CA1295244C - Treatment of actinic keratoses with alpha interferon - Google Patents
Treatment of actinic keratoses with alpha interferonInfo
- Publication number
- CA1295244C CA1295244C CA000544172A CA544172A CA1295244C CA 1295244 C CA1295244 C CA 1295244C CA 000544172 A CA000544172 A CA 000544172A CA 544172 A CA544172 A CA 544172A CA 1295244 C CA1295244 C CA 1295244C
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- interferon
- alpha
- actinic keratoses
- treatment
- alpha interferon
- Prior art date
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Abstract
ABSTRACT
A method of treating actinic keratoses with alpha interferon, especially alpha-2 interferon, is disclosed.
A method of treating actinic keratoses with alpha interferon, especially alpha-2 interferon, is disclosed.
Description
S2~
TREATMENT OF ACTINIC KERATOSES
_ WITH ALPHA INTERFERON
Summary of the Invention This invention relates to a method of treating actinic keratoses with recombinant human alpha interferon by administering the inter~eron directly into the lesion, i.e., intralesionally.
In particular, this invention relates to a specific dosage regimen for administering alpha-2 inter-feron in the treatment of actlnlc keratoses.
Background Actinic keratoses represent areas of dysplastic keratinocytes which develop within the epidermis in response to chronic exposure to ultravioIet radiation.
These erythematous, scaling lesions are a cosmetic nui-sance and may cause tenderness or pruritus in some patients. More importantly, some actinic keratoses pro-gress into invasive squamous cell carcinomas which not only are locally destructive but also may rarely metastasize. Although ther0 are several efficient methods of removing actinic keratoses, including liquid nitrogen cryotherapy, topical treatment with 5-fluorouracil and surgicaI excision, each of these is destructive. A treatment which could nontraumatically remove actinic keratoses would be of great benefit to patients.
. ~ .
, ., ~L f d V' 5 2 ~
Interferons are a family of proteins which exhibit antiviral activity against certain viruses and anticancer activity against certain cancers. There are three types of interferons: alpha or leukocyte inter-feron, beta or fibroblast interferon, and gamma or immune interferon. Human alpha interferon is a naturally occurring mixture of at least eleven components including those designated alpha-l interferon and alpha-2 inter-feron. Human alpha interferon exhibiting biological properties similar to those of naturally occurring human leukocyte interferon can be made by recombinant methods.
The anticancer activity of alpha interferon is based on its anti-proliferative action. It has been suggested that because interferons possess anti-proliferative activity, alpha interferon might be useful in the treatment of proliferative diseases of the skin such as psoriasis (See K.B. ~ancey and J.G. Smith, Jr., "Interferon: Status in treatment of skin disease", Am.
Acad. Dermatol., 3, No. 6 (1980), 585-595), but no report of the treatment of actinic keratoses has been published.
A number of alpha interferon species or compon-ents are known and are usually designated by a numeral after the Greek letter alpha, and all are contempIàted for use in this invention. Thus, the species designated human alpha-l interferon and human alpha-2 interferon (sometimes called human alpha-2b interferon or abbreviated hIFN-~2; USAN: Interferon Alfa-2b) are preferred, and human alpha-2 interferon is especially preferred. Alpha-2 interferon can be produced in bacteria using recombinant techniques as disclosed by Rubenstein, ~iochem. BiophYs. Acta, 695, 5-16 (1982). In addition, alpha-2 interferon may be prepared by recombinant-DNA methods disclosed by Nagata et_al., Nature, 284, 316-320 (1980), in European Patent 32l134, and in U.S. Patent 4,289,690. Various alpha-2 interferon species are disclosed in U.S. Patent 4,503,035.
%~
Detailed Descri~tion We have found that actinic keratoses favorably respond to intralesional injections of alpha interferon, especially alpha-2 interferon, and that this response is dose-dependent and dose-schedule-dependent. One study indicates that the concentration of alpha interferon per dose is a significant factor in the treatment of actinic keratoses, and a second study indicates that some minimum dosage is required over a specified period of time.
Following are detailed descriptions of those studies (i.e., Phase I and Phase II).
Patients and Methods In Phase I of the study, the dose-dependency of the therapeutic effect was investigated.
Patients Sixteen patients each having multiple lesions were divided into two groups, eight with predominantly hand and arm lesions, and eight with actinic keratoses of the face. Within each group, patients were randomly assigned to one of four treatment groups of two subjects each. Three typical actinic keratoses which were at least three centimeters apart from one another were selected on each subject. These lesions were then measured, characterized as to degree of erythema and scale, and photographed as a baseline evaluation before treatment. Scaling and erythema were quantitated on a seven-point scale ranging from absent to marked. An additional one to four actinic keratoses were similarly evaluated, although not treated, in order to study the possible systemic effects of intralesional alpha inter-feron. The patients had received no therapy for their lesions during the six weeks prior to the study, and none had reported a history of exposure to radiation, tars, .
-arsenic, or immunosuppressive agents. Acetaminophen, thiazide diuretics and potassium supplements were the only concomitant medications permitted during the study.
Laboratory Tests Laboratory monitoring consisted of a pre-treatment complete blood count with differential and a platelet count, blood chemistry analysis, and urinalysis. These were repeated weekly during therapy, and one week and one month after termination of therapy. An additional white blood cell count was done 24 hours after the first injection of the test medication. Serum interferon-neutralizing factor was assayed before treatment and at one and four weeks after completion of therapy.
Treatment Treatments were conducted with reconstituted solutions of lyophilized human recombinant alpha-2 interferon prepared immediately before injection by the addition of sterile water and normal saline to the lyophilizate to obtain the desired doses of 5 x 105 IU/O.lcc, 1 x 105 IU/O.lcc, and 1 x 104 IU/O.lcc.
Treatment consisted of injections of one of the above doses of interferon or placebo into each of three designated actinic keratoses three times weekly for three weeks, for a total of nine injections. Placebo-treated patients received the same course of~treatment~with O.lcc injections of sterile water and normal saline. Patients were observed in the office for thirty minutes after the injections for symptoms and signs of systemic reactions to the treatment.
~2~i2;~
Response Criteria The size of the treated and untreated lesions was measured and compared to the baseline measurement, and the degree of erythema and scaling was re-evaluated on the seven-point scale discussed above. Follow-up evaluations also included a global assessment of changes in lesion characteristics which was expressed in a six-point scale ranging from clear to exacerbation.
In Phase II of the study, five different dosing schedules were evaluated.
Patients Forty five patients meeting the same criteria as in Phase I (except that any concommitant medication not known to interfere with interferon was permitted) were included. These patients were divided into five treatment groups.
Laboratory Tests Same as Phase I.
Treatment Treatments were conducted with reconstituted solutions of lyophilized human recombinant alpha-2 interferon. The alpha-2 interferon solutions were prepared immediately before injection by the addition of sterile water and normal saline to yield a dose of 5 x 105 IU per O.lcc.
Within each of the five treatment groups, three patients received placebo, and from five to seven sub-jects received alpha-2 interferon, 5 x 105 IU per injec-tion. Each trsatment group was injected according to a different dosing regimen. These regimens were 1) one injection per lesion, 2) three injections per lesion in - ~L2~52 ~
one!week, 3) three injections per lesion one week apart, 4) six injections per lesion over two weeks, and 5) nine injections per lesion over three weeks. Where multiple injections were given, they were administered every other day (e.g., Monday, Wednesday and Friday).
Response Criteria Evaluations of the actinic keratoses and adverse reactions, as described for Phase I, were carried out weekly during the treatment phase, and weekly or bimonthly in the post-treatment phase.
The following Table 1 shows the results of the dose-dependence study (Phase I).
Effect of 9 Injections of Alpha-2 Interferon at Variable Doses on Actinic Keratoses marked moderate mild Treatment (75%*) (50%*) (25%*) No Group Cleared Improvement Improvement Improvement Change 5x105 IU/Inj 11 (92~) 1 (8%) lx105 IU/Inj 5 (42%) 6 ~50%) 1 t8%) lx104 IU/Inj 7 (58%) 1 (8%) 2 (17%) 2 (17~) Placebo 2 (17~) 4 (33%) 2 (17~) 4 (33%) *percent improvement is measured by reduction in size and scaling As is apparent from the data in Table 1, the therapeutic response of actinic keratoses to treatment with alpha-2 interferon is dose-dependent, that is, administration of higher doses has a greater therapeutic effect. Statistically, the difference be-tween the improvement of the actinic keratoses treated with high dose alpha-2 interferon and that of the keratoses treated with placebo was significant at P=0.01.
i2~
The following Table 2 shows the results of the dosing schedule study.
Effect of Different Dosing Schedules of Intralesional Alpha-2 Interferon (5xlO5 IU~ on Actinic Keratoses Marked Moderate Mild Treatment Total # (75%*) (50%*) (25%*) No Lesions Cleared Improvement Improvement Improvement Change lInj IFN 18 2 (11%) 5 (28%) 4 (22%) 3 (17%) 4 (22~) Placebo 9 1 (11%) 7 (78%) 1 (11%) 3Inj/l Wk IFN 21 10 (48~) 6 (29%) 2 (10%) 1 (5%) 2 (10%) Placebo 9 2 (20%) 3 (33%) 1 (11%) 3 (33%) 3Inj/3Wks IFN 18 9 (50%) 3 (17%) 2 (11%) 4 (22%) Placebo 9 1 (11%) 1 ~11%) 7 (78%) 6Inj/2WXs IFN 15 14 (93%) 1 (7~) Placebo 9 5 (56%) 1 (11%) 2 (22%) 1 (11%) 9Inj/3Wks IFN 15` 7 (47%) 3 (20%) 3 (20%) 2 (13%) Placebo 9 4 ~44%) 2 (22%) 3 (33%) *percent improvement is measured by reduction in size and scaling Inj = Injection(s) 5~:~4 Table 2 indicates that for a given dosage unit, i.e.,-5 x 105 IU per injection, different numbers of injections (i.e., 1, 3, 6 or 9) over different lengths of time (i.e., once, 3/week, 3/3 weeks, 6/2 weeks and 9/3 weeks) produce different rates of response. Table 2 indicates that one injection is no more effective than placebo, and that three injections, either in one week or over three weeks, produce poor response rates. Six injections over two weeks produce the greatèst response (93~ cleared), while in contrast to the results in Table 1, only 47% of the lesions treated with nine injections over three weeks cleared. While the discrepancy in the last ~wo results is unexplained at present, it is clear from the data that at least 3 x 106 IU alpha interferon (i.e., the equivalent of six injections at 5 x 105 IU each) administered to each actinic keratosis lesion is necessary to produce a clinically important effect.
Interferon is able to exert its effects both locally and systemically. Although some patients did develop systemic side effects sometimes associated with intralesional injection of interferon (e.g., local inflammation, m~algias), the beneficial effects of intralesional interferon were most likely due to the local effect of a higher concentration of medication, since distant actinic keratoses were not significantly afected.
For intralesional administration, injectable pharmaceutically acceptable compositions are used. Such compositions--can, for example, be prepared by diluting freeze-dried human alpha interferon, preferably alpha-2 interferon, with sterile preservative-free water to produce an isotonic solution containing the appropriate concentration of interferon. Other injectable carrier compositions using saline, aqueous dextrose, glycerol, ethanol and the like, which yield a solution or suspension for injection, can also be used. If desired, minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, preservatives, pH-buffering agents and the like, for example, sodium acetate or sorbitan monolaurate, can be incorporated into the compositions. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in this art; see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 16th Edition, 1980.
In viaw of the inconvenience attendant upon treatment with multiple injections (e.g. the inconvenience of repeated office visits, the discomfort of the injection procedure), the use of a sustained-release formulation comprising alpha-2 interferon which releases the required amount of alpha-2 interferon over the required time period is a feature of the invention.
Furthermore, the treatment period may yet be reduced when a sustained release formulation is used since alpha-2 interferon is being constantly administered to the lesion, as opposed to the intermittant administration of alpha-2 interferon in the multiple-injection method.
TREATMENT OF ACTINIC KERATOSES
_ WITH ALPHA INTERFERON
Summary of the Invention This invention relates to a method of treating actinic keratoses with recombinant human alpha interferon by administering the inter~eron directly into the lesion, i.e., intralesionally.
In particular, this invention relates to a specific dosage regimen for administering alpha-2 inter-feron in the treatment of actlnlc keratoses.
Background Actinic keratoses represent areas of dysplastic keratinocytes which develop within the epidermis in response to chronic exposure to ultravioIet radiation.
These erythematous, scaling lesions are a cosmetic nui-sance and may cause tenderness or pruritus in some patients. More importantly, some actinic keratoses pro-gress into invasive squamous cell carcinomas which not only are locally destructive but also may rarely metastasize. Although ther0 are several efficient methods of removing actinic keratoses, including liquid nitrogen cryotherapy, topical treatment with 5-fluorouracil and surgicaI excision, each of these is destructive. A treatment which could nontraumatically remove actinic keratoses would be of great benefit to patients.
. ~ .
, ., ~L f d V' 5 2 ~
Interferons are a family of proteins which exhibit antiviral activity against certain viruses and anticancer activity against certain cancers. There are three types of interferons: alpha or leukocyte inter-feron, beta or fibroblast interferon, and gamma or immune interferon. Human alpha interferon is a naturally occurring mixture of at least eleven components including those designated alpha-l interferon and alpha-2 inter-feron. Human alpha interferon exhibiting biological properties similar to those of naturally occurring human leukocyte interferon can be made by recombinant methods.
The anticancer activity of alpha interferon is based on its anti-proliferative action. It has been suggested that because interferons possess anti-proliferative activity, alpha interferon might be useful in the treatment of proliferative diseases of the skin such as psoriasis (See K.B. ~ancey and J.G. Smith, Jr., "Interferon: Status in treatment of skin disease", Am.
Acad. Dermatol., 3, No. 6 (1980), 585-595), but no report of the treatment of actinic keratoses has been published.
A number of alpha interferon species or compon-ents are known and are usually designated by a numeral after the Greek letter alpha, and all are contempIàted for use in this invention. Thus, the species designated human alpha-l interferon and human alpha-2 interferon (sometimes called human alpha-2b interferon or abbreviated hIFN-~2; USAN: Interferon Alfa-2b) are preferred, and human alpha-2 interferon is especially preferred. Alpha-2 interferon can be produced in bacteria using recombinant techniques as disclosed by Rubenstein, ~iochem. BiophYs. Acta, 695, 5-16 (1982). In addition, alpha-2 interferon may be prepared by recombinant-DNA methods disclosed by Nagata et_al., Nature, 284, 316-320 (1980), in European Patent 32l134, and in U.S. Patent 4,289,690. Various alpha-2 interferon species are disclosed in U.S. Patent 4,503,035.
%~
Detailed Descri~tion We have found that actinic keratoses favorably respond to intralesional injections of alpha interferon, especially alpha-2 interferon, and that this response is dose-dependent and dose-schedule-dependent. One study indicates that the concentration of alpha interferon per dose is a significant factor in the treatment of actinic keratoses, and a second study indicates that some minimum dosage is required over a specified period of time.
Following are detailed descriptions of those studies (i.e., Phase I and Phase II).
Patients and Methods In Phase I of the study, the dose-dependency of the therapeutic effect was investigated.
Patients Sixteen patients each having multiple lesions were divided into two groups, eight with predominantly hand and arm lesions, and eight with actinic keratoses of the face. Within each group, patients were randomly assigned to one of four treatment groups of two subjects each. Three typical actinic keratoses which were at least three centimeters apart from one another were selected on each subject. These lesions were then measured, characterized as to degree of erythema and scale, and photographed as a baseline evaluation before treatment. Scaling and erythema were quantitated on a seven-point scale ranging from absent to marked. An additional one to four actinic keratoses were similarly evaluated, although not treated, in order to study the possible systemic effects of intralesional alpha inter-feron. The patients had received no therapy for their lesions during the six weeks prior to the study, and none had reported a history of exposure to radiation, tars, .
-arsenic, or immunosuppressive agents. Acetaminophen, thiazide diuretics and potassium supplements were the only concomitant medications permitted during the study.
Laboratory Tests Laboratory monitoring consisted of a pre-treatment complete blood count with differential and a platelet count, blood chemistry analysis, and urinalysis. These were repeated weekly during therapy, and one week and one month after termination of therapy. An additional white blood cell count was done 24 hours after the first injection of the test medication. Serum interferon-neutralizing factor was assayed before treatment and at one and four weeks after completion of therapy.
Treatment Treatments were conducted with reconstituted solutions of lyophilized human recombinant alpha-2 interferon prepared immediately before injection by the addition of sterile water and normal saline to the lyophilizate to obtain the desired doses of 5 x 105 IU/O.lcc, 1 x 105 IU/O.lcc, and 1 x 104 IU/O.lcc.
Treatment consisted of injections of one of the above doses of interferon or placebo into each of three designated actinic keratoses three times weekly for three weeks, for a total of nine injections. Placebo-treated patients received the same course of~treatment~with O.lcc injections of sterile water and normal saline. Patients were observed in the office for thirty minutes after the injections for symptoms and signs of systemic reactions to the treatment.
~2~i2;~
Response Criteria The size of the treated and untreated lesions was measured and compared to the baseline measurement, and the degree of erythema and scaling was re-evaluated on the seven-point scale discussed above. Follow-up evaluations also included a global assessment of changes in lesion characteristics which was expressed in a six-point scale ranging from clear to exacerbation.
In Phase II of the study, five different dosing schedules were evaluated.
Patients Forty five patients meeting the same criteria as in Phase I (except that any concommitant medication not known to interfere with interferon was permitted) were included. These patients were divided into five treatment groups.
Laboratory Tests Same as Phase I.
Treatment Treatments were conducted with reconstituted solutions of lyophilized human recombinant alpha-2 interferon. The alpha-2 interferon solutions were prepared immediately before injection by the addition of sterile water and normal saline to yield a dose of 5 x 105 IU per O.lcc.
Within each of the five treatment groups, three patients received placebo, and from five to seven sub-jects received alpha-2 interferon, 5 x 105 IU per injec-tion. Each trsatment group was injected according to a different dosing regimen. These regimens were 1) one injection per lesion, 2) three injections per lesion in - ~L2~52 ~
one!week, 3) three injections per lesion one week apart, 4) six injections per lesion over two weeks, and 5) nine injections per lesion over three weeks. Where multiple injections were given, they were administered every other day (e.g., Monday, Wednesday and Friday).
Response Criteria Evaluations of the actinic keratoses and adverse reactions, as described for Phase I, were carried out weekly during the treatment phase, and weekly or bimonthly in the post-treatment phase.
The following Table 1 shows the results of the dose-dependence study (Phase I).
Effect of 9 Injections of Alpha-2 Interferon at Variable Doses on Actinic Keratoses marked moderate mild Treatment (75%*) (50%*) (25%*) No Group Cleared Improvement Improvement Improvement Change 5x105 IU/Inj 11 (92~) 1 (8%) lx105 IU/Inj 5 (42%) 6 ~50%) 1 t8%) lx104 IU/Inj 7 (58%) 1 (8%) 2 (17%) 2 (17~) Placebo 2 (17~) 4 (33%) 2 (17~) 4 (33%) *percent improvement is measured by reduction in size and scaling As is apparent from the data in Table 1, the therapeutic response of actinic keratoses to treatment with alpha-2 interferon is dose-dependent, that is, administration of higher doses has a greater therapeutic effect. Statistically, the difference be-tween the improvement of the actinic keratoses treated with high dose alpha-2 interferon and that of the keratoses treated with placebo was significant at P=0.01.
i2~
The following Table 2 shows the results of the dosing schedule study.
Effect of Different Dosing Schedules of Intralesional Alpha-2 Interferon (5xlO5 IU~ on Actinic Keratoses Marked Moderate Mild Treatment Total # (75%*) (50%*) (25%*) No Lesions Cleared Improvement Improvement Improvement Change lInj IFN 18 2 (11%) 5 (28%) 4 (22%) 3 (17%) 4 (22~) Placebo 9 1 (11%) 7 (78%) 1 (11%) 3Inj/l Wk IFN 21 10 (48~) 6 (29%) 2 (10%) 1 (5%) 2 (10%) Placebo 9 2 (20%) 3 (33%) 1 (11%) 3 (33%) 3Inj/3Wks IFN 18 9 (50%) 3 (17%) 2 (11%) 4 (22%) Placebo 9 1 (11%) 1 ~11%) 7 (78%) 6Inj/2WXs IFN 15 14 (93%) 1 (7~) Placebo 9 5 (56%) 1 (11%) 2 (22%) 1 (11%) 9Inj/3Wks IFN 15` 7 (47%) 3 (20%) 3 (20%) 2 (13%) Placebo 9 4 ~44%) 2 (22%) 3 (33%) *percent improvement is measured by reduction in size and scaling Inj = Injection(s) 5~:~4 Table 2 indicates that for a given dosage unit, i.e.,-5 x 105 IU per injection, different numbers of injections (i.e., 1, 3, 6 or 9) over different lengths of time (i.e., once, 3/week, 3/3 weeks, 6/2 weeks and 9/3 weeks) produce different rates of response. Table 2 indicates that one injection is no more effective than placebo, and that three injections, either in one week or over three weeks, produce poor response rates. Six injections over two weeks produce the greatèst response (93~ cleared), while in contrast to the results in Table 1, only 47% of the lesions treated with nine injections over three weeks cleared. While the discrepancy in the last ~wo results is unexplained at present, it is clear from the data that at least 3 x 106 IU alpha interferon (i.e., the equivalent of six injections at 5 x 105 IU each) administered to each actinic keratosis lesion is necessary to produce a clinically important effect.
Interferon is able to exert its effects both locally and systemically. Although some patients did develop systemic side effects sometimes associated with intralesional injection of interferon (e.g., local inflammation, m~algias), the beneficial effects of intralesional interferon were most likely due to the local effect of a higher concentration of medication, since distant actinic keratoses were not significantly afected.
For intralesional administration, injectable pharmaceutically acceptable compositions are used. Such compositions--can, for example, be prepared by diluting freeze-dried human alpha interferon, preferably alpha-2 interferon, with sterile preservative-free water to produce an isotonic solution containing the appropriate concentration of interferon. Other injectable carrier compositions using saline, aqueous dextrose, glycerol, ethanol and the like, which yield a solution or suspension for injection, can also be used. If desired, minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, preservatives, pH-buffering agents and the like, for example, sodium acetate or sorbitan monolaurate, can be incorporated into the compositions. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in this art; see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 16th Edition, 1980.
In viaw of the inconvenience attendant upon treatment with multiple injections (e.g. the inconvenience of repeated office visits, the discomfort of the injection procedure), the use of a sustained-release formulation comprising alpha-2 interferon which releases the required amount of alpha-2 interferon over the required time period is a feature of the invention.
Furthermore, the treatment period may yet be reduced when a sustained release formulation is used since alpha-2 interferon is being constantly administered to the lesion, as opposed to the intermittant administration of alpha-2 interferon in the multiple-injection method.
Claims (7)
1. Use of a sufficient amount of recombinant human alpha interferon to be effective as an anti-actinic keratoses agent for intralesionally treating human actinic keratoses.
The use as claimed in claim 1 wherein the sufficient amount of alpha interferon is at least 3 x 106 International Units.
3. The use as claimed in claim 1 wherein alpha interferon is administered in divided dosages.
4. Use of recombinant human alpha interferon in the preparation of a pharmaceutical composition for intralesionally treating human actinic keratoses comprising a sufficient amount of human alpha interferon to be effective against actinic keratoses and a pharmaceutically acceptable carrier therefor.
5. The use as claimed in claim 4 wherein the pharmaceutical composition comprising alpha interferon is a sustained release composition.
6. The use as claimed in any one of claims 1 to 5 wherein the alpha interferon is alpha-2 interferon.
7. The use as claimed in any one of claims 1 to 5 wherein the alpha interferon is alpha-2b interferon.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89616986A | 1986-08-12 | 1986-08-12 | |
| US896,169 | 1986-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1295244C true CA1295244C (en) | 1992-02-04 |
Family
ID=25405741
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000544172A Expired - Fee Related CA1295244C (en) | 1986-08-12 | 1987-08-11 | Treatment of actinic keratoses with alpha interferon |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1295244C (en) |
-
1987
- 1987-08-11 CA CA000544172A patent/CA1295244C/en not_active Expired - Fee Related
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