US3317384A - Treatment of topical viral infections with glucocorticoids and nucleosides - Google Patents

Treatment of topical viral infections with glucocorticoids and nucleosides Download PDF

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US3317384A
US3317384A US373501A US37350164A US3317384A US 3317384 A US3317384 A US 3317384A US 373501 A US373501 A US 373501A US 37350164 A US37350164 A US 37350164A US 3317384 A US3317384 A US 3317384A
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topical
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Gerald E Underwood
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Pharmacia and Upjohn Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

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  • This invention relates to pharmaceutical preparations, more particularly pharmaceutical preparations adapted for topical pharmaceutical applications.
  • the preparations of the instant invention are advantageously useful in topical pharmaceutical applications to mammals, for they demonstrate unexpected activity in ophthalmic disorders as shown by their effectiveness in treating herpetic conditions in the eyes.
  • the pharmaceutical application of glucocorticoids in such conditions is widespread but often hazardous and accompanied by deleterious side effects. Secondary encephalitis is a hazard of such application and can result in death. Perforation does not occur during such application in disciform keratitis. Keratitis profunda and keratouveitis sometimes occur during or following glucocorticoid applications. Prolonged persistence of herpes simplex virus in the cornea often occurs.
  • glucocorticoids are known to mask progress of herpetic conditions in the eye whereby infection progresses despite apparent improvement of the eye. It has now been found that the pharmaceutical preparations of the instant invention unexpectedly minimize or abolish such hazards and deleterious side effects while providing beneficial effectiveness in treating herpetic involvement.
  • Other beneficial topical pharmaceutical applications to mammals are in viral skin lesions of vaccinia and herpes simplex.
  • compositions comprising in combination a topical anti-inflammatory glucocorticoid and a topical antiviral nucleoside.
  • topical pharmaceutical means which adapt the preparations for topical pharmaceutical applications are added to the combination.
  • topical anti-inflammatory glucocorticoid means steroids of natural and synthetic origin which demonstrate topical anti-inflammatory properties; for example, cortisone acetate, dexamethasone, deXa-methasone phosphate sodium, fludrocortisone acetate,fiuorometholone, hydrocortamate hydrochloride, hydrocortisone, hydrocortisone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone phosphate sodium, and triamcinolone acetonide.
  • topical antiviral nucleoside means those nucleosides demonstrating beneficial activity in the treatment of viral ophthalmic conditions and viral skin lesions.
  • the antiviral nucleosides are arabinofuranosyl nucleosides of uracil and cytosine and are selected from the group consisting of 1- ⁇ 3- D-arabinofuranosyluracil, its S-bromo, -chloro, -fluoro, -iodo, and -methyl derivatives, 1-B-D-arabinofuranosy1cytosine, its S-methyl derivative, and the pharmaceutically acceptable acid addition salts thereof, such as the hydrochloride, citrate, succinate and tartrate.
  • Topical pharmaceutical means which adapt the preparation for topical pharmaceutical applications means lotion vehicles; ointment bases; cream bases; hydrogel pastes; fatty pastes; aqueous solutions, preferably isotonic, especially lbufiered ophthalmic solutions containing a surfactant such as polysorbate 80 and p-isoocytyl polyoxyethylene phenol (Triton WR-1339); aqueous suspending vehicles;
  • micronized diluents preferably make up a major amount of the weight or volume of the preparation.
  • Such topical pharmaceutical means preferably are sterile and contain a nontoxic bactericidal or bacteriostatic agent.
  • the topical anti-inflammatory glucocorticoid and the topical antiviral nucleoside are the essential active ingredients. They are preferably micronized. However, nontoxic antibacterial agents, preferably topically effective antibiotics such as neomycin, polymycin, and bacitracin, can be added to control any secondary bacterial infections.
  • the percentage of the topical anti-inflammatory glucocorticoid ranges from about 0.025% to about 2.5% of the preparation.
  • the percentage in a liquid vehicle adapted for aerosol formation varies from about 0.01% to about 0.3%.
  • the percentage of the antiviral component ranges from about 0.1% to about 10% within which the prefered range is from about 0.5 to about 2%.
  • Herpes simplex virus was isolated from a herpetic lip lesion and was subjected to 8 passages in rabbit kidney cell cultures. A titer of approximately 10 plaque forming units per milliliter was obtained. A culture of this titer was used undiluted for infecting rabbit eyes by rubbing the cornea thoroughly with a cotton swab saturated with the culture. 16 rabbits were so infected in all eyes and separated into 4 groups of 4 rabbits each.
  • the treatment schedule was identical to that for the control group.
  • TOPICAL ANTIVIRAL NUCLEOSI-DE GROUP A sterile ointment was compounded of wool fat, liquid petrolatum, white petrolatum, 0.5 of neomycin sulfate as antibacterial agent to prevent secondary infection and 1% of l-,8-D-arabinofuranosylcytosine hydrochloride. The treatment schedule was identical to that for the control group.
  • Example 3 .-C0mbinati0n 0 f glucocorticoid and nucleoside
  • a topical cream base is prepared. 0.5% of micronized prednisolone and 5.0% of micronized l-fi-D-arabinofuranosylcytosine are incorporated therein.
  • the cream is used in topical pharmaceutical applications to rabbit eyes infected with herpes simplex virus. Equally beneficial unexpected results to those with the previous examples are obtained.
  • Example 4.-C0ml7inati0n of glucocorticoid and nucleoside A sterile topical ointment base is prepared. 0.1% of sterile methylprednisolone and 10.0% of sterile l-fl-D- arabinofuranosylcytosine are incorporated therein. The sterile preparation is used in topical pharmaceutical applications to rabbit eyes infected with herpes simplex virus. Equally beneficial unexpected results to those with the previous examples are obtained.
  • Example 5 Combination of glacocorticoid and nucleoside An aqueous lotion vehicle is prepared. An amount of triamcinolone acetonide equivalent to 1 mg. per ml. of the vehicle and an amount of I-B-D-arabinofuranosylcytosine hydrochloride equivalent to 25 mg. per ml. are prepared.
  • Example 7.--C0mbinati0n of glucocorticoid and nucleoside A finely divided powder for topical pharmaceutical applications is prepared by blending parts by Weight of micronized 1-,8-D-arabinofuranosylcytosine hydrochloride and 1 part by Weight of micronized fiuorometholone. The powder is applied topically with beneficial results in herpes simplex skin lesions in rabbits and vaccinia skin lesions in monkeys.
  • Example 8.Other combinations of glucocorticoid and nucleoside Pharmaceutical preparations combining the following concentrations of glucocorticoid and nucleoside are prepared with topical pharmaceutical means.
  • the S-halo derivatives of 1-fi-D-arabinofuranosyluracil ar prepared by direct halogenation by reacting the parent compound with, for example, chlorine, bromine and iodine in the presence of an inert solvent which can be aqueous or nonaqueous.
  • the inert solvent depends on the particular halogen, for example, chlorination in a mixture of acetic acid and carbon tetrachloride, bromination in water alone.
  • the halo compounds are recovered 'by removing excess halogen, evaporating the volatile components, solvent extraction and crystallization. See Ser. No. 51,301 filed Aug. 23, 1960. Brown et a1., Chem. Soc. J.
  • a process for minimizing deleterious effects of topical anti-inflammatory glucocorticoids in topical viral infections which comprises application to the infected area of a pharmaceutical preparation comprising in combination (a) from about 0.025% to about 2.5% of a topical anti-inflammatory glucocorticoid,
  • topical pharmaceutical means which adapt the preparation for topical pharmaceutical application.
  • topical antiviral nucleoside is present in an amount of from about 0.5% to about 2% 3.
  • the l-fi-D-arabinofuranosylcytosine hydrochloride is present in an amount of about 1%.
  • LEWIS GOTTS Primary Examiner.
  • RICHARD L. HUFF Assistant Examiner.

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Description

United States Patent O 3,317,384 TREATMENT OF TOPICAL VIRAL INFECTIONS WiTlli GLUCOCORTHCOIDS AND NUCLEOSIDES Gerald E. Underwood, Galesburg, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed June 8, 1964, Ser. No. 373,501
3 Claims. (Cl. 16758) This application is a continuation-in-part of copending application Ser. No. 296,095, filed July 18, 1963, now abandoned.
This invention relates to pharmaceutical preparations, more particularly pharmaceutical preparations adapted for topical pharmaceutical applications.
The preparations of the instant invention are advantageously useful in topical pharmaceutical applications to mammals, for they demonstrate unexpected activity in ophthalmic disorders as shown by their effectiveness in treating herpetic conditions in the eyes. The pharmaceutical application of glucocorticoids in such conditions is widespread but often hazardous and accompanied by deleterious side effects. Secondary encephalitis is a hazard of such application and can result in death. Perforation does not occur during such application in disciform keratitis. Keratitis profunda and keratouveitis sometimes occur during or following glucocorticoid applications. Prolonged persistence of herpes simplex virus in the cornea often occurs. Moreover, glucocorticoids are known to mask progress of herpetic conditions in the eye whereby infection progresses despite apparent improvement of the eye. It has now been found that the pharmaceutical preparations of the instant invention unexpectedly minimize or abolish such hazards and deleterious side effects while providing beneficial effectiveness in treating herpetic involvement. Other beneficial topical pharmaceutical applications to mammals are in viral skin lesions of vaccinia and herpes simplex.
In accordance with the present invention, there are provided pharmaceutical preparations comprising in combination a topical anti-inflammatory glucocorticoid and a topical antiviral nucleoside. Suitably, topical pharmaceutical means which adapt the preparations for topical pharmaceutical applications are added to the combination.
The term topical anti-inflammatory glucocorticoid means steroids of natural and synthetic origin which demonstrate topical anti-inflammatory properties; for example, cortisone acetate, dexamethasone, deXa-methasone phosphate sodium, fludrocortisone acetate,fiuorometholone, hydrocortamate hydrochloride, hydrocortisone, hydrocortisone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone phosphate sodium, and triamcinolone acetonide. The term topical antiviral nucleoside means those nucleosides demonstrating beneficial activity in the treatment of viral ophthalmic conditions and viral skin lesions. The antiviral nucleosides are arabinofuranosyl nucleosides of uracil and cytosine and are selected from the group consisting of 1-{3- D-arabinofuranosyluracil, its S-bromo, -chloro, -fluoro, -iodo, and -methyl derivatives, 1-B-D-arabinofuranosy1cytosine, its S-methyl derivative, and the pharmaceutically acceptable acid addition salts thereof, such as the hydrochloride, citrate, succinate and tartrate. Topical pharmaceutical means which adapt the preparation for topical pharmaceutical applications means lotion vehicles; ointment bases; cream bases; hydrogel pastes; fatty pastes; aqueous solutions, preferably isotonic, especially lbufiered ophthalmic solutions containing a surfactant such as polysorbate 80 and p-isoocytyl polyoxyethylene phenol (Triton WR-1339); aqueous suspending vehicles;
micronized diluents; propellent-containing liquid vehicles adapted to form an aerosol; and the like. Any utilized means preferably makes up a major amount of the weight or volume of the preparation. Such topical pharmaceutical means preferably are sterile and contain a nontoxic bactericidal or bacteriostatic agent.
The topical anti-inflammatory glucocorticoid and the topical antiviral nucleoside are the essential active ingredients. They are preferably micronized. However, nontoxic antibacterial agents, preferably topically effective antibiotics such as neomycin, polymycin, and bacitracin, can be added to control any secondary bacterial infections.
The percentage of the topical anti-inflammatory glucocorticoid ranges from about 0.025% to about 2.5% of the preparation. The percentage in a liquid vehicle adapted for aerosol formation varies from about 0.01% to about 0.3%. The percentage of the antiviral component ranges from about 0.1% to about 10% within which the prefered range is from about 0.5 to about 2%.
The following examples describe the manner and process of making and using the invention and set forth the best mode contemplated by the inventor of carrying out in the invention but are not to be construed as limiting.
Treatment of rabbit eyes infected with herpes simplex virus demonstrates beneficial unexpected activity of the novel topical pharmaceutical preparation.
Herpes simplex virus was isolated from a herpetic lip lesion and was subjected to 8 passages in rabbit kidney cell cultures. A titer of approximately 10 plaque forming units per milliliter was obtained. A culture of this titer was used undiluted for infecting rabbit eyes by rubbing the cornea thoroughly with a cotton swab saturated with the culture. 16 rabbits were so infected in all eyes and separated into 4 groups of 4 rabbits each.
CONTROL GROUP 42 hours after infection, treatment of all eyes in this group was started with a sterile ointment composed of wool fat, liquid petrolatum and white petrolatum with 0.5% of neomycin sulfate as antibacterial agent to prevent secondary infection. The treatment was continued every hour from 8 a.m. to 5 pm. for six consecutive days.
ANTI-INFLAMMATORY GLUCOCORTICOID GROUP 42 hours after infection, treatment of all eyes in this group was started with a sterile ointment composed of wool fat, liquid petrolatum, white petrolatum, 0.5 neomycin sulfate as antibacterial agent to prevent secondary infection and 1.5% of hydrocortisone acetate. The treatment schedule was identical to that for the control group.
TOPICAL ANTIVIRAL NUCLEOSI-DE GROUP A sterile ointment was compounded of wool fat, liquid petrolatum, white petrolatum, 0.5 of neomycin sulfate as antibacterial agent to prevent secondary infection and 1% of l-,8-D-arabinofuranosylcytosine hydrochloride. The treatment schedule was identical to that for the control group.
Example 1.-C0mbinati0n of glucocorticoid and nucleoside A sterile ointment was compounded of wool fat, liquid petrolatum, white petrolatum, 0.5% of neomycin sulfate as antibacterial agent to prevent secondary infection, 1.5 of hydrocortisone acetate, and 1% of l-B-Darabinofuranosylcytosine hydrochloride. The same treatment regimen was followed.
METHOD OF OBSERVING AND RECORDING RESULTS Each eye was observed daily with the aid of an ophthalmoscope to ascertain the degree of herpetic involvement, which was recorded as the latter showing deep .stromal involvement with cloudy cornea. In the following recapitulation the digits represent the number of observed eyes.
to form an aerosol. Equally beneficial unexpected results are obtained therefrom in topical application to monkey eyes infected with herpes simplex virus.
Day 2 of Treatment Day 4 of Treatment Day 6 of Treatment Day 2 Post Treatment Treatment Group Control 3 4 1 0 0 0 5 0 0 1 7 O 0 2 6 Glueocorticold 4 4 0 0 0 1 7 0 0 0 4 4 2 4 (1 dead) Nucleoside 8 0 0 0 8 0 0 0 7 1 0 0 7 1 0 0 Example 1 8 0 0 0 7 1 0 0 7 0 1 0 5 1 1 1 Day 4 Post Treatment Day 6 Post Treatment Day 9 Post Treatment Day 14 Post Treatment Treatment Group Control 1 2 0 5 4 0 2 2 2 0 4 2 3 3 2 0 Glucocortieoid 1 3 1 1 1 1 1 1 (2 dead) (3 dead) (3 dead) (3 dead) Nucleoside 4 3 1 0 3 0 5 0 3 1 4 0 5 2 1 0 Example 1- 3 2 1 1 4 3 0 1 5 2 0 1 5 2 0 1 The data show that the glucocorticoid-nucleoside com- Example 6 ggiratign prsgll ctm ft 23 P ;vili ffig zleiggggl 82 5: A topical cream base is prepared. 0.025% by weight P6 16 n ve en P S of m-rcronized fiuorometholone, 2% by weight of micronetfects of the glucocortrcoid.
Example 2.C0mbinati0n of glucocorticoid and nucleoside Example 3 .-C0mbinati0n 0 f glucocorticoid and nucleoside A topical cream base is prepared. 0.5% of micronized prednisolone and 5.0% of micronized l-fi-D-arabinofuranosylcytosine are incorporated therein. The cream is used in topical pharmaceutical applications to rabbit eyes infected with herpes simplex virus. Equally beneficial unexpected results to those with the previous examples are obtained.
Example 4.-C0ml7inati0n of glucocorticoid and nucleoside A sterile topical ointment base is prepared. 0.1% of sterile methylprednisolone and 10.0% of sterile l-fl-D- arabinofuranosylcytosine are incorporated therein. The sterile preparation is used in topical pharmaceutical applications to rabbit eyes infected with herpes simplex virus. Equally beneficial unexpected results to those with the previous examples are obtained.
Example 5 .Combination of glacocorticoid and nucleoside An aqueous lotion vehicle is prepared. An amount of triamcinolone acetonide equivalent to 1 mg. per ml. of the vehicle and an amount of I-B-D-arabinofuranosylcytosine hydrochloride equivalent to 25 mg. per ml. are
ized 1-;8-D-a-rabinofuranosylcytosine and 0.5% of neomycin sulfate are incorporated therein. The cream is used in topical pharmaceutical applications to rabbit eyes infected with herpes simplex virus. Equally beneficial unexpected results to those with the previous examples are obtained.
Example 7.--C0mbinati0n of glucocorticoid and nucleoside A finely divided powder for topical pharmaceutical applications is prepared by blending parts by Weight of micronized 1-,8-D-arabinofuranosylcytosine hydrochloride and 1 part by Weight of micronized fiuorometholone. The powder is applied topically with beneficial results in herpes simplex skin lesions in rabbits and vaccinia skin lesions in monkeys.
Example 8.Other combinations of glucocorticoid and nucleoside Pharmaceutical preparations combining the following concentrations of glucocorticoid and nucleoside are prepared with topical pharmaceutical means.
Percent Cortisone acetate 0.5 to 2.5 Fludrocortisone acetate 0.05 to 0.25
5 -methyl derivative of 1-[i-D-arabinofuranosylcytosine 1 These combinations are prepared preferably with the said topical pharmaceutical means to provide preparations which are also beneficial .in topical pharmaceutical applications.
The S-halo derivatives of 1-fi-D-arabinofuranosyluracil ar prepared by direct halogenation by reacting the parent compound with, for example, chlorine, bromine and iodine in the presence of an inert solvent which can be aqueous or nonaqueous. The inert solvent depends on the particular halogen, for example, chlorination in a mixture of acetic acid and carbon tetrachloride, bromination in water alone. The halo compounds are recovered 'by removing excess halogen, evaporating the volatile components, solvent extraction and crystallization. See Ser. No. 51,301 filed Aug. 23, 1960. Brown et a1., Chem. Soc. J. 23882393 (July) 1956 describes B-B-D-arabofuranosyluracil (1 B D-arabinofuranosyluracil). The procedure of Fox et al., J.A.C.S., 79, 2775-2778 (1957) yields the S-methyl derivative, also known as phongothymidine. Walwich et =al., Proc. Chem. Soc., 84 (March), 1959 describes 3-fl-Darabinofuranosylcytosine (l-B-D- ara'binofuranosylcytosine). Its S-methyl derivative is de- .scribed in U.S. 3,116,282.
What is claimed is:
1. A process for minimizing deleterious effects of topical anti-inflammatory glucocorticoids in topical viral infections which comprises application to the infected area of a pharmaceutical preparation comprising in combination (a) from about 0.025% to about 2.5% of a topical anti-inflammatory glucocorticoid,
(b) from about 0.1% to about of a topical antiviral nucleoside selected from the group consisting of 1 ,8 D arabinofuranosyluracil, its 5-bromo,
6 -chloro, -fluoro, -iodo, and -methyl derivatives, l-B- D-arabinofuranosylcytosine, its S-methyl derivative, and pharmaceutically acceptable acid addition salts thereof, and (c) topical pharmaceutical means which adapt the preparation for topical pharmaceutical application. 2. The process of claim 1 wherein the topical antiviral nucleoside is present in an amount of from about 0.5% to about 2% 3. The process of claim 2 wherein the l-fi-D-arabinofuranosylcytosine hydrochloride is present in an amount of about 1%.
Kaufman et al.: Arch. Ophthalmol, vol. 69 pp. 626- 629, May 1963.
Underwood: Society for Experimental Biology and Medicine, Proceedings, vol. 111, No. 3, pp. 660-664, December 1962.
LEWIS GOTTS, Primary Examiner. RICHARD L. HUFF, Assistant Examiner.

Claims (1)

1. A PROCESS FOR MINIMIZING DELETERIOUS EFFECTS OF TOPICAL ANTI-INFLAMMATORY GLUCOCORTICOIDS IN TOPICAL VIRAL INFECTIONS WHICH COMPRISES APPLICATION TO THE INFECTED AREA OF A PHARMACEUTICAL PREPARATION COMPRISING IN COMBINATION (A) FROM ABOUT 0.025% TO ABOUT 2.5% OF A TOPICAL ANTI-INFLAMMATORY GLUCOCORTICOID, (B) FROM ABOUT 0.1% TO ABOUT 10% OF A TOPICAL ANTIVIRAL NUCLEOSIDE SELECTED FROM THE GROUP CONSISTING OF 1 - B - D - ARABINOFURANOSYLURACIL, ITS 5-BROMO, -CHLORO, -FLUORO, -IODO, AND -METHYL DERIVATIVES, L-BD-ARABINOFURANOSYLCYTOSINE, ITS 5-METHYL DERIVATIVE, AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, AND (C) TOPICAL PHARMACEUTICAL MEANS WHICH ADAPT THE PREPARATION FOR TOPICAL PHARMACEUTICAL APPLICATION.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3898330A (en) * 1973-08-01 1975-08-05 Squibb & Sons Inc Corticosteroid phosphate salts/neomycin sulfate ophthalmic
WO1996024355A1 (en) * 1995-02-06 1996-08-15 Astra Aktiebolag Novel pharmaceutical combination
WO1997026882A1 (en) * 1996-01-26 1997-07-31 Smithkline Beecham Plc Nucleoside analogs in combination therapy of herpes simplex infections

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA588163A (en) * 1959-12-01 P. Aterno Joseph Ophthalmic composition
US3116282A (en) * 1960-04-27 1963-12-31 Upjohn Co Pyrimidine nucleosides and process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA588163A (en) * 1959-12-01 P. Aterno Joseph Ophthalmic composition
US3116282A (en) * 1960-04-27 1963-12-31 Upjohn Co Pyrimidine nucleosides and process

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3898330A (en) * 1973-08-01 1975-08-05 Squibb & Sons Inc Corticosteroid phosphate salts/neomycin sulfate ophthalmic
EP1419803A2 (en) * 1995-02-06 2004-05-19 Medivir Ab Pharmaceutical composition for topical administration comprising an antiviral substance and a glucocorticoid
KR100431042B1 (en) * 1995-02-06 2004-06-16 메디비르 아베 Novel Pharmaceutical Combination
AU716809B2 (en) * 1995-02-06 2000-03-09 Medivir Ab Novel pharmaceutical combination
US6337324B1 (en) 1995-02-06 2002-01-08 Medivir, Ab Pharmaceutical combination
EP1419803A3 (en) * 1995-02-06 2004-06-09 Medivir Ab Pharmaceutical composition for topical administration comprising an antiviral substance and a glucocorticoid
CN1131034C (en) * 1995-02-06 2003-12-17 阿斯特拉公司 Novel pharmaceutical composition
USRE39264E1 (en) * 1995-02-06 2006-09-05 Medivir Ab Pharmaceutical combination
WO1996024355A1 (en) * 1995-02-06 1996-08-15 Astra Aktiebolag Novel pharmaceutical combination
MY119365A (en) * 1995-02-06 2005-05-31 Medivir Ab Novel pharmaceutical combination
CN1133433C (en) * 1996-01-26 2004-01-07 诺瓦蒂斯国际药品有限公司 Nucleoside analogs in combination therapy of herpes simplex infections
US20040185433A1 (en) * 1996-01-26 2004-09-23 Boyd Malcolm Richard Nucleoside analogs in combination therapy of herpes simplex infections
US6514980B1 (en) 1996-01-26 2003-02-04 Novartis International Pharmaceutical Ltd. Nucleoside analogs in combination therapy of herpes simplex infections
US20050222016A1 (en) * 1996-01-26 2005-10-06 Boyd Malcolm R Nucleoside analogs in combination therapy of herpes simplex infections
WO1997026882A1 (en) * 1996-01-26 1997-07-31 Smithkline Beecham Plc Nucleoside analogs in combination therapy of herpes simplex infections
CZ297841B6 (en) * 1996-01-26 2007-04-11 Novartis International Pharmaceutical Ltd. Combined pharmaceutical compositions containing famciclovir or penciclovir and immunosuppressant for treating herpes simplex virus infections
US20080287389A1 (en) * 1996-01-26 2008-11-20 Malcolm Richard Boyd Nucleoside analogs in combination therapy of herpes simplex infections

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