MX2008013140A - Intramuscular antiviral treatments. - Google Patents

Abstract

The invention provides unit dosage forms, kits, and methods useful for treating viral infections.

Description

INTRAMUSCULAR ANTIVIRAL TREATMENTS Background of the Invention Neuraminidase inhibitor peramivir of influenza virus has marked activity against influenza virus in vitro and in experimentally infected mice (Govorkova et al., Antimicrobial Agents and Chemotherapy, 45 (10), 2723-2732 (2001 ), and Smee et al., Antimicrobial Agents and Chemotherapy, 45 (3), 743-748 (2001)). Unfortunately, clinical trials using peramivir showed low inhibitory effect in influenza in humans who continue oral administration in a period of days. Currently, methods and formulations are still needed that are useful for treating viral infections such as influenza infections. Brief Description of Some Modes of the Invention It has been unexpectedly discovered that a single intramuscular administration of peramivir to a mouse is effective in treating influenza. These encounters are unexpected not only because of their high effectiveness of a single administration of the compound, but also because of the low dose of the compound that was found to provide an effective treatment. The ability to obtain therapeutically useful effects with a single administration is important, inter alia, because it minimizes patient complications that result from the need for multiple administrations.

In addition, the administration of a low dose is important because it minimizes cost and potential side effects. Accordingly, in one embodiment of the invention it provides a method for treating a viral infection (e.g., an influenza infection) in a human comprising administering an effective antiviral amount of a compound of formula I, II, III or IV : (IV), or a pharmaceutically acceptable salt thereof, to a human intramuscularly. The invention also provides a method for inhibiting a neuraminidase in a human comprising administering an effective inhibitory amount of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof to a human intramuscularly.

The invention also provides in a single dose form that is suitable for intramuscular administration to a human comprising up to about 500 mgs (e.g., about 150 mg) of a compound of formula I, II, III or IV, or a pharmaceutically salt acceptable of it. The invention also provides a kit comprising packaging materials, a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound to a human intramuscularly.

The invention also provides the use of a compound of formula I, II, III or IV or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection to increase life expectancy and / or reduce mortality in a a group of mammals, i.e. humans, exposed to a source of influenza virus, by intramuscular injection of a dose, eg, an effective antiviral dose, of the drug into each member of the group exhibiting clinical symptoms of infection. The invention also provides the use of a compound of formula I, II, III or IV or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection to increase life expectancy or reduce mortality in a group of mammals, for example, humans exposed to a source of influenza virus, by intramuscular injection of a dose of the drug in each member of the group. Detailed Description of the Invention Influenza virus neuraminidase inhibitor peramivir has previously been shown to have activity against influenza virus in vitro and in experimentally infected mice (Govorkova et al. (2001) and Smee et al. ( 2001)). Unfortunately, the trials Clinicians who used this medicine showed an inadequate inhibitory effect on influenza in humans. It has been discovered that a single intramuscular injection of peramivir significantly reduces weight and mortality in mice infected with influenza A / H1N1. A single intramuscular injection of peramivir can be used to treat influenza infections and to provide an alternative option to oseltamivir during an influenza outbreak. Peramivir was tested as a simple intramuscular injection in an influenza mouse model and was found to be active when administered intramuscularly. In three different studies of the prophylaxis model using two different strains (H1N1 and H3N2) of influenza A virus, the efficacy of a single intramuscular injection of peramivir was compared with oral treatment (q.d.x5 days) either with oseltamivir or peramivir. Although 5 days (b.í.d.) of oseltamivir is normally used in clinic for the treatment of influenza, once the dosage for 5 days was also shown to be effective. In all In all three studies, the efficacy of a single intramuscular injection of peramivir at doses of 10 or 20 mg / kg was comparable to oral treatment (qd x5 days) of oseltamivir or peramivir in the same dose in terms of survival, it means days of death , and weight loss. At a dose of 2 mg / kg, as a single intramuscular injection, peramivir demonstrated comparable efficacy in terms of survival. However, the maximum weight loss was greater in the group treated with peramivir with a single intramuscular dose compared with the group treated with oseltamivir (q.d. x 5 days). The maximum loss for the treatment groups was observed around 8-10 days. It should be noted that while the minimum dose of peramivir (1 mg / kg) was not effective in terms of survival, there was a significant increase in days until death. Peramivir was highly effective in mice with a viral challenge that caused 70% lethality when treatment was started at least 48 hours after infection. The unique intramuscular injections of peramivir or oseltamivir were also compared in the model mouse with H1N1 influenza. Survival information indicated that a single intramuscular injection of peramivir is effective and provides complete protection against lethality. In contrast, a single intramuscular injection of oseltamivir did not provide significant protection against lethality. The weight loss information is consistent with the survival data and it indicates that a single intramuscular injection of peramivir is effective for the prevention of weight loss in infected mice, as in the oseltamivir group. These studies indicate that peramivir is effective when given as a single intramuscular injection, while oseltamivir is not effective by the same route of administration in the model mouse with influenza. A single intramuscular injection of oseltamivir carboxylate in mice showed a similar effect as a single intramuscular injection of oseltamivir. Cl50 of peramivir and oseltamivir carboxylate are sub nanomolar against H1N1 with 0.11 and 0.69nM (Bantia et al., Antimicrob Agents Chemother, 45, 1162-1167 (2001)) and H3N2 with 0.59 and 0.55 nM, respectively. Even with similar potency against neuraminidase enzymes, a single intramuscular injection of oseltamivir (carboxylate) is not effective. However, peramivir as a single intramuscular injection is superior to oseltamivir (carboxylate) determined as simple intramuscular injections. Although the prolonged release of peramivir was demonstrated with neuraminidase N9, it would be expected that peramivir would bind neuraminidases N1 and N2 since the amino acid residues at the active site are highly conserved among the different neuraminidase subtypes. In summary, peramivir is a potent inhibitor of neuraminidase activity. Intramuscular administrations Only prolonged and prophylactic treatments were effective in the prevention of lethality and weight loss in the model mouse with influenza. In view of the in vivo and in vitro information, peramivir is effective as a simple intramuscular injection and the treatment of infection with influenza virus in humans can be used. Accordingly, in one embodiment, the invention provides a method for treating a viral infection in a human which comprises administering an effective amount of a compound of formula I, II, III or IV or a pharmaceutically acceptable salt thereof, to a human human by intramuscular administration. Typically, the effective amount is administered in a single intramuscular administration. The methods of the invention provide high compliance in patients since it contains a low dose of effective agent. In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III or IV is up to about 500 mg (eg, from 10 mg to about 500 mg). In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III or IV is up to about 150 mg. In one embodiment of the invention, the effective inhibitory amount of the compound of formula I, II, III or IV is about 150 mg.

According to the methods of the invention, a compound of formula I, II III or IV is administered to a human intramuscularly. In one embodiment of the invention, the compound of formula I, II, III or IV is administered once to a human intramuscularly. In another embodiment of the invention, a neuraminidase inhibitor is also administered to the human orally. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of the formula, Na, Illa or IVa: or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the neuraminidase inhibitor that is administered orally is a compound of the formula, or a pharmaceutically acceptable salt thereof. According to the methods of the invention, the compound of the formula I, II, III or IV, or a pharmaceutically acceptable salt, can also be administered with one or more additional therapeutic agents, such as antiviral agents (for example active agents in against influenza) or antibiotics. The intramuscular formulations of the invention may also comprise one or more additional therapeutic agents, such as antiviral agents (e.g., active agents against influenza) and antibiotics. The compounds used in the invention are known in the art and can be synthesized by those skilled in the art using the available methods (see, for example, U.S. Patent No. 6,562,861). The specific values listed here for radicals, substituents and ranges, are for illustration only; they do not exclude other defined values or other values within the ranges defined for the radicals and substituents. A specific compound of formula I, II, III or IV is a compound of formula la, Ha, Illa or IVa: or a pharmaceutically acceptable salt thereof. A specific compound of formula I, II, III or IV is (1S, 2S, 3R, 4R) -3- (1-Acetamido-2-ethylbutyl) -4-guanidino-4-hydroxycyclopentanecarboxylic acid; (1S, 2S, 3R, 4R) -3- (1-Acetamido-2-propylpentyl) -4-guanidino-2-propylpentyl) -4-guanidino-2-propylpentyl) -4-guanidinocyclopentanecarboxylic acid; or (1 R, 3R, 4R) -3- (1-Acetamido-2-ethylbutyl) -4-guanidinocyclopentanecarboxylic acid; or a pharmaceutically acceptable salt thereof. A specific compound of formula I is a compound of formula I, or a pharmaceutically acceptable salt thereof. It will be appreciated by those skilled in the art that compounds having one or more chiral centers may exist and be isolated in optically active racemic forms. Some compounds may show polymorphism. It should be understood that the present invention encompasses the use of racemic form, active optically, polymorphically or stereoisomerically or mixtures thereof, of a compound of formula I, II, III and / or IV, which possesses the useful properties here described, the same it being well known in the art how to prepare active forms optically (for example, by resolution in racemic form by recrystallization techniques, by synthesis of optically active prime materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase ) and how to determine the antiviral activity (for example anti-influenza) using the standard tests described herein, or using other similar tests which are well known in the art. In cases when the compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts. Administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ct-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate and carbonate salts. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as amine with an appropriate acid to obtain a physiologically acceptable anion. The alkali metals (for example, sodium, potassium or lithium) or terrestrial alkali metal salts (by calcium example) of carboxylic acid can also be processed.

The compounds of formula I, II, III or IV can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, intramuscularly. The solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. In some embodiments of the invention, the compounds of formula I, II, III or IV are formulated with a saline solution, for example a citrate, for example sodium citrate. The pharmaceutical dosage forms suitable for injection and infusion may include sterile aqueous solutions or dispersions, or sterile powders comprising active ingredients, which are adapted for the extemporaneous preparation of sterile injectables or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the last dosage form must be sterile, fluid and stable under the conditions of processing and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example glycerol, propylene glycol, liquid polyethylene glycols and the like), vegetable oils, non-toxic glyceryl esters, and appropriate mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in case of dispersions or by the use of surfactants. The prevention of the action of the microorganisms can be carried out with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimeric and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, salicin solutions (for example sodium citrate) or sodium chloride. Prolonged absorption of injectable compositions can be realized by the use in the compositions of agents that delay absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in a suitable solvent with other optional ingredients, for example listed above, optionally followed by fertile sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation of the active ingredient plus any other desired ingredient present in the above sterile-filtered solutions. As used herein, the terms "treat", "treating" and "treatment" include administering a compound prior to the onset of symptoms of a disease condition / condition for preventing the development of any symptom, as well as administering a compound after the appearance of one or more clinical symptoms of a disease state / condition to reduce or eliminate any symptom, aspect or characteristic of the condition / condition of the disease. This treatment does not need to be absolute to be useful. As will be demonstrated below, the active compounds can be administered prior to exposure to the virus. The agents can be administered later (for example within 1, 2, 3, 4 or 5 days) upon exposure to the virus. As used herein, the term "unit dosage form" refers to an intramuscular formulation that contains a specific amount of a drug (e.g., from 10 to about 500 mg, e.g., about 150 mg), the total of which is try to administer as a single dose. It is distinguished from a supply of an indefinite quantity of a medicament, for example a medicine bottle, of which a dose was measured. The invention will now be illustrated by the following non-limiting example. Example 1. Intramuscular treatment of influenza with peramivir The efficacy of a single intramuscular injection of peramivir in the mouse model with influenza was evaluated. To summarize, peramivir was found to be effective when administered intramuscularly in a mouse model with influenza virus infection. Peramivir strongly inhibited the N9 neuraminidase enzyme of the H1N9 virus in vitro with 50% inhibitory concentration (IC50) of 1.3 ± 0.4 nM. The dissociation studies at the site indicated that peramivir remains strongly bound to the neuraminidase N9 (t1 / 2 = 1.25h). A single intramuscular injection of peramivir (10 mg / kg) significantly reduced weight loss and mortality in mice infected with influenza A / H1N1, while oseltamivir did not demonstrate efficacy with the same treatment regimen. Additional efficacy studies indicated that a single injection of peramivir (2-20 mg / kg) was comparable to a 5-day qdx of oseltamivir administered orally (2-20 mg (kg / day) to prevent lethality in models with influenza H3N2 and H1Na Therefore, a single intramuscular injection of peramivir can be used to treat influenza infections and provides an alternative option of oseltamivir during the outbreak of influenza Results The ability of peramivir to inhibit the N9 neuraminidase activity of the H1N9 virus was tested and compared with zanamivir and oseltamivir carboxylate IC50 for peramivir (1.3 +/- 0.4 nM), oseltamivir carboxylate (2.1 +/- 0.4 nM), and zanamivir (1.6 +/- 0.3 nM) against the N9 enzyme were not significantly different.The IC90 values were: for peramivir 5.0 +/- 1.1 nM, for oseltamivir carboxylate 10.4 +/- 0.7 nM; and to zanamivir 10.0 + /-1.2 nM. In the mouse model with influenza, viral infection leads to loss of body weight and high mortality, and this decrease in body weight is correlated with pulmonary viral titration and lung injury interval. In this way, the efficacy of peramivir, ose.ltamivir and zanamivir administered intramuscularly and orally, was evaluated based on weight loss, days to death and survival interval, measured from 16 to 21 days after infection. treated animals, infected in relation to animals (control) without treatment, infected. The prophylactic model, a single intramuscular injection of peramivir, administered 4 hours before the viral challenge with H1N1 virus, was compared with an oral treatment of peramivir once a day for 5 days with doses of 1 and 10 mg / kg / day. Complete protection against lethality was observed in mice treated with 10 mg / kg in both regimens. However, at doses of 1 mg / kg, 60% of the mice survived in the oral treatment group compared to 40% survival in the intramuscular group, mice treated with a single intramuscular injection of peramivir (10 mg / kg) showed no weight loss on day 5, while mice that took oral peramivir for 5 days with the same dose lost 0.22 g. Peramivir was administered at 2, 10, and 20 mg / kg as a single intramuscular injection 4 hours before viral infection with H1N1 virus. Complete protection against lethality was observed at all doses. However, none of the five control mice treated with saline survived. In comparison, complete protection against lethality was also observed in mice treated orally with oseltamivir at doses of 2 and 10 mg / kg / day (q.d.x5 days). No sign of drug-related toxicity was observed when peramivir was administered intramuscularly at higher doses (20 mg / kg). Ppramivir and oseltamivir showed a dose relationship when following the weight loss of the infected scratches over time. On day 7, the maximum weight loss in groups treated with peramivir at doses of 2, 0 and 20 mg / kg were 3.3, 0.98 and or g, respectively. In addition, oseltamivir showed a similar effect with the large average weight loss of 1.34 and Og that occurred on day 8 for groups treated with 2, 10 and 20 mg / kg, respectively. The weight loss on day 5 showed similar trends. In general, a lower dose resulted in greater weight loss when compared with a higher dose. Single intramuscular injections of peramivir or oseltamivir at doses of 10 mg / kg were evaluated when administered 4 hours before inoculation with H1N1 virus. Oseltamivir provided only 3% protection, which does not it is significantly different from the control group in which 90% of the mice died. In the group treated with peramivir, complete protection against lethality was observed. The peramivir group did not show any substantial weight loss (approximately 1.7 &of the initial weight). On the other hand, the oseltamivir group lost significant weight, approximately 4g (25% of initial weight), and only 3 of the 10 survived. In the same model, a comparison of simple oral treatments of 10 mg / kg dose of peramivir or oseltamivir was carried out. Peramivir provided better oral protection with a 50% survival interval, while only 10% of mice survived in the oseltamivir group. To determine if similar protective effects were observed during different viruses, the efficacy of a simple intramuscular injection of peramivir was compared with the oral treatment of oseltamivir (q.d.x 5 days) in mice infected with H3N2 virus. In this study, the drug was administered 1 hour before viral inoculation. Simple intramuscular treatment of peramivir at a dose of 20 mg / kg showed almost complete protection against lethality d9 / 10 survived). Oseltamivir also showed similar protective effects (9/10 survived). The average weight loss was almost identical in both treatment groups because mice treated with oseltamivir lost 28% of their weight (approximately 5.1 g) compared to 25% (4.5 g) of Weight loss in the peramivir group by day 8. In the long-term treatment model, intramuscular administration of a single dose of 10 mg / kg of peramivir 24 hours or 48 hours after infection obtained complete protection against the lethality, while in the saline group, 70% lethality was observed. There was no significant weight loss by day 5 in both groups of 24 and 48 hours treated with peramivir both administered orally (q.d. x 5 days) and by single intramuscular injection, while the group treated with saline lost 2.1 g. Materials and methods Influenza A viruses used in the study were observed with American Type Culture Collection, Manassas, VA, USA (A / NWS / 33; H1 N1) and Dr. Robert Sidwell, Utah State University, Logan, UT, USA (A / Victoria / 3/75; H3N2) and the mice were adapted. The purified N9 crystals A / H1N9 (NWS / G70) of avian virus was obtained from DR. Graeme Laver, Australian National University, Canberra, Australia. The specific mouse females free of pathogenic BALB / c (10-19 g) were obtained from Charles Rivers Laboratories (Raleigh, NC, USA). They were quarantined for 24 hours before infection and kept on the rodent diet of Harlan Teklad and tap water. The peramivir, oseltamivir, oseltamivir carboxylate and zanamivir were synthesized by BioCryst Pharmaceuticals, Inc.

(Birmingham, AL, USA). Each compound was prepared in sterile 0.9% sodium chloride for in vivo experiments. A mixture of 5% isoflurane / 95% oxygen was administered as an anesthetic. A standard fluorometric assay was used to measure the neuraminidase activity of the influenza virus (Potier et al., Anal. Biochem., 94, 287-296 (1979)). The substrate (2 '- (4-methylumbelliferyl) -a-D-acetylneuraminic acid, MuNANA) is released by neuraminidase to obtain a fluorescent product that can be quantified. The assay mixture contained inhibitor in various concentrations and neuraminidase enzyme in 32.5 mM MES (2- (N-morpholino) -salt (acid) ethanesulfonic solution, calcium chloride 4mM with pH 6.5 and incubated for 10-30 minutes. It was started by adding the substrate, after incubation for 30-120 min, the fluorescence was recorded (excitation: 360 nm and emission: 450 nm) and the blank substrates were extracted from the sample readings. inhibition in percentage of neuraminidase activity compared to the inhibitory concentration.The results are reported in average of the three experiments.The mice were anesthetized with isoflurane and exposed to 100μg of the virus by intranasal instillation.In the prophylactic model, the drug was administered 1 or 4 hours before the viral infection, in the treatment model, the drug was administered at the indicated time after the viral infection.

Each infected group, treated with drug or saline, contained 5-10 mice. All the mice were observed daily for changes in the body and deaths. The parameters for the evaluation of antiviral activity include weight loss, reduction in mortality and / or increase in average days determined during 16 or 21 days. Mice were infected intranasally with approximately 70-90% lethal dose of A / N WS / 33 (H 1 N 1) or A / Victoria / 3/75 (H3N2) influenza virus. Oral treatment with peramivir or oseltamivir (prepared in saline with injection grade) started 1 or 4 hours before exposure to the virus (prophylactic model) and continued once a day for 5 days unless otherwise indicated. A single intramuscular treatment was administered 1 or 4 hours before exposure to the virus or at the indicated time (treatment model). Normal or saline-treated control mice were included in the same treatment schedule. The information was used by Sigma Plot (Windows version 4.01, SPSS, Chicago, IL, USA) and Sigma Stat (Windows version 2.9, Jandel Corporation, San Rafael, CA, USA). The t-test was used to evaluate the differences in average days of death. The one-way analysis of variants (ANOVA) was carried out using the Holm-Sidak test as a whole to evaluate the differences in weight loss. The Kaplan-Meier survival analysis (loh interval or tests Gehan-Breslow) were applied to survival number differences. These encounters, including methods, results and discussions are provided in Bantia et al., Antiviral Research, 69, 39-45 (2006). All publications, patents and patent applications cited herein are incorporated by reference. While in the description this invention has been described in relation to some embodiments, and many details have been established for purposes of illustration, it would be obvious to those skilled in the art that the invention is susceptible to additional modalities and that the details described herein may vary considerably without departing from the basic principles of the invention. The use of the terms "a" and "an" and "the, the, the," and the like relating to the context to describe the invention is included to cover the singular and plural, even when indicated differently or contradicted in the context . The terms "comprising", "having", "including" and "containing" are included as open terms (ie, meaning "including but not limited to") or until differently noted. The recitation of ranges of values are intended to serve as abbreviated methods to refer individually to each separate value that is within the range, or until otherwise indicated, and each separate value is incorporated into the description as if they were Individually recited All methods described may be carried out in any order or until otherwise indicated or differently contradicted by the text. The use of any and all examples, or exemplary language (eg, "as" provided herein, is intended to better illuminate the invention and does not place a limit on the scope of the invention or until otherwise indicated.

Claims (61)

1. A method for treating a viral infection in a human comprises administering an antiviral effective amount of a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof, to the human intramuscularly.

2. The method according to claim 1, wherein the compound of the formula I, II, III or IV is a compound of the formula la, lia, Illa or IVa: or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or 2, wherein the viral infection is an infection with influenza.

4. The method according to claim 3, wherein the viral infection is an A or B type infection. The method according to claim 3, wherein the influenza is avian H3N2, H1N1, H5N1, or influenza. seasonal. 6. The method according to claims 1-5, wherein the effective antiviral amount is up to about 500 mg. The method according to any of claims 1-5, wherein the effective antiviral amount is up to about 150 mg. 8. The method according to any of claims 1-5, wherein the effective antiviral amount is about 150 mg. 9. The method according to any of the claims 1-8, wherein the total effective amount is administered in an intramuscular administration. The method according to any of claims 2-9, wherein a compound of the formula, or a pharmaceutically acceptable salt thereof, is administered. 11. A method for inhibiting a neuraminidase in a human comprises administering an effective inhibitory amount of a compound of formula I, II, III or IV: (??) (IV), or a pharmaceutically acceptable salt thereof, to a human intramuscularly. The method according to claim 11 wherein the compound of the formula I, II, III or IV is a compound of the formula la, lia, Illa or IVa: 27 or a pharmaceutically acceptable salt thereof. The method according to claims 11 or 12 wherein the effective inhibitory amount is up to about 500 mg. The method according to claim 11 or 12, wherein the effective inhibitory amount is up to about 150 mg. 1

5. The method according to claim 11 or 12 wherein the effective inhibitory amount is about 150 mg. 1

6. The method according to any of claims 11-15 wherein the total effective inhibitory dose is administered in an intramuscular administration. 1

7. The method according to any of the claims 11-16 wherein the compound of the formula I, or a pharmaceutically acceptable salt thereof is administered. 1

8. The method according to any of claims 1-17 further comprising orally administering a neuraminidase inhibitor to a human. 1

9. The method according to claim 18 wherein the neuraminidase inhibitor that is administered orally is oseltamivir carboxylate. The method according to claim 18 wherein the neuraminidase inhibitor that is administered orally is a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof. 21. The method according to claim 18 wherein the neuraminidase inhibitor that is administered via oral is a compound of the formula la, Na, Illa or IVa: or a pharmaceutically acceptable salt thereof. 22. The method according to claim 21, wherein the neuraminidase inhibitor that is administered orally is a compound of the formula, or a pharmaceutically acceptable salt thereof. 23. The method according to any of claims 18-22 wherein the neuraminidase inhibitor that is administered orally is administered for up to 20 days. The method according to any of claims 18-22 wherein the neuraminidase inhibitor that is administered orally is administered for up to 10 days. 25. The method according to any of claims 18-22, wherein the neuraminidase inhibitor which is administered orally is administered up to 5 days. 26. A single dosage form that is suitable for intramuscular administration to a human, comprises up to about 500 mg of the compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof. 27. The single dosage form according to claim 26 wherein the compound of the formula I, II, III or IV is a compound of the formula, Na, Illa or IVa: or a pharmaceutically acceptable salt thereof. 28. A single dosage form according to claim 25 or 27 comprising up to about 500 mg of the compound or the salt. 29. The single dosage form according to claim 26 or 27 comprising about 150 mg of the compound or the salt. 30. A kit, comprising packaging materials, a compound of formula I, II, III or IV: (IV), or a pharmaceutically acceptable salt thereof and instructions for administering the compound to a human intramuscularly. 31. The kit according to claim 30, wherein the compound is provided in a formulation suitable for intramuscular administration. 32. The kit according to claim 30 or 31 comprising up to about 500 mg of compound or salt. 33. The kit according to claim 30 or 31 comprising up to about 150 mg of the compound or the salt. 34. The kit according to claim 30 or 31 comprising about 150 mg of the compound or the salt. 35. A kit comprising packaging materials, a single dosage form as described in any of claims 26-34 and instructions for administering the compound to a human intramuscularly. 36. The use of a compound of formula I, II, III or IV: (??) (IV), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for intramuscular injection to increase the life expectancy or reduce the mortality in a group of mammals exposed to a source of influenza virus, by intramuscular injection of a dose of the drug in the which each member of the group presents clinical symptoms of the infection. 37. The use according to claim 36 wherein the compound of the formula Na, Illa or IVa: (Day) (IVa), or a pharmaceutically acceptable salt thereof. 38. The use according to claim 36 or 37 wherein the influenza virus is an avian influenza virus. 39. The use according to claim 38, wherein the avian influenza virus is H5N1, or a mutant strain thereof. 40. The use according to any of claims 36-39 in which each member of the group having symptoms of infection receives only an intramuscular dose of the medicament. 41. The use according to any of claims 36-40 to increase the life expectancy and reduce the mortality in a group of mammals where the members of the group having clinical symptoms of infection are treated orally with an inhibitor of neuraminidase. 42. The use according to claim 41 in which the neuraminidase inhibitor is oseltamivir carboxylate. 43. The use according to claim 41, wherein the neuraminidase inhibitor is a compound of formula I, II, III or IV: (I) (?) (??) (IV), or a pharmaceutically acceptable salt thereof. 44. The use according to claim 41, wherein the neuraminidase inhibitor is a compound of the formula Ha, Illa or IVa: (Hla) (IVa), or a pharmaceutically acceptable salt thereof. 45. The use according to claim 41 in which the neuraminidase inhibitor is a compound of the formula la, or a pharmaceutically acceptable salt. 46. Use according to any of the claims 36-45 in which the source of the virus is an infected bird. 47. The use according to any of claims 36-45 wherein the source of the virus is a mammal exhibiting symptoms of infection. 48. The use according to any of claims 36-47 which is reducing mortality. 49. The use of a compound of formula I, II, III or IV: my V), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intramuscular injection to increase the life expectancy or reduce the mortality in a group of mammals exposed to a source of influenza virus, by intramuscular injection of a dose of the drug in each member of the group. 50. The use according to claim 49, wherein the compound of formula I, II, III or IV is a compound of formula I, Na, Illa or IVa: or a pharmaceutically acceptable salt thereof. 51. The use according to claim 49 or 50, wherein the influenza virus is an avian influenza virus. 52. The use according to claim 51, wherein the influenza virus is H5N1, or a mutant strain thereof. 53. The use according to any of claims 49-52, wherein each member of the group receives only an intramuscular dose of the medication. 54. The use according to any of claims 49-53, to increase the life expectancy or reduce the mortality in a group of mammals where the members of the group are treated orally with an inhibitor of neuraminidase. 55. The use according to claim 54, wherein the neuraminidase inhibitor is oseltamivir carboxylate. 56. The use according to claim 54 in which the neuraminidase inhibitor is a compound of formula I, II, III or IV: m (iv), or a pharmaceutically acceptable salt. 57. The use according to claim 54 in which the neuraminidase inhibitor is a compound of the formula Na, Illa or IVa: or a pharmaceutically acceptable salt thereof. 58. The use according to claim 54 wherein the neuraminidase inhibitor is a compound of the formula, or a pharmaceutically acceptable salt thereof. 59. The use according to any of claims 49-58, in which the source of the virus is an infected bird. 60. The use according to any of claims 49-58 in which the source of the virus is a mammal exhibiting symptoms of infection. 61. The use according to any of claims 49-60 which is to reduce mortality.