fibroblast interferon in vivo: Skin reactions and effect of bone marrow precursor cells. Cancer Lett. 7: 243-249. Cesario, T. and Tilles, J.G. (1973). Inactivation of human interferon by urine. J. Infect. Dis. 127(3):311-314 Cheeseman, S.H., Rubin, R.H., Stewart, J.A., Tolkoff-Rubin, N.E., Cosimi, A.B., Cantell, K., Gilbert, J., Winkle, S., Herrin, J.T., Black, P.H., Russell, P.S. and Hirsch, M.S. (1979). Controlled clinical trial of prophylactic humanleukocyte interferon in renal transplantation. New En~l. J. Med. ~00(24): 1345-1349. Desmyter, J., Groote, J., Desmet, V.J., Billiau, A., Ray, M.B., Bradburne, A.F., Edy, V.G. and De Somer, P. (1976). Administration of human fibroblast interferon in chronic hepatitis-B infection. Lancet ii:645-647. De Somer, P., Edy, V.G. and Billiau, A. (1977). Interferon-induced skin reactivity in man. Lancet ii:47-48. Dolen, J.G., Carter, W.A., Horoszewicz, J.S., Vladutiu, A.0o, Leibowitz, A.I. and Nolan, J.P. (1979). Fibroblast interferon treatment of a patient with chronic active hepatitis. Increased number of circulating T lymphocytes and elimination of Rosette-Inhibitory Factor. Am. J. Med. 67:127-131. Dunnick, J.K. and Galasso, G.J. (1979). Clinical trials with exogenous interferon: Summary of a meeting. J. Infect. Dis. 1~9(1):109-123 Edy, V.G., Billiau, A. and De Somer, P. (1978). Non-appearance of injected fibroblast interferon in circulation. Lancet i:451-452. EmSdi, G. and Just, M. (1974). Impaired interferon response of children with congenital cytomegalovirus disease° Acta. paediat, scand. 6_/:183-187. E~Sdi, G. and Rufli, T. (1977). Antiviral action of interferon in man: Use of interferon in varicella-zoster infections in man. Tex Rep. Biol. Med. 35:

5A1-515. Emodi, G., Rufli, T., Just, M. and Hernandez, R. (1975a). Human interferon therapy for Herpes zoster in adults. Scand. J. Infect. Dis. ~:i-5. Em~di, G., Just, M., Hernandez, R. and Hilt, H.R. (1975b). Circulating interferon in man after administration of exogenous human leukocyte intel~feron. J. nat. Cancer Inst. ~__~:i045-i049 Galasso, G.J. and D--~nick] ~.K. (1977). Interferon, an antivira_l drug for use in man. Tex. Rep. Biol. Med. 35:478-485. Greenberg, H.B., Pollard, R.B., Lutwick, L.I., Gregory, P.B., Robinson, W.So and Merigan, T.C. (1976). Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. New ~61. J. Med. 295(i0) :517-522. Creenberg, S.B. Harmon, M.W. and Johnson, P.E. (1977). Activity of exogenous interferon in the human nasal mucosa. Tex. Rep. Biol. Med. 35:491-496.

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Cresset, Io, Tovey, M.G., Bandu, M.T., Maury, C. and Brouty-Boye, D. (1976a). Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. Io Rapid evolution of encephalomyocarditis virus infection. J. exp. Med. 144:1305-1315. Gresser, I., Tovey, M.G., Maury, C. and Bandu, M.T. (1976b). Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. II. Studies with Herpes simplex, moloney sarcoma, vesicular stomatitis, Newcastle disease, and influenza viruses. J. exp. Med. 144:1316-1323. Guerra, R., Galin, M.A. and Frezzotti, R. (1977). Use of interferon in eye infections of man. Tex. Rep. Biol. Med. 35:497-500. Hirsch, M.S. and Swartz, M.N. (1980). Drug therapy: Antiviral agents (second of two parts). New En61. J. Med. ~02(17):949-943. Jones, B.R., Coster, D.J., Falcon, M.G. and Cantell, K. (1976). Topical therapy of ulcerative herpetic keratitis with human interferon. Lancet ii:128o Jordan, G.W., Fried, R.P. and Merigan, T.C. (1974). Administration of human leukocyte interferon in Herpes zoster. I. Safety, circulating antiviral activity, and host responses to infection. J. Infect. Dis. 1~0(1):56-62. Khan, A. and Hill, N.O. (1980). Interferon treatment in immunosuppressed patients. Ann. Aller~, 44:289. Kingham, J.G.C., Ganguly, N.K., Shaari, Z.D., Holgate, S T., McGuire, M.J., Mendelson, R., Cartwright, T., Scott, G.M., Richards, B.M. and Wright, R. (1977). Treatment of Hbs-Ag-positive chronic active hepatitis with human fibroblast interferon. Gut. (B) 18:A952. Merigan, T.C. (1977). Pham~macokinetics and side effects of interferon in man. Tex. Rep. Biol. Med. 35:541-547. Merigan, T.C., Hall, T.S., Reed, S.E. and Tyrrell, D.A.J. (1973). Inhibition of respiratory virus infection by locally applied interferon. Lancet i:563-567. Merigan, T.C., Rand, K.H., Pollard, R.B., Abdallah, P.S., Jordan, G.W. and Fried, R.P. (1978). Human leukocyte interferon for the treatment of Herpes zoster in patients with cancer. New Engl. Jo Med. 298(18):981-988. Merigan, T.C., Robinson, W.S. and Gregory, P.B. (1980). Interferon in chronic hepatitis B infection. Lancet i:422-423. Meyers, J.D., McGuffin, R.W., Neiman, P.E., Singer, J.W. and Thomas, E.D. (1980). Toxicity and efficacy of human leukocyte interferon for treatment of cytomegalovirus pneumonia after marrow transplantation. Jo Infect. Dis. 141(~):

555-562. Pazin, G.J., Armstrong, J.A., Lam, M.T., Tart, C.C., Jannetta, P.J. and Ho, M. (1979). Prevention of reactivated Herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. New En~l. J. Med. 301(5):225-230. Petralli, J.K., Merigan, T.C. and Wilbur, J.R. (1965a). Circulating interferon after measles vaccination. New En~l. J. Med. 273(4):198-202. Petralli, J.K., Merigan, T.C. and Wilbur, J.R. ( 1 9 ~ . Action of endogenous interferon against vaccinia infection in children. Lancet ii:401-405. Rytel, M.W. and Balay, J. (1973). Impaired production of interferon in lymphocytes from immunosuppressed patients. J. Infect. Dis. 127(4):445-449. Schofer, T.W., Lieberman, M., Cohen, M., et al. (1972). Interferon administered orally: Protection of neonatal mice from lethal virus challenge. Science 176: 1326-1327. Scientific Committee on Interferon (1962). Effect of interferon on vaccination in volunteers. Lancet i:873-875. Scott~ COM., Butler, J.K., Cartwright, T., Richards, B.M., Kingham, J.G. and Wright, R. (1977). Interferon skin reactivity and pyrexial reactions. Lancet ii:402-403. Scott, G.M., Cartwright, T., LeDu, G. and Dicker, D. (1978). Effect of human fibroblast interferon on vaccination in volunteers. J. biol. Stand. 6:73-76. Soloviev, V.D. (1969). The results of controlled observations on the -prophylaxis of influenza with interferon. Bull. W.H.O. 41:683-688.

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207

Stevens, D.A., Jordan, G.W., Waddell, T.Fo et al. (1973). Adverse effect of cytosine arabinoside in disseminated zoster in a controlled trial. New En~i. J. Med. 289:873-874. Stewart, W.E. (1979) The Interferon System. Springer-Verlag, New York. Strander, H., Cantell, K., Carlstrom, and Jakobsson, Ao (1973a). Clinical and Laboratory investigations on man: Systemic administration of potent interferon to man. J. natn. Cancer Inst. ~1(3):733-742. Strander, H.B., Cantell, K., Carlstrom, et a&.(1973b). Systemic administration of potent interferon to man. J. natno Cancer Inst. ~1:733-742. Sundmacher, R., Cantell, K., Haug, P. and Neumann-Haefelin, Do (1978). Role of debridement and interferon in the treatment of dendritic keratitiso Albrecht yon Graefes. Arch. Opthalmol. 207:?7-82. Weimar, W., Heijtink, R.A., Schalm, S.W. and Schellenkens, H. (1979). Differential effects of fibroblast and leukocyte interferon in HBsAg positive chronic active hepatitis. Eur. J. clin. Invest. 2: 151-154. Weimar, W., ten Kate, F.JoP., Masurel, N., Heijtink, R.A., Schalm, S.W. and Schellenkens, H. (1980). Double-blind study of leukocyte interferon administration in chronic HBsAg-positive hepatitis. Lancet i:336-338. Weimar, W., Schellenkens, H., Lameijer, L.D.Fo, Masurel, N., Edy, V.Go, Billiau, Ao and De Somer, P. (1978). Double-blind study of interferon administration in renal transplant recipients. Eur. J. clin. Invest. 2: 255-258. Weimar, W. and Schellekens, Ho (1980). Interferon therapy for chronic hepatitis Bo Lancet i:350. Wheelock, E.G. and Sibley, W.Ao (1965). Circulating virus, interferon and antibody after vaccination with the 17-D strain of yellow-fever virus. New En61. J. Med. 273:194-198.

Note Added in Proof In a placebo controlled study, human leukocyte interferon given for the treatment of varicella in children with cancer resulted in fewer days of new lesion formation and in fewer patients with life threatening dissemination [Arvin, A.M., Kushner, J.H., Feldman, S., Baehner, R.L., Hammond, D., and Merigan, ToC. (1982). Human leukocyte interferon for the treatment of varicella in children with cancer. New En~l. J. Medo 306(13):761-765].