WO2017174593A1

WO2017174593A1 - Novel antiviral compositions for the treatment of influenza

Info

Publication number: WO2017174593A1
Application number: PCT/EP2017/058009
Authority: WO
Inventors: Manuel Rosa-Calatrava; Olivier Terrier; Mario PIZZORNO; Guy Boivin; Blandine PADEY; Julien Textoris
Original assignee: Universite Claude Bernard Lyon 1; Institut National De La Sante Et De La Recherche Medicale (Inserm); Hospices Civils De Lyon; Universite Laval
Priority date: 2016-04-07
Filing date: 2017-04-04
Publication date: 2017-10-12
Also published as: FR3049861A1

Abstract

The invention relates to a veterinary or pharmaceutical composition for use in the prevention and/or treatment of an infection from at least one influenza virus, characterised in that it comprises, in a suitable pharmaceutical carrier, at least one antiviral compound selected from roxithromycin and sulfadimethoxine.

Description

NEW ANTIVIRAL COMPOSITIONS FOR THE

TREATMENT OF INFLUENZA

The invention relates to compositions for their use in the treatment of viral infections related to influenza viruses, in humans and in animals.

Influenza is a common and contagious viral infectious disease. The influenza viruses are the influenza viruses of the family Orthomyxoviridae, which are divided into three types: A, B and C. At the surface of the viruses are two glycoproteins which play an important role in the infected cells of the infected body: hemagglutinin (HA) and neuraminidase (NA). There are different subtypes of influenza A virus depending on the nature of the HA and NA glycoproteins on their surface: 16 types of HA and 9 types of NA have been identified in circulating viruses in the animal world and in particular among marine migratory birds . It is thus possible to define the influenza viruses according to the type of glycoproteins they possess on their surface.

Type A and B viruses are responsible for annual influenza epidemics, but only influenza A viruses cause influenza pandemics. Type C virus appears to be sporadic and most often causes moderate influenza.

In humans, viruses circulating for several decades are type A viruses, subtypes H1N1, H2N2 and H3N2, with occasional inter-species transmissions, particularly from animals to humans, for example viruses avians H5N1, H7N7, H7N9, H5N2 and H9N2. As the recent emergence of a new H1N1 pandemic influenza virus of porcine, avian and human origin (swine, avian and human reassortant viruses) highlights, influenza A viruses represent a serious threat to public health. Influenza pandemics are the result of antigenic breaks that correspond to the appearance of viruses with new surface glycoproteins (HA and NA) in the human population. These breaks allow the direct transmission to humans of animal and especially avian viruses: this is the case of highly pathogenic avian H5N1 outbreaks since 2003 in Asia, or outbreaks of H7N7 influenza in the Netherlands in 2003 and H7N9 in the Netherlands. in South-East Asia in 2013. Antigenic breaks are the result of genetic rearrangements between avian, porcine and human viruses, with pigs acting as intermediate hosts, for example. These rearrangements In particular, seasonal influenza epidemics, which are notably the result of genetic drift (appearance of mutations in surface glycoproteins in particular) are a major cause of the spread of H1N1. morbidity and increased mortality, especially in the human population, especially in very young individuals, the elderly, immunocompromised individuals and carriers of cardiopulmonary diseases.

Vaccination remains the cornerstone of influenza prevention. However, when a new virus appears, 6 to 9 months is needed for the development and delivery of a new vaccine, and the use of antiviral drugs should be considered for treatment. and / or prevention.

Common antivirals are M2 channel blockers such as amantadine, and neuraminidase inhibitors such as zanamivir and POseltamivir. The use of these drugs is limited by the recurring appearance of resistance, particularly observed for the pandemic H1N1 virus. In particular, it is not excluded that new emerging viruses are already resistant to these antiviral molecules. Finally, most of these molecules must be administered quickly after the onset of symptoms to be effective.

It therefore seems necessary to identify new antiviral compounds with the following advantages:

a broad spectrum of action, that is to say that these antiviral compounds would be able to act on different types and subtypes of viruses, and

- a minimized risk of inducing resistance in targeted viruses.

A solution for the development of new broad-spectrum therapeutic molecules is to identify molecules having an action on the pathways and cellular factors that target and / or divert the viruses to their advantage in order to carry out their replicative cycle. This strategy, presented in the article by Josset et al. (Plos One, 2010), allowed the identification of a first series of molecules with unexpected antiviral activity, such as the molecules presented in the patent application FR 2 953 410.

In the context of the present invention, several molecules have been selected and evaluated in a viral infection cell test as well as in a murine model in vivo. Some molecules have thus presented an antiviral effect not only on an influenza A strain of subtype H1N1, but also on a strain of subtype H3N2, and on a strain of virus type B.

The selected compounds had previously been described as antibiotics, and were used for the treatment of bacterial infections. Unexpectedly, it has now been shown that some of these compounds have antiviral activity in addition to their anti-bacterial activity.

SUMMARY OF THE INVENTION

The subject of the invention is pharmaceutical or veterinary compositions for their use in preventing and / or treating an infection by at least one influenza virus, characterized in that it comprises, in a suitable pharmaceutical vehicle, at least one antiviral compound selected from Roxithromycin and Sulfadimethoxine.

According to a particular aspect of the invention, the pharmaceutical or veterinary composition, for its use according to the invention, is in a dosage form intended for administration by inhalation.

These pharmaceutical or veterinary compositions may advantageously also comprise at least one other antiviral agent, and / or a bacterial agent.

The invention also relates to pharmaceutical or veterinary compositions comprising at least one antiviral agent in combination with Sulfadimethoxine, or with a combination of Roxithromycin and Sulfadimethoxine.

The invention also relates to pharmaceutical or veterinary compositions, comprising in a suitable pharmaceutical vehicle, a combination of Roxithromycin and Sulfadimethoxine.

According to a particular aspect of the invention, said compositions are in a dosage form intended for administration by inhalation.

FIGURES

Figure 1. In vitro evaluation of the antiviral effect of the compounds tested on A549 cells infected with the H1N1 virus pdm09.

(A) Experimental protocol, with pre-infection and post-infection treatments; (B) Effect of a compound known for its direct antiviral activity (Oseltamivir) and tested compounds: (C) Roxithromycin, (D) Sulfadimethoxine, (E) Sulfamonomethoxine, and (F) Benzathine bencylpenicillin.

The black line represents the evolution of normalized viral production (percentage) as a function of the concentration of the compounds (μΜ). The gray line represents normalized cell viability (percentage) as a function of compound concentration (μΜ).

Figure 2. In vitro evaluation of the antiviral effect of the compounds tested on A549 cells infected with the H1N1 virus pdm09.

(A) Experimental protocol, without pre-infection treatment and with post-infection treatment;

(B) Effect of a compound known for its direct antiviral activity (Oseltamivir) and tested compounds: (C) Roxithromycin, (D) Sulfadimethoxine, (E) Benzathine bencylpenicillin, and (F) Sulfamonomethoxine.

The black line curve represents the evolution of normalized viral production

(percentage) as a function of the concentration of the compounds (μΜ). The gray line represents normalized cell viability (percentage) as a function of compound concentration (μΜ).

Figure 3. In vitro evaluation of the antiviral effect of POseltamivir (A), Roxithromycin (B) and Sulfadimethoxine (C) on A549 cells infected with H3N2 virus (H3N2 A / Moscow / 10/1999) according to the same experimental protocol as that presented in FIG. 2A.

Figure 4. In vitro evaluation of the antiviral effect of POseltamivir (A), Roxithromycin (B) and Sulfadimethoxine (C) on A549 cells infected with a strain of influenza B virus (Massachusset / 2 / 2012) according to the same experimental protocol as that presented in Figure 2 A.

The black line represents the evolution of normalized viral production (percentage) as a function of the concentration of the compounds (μΜ). The curve in gray line represents the normalized cell viability (percentage) as a function of the concentration of the compounds (μΜ).

Figure 5. In vivo evaluation of the antiviral effect of the compounds Oseltamivir (solid black line), Roxithromycin (solid gray line) and Sulfadimethoxine (dashed black line) in a mouse model infected with H1N1 pdm09, in comparison with groups of uninfected, untreated mice (black dots) and mice infected with H1N1 pdm09 and untreated (gray dots).

(A) experimental protocol; the compounds are administered in pre-infection treatment (6 hours before infection with H1N1 pdm09 mice) and up to 4 days post-infection (1 daily administration by gavage);

(B) survival rate over time, up to 14 days post-infection;

(C) weight loss observed over time.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical or veterinary composition for its use in the prevention and / or treatment of an infection with at least one influenza virus, characterized in that it comprises, in a suitable pharmaceutical vehicle, at least one antiviral compound selected from Roxithromycin, Sulfadimethoxine, and derivatives thereof.

These compounds are known for use in other therapeutic applications not directly related to antiviral activity against influenza viruses in humans or animals. These compounds are in particular known for their antibacterial activity. It has now been shown that these compounds unexpectedly exhibit antiviral activity against different subtypes of influenza A and B viruses.

Roxithromycin

Roxithromycin, CAS number 80214-83-1, is an antibiotic of the family of semi-synthetic macrolides, very close to erythomycin, because of its chemical structure and its mechanism of antibacterial action. It has been described for the first time in the patent EP 033 255 ROUSSEL UCLAF. It presents the following chemical formula:

Formula (1) Roxithromycin is used in therapy to control certain sexually transmitted diseases of bacterial origin, bacterial infections of the upper and lower respiratory tract, asthma, bacterial infections of the gums, and against bacterial infections. associated with gastric and intestinal ulcers.

Roxithromycin is also used for the treatment of opportunistic bacterial infections occurring in HIV-infected patients, due to its activity against Cryptosporidium spp., Mycobacterium avium, Pneumocystis carinii and Toxoplasma gondii.

The use of Roxithromycin has also been proposed for the prevention of opportunistic bacterial infections occurring in patients infected with influenza viruses (D'Silva et al, 2009).

Its mechanism of action is based on the inhibition of the biosynthesis of bacterial proteins.

In view of its anti-inflammatory action, this molecule has also been proposed for the treatment of osteoarthritis and rheumatism, as well as for the relief of associated symptoms such as joint sensitivity and cartilage destruction (WO 2004/084911).

Recently, the use of Roxithromycin has been proposed for the treatment of acne and androgenic hair loss (WO2014 / 077712).

Patent EP 0876387 describes the use of Roxithromycin in the treatment of viral infections, in particular by the HIV virus: in combination with a treatment based on protease inhibitors, the presence of Roxithromycin makes it possible to optimize said treatment, increasing the capture by the cell of said inhibitor. It is not reported that Roxithromycin has a direct effect on the virus and / or its replication cycle.

Roxithromycin is currently available in two forms, the anhydrous form and the monohydrate form. It is sold under the brand names Surlid®, Rulide®, Biaxsig®, Roxar®, and Roximycin®, in the form of tablets or oral suspensions.

The half-life of Roxithromycin is approximately 10 to 12 hours. The typical human dosage is 300 mg once daily for two to five days for five to ten days.

For the purpose of the present invention, the term "Roxithromycin" refers to the

Roxithromycin in all its forms, especially in the form of salts, as well as all the molecules derived from the formula (1) presented above, having the same antiviral activity.

Roxithromycin is commercially available in particular in the following dosage forms: coated tablet, scored tablet, and oral suspension.

It has also been described in dosage forms such as injectable solutions and sustained release tablets.

The inventors have surprisingly identified that Roxithromycin acts globally on the target cells of the viruses, by strongly modulating the expression of a certain number of genes of these cells, and thus inducing a cellular state which is generally unfavorable to the cells. a viral infection.

In addition, a new galenic form of administration of Roxithromycin is proposed: it is a dosage form intended for administration by inhalation. Sulfadimethoxine

Sulfadimethoxine is an antibiotic compound of the family of sulfonamides, an antibiotic class characterized by the presence of a radical -SO2-NH. This family has been described in US Pat. No. 3,461,206.

From CAS number 122-11-2, Sulfadimethoxine, formerly called madribon, has the following chemical formula:

Formula (2)

Sulfadimethoxine is widely used in veterinary applications to prevent and / or treat bacterial infections that may affect livestock. For example, US Pat. No. 5,063,219 describes an anti-bacterial composition comprising Sulfadimethoxine for combating coccidiosis in farms, especially poultry farms.

Sulfadimethoxine can also be used in humans, where its anti-bacterial action has been demonstrated (US 4,470,978), for example for the treatment of respiratory and urinary tract infections. It is also proposed for the treatment of malaria, an infectious disease caused by a parasite of the genus Plasmodium (JPH0859471). It has also been used to treat patients with bacterial superinfection following Influenza virus infection (Puech et al., 1963).

Sulfadimethoxine acts on bacteria by inhibiting the bacterial synthesis of folic acid from para-aminobenzoic acid, thereby disrupting the metabolism of the bacterial cell.

For the purpose of the present invention, the term "Sulfadimethoxine" means Sulfadimethoxine in all its forms, especially in the form of salts, and all the molecules derived from the formula (2) presented above, having the same activity. antiviral. Sulfadimethoxine is commercially available in particular in the following dosage forms: premix medications and oral solutions.

It has also been described in galenic forms such as injectable solutions and chewable tablets.

The inventors have surprisingly identified that Sulfadimethoxine acts globally on the target cells of the viruses, by strongly modulating the expression of a certain number of genes of these cells, and thus inducing a cellular state that is generally unfavorable to the cells. a viral infection.

Moreover, a new galenic form of administration of Sulfadimethoxine is proposed: it is a dosage form intended for administration by inhalation.

Table 1 below shows the pharmacological data of the compounds mentioned above:

Table 1

Influenza viruses

Within the meaning of the invention, the term "influenza virus" means the etiologic agents of type A, B or C influenza, and in particular influenza type A and type B viruses, having for host the human or the animal. The terms "influenza virus" and "influenza virus" are used interchangeably in the application and refer to the same viruses.

The compositions according to the invention are in particular intended for use in the prevention of infection by influenza viruses. The term "prevention" refers to preventing, or at least decreasing the probability of occurrence, an infection in a human or animal body by at least one influenza virus. By administering at least one composition according to the invention, the human or animal cells of said organism become less permissive to infection, and are thus more likely not to be infected by said virus.

The compositions according to the invention may also be intended for use in the treatment of influenza virus infection.

The term "treatment" refers to fighting infection with at least one influenza virus in a human or animal organism. Thanks to the administration of at least one composition according to the invention, the rate of viral infection in the body will gradually decrease until disappearing completely. The term "treatment" also refers to the fact of alleviating the symptoms associated with the viral infection (fever, fatigue, etc.).

According to one aspect of the invention, the compositions of the present invention are used for the prevention and / or treatment of infections with at least one type A influenza virus. Advantageously, the compositions of the present invention have a spectrum of action against the different subtypes of type A influenza viruses.

In one embodiment, the compositions of the present invention are used for the prevention and treatment of circulating type A virus infections primarily in humans and animals. There are different subtypes of influenza A virus depending on the nature of the HA and NA glycoproteins on their surface.

According to one particular aspect, the influenza virus is a type A virus selected from the subtypes H1N1, H2N2, H3N2, H5N1, H7N7, H7N9, H5N2 and H9N2.

According to another aspect of the invention, the compositions of the present invention are used for the prevention and / or treatment of infections with at least one type B influenza virus.

The invention thus relates to the prevention and / or treatment of infections by influenza viruses in humans, ie to a pharmaceutical composition for its use in the prevention and / or treatment of a infection with influenza viruses.

The invention also relates to the prevention and / or treatment of infections with influenza viruses in animals, particularly in farm animals such as pigs, horses and poultry. More particularly, the subject of the invention is prevention and / or treatment of influenza virus infections in poultry, especially hens, ducks, geese, turkeys and turkeys. The invention also relates to the prevention and treatment of influenza virus infections in mammals such as horses, cats, dogs and felines.

According to this aspect, the invention therefore relates to a veterinary composition for its use in the prevention and / or treatment of infection with influenza viruses. Therapies commonly used by those skilled in the art

Conventional therapy of a viral infection by an influenza virus in an organism, especially in a human patient, generally includes two stages, simultaneous or not, and their order being indifferent:

(1) administering antiviral compounds for controlling the virus or viruses, either by acting directly on the virus or by acting on the overall state of the target cells of the organism, so as to make them less sensitive to the virus; viral infection, and thus ultimately reducing the viral load;

(2) administration of anti-bacterial compounds to prevent the occurrence of so-called opportunistic bacterial infections, also referred to as "bacterial superinfections".

The term "anti-bacterial compounds" refers to compounds that act directly on bacteria by inhibiting their access to an organism and / or by inhibiting their proliferation and / or their biosynthesis and secretion of toxic products for the organism harboring said bacteria.

In the context of step (2), a person skilled in the art may decide to administer antibiotic compounds of the macrolide family, such as Roxithromycin, and / or the family of sulfonamides, such as Sulfadimethoxine. , in order to fight against a possible bacterial superinfection.

US Patent Application No. 2005/0043253 discloses, in particular, healing compositions containing antibiotic compounds, such as Roxithromycin and / or Sulfadimethoxine, used for their antibacterial properties. These compositions are intended for topical intranasal application, and prevent the entry of influenza viruses in an organism treated, the skin being repaired and therefore less conducive to penetration by infectious agents. Thus, in these compositions, the agents for preventing viral infection are the cicatrizing agents such as bacitracin, polymyxin, and neomycin, prepared under a suitable dosage form such as a cream, and the antibiotic agents mentioned above are present to prevent possible bacterial superinfection.

The present invention specifically relates to the use of Roxithromycin and / or Sulfadimethoxine in step (1), for their antiviral action against influenza virus (s) having infected or likely to infect a host organism.

Indeed, until now it has never been observed that Roxithromycin and / or Sulfadimethoxine may be particularly effective in inhibiting the replication and / or spread and / or penetration of a virus. influenza in an organism, in particular a mammalian organism, and more particularly a human organism.

As indicated in the examples, this anti-viral action is evaluated by measuring various factors such as viral production in infected cells in vitro, and survival of mice infected with the virus in vivo.

By "antiviral action" or "antiviral action" is meant an action on the influenza virus or its target cells, including the action of inhibiting the replication cycle of the virus or its ability to infect and reproduce in host cells, this antiviral effect being obtainable by the modulation of a number of genes of the target cells.

Thus, within the meaning of the present invention, the terms "antiviral agent" or "antiviral compounds" are understood to mean active agents that act on viral load, by inhibiting either directly or indirectly replication and / or dissemination. influenza viruses in an infected organism.

As indicated above, these antiviral compounds can act on the virus (direct action) or on its target cells (indirect action).

By 'target cells' are meant cells that are infected with the virus and / or likely to be infected soon, because of their immediate proximity to infected cells.

Such an anti-viral effect is different from an anti-bacterial effect whose therapeutic effect can be observed on patients infected with an influenza virus which are thus protected from bacterial superinfections, but which is not the object of this present invention. invention. Specific implementations of the invention

According to a first aspect of the invention, the pharmaceutical or veterinary composition comprises an effective amount of Roxithromycme or a derivative thereof, for its use in the prevention and / or treatment of infection with at least one influenza virus.

According to a second aspect of the invention, the pharmaceutical or veterinary composition comprises an effective amount of Sulfadimethoxine or a derivative thereof for use in the prevention and / or treatment of infection with at least one influenza virus.

For the purposes of the invention, the term "effective amount" is intended to mean an amount of antiviral compound which is sufficient to inhibit the proliferation and / or replication of the virus, and / or the development of the viral infection in the body. This inhibition can be quantified, for example by measuring virus production as presented in the examples of the present application.

According to a third aspect of the invention, the pharmaceutical or veterinary composition comprises a combination of Roxithromycme and Sulfadimethoxine, for its use in the prevention and / or treatment of infection with at least one influenza virus.

Such a combination comprises either the same dose of each antiviral compound (50/50 by weight composition) or unequal doses of each antiviral compound, such as 90% Roxithromycin and 10% Sulfadimethoxine, 80% Roxithromycin and 20% of Sulfadimethoxine, 70% Roxithromycin and 30% Sulfadimethoxine, 60% Roxithromycin and 40% Sulfadimethoxine, 40% Roxithromycin and 60% Sulfadimethoxine, 30% Roxithromycin and 70% Sulfadimethoxine, 20% Roxithromycin and 80% Sulfadimethoxine, or alternatively 10% Roxithromycme and 90% Sulfadimethoxine.

Combination with another anti-viral agent

According to a particular aspect of the invention, the pharmaceutical or veterinary composition comprising an effective amount of Roxithromycme and / or Sulfadimethoxine for use as described above is characterized in that it further comprises another anti viral agent. Indeed, Roxithromycin and Sulfadimethoxine or mixtures thereof can be used in therapy alone, or in combination with at least one other active agent.

They may be compounds which make it possible to improve the activity of the antiviral compounds Roxithromycin and / or Sulfadimethoxine, or else other active agents known for their use as antiviral agents in the treatment of influenza virus infections.

According to one particular aspect of the invention, the pharmaceutical or veterinary composition for its use in the prevention and / or treatment of an infection with at least one influenza virus, comprises, in addition to Roxithromycin and / or Sulfadimethoxine, a another antiviral agent having a direct inhibitory activity on at least one influenza virus.

As previously stated, the term "antiviral agent having a direct inhibitory activity on at least one influenza virus" an antiviral agent acting directly on the virus and / or one of its determinants, inhibiting its replication or preventing its penetration or its propagation in an infected organism.

According to a preferred aspect, the antiviral agent is chosen from antiviral agents well known to those skilled in the art, conventionally used to prevent or treat influenza.

Such antiviral agents active on at least one influenza virus are commercially available, and described in reference works such as The Vidal Dictionary.

According to a first aspect of the invention, the pharmaceutical or veterinary composition comprises Roxithromycin and at least one other antiviral agent, in particular having a direct inhibitory activity on at least one influenza virus, for its use in the prevention and / or treatment Infection with influenza viruses.

According to a second aspect of the invention, the pharmaceutical or veterinary composition comprises Sulfadimethoxine and at least one other antiviral agent, in particular having a direct inhibitory activity on at least one influenza virus, for its use in the prevention and / or treatment Infection with influenza viruses.

According to a third aspect of the invention, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, and at least one other antiviral agent, in particular having a direct inhibitory activity on at least one influenza virus, for its use in prevention. and / or treating an infection with influenza viruses. In particular, this other antiviral agent having a direct inhibitory action on at least one influenza virus is chosen from the following compounds: POseltamivir (also called Tamiflu), Zanamivir, Peramivir, Amantadine, Rimantadine, Ribavirin and Arbidol.

This antiviral agent can also be chosen from:

• viral polymerase inhibitors (eg T705);

• nucleoprotein inhibitors;

• hemagglutinin inhibitors;

• neuraminidase inhibitors;

· NS 1, M 1, M2, Pb 1 -F 2, and NEP inhibitors.

This other antiviral agent may also be chosen from active agents on the target cells, inducing cellular conditions that are generally unfavorable to a viral infection, and therefore having an indirect so-called antiviral action.

These antiviral agents having an indirect action can be chosen from the following compounds: Midodrine, Desglymidodrine, Rilmenidine, Brinzolamide, Diltiazem, Etiléfrine, Monensine and Biperidene.

This other antiviral agent can also be chosen from:

Recombinant sialidases (ex D AS 181);

• inhibitors of NFKB;

· HSP90 inhibitors; and

• Raf, Mek, Erk or PKC cellular protein kinase inhibitors.

According to another aspect of the invention, the other antiviral agent is chosen from the following compounds: Diltiazem, Etiléfrine, Monensine and Biperidene.

It is understood that this other antiviral agent will be used at the doses necessary to have an antiviral action, this dose being designated as being "effective", this dosage can be easily determined by those skilled in the art.

Combinations with Roxithromycin

According to a first aspect of the invention, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Oseltamivir, for its use in the prevention and / or treatment of infection with at least one influenza virus. In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Zanamivir, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Peramivir, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Amantadine, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Rimantadine, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Ribavirin, for use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Arbidol, for use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Monensin, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Diltiazem, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Etilofine, for its use in the prevention and / or treatment of infection with at least one influenza virus. In a particular aspect, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with Biperidene, for use in the prevention and / or treatment of infection with at least one influenza virus. Combinations with Sulfadimethoxine

According to a second aspect of the invention, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Oseltamivir, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Zanamivir, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Peramivir, for use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Amantadine, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Rimantadine, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Ribavirin, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Arbidol, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Monensine, for its use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Diltiazem, for its use in preventing and / or treating an infection by at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Etilofine, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with Biperidene, for its use in the prevention and / or treatment of infection with at least one influenza virus. Combinations with Sulfadimethoxine and Roxithromycin

According to a third aspect of the invention, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, in combination with Oseltamivir, for its use in the prevention and / or treatment of influenza virus infection. .

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Zanamivir, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Peramivir, for use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Amantadine, for use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Rimantadine, for its use in the prevention and / or treatment of infection with at least one influenza virus. In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Ribavirin, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Arbidol, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Monensin, for use in preventing and / or treating an infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Diltiazem, for its use in preventing and / or treating an infection by at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Etilofine, for its use in the prevention and / or treatment of infection with at least one influenza virus.

In a particular aspect, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, with Biperidene, for its use in the prevention and / or treatment of infection with at least one influenza virus.

Combination with an anti-bacterial agent

The pharmaceutical or veterinary composition for its use according to the invention may also comprise at least one antibacterial agent. Such an agent will be in particular an antibiotic, intended to prevent bacterial superinfections conventionally observed in complications of influenza virus infections.

Advantageously, this antibacterial compound will be different from the

Roxithromycin and Sulfadimethoxine. According to a first aspect of the invention, the pharmaceutical or veterinary composition comprises Roxithromycin, in combination with an antibacterial agent, for its use in the prevention and / or treatment of influenza virus infection.

According to a second aspect of the invention, the pharmaceutical or veterinary composition comprises Sulfadimethoxine, in combination with an antibacterial agent, for its use in the prevention and / or treatment of influenza virus infection.

According to a third aspect of the invention, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, in combination with an antibacterial agent, for its use in the prevention and / or treatment of influenza virus infection.

According to a fourth aspect of the invention, the pharmaceutical or veterinary composition comprises a combination of Roxithromycin and Sulfadimethoxine, in combination with another antiviral agent, in particular Oseltamivir, and an antibacterial agent, for its use in the prevention and / or or treating an infection with influenza viruses.

It is understood that all the combinations of two or three active compounds mentioned above may each comprise, in addition, at least one antibacterial agent, in particular an antibiotic, and in particular an antibiotic other than the

Roxithromycin and Sulfadimethoxine.

Galenic pharmaceutical compositions

According to the invention, the term "suitable pharmaceutical vehicle" designates pharmaceutically acceptable vehicles or excipients according to the invention, ie vehicles or excipients whose administration to an individual or an animal is not accompanied by significant deleterious effects, and which are well known to those skilled in the art.

The pharmaceutical and veterinary compositions for use according to the present invention are suitable for oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, ocular or rectal administration.

According to a particular aspect of the invention, the pharmaceutical and veterinary compositions for use according to the present invention are not formulated for a topical application, especially are not formulated for topical intranasal application.

According to a preferred aspect of the invention, the pharmaceutical or veterinary composition for its use in the prevention and / or treatment of infection with at least one influenza virus is characterized in that it is in a dosage form intended for a inhalation administration.

Inhalation refers to absorption through the respiratory tract. It is in particular a method of absorbing compounds for therapeutic purposes, certain substances in the form of gas, microdroplets or powder in suspension.

The administration of pharmaceutical or veterinary compositions by inhalation, that is to say by the nasal and / or oral routes, is well known to those skilled in the art.

There are two types of administration by inhalation:

Insufflation administration when the compositions are in the form of powders, and

The administration by nebulization when the compositions are in the form of aerosols (suspensions) or in the form of solutions, for example of aqueous solutions, put under pressure. The use of a nebulizer or a sprayer will then be recommended for administering the pharmaceutical or veterinary composition.

The dosage form considered here is therefore chosen from: a powder, an aqueous suspension of droplets or a solution under pressure.

Combination product

The present invention also relates to a combination product comprising at least one antiviral compound selected from Roxithromycin and Sulfadimethoxine, and at least one antiviral agent and / or an antibacterial agent, for simultaneous, separate or sequential use to prevent and / or treat infection with at least one influenza virus, in humans or animals.

Such a combination product may be used in the prevention and / or treatment of infection with at least one influenza virus, in the context of simultaneous, separate or sequential use. Thus, the two antiviral agents included in the combination product may be administered simultaneously, separately or sequentially.

It is understood that all the combinations of two, three or four active compounds mentioned above may each be in the form of a combination product, i.e. the two, three or four active compounds may be administered simultaneously, separately or sequentially, to prevent and / or treat an infection with at least one influenza virus.

The invention also relates to a therapeutic method for preventing and / or treating an infection with at least one influenza virus (influenza virus) in humans, wherein a patient is administered an effective amount of an antiviral compound selected from Roxithromycin and Sulfadimethoxine, or a mixture of both, optionally in combination with another antiviral compound.

The invention also relates to a therapeutic method for the prevention and / or treatment of an influenza virus infection in animals in which an animal is administered an effective amount of an antiviral compound selected from Roxithromycin and Sulfadimethoxine, optionally in combination with another antiviral compound. Advantageously, the animal is a farm animal such as, for example, pork, horse or even poultry and domestic animals (dogs, cats, etc.).

Pharmaceutical or veterinary compositions

The present invention also relates to a pharmaceutical or veterinary composition, comprising in a suitable pharmaceutical vehicle, at least one antiviral agent in combination with Sulfadimethoxine, or with a combination of

Roxithromycin and Sulfadimethoxine.

In a preferred aspect, the antiviral agent other than sulfadimethoxine is selected from antiviral agents well known to those skilled in the art, and conventionally used to prevent or treat influenza.

According to a particular aspect of the invention, the pharmaceutical or veterinary composition comprises, besides Sulfadimethoxine and optionally Roxithromycin, an antiviral agent having a direct inhibitory activity on at least one influenza virus. The antiviral agents other than Sulfadimethoxine having a direct inhibitory action on at least one influenza virus will be chosen in particular from the following agents: Oseltamivir, Zanamivir, Peramivir, Amantadine, Rimantadine, Ribavirin and Arbidol.

This other antiviral agent can also be chosen from:

• viral polymerase inhibitors (eg T705);

• nucleoprotein inhibitors;

• hemagglutinin inhibitors;

• neuraminidase inhibitors;

· NS 1, M 1, M2, Pb 1 -F 2, and NEP inhibitors.

According to one embodiment of the invention, the pharmaceutical or veterinary composition comprises, in a suitable pharmaceutical vehicle, Oseltamivir in combination with Sulfadimethoxine, or a combination of Sulfadimethoxine and Roxithromycin.

According to one embodiment, said composition comprises

Sulfadimethoxine and Oseltamivir.

In another embodiment, said composition comprises a combination of Roxithromycin and Sulfadimethoxine and Oseltamivir.

This antiviral agent, other than Sulfadimethoxine, may also be chosen from agents that are active on the target cells of the virus, inducing cellular conditions that are generally unfavorable to a viral infection, whose action is said to be indirect.

These antiviral compounds having an indirect action may especially be selected from the following compounds: Midodrine, Desglymidodrine, Rilmenidine, Brinzolamide, Diltiazem, Etiléfrine Monensine and Biperidene.

This antiviral agent having an indirect action may also be chosen from the following compounds:

Recombinant sialidases (ex D AS 181);

• inhibitors of NFKB;

• HSP90 inhibitors; and

· Raf, Mek, Erk or PKC cellular protein kinase inhibitors. According to a preferred aspect of the invention, the antiviral agent other than Sulfadimethoxine is chosen from the following compounds: Diltiazem, Etiléfrine, Monensine and Biperidene.

It is understood that all the combinations of two, three or four active compounds mentioned above are pharmaceutical or veterinary compositions according to the invention.

The invention therefore relates specifically to:

a pharmaceutical or veterinary composition comprising, in a suitable pharmaceutical vehicle, at least one antiviral agent with Sulfadimethoxine; and

a pharmaceutical or veterinary composition comprising, in a suitable pharmaceutical vehicle, at least one antiviral agent with Sulfadimethoxine and Roxithromycin.

This antiviral agent will preferably be selected from those listed in the present application.

In yet another aspect, the pharmaceutical or veterinary composition according to the invention comprises, in a suitable pharmaceutical vehicle, a combination of Roxithromycin and Sulfadimethoxine.

This combination comprises either the same dose of each antiviral compound (50/50 by weight composition) or unequal doses of each antiviral compound, such as 90% Roxithromycin and 10% Sulfadimethoxine, 80% Roxithromycin and 20% Sulfadimethoxine, 70% Roxithromycin and 30% Sulfadimethoxine, 60% Roxithromycin and 40% Sulfadimethoxine, 40% Roxithromycin and 60% Sulfadimethoxine, 30% Roxithromycin and 70% Sulfadimethoxine, 20% Roxithromycin and 80% Sulfadimethoxine. Sulfadimethoxine, or alternatively 10% Roxithromycin and 90% Sulfadimethoxine.

The pharmaceutical compositions of the present invention are suitable for oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, ocular or rectal administration, wherein the active compound (antiviral compound) can be administered in unit dosage forms, in a mixture with conventional pharmaceutical carriers, animals or humans.

According to a preferred aspect of the invention, the pharmaceutical or veterinary composition is in a dosage form intended for local administration, such as a administered via the mucous membranes of the respiratory tract, that is to say an administration by inhalation.

Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.

When a solid composition in tablet form is prepared, the main active compound is mixed with a suitable pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

A preparation in capsules is obtained by mixing the active compound with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A syrup or elixir preparation may contain the active compound together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.

The water-dispersible powders or granules may contain the active compound in admixture with dispersants or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.

EXAMPLES

Introduction

Studies of the cellular transcriptomic response during an influenza infection have made it possible to highlight the signaling pathways solicited and / or diverted during infection, in vitro in cells in culture. This allowed to characterize in vitro "transcriptomic signatures" specific for infection with different influenza viruses, both human and avian (Josset et al., PLoS One, 2010, Terrier et al., Virol J, 2011, Terrier et al., J Gen Virol, 2013). The same strategy was optimized and applied to in vivo cell samples from nasal washings of 9 patients to characterize the in vivo signatures of pandemic H1N1 infection (pdm09). These transcriptomic signatures were obtained on the Affymetrix 450 fluid platform (GeneChip Human Genome U133 plus 2.0 chip), using various bioinformatic analysis tools. After an "in silico" screening in public databases such as Connectivity Map (Broad Institute, MIT), 34 molecules were selected, including Etiléfrine, Diltiazem (see PCT application / EP2016 / 056036), Monensin, Biperidene, Roxithromycin, Sulfadimethoxine, Sulfamonomethoxine and Benzathine Bencylpenicillin.

We chose to evaluate four candidate molecules known for their anti-bacterial activity:

Roxythromycin (sub-family of macrolides)

Sulfadimethoxine (sub-family of sulfonamides)

Sulfamonomethoxine (sub-family of sulfonamides)

Benzathine benzylpenicillin (subfamily penicillin).

These molecules were evaluated for their antiviral activity in cellular infection model in vitro, on the A549 line of human lung epithelium, and in vivo in an infectious murine model.

Detailed protocol for culture and infection:

A. Culture of human cells A549

A549 cells (human lung epithelial carcinoma line) are maintained in culture in DMEM medium (Dulbecco modified medium, BioWhittaker) supplemented with 10% (v / v) fetal calf serum, 2 mM L-glutamine, 100 ml. U / mL penicillin and 100 μg / mL streptomycin, in a 37 ° C incubator, at a saturated humidity atmosphere containing 5% CO 2. At confluence, the cells are detached from the support by treatment with trypsin-EDTA and re-seeded in a culture flask containing 15 ml of fresh medium. Three days before the infection stage, 0.75 × 10 ⁶ cells are distributed by 25 cm ² flasks (T25), in medium at 10% fetal calf serum so as to obtain 70-80% confluence during 'infection. B. Infection of cells with representative influenza viruses

The cells are infected with the different influenza viruses at a multiplicity of infection (moi) of 0.1 in DMEM, 2 mM of L-glutamine, 100 U / mL of penicillin and 100 μg / mL of streptomycin, and 0, 5 μg / mL of trypsin.

The viruses used are, depending on the examples:

Examples 1 and 2 (FIGS. 1 and 2): human influenza A H1N1 virus (H1N1 A / Pdm / 09),

Example 3 (FIG. 3): human influenza A virus H3N2 (Ή3Ν2 A / Moscow / 10/99

Example 4 (FIG. 4): Human influenza B virus (Massachusset / 2/2012)

C. Pre-infection treatment and in vitro post-infection treatment

The molecules were tested on A549 cells at 70-80% confluency. The cells are incubated for 6 h with different concentrations of indicated molecules, then they were infected by the different viruses for 1 h, and were returned to the presence of the molecules at the same concentrations. Under controlled conditions, the A549 cells are incubated in the same medium and the same culture conditions described above and without treatment.

D. Pre-infection treatment and in vivo post-infection treatment

The molecules were tested in C57BL / 6 mouse model (7-8 weeks of age). The mice were treated with the molecules (by gavage of different doses) 6 hours before infection with the H1N1 pdm09 virus (10 ⁵ PFU) and then treated with the same molecules (by gavage of different doses) once a day, during 5 days. Under controlled conditions, the mice were force-fed with a so-called "Saline" solution consisting of PBS (phosphate buffer solution).

E. Measures

A cytotoxicity test and a virus quantification test are performed after 48 hours of incubation at 37 ° C. under 5% CO 2. The cytotoxicity of the different molecules is determined at each test in a non-infected cell plate by a viability test (MTS test, Promega). This test is based on the measurement of the metabolic activity of cells, which transforms a substrate (MTS tetrazolium) into a product (Formazan), soluble in the medium and whose absorbance measured at 490 nm proportionally reflects the number of living cells. . The ratio of the absorbance in each well to the average absorbance control cell wells (untreated by the molecules) are calculated and indicated in the schemes as an index of cell viability (relative cell viability).

The effect on viral production in vitro is measured by determination of infectious titres (DITC50 / mL) performed in MDCK cells, the titres being calculated according to the technique of Reed and Muench. The ratio of infectious titer in each condition was expressed according to the infectious titer measured in the control condition (without treatment).

The in vivo antiviral effect is assessed by survival rate and weight loss and gain over time, up to 14 days post-infection, compared to control (saline).

Example 1. In vitro evaluation of the antiviral effect of various selected compounds on H1N1-infected A549 cells.

The protocol for pre-infection treatment and post-infection treatment of the cells is shown schematically in FIG. 1A. Several concentrations were tested and are plotted on the abscissa for each graph.

The cells are pre-treated for 6 hours with the different molecules tested and at different concentrations, and are then subjected to infection with the H1N1 virus pdm09 for one hour. The treatment with the different molecules tested is then resumed for 48 hours after infection. The measurements made at the end of the treatment as described above make it possible to determine the effect of the compounds tested on the viral production.

Figure 1 shows the results obtained for the following molecules: Oseltamivir (Fig. 1B), Roxithromycin (Fig. 1C), Sulfadimethoxine (Fig. 1D), Sulfamonomethoxine (Fig. 1E) and Benzathine bencylpenicillin (Fig. 1F). The black curves represent normalized virus production, the gray curves the normalized cell viability.

As expected, the Oseltamivir compound known for its antiviral activity induces a significant decrease in normalized viral production.

More surprisingly, Roxithromycin and Sulfadimethoxine also show a significant decrease in normalized virus production. In this administration protocol, Sulfamonomethoxine and Benzathine bencylpenicillin also show a significant decrease in normalized viral production. Example 2. In vitro evaluation of the antiviral effect of various selected compounds on A549 cells infected with H1N1, without pre-infection treatment.

The cell treatment protocol is shown schematically in FIG. 2A. Several concentrations were tested and are plotted on the abscissa for each graph.

The cells are first infected with H1N1 virus pdm09 for one hour. The treatment with the different molecules tested starts at 6 hours post-infection. The measurements made at the end of the treatment as described above make it possible to determine an antiviral dose-effect curve.

Figure 2 shows the results obtained for the following molecules: Oseltamivir (Figure 2B), Roxithromycin (Figure 2C), Sulfadimethoxine (Figure 2D), Benzathine bencylpenicillin (Figure 2E) and Sulfamonomethoxine (Figure 2F). The black curves represent normalized virus production, the gray curves the normalized cell viability.

More surprisingly, Roxithromycin and Sulfadimethoxine also show a significant decrease, although less marked than that observed with Oseltamivir, in normalized virus production.

On the other hand, Sulfamonomethoxine and Benzathine bencylpenicillin, without the pre-treatment phase, do not make it possible to reduce viral production, whatever the concentration tested.

Example 3 In vitro evaluation of the antiviral effect of various selected compounds on A549 cells infected with the H3N2 viral subtype, without pre-infection treatment.

The treatment protocol is shown schematically in FIG. 2A, and the experimental conditions are the same as those described in example 2. The H3N2 virus used for the infection is: A / Moscow / 10/99 strain.

Figure 3 shows the results obtained for the following molecules: Oseltamivir (Figure 3A), Roxithromycin (Figure 3B), Sulfadimethoxine (Figure 3C). Black curves represent normalized virus production, gray curves normalized cell viability. As expected, Oseltamivir significantly reduces viral production.

Surprisingly, Roxithromycin and Sulfadimethoxine show a significant decrease in normalized virus production.

Example 4 In vitro evaluation of the antiviral effect of various selected compounds on A549 cells infected with a strain of Influenza B virus, without pre-infection treatment

The treatment protocol is shown schematically in FIG. 2A, and the experimental conditions are the same as those described in example 2. The type B virus used for the infection is the strain Massachusset / 2/2012.

Figure 4 shows the results obtained for the following molecules: Oseltamivir (Figure 4A), Roxithromycin (Figure 4B), Sulfadimethoxine (Figure 4C). Black curves represent normalized virus production, gray curves normalized cell viability.

As expected, Oseltamivir significantly reduces viral production. The compounds Roxithromycin and Sulfadimethoxine are also effective in inhibiting viral production. Example 5 In vivo evaluation in mice of the effects of the following molecules: Oseltamivir, Roxithromycin, and Sulfadimethoxine.

The B57BL / 6 mice at 7-8 weeks of age are treated by gavage 6 hours before infection with the HlN1 pdm09 virus (10 ⁵ PFU), according to the protocol shown schematically in FIG. 5A.

Two negative witnesses are put in place:

• "Uninfected / untreated" means mice that are not exposed to either the virus or the evaluated molecules;

• "Infected / Saline gavage" refers to infected mice that have been treated with PBS buffer.

The following daily amounts were administered by gavage to mice from day 0 to day 4 after infection:

- Oseltamivir: 10 mg / kg / day Roxithromycin: 400 μg / day per mouse (20 mg / kg)

Sulfadimethoxine: 500 μg / day per mouse (25 mg / kg)

The following parameters are evaluated over time:

Fig 5B: survival rate over time, up to 14 days post-infection;

Fig 5C: loss and weight gain observed over time.

Roxithromycin (continuous gray curve) and Sulfadimethoxine (dashed black curve) are almost completely superimposed, they allow survival of infected mice by approximately 45%, a slightly lower survival rate than that obtained with treatment with Oseltamivir (continuous black curve, 55% survival).

In contrast, control mice infected and then force-fed with a solution of PBS (gray dashed curve) allow only a low survival rate, around 15%.

The weight loss curve of the mice treated with Roxithromycin or Sulfadimethoxine is correct, of the same nature as that observed for Oseltamivir (minimum weight reached at 8 days post-infection, then recovered).

REFERENCES

PATENTS

FR 2,953,410

EP 033 255

WO 2004/084911

EP 876,387

WO 2014/077712

US 3,461,206

US 5,063,219

US 4,470,978

JPH 0859471

US 2005/0043253 SCIENTIFIC LITERATURE

- Josset L, Textoris J, Loriod B, Ferraris O, V Molds, Lina B, N'guyen C, Diaz JJ, Rosa-Calatrava M. "Gene signature-based expression screening identified new broadly effective influenza antiviral. »PLoS One. 2010 Oct 4; 5 (10).

- Terrier O, Josset L, Textoris J, Marcel V, Cartet G, Ferraris O, N'guyen C, Lina B, Diaz JJ, Bourdon JC, Rosa-Calatrava M. "Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway. Virol J. 2011 Jun 8; 8: 285.

Terrier O, Textoris J, Carron C, Marcel V, Bourdon JC, Rosa-Calatrava M. "Host microRNA molecular signatures associated with human H1N1 and H3N2 influenza A viruses reveal anantanticipated antiviral activity for miR-146a. J Gen Virol. 2013 May; 94 (Pt 5): 985-95.

- Silva, Hewagama S, Doherty R, Korman TM, Buttery J. "Melting muscles: novel H1N1 influenza A associated rhabdomyolysis." Pediatr Infect Dis J. 2009 Dec; 28 (12): 1138-9.

- Puech A, Pilon R, Ciurana AJ. 'New antibacterial sulfonamide: Madribon.

Its application in the treatment of bronchopneumopathies primarily in aged persons. "Rev Fr Gerontol, 1963 Feb; 9: 85-9.

Claims

A pharmaceutical or veterinary composition for use in the prevention and / or treatment of an infection with at least one influenza virus, characterized in that it comprises, in a suitable pharmaceutical vehicle, at least one antiviral compound selected from the group consisting of Roxithromycin and Sulfadimethoxine.

2. Pharmaceutical or veterinary composition for its use according to claim 1, characterized in that the influenza virus is selected from type A viruses, such as the subtypes H1N1, H2N2, H3N2, H5N1, H7N7, H7N9, H5N2 and H9N2.

3. Pharmaceutical or veterinary composition for its use according to claim 1, characterized in that the influenza virus is selected from type B viruses.

4. Pharmaceutical or veterinary composition for its use according to one of claims 1 to 3, characterized in that it comprises a combination of

Roxithromycin and Sulfadimethoxine.

5. Pharmaceutical or veterinary composition for use according to one of claims 1 to 4, characterized in that it further comprises another antiviral agent.

6. Pharmaceutical or veterinary composition for its use according to claim 5, characterized in that the other antiviral agent is chosen from the following compounds: Oseltamivir, Zanamivir, Peramivir, Amantadine, Rimantadine, Ribavirin, Arbidol, Diltiazem, Etilefrine, Monensin and Biperidene

7. Pharmaceutical or veterinary composition for use according to one of claims 1 to 6, characterized in that it further comprises at least one antibacterial agent.

8. Pharmaceutical or veterinary composition for use according to one of claims 1 to 7, characterized in that it is in a dosage form for administration by inhalation.

9. A pharmaceutical or veterinary composition, comprising in a suitable pharmaceutical vehicle, at least one antiviral agent in combination with Sulfadimethoxine, or with a combination of Roxithromycin and Sulfadimethoxine.

A pharmaceutical or veterinary composition according to claim 9, wherein the antiviral agent is selected from the following compounds: Oseltamivir, Zanamivir, Peramivir, Amantadine, Rimantadine, Ribavirin, Arbidol, Diltiazem , Etilefrine, Monensine and Biperidene.

11. A pharmaceutical or veterinary composition, comprising in a suitable pharmaceutical vehicle, a combination of Roxithromycin and Sulfadimethoxine.

12. Pharmaceutical or veterinary composition according to one of claims 9 to 11, characterized in that it is in a dosage form intended for administration by inhalation.