GB2292081A - The use of a Neuraminidase Inhibitor in combination with an Influenza Vaccine - Google Patents
The use of a Neuraminidase Inhibitor in combination with an Influenza Vaccine Download PDFInfo
- Publication number
- GB2292081A GB2292081A GB9515754A GB9515754A GB2292081A GB 2292081 A GB2292081 A GB 2292081A GB 9515754 A GB9515754 A GB 9515754A GB 9515754 A GB9515754 A GB 9515754A GB 2292081 A GB2292081 A GB 2292081A
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- GB
- United Kingdom
- Prior art keywords
- influenza
- vaccine
- pharmaceutically acceptable
- administration
- acetamido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- 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
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
Compositions and methods are disclosed for the co-administration of the neuraminidase inhibitor 5-acetamido-2,3,4,5-tetradeoxy-4- guanidino-D-glycero-D-galacto-non-2-enopyranosonic acid (known as GG167) or a pharmaceutically acceptable salt thereof, and conventional influenza vaccine to prevent or treat symptomatic influenza. GG167 and the vaccine may be administered either together in a single formulation separately or sequentially, typically within 24 hours and preferably within 12 hours of each other. GG167 may be delivered by inhalation or insufflation through either the nose or mouth; preferably it is taken intranasally in the form of drops or sprays.
Description
COMPOSITIONS AND METHODS FOR THE PREVENTION OF SYMPTOMS
OF VIRAL INFECTION
The present invention relates to medicaments for the prevention of symptoms of viral infection.
PCT/AU91/00161 (publication no. WO91/16320) describes a number of derivatives of 5-acetamidino-2, 3, 5-trideoxy-P-glycero-P-galactonon-2- enopyranosonic acid (2,3,-dideoxy-2,3-didehydro-N-acetyl-neuraminic acid;
DANA) including the 4-guanidino analogue of DANA, which has the following structure:
4-guanidino analogue of DANA and the chemical name 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D- galacto-non-2-enopyranosonic acid, and is also known as GG167.
The compound of formula (1) has antiviral activity. In particular, this compound is an inhibitor of viral neuraminidase, for example, the viral neuraminidase of influenza A and B.
Pharmaceutical formulations, in particular formulations for intranasal administration, are also described in WO91116320.
Viral infections, for example, influenza, may be prevented by administration of a vaccine. Vaccines are preparations of antigenic materials which are capable of inducing in a mammalian recipient a specific active immunity. Vaccines for the prevention of influenza typically comprise a suitable strain or strains of influenza virus (or part thereof), types A and B, inactivated or attenuated so that they are non-infective but retain their antigenic properties.
As a means of preventing influenza virus infection, vaccination has a number of drawbacks. The production of antibodies in response to the vaccine is a relatively slow process and the recipient of the vaccine remains vulnerable to infection until a protective level of antibodies has been acquired. This is of particular importance since vaccination programmes, particularly involving vulnerable individuals such as the sick, the elderly and the immunologically comprised, are typically not initiated until an influenza epidemic is established. Furthermore, the subject may fail to respond to the vaccine by producing a protective level of antibodies and therefore remain susceptible to infection. Conversely, in the case of a poorly attenuated vaccine, the subject may become infected as a result of vaccination.
Also the strain or strains of influenza virus comprised in the vaccine are not able to confer immunity against new strains of virus if these are significantly different.
There is therefore a need to enhance the protection against influenza virus infection afforded by vaccination. We have now found that such enhanced protection can be achieved by co-administration of the compound of formula (I) with an influenza vaccine.
In a first aspect, the present invention accordingly provides a method for the prevention of symptomatic influenza virus infection in a mammalian subject which method comprises administration to said subject of an effective amount of an influenza vaccine and an effective amount of Sacetamido-2,3,4,5-tetradeoxy4- guanidino-I2-glycero-a-galacto-non-2-enopyranosonic acid or a pharmaceutically acceptable salt or solvate thereof.
As used herein, "symptomatic influenza virus infection" means an infection of influenza virus which is accompanied by the well known symptoms of such an infection and is used to distinguish infection accompanied by disease symptoms from the process involving generation of antibodies in response to virus.
In a second or altemative aspect, the present invention provides the use of (i) 5 acetamido-2, 3,4, 5-tetradeoxy-4-guanid ino-P-g lycero-P-galacto-non-2- enopyranosonic acid or a pharmaceutically acceptable salt or solvate thereof and (ii) influenza vaccine in the manufacture of a medicament for simultaneous, separate or sequential use in the prevention or treatment of symptomatic influenza.
In a further or altemative aspect, the present invention provides a product containing 5-acetamido-2,3,4,5-tetradeoxyXguanidino-aslycero-12-galacto-non- 2-enopyranosonic acid or a pharmaceutically acceptable salt or solvate thereof and influenza vaccine as a combined preparation for simultaneous, separate or sequential use for the prevention or treatment of symptomatic influenza.
The compound of formula (I) and the influenza vaccine are preferably coadministered in the form of separate pharmaceutical compositions for simultaneous andlor sequential use. Altematively, the compound of formula (I) and the vaccine may be administered as a single pharmaceutical composition.
Vaccines suitable for use in the method of the present invention include vaccines containing living or killed influenza virus or antigenic material from particular parts of such virus. Single-component vaccines and mixed combined vaccines are included.
Pharmaceutically acceptable salts of the compound of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of pharmaceutically acceptable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Salts derived from appropriate bases include alkali metal (e.g. sodium), alkali earth metal (e.g. magnesium), ammonium and NR+4 (where R is Ct,alkyl) salts.
Pharmaceutically acceptable solvates include hydrates.
For use in the methods according to the invention, the influenza virus vaccine may be administered by any convenient route, but will preferably be administered parenterally or by inhalation or insufflation.
The compound of formula (I) is administered by inhalation or insufflation via the nose or mouth. Suitable formulations for intranasal administration are described in WO91/16320, incorporated herein by reference. For administration via the mouth the compound of formula (I) may be administered by any of the methods and formulations employed in the art for administration by inhalation or insufflation through the mouth. Thus in general the compound of formula (I) may be administered to the lung in the form of a solution or a suspension or a dry powder.
The compound of formula (I) may be formulated with conventional pharmaceutically acceptable excipients. The compound of formula (I) may be micronised or non-micronised. The delivery systems currently available are pressurised metered dose inhalers, nebulisers and dry powder inhalers.
Suitable dosages for the compound of formula (I) are described in WO91/16320.
It will be appreciated that the amount of compound of formula (I) required will ultimately be determined by the attendant physician. For use in the methods of the present invention, it is necessary to select a dose which is effective in preventing the subject from developing symptomatic influenza or limiting influenzalike illness without preventing the production of antibodies to the influenza virus.
In general, a suitable daily dose will be in the range of about 0.01 to 750mg/kg of bodyweight preferably 0.1 to 100mgn < g, most preferably 0.5 to 25mgn < g, which may be administered as a single dose or as 2, 3, 4, 5, 6, 7, 8, 9 or 10 unit doses.
The compound of formula (I) is conveniently administered in unit dosage form, for example containing 0.5 to 1 500mg, such as 1 to 150 mg, for example 2 to 25mg of the compound of formula (I) per unit dosage form.
The methods of the present invention comprise administering the influenza virus vaccine and the compound of formula (I) either concurrently or non-concurrently.
The term "concurrently", as used herein, means that the two agents are administered within 24 hours of each other, preferably within about 12 hours of each other, more preferably within about 1 hour of each other and most preferably within about 5 minutes of each other. The term 'non-concurrently", as used herein, means that the two agents are administered more than 24 hours apart.
As stated hereinabove, where administration of the influenza virus vaccine and the compound of formula (I) takes place concurrently, the two agents may, if desired, be co-administered in a single composition. Such compositions are new and form a further aspect of the present invention.
Thus, the invention provides a pharmaceutical composition suitable for administration by inhalation or insufflation which composition comprises an influenza virus vaccine, 5-acetamido-2,3,4,Stetradeoxy-4-guanidino-a-glycero-x2- galacto-non-2-enopyranosonic acid or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier therefor.
Suitable pharmaceutically acceptable carriers are described in WO91/16320 and are incorporated herein by reference.
The compositions may be prepared according to a conventional techniques well known in the pharmaceutical industry. Thus, for example, the compound of formula (I) and the vaccine may be admixed together, if desired, with suitable excipients.
Preferably the compositions according to the invention will be formulated for intranasal administration, for example, in the form of drops or sprays.
The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. Where the compound of formula (I) and the vaccine are intended for administration as separate compositions, these may be presented in the form of, for example, a twin pack.
Thus, according to a further aspect, the present invention provides a twincontainer pack for use in the prevention of symptomatic influenza virus infection, one of the containers containing Sacetamido-2,3,4,Stetradeoxy-4-guanidino-X2- glycero-i2-galacto-non-2-enopyranosonic acid and the other containing influenza vaccine.
The methods of the present invention in which the agents are administered concurrently include any dosing regimen in which part or all of the dosing of the agents is performed concurrently. Typically, the dosing regimen employed will begin with concurrent administration of influenza virus vaccine and the compound formula (I) and proceed with administration of the compound of formula (I) alone.
Examples of suitable dosing regimes include: 1. Administration of a pharmaceutical composition according to the invention followed by administration of a unit dose of the compound of formula (I) within 12 hours and subsequent twice daily administration of unit doses of the compound of formula (I).
2. Administration of influenza virus vaccine and the compound of formula (I) simultaneously (i.e. within about 5 minutes of each other) followed by up to 7 days treatment with the compound of formula (I) .
3. Administration of the compound of formula (I) followed within 12 hours by administration of influenza virus vaccine and subsequent treatment with the compound of formula (I) for up to 7 days.
The following Example is illustrative of the use of 5-acetamido-2,3,4,5-tetradeoxy- 4-guanidino-fl-glycern-fl-galacto-non-2-enopyranosonic acid in the prevention of symptomatic influenza infection.
Example
ExPerimental desian. Four trials were conducted over six months. All were randomised, double-blind, placebo-controlled in design and followed similar protocol utilising the same challenge virus, influenza A/Texas/91 (HINI). The trials evaluated prophylaxis (dosing initiated 4 hours prior to viral inoculation), early treatment during the incubation period (dosing initiated 26 or 32 hours post inoculation), or delayed treatment (dosing initiated 50 hours post inoculation).
Dosing continued for 4 (treatment) or 5 (prophylaxis) days.
The first trial administered study drug six times daily every 3 hours while awake for either prophylaxis or early treatment. The second trial compared twice and six times daily early treatment, and six times daily delayed treatment. The third trial compared six times or twice daily prophylaxis. The fourth trial evaluated twice daily prophylaxis with nasal drops or sprays. To maintain the blind in the second and third trials, subjects received six daily doses with substitution of placebo at appropriate times in the twice daily or delayed treatment groups.
Drua administration. In the first three trials, GG167 16mg or a matching placebo of isotonic saline was administered as nasal drops (0.45ml per nostril). The same procedure was used for administering the viral inoculum. In the fourth trial reduced doses of GG167 were used (3.6 or 7.2mg), and volunteers were randomised to receive study drugs by drops or by intranasal sprays (0.1 my per spray) as one or two sprays per nostril twice daily. The total daily dose of GG167 ranged from 7.2 to 96mg.
RESULTS
Subiects. The four trials included 166 volunteers, of whom 125 were males. The mean (range) age 23 (18-41) years. Demographic characteristics were comparable across the GG167 and corresponding placebo groups. Six subjects (1 placebo, 5 GG167) were excluded from efficacy assessments because of preinoculation samples retrospectively detected shedding of a nonchallenge virus (2) andlor an elevated baseline HI antibody titer > 1:8 (5).
Prophylaxis. When all GG167 groups were combined for analysis, the frequency of viral shedding was reduced by 96% and the frequency of infection by 82% compared to placebo (p < 0.001 for each comparison). Those receiving intranasal drops of GG167, regardless of the dose or dosing frequency, had no evidence of viral shedding and marked reductions in the frequencies of infection (0 to 13%).
The protective efficacy of GG167 nasal drops was 100% against viral shedding (p < 0.001) and 90% against infection (73 versus 7 per cent, p < 0.001).
When GG167 was administered by nasal spray, 29% given one (3.6mg) or two
(7.2mg) applications per nostril became infected. Virus shedding was detected in
two subjects for one and six days post inoculation. The overall protective efficacy
of GG167 intranasal sprays was 83% for virus shedding and 60% for infection
( < 0.05 for each comparison).
Treatment. When GG167 was initiated one or two days after inoculation, the
infection rates in the GG167 groups (69 - 92%) did not differ significantly from the
corresponding placebo groups (73 - 92%).
Clinical efficacv.
Prophylaxis. Except for one subject receiving six intranasal doses daily, GG167
prophylaxis was completely protective against febrile illness. The overall efficacy
of GG167 was 94% in preventing fever (p < 0.001). Significant overall reductions
were also observed in total symptom scores1 nasal mucus weights, and the
frequencies of URI and cough, middle ear pressure abnormalities, and
acetaminophen' use. Each of these illness measures was reduced approximately
50 to 75% in the GG167 prophylaxis group compared to placebo.
Treatment. Early GG167 treatment also reduced the occurrence of febrile illness
with overall efficacy of 84% (38 versus 6%, p < 0.01). In addition, treatment was
associated with approximate 50% reductions in total symptoms scores, frequency
of cough, and nasal mucus weights (Table 4). The proportion of infected subjects
with middle ear pressure abnormalities was reduced by 58% and the average
number of days with abnormalities by 68% (p < 0.05 for each comparison).
Similarly, the proportion using acetaminophen was reduced by 66% and the
average number of days of use by 71% in the GG167 group (p < 0.05 for each
comparison). Early treatment with GG167 reduced illness severity as reflected in
lower symptom scores beginning on the evening of the second study day.
Acetaminophen was allowed for fever and discomfort
Whilst GG167 was effective in preventing infection, some subjects, particularly at the lower doses and with spray administration, achieved serologic conversion without viral shedding and associated illness.
In the delayed treatment group, the majority of subjects were already ill at the time of initiating GG167 administration. No obvious differences in symptom scores or other illness measures were noted in comparison to placebo, but this analysis was limited by small sample sizes and confounded by a higher illness frequency before initiating treatment in the GG167 group than the corresponding placebo group.
Claims (6)
1. The use of (i) Sacetamido-2,3,4,5-tetradeoxyXguanidino-aslycero-12- galacto-non-2-enopyranosonic acid or a pharmaceutically acceptable salt
or solvate thereof and (ii) influenza vaccine in the manufacture of a
medicament for simultaneous, separate or sequential use in the
prevention or treatment of symptomatic influenza.
2. The use as claimed in Claim 1 in which (i) and (ii) are presented as
separate compositions for said use.
3. A product containing 5-acetamido-2,3,4,5-tetradeoxyAguanidino-- glycero-D-galacto-non-2-enopyranosonic acid or a pharmaceutically
acceptable salt or solvate thereof and influenza vaccine as a combined
preparation for simultaneous, separate or sequential use for the
prevention or treatment of symptomatic influenza.
4. A pharmaceutical composition suitable for administration by inhalation or
insufflation which composition comprises an influenza virus vaccine, 5 acetamido-2,3,4,5-tetradeoxy4guanidino-12glycero-asalacto-non-2- enopyranosonic acid or pharmaceutically acceptable salt or solvate
thereof, and a pharmaceutically acceptable carrier therefor.
5. A twin-container pack for use in the prevention of symptomatic influenza
virus infection, one of the containers containing 5-acetamido-2,3,4,5 tetradeoxy-4guanidino-Dglycero-Dgalacto-non-2-enopyranosonic acid
and the other containing influenza vaccine.
6. A method for the prevention of symptomatic influenza virus infection in a
mammalian subject which method comprises administration to said
subject of an effective amount of an influenza vaccine and an effective
amount of 5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-Dglycero-Q- galacto-non-2-enopyranosonic acid or a pharmaceutically acceptable salt
or solvate thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9416365A GB9416365D0 (en) | 1994-08-12 | 1994-08-12 | Medicaments |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9515754D0 GB9515754D0 (en) | 1995-10-04 |
| GB2292081A true GB2292081A (en) | 1996-02-14 |
Family
ID=10759813
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9416365A Pending GB9416365D0 (en) | 1994-08-12 | 1994-08-12 | Medicaments |
| GB9515754A Withdrawn GB2292081A (en) | 1994-08-12 | 1995-08-01 | The use of a Neuraminidase Inhibitor in combination with an Influenza Vaccine |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9416365A Pending GB9416365D0 (en) | 1994-08-12 | 1994-08-12 | Medicaments |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB9416365D0 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072108A1 (en) * | 2001-03-12 | 2002-09-19 | Glaxo Group Limited | Use of fluticasone propionate in the treatment of diseases ameliorated by enhancement of epithelial/matrix adhesion such as asthma, cystic fibrosis and influenza |
| US6455571B1 (en) | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
| US6593314B1 (en) | 1999-10-19 | 2003-07-15 | Abbott Laboratories | Neuraminidase inhibitors |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991016320A1 (en) * | 1990-04-24 | 1991-10-31 | Biota Scientific Management Pty Ltd | Derivatives and analogues of 2-deoxy-2,3-didehydro-n-acetyl neuraminic acid and their use as antiviral agents |
-
1994
- 1994-08-12 GB GB9416365A patent/GB9416365D0/en active Pending
-
1995
- 1995-08-01 GB GB9515754A patent/GB2292081A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991016320A1 (en) * | 1990-04-24 | 1991-10-31 | Biota Scientific Management Pty Ltd | Derivatives and analogues of 2-deoxy-2,3-didehydro-n-acetyl neuraminic acid and their use as antiviral agents |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6455571B1 (en) | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
| US6593314B1 (en) | 1999-10-19 | 2003-07-15 | Abbott Laboratories | Neuraminidase inhibitors |
| WO2002072108A1 (en) * | 2001-03-12 | 2002-09-19 | Glaxo Group Limited | Use of fluticasone propionate in the treatment of diseases ameliorated by enhancement of epithelial/matrix adhesion such as asthma, cystic fibrosis and influenza |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9416365D0 (en) | 1994-10-05 |
| GB9515754D0 (en) | 1995-10-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |