BRPI0621552A2 - intramuscular antiviral treatments - Google Patents

Abstract

INTRAMUSCULAR ANTIVIRAL TREATMENTS. The present invention relates to unit dosage forms, kits and methods useful for treating viral infections.

Description

Report of the Invention Patent for "INTRAMUSCULAR ANTIVIAL TREATMENTS".

Background

The peramivir influenza neuraminidase inhibitor has remarkable activity against the 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 have shown an undesirable low inhibitory effect on influenza in humans following oral administration over a period of days. There is still a need for methods and formulations that are useful for treating viral infections such as influenza infections.

Summary of Certain Modes of the Invention

It has been unexpectedly found that a single intramuscular administration of peramivir to a mouse is effective for treating influenza. These findings are unexpected not only because of the high efficacy of a single administration of the compound, but also because of the low dose of the compound that has been found to provide effective treatment. The ability to achieve therapeutically useful effects with a single administration is important, inter alia, because it minimizes patient compliance issues that result from the need for multiple administrations. Additionally, administering a low dose is important because it minimizes cost and potential for side effects.

Thus, in one embodiment the invention provides a method for treating a viral infection (e.g., an influenza infection) in a human comprising administering an effective anti-viral amount of a compound of formula I, II, III. or IV: <formula> formula see original document page 3 </formula>

or a pharmaceutically acceptable salt thereof, to humans via an intramuscular route.

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 the human via of an intra-muscular route.

The invention also provides a unit dosage form which is suitable for intramuscular administration to a human comprising up to about 500 mg (e.g. about 150 mg) of a compound of formula I, II, III or IV. or a pharmaceutically acceptable salt thereof.

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 via an intramuscular route.

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 group. of mammals, for example humans, exposed to a source of an influenza virus by intramuscular injection of a dose, for example an effective antiviral dose, of the drug into each member of the group showing 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 mammalian group. for example, humans exposed to a source of an influenza virus by intramuscular injection of a dose of the drug into each member of the group.

Detailed Description

The peramivir influenza neuraminidase inhibitor has previously been shown to have remarkable activity against influenza viruses in vitro and in experimentally infected mice (Govorkova et al. (2001); and Smee et al. (2001)). Unfortunately, clinical trials using this drug have shown an inappropriate inhibitory effect on influenza in humans.

A single intramuscular injection of peramivir has been found to significantly reduce weight loss and mortality in influenza A / H1N1-infected mice. A single intramuscular injection of pedivir can then be used to treat influenza infections and provide an alternative option for oseltamivir during an influenza outbreak.

Peramivir was tested as a single intramuscular injection in the mouse influenza model and was found to be active when administered intramuscularly. In three different studies of a 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 (qd x5 days) or oseltamivir or peramivir. . Although 5 days (b.i.d.) of oseltamivir is usually used in the clinic for influenza treatment, a single daily dosage for 5 days has also been shown to be effective. 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) for oseltamivir or peramivir at the same dose in survival, mean days. for death and weight loss. At doses of 2 mg / kg as a single intramuscular injection peramivir has shown comparable efficacy in survival. However, the maximum weight loss was higher in the single intramuscular peramivir group versus the oral oseltamivir group (q.d. x5 days). The maximum weight loss for the treatment groups was observed around 8-10 days. It should be noted that although the lower dose of peramivir (1 mg / kg) was not effective in survival, there was a significant increase in the average days to death. Peramivir was highly effective in mice with a viral challenge that caused 70% lethality when treatment was started within 48 hours post infection.

Single intramuscular injections of either peramivir or oseltamivir were also compared with the H1N1 mouse influenza model. Survival data indicate that a single intramuscular injection of peramivir is effective and provides complete protection against lethality. On the other hand, a single intramuscular injection of oseltamivir provided no significant protection against lethality. Weight loss data are consistent with survival data and indicate that a single intramuscular injection of peramivir is effective in preventing weight loss in infected mice, unlike 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 mouse influenza model. A single intramuscular injection of oseltamivir carboxylate in mice showed an effect similar to the single intramuscular injection of oseltamivir.

The IC50S of peramivir and oseltamivir carboxylate are subnolar molars against 0.11 and 0.69 nM H1N1 (Bantia et al., Antimicrob. Agents Chemother. 45, 1162-1167 (2001)) and H3N2 at 0.59 and 0 55 nM, respectively. Despite similar potency against neuraminidase enzymes, a single intramuscular injection of oseltamivir (carboxylate) is ineffective. However, peramivir as a single intramuscular injection is superior to oseltamivir (carboxylate) given as single intramuscular injections. Although slow peramivir dissociation has been demonstrated with neuraminidase N9, one might expect peramivir to firmly bind to both N1 and N2 neuraminidases since amino acid residues at the active site are highly conserved among different neuraminidase subtypes.

In short, peramivir is a potent inhibitor of neuraminidase activity. Prophylactic and delayed single intramuscular administrations were effective in preventing etiology and weight loss in the mouse influenza model. In view of in vitro and in vivo data, peramivir is effective as a single intramuscular injection and can be used to treat human influenza virus infections.

Thus, in one embodiment the invention provides a method for treating a viral infection in a human comprising administering an effective amount of a compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, to a human. by intramuscular administration. Typically, the effective amount is administered as a single intramuscular administration. The methods of the invention provide for high patient compliance as they involve 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 (e.g. from about 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 VI is about 150 mg.

According to the method 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 by being orally human. In one embodiment of the invention, the orally administered neuraminidase inhibitor is oseltamivir carboxylate. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula I, II, III or IV or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, IIIaou IVa:

<formula> formula see original document page 7 </formula>

or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia or a pharmaceutically acceptable salt thereof.

According to the methods of the invention, the compound of formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, may also be administered in combination with one or more additional therapeutic agents, such as antiviral agents (e.g. active agents against influenza) or antibiotics.

Intramuscular formulations of the invention may also comprise one or more additional therapeutic agents, such as antiviral agents (e.g., influenza active agents) and antibiotics.

The compounds used in the invention are known in the art and can be synthesized by one of ordinary skill in the art using available methods (see, for example, U.S. Patent No. 6,562,861).

Specific values listed here for radicals, substituents and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.

A specific compound of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa:

<formula> formula see original document page 8 </formula>

or a pharmaceutically acceptable salt thereof.

A specific compound of formula I, II, III or IV is (1S, 2S, 3S, 4R) -3- (1-Acetamido-2-ethylbutyl) -4-guanidine-2-hydroxycyclopentane carboxylic acid; (1S, 2S, 3R, 4R) -3- (1-Acetamido-2-propylpentyl) -4-guanidino-2-hydroxycyclopentanecarboxylic acid; (1R, 3R, 4R) -3- (1-Acetamido-2-propenylpentyl) -4-guanidinocyclopentanecarboxylic acid; or (1R, 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 1a or a pharmaceutically acceptable salt thereof.

It will be understood by those skilled in the art that compounds having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention comprises the use of any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, of a compound of formula I, II, III and / or IV, which has the useful properties described herein. It is well known in the art to prepare optically active forms (e.g., through racemic form separation through recrystallization techniques, through synthesis from optically active starting materials, via chiral synthesis). or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity (e.g., anti-influences) using the standard tests described herein, or using other similar tests that are well known in the art.

In cases where 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 which form a physiologically acceptable anion, for example tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate. benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts may also be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid giving a physiologically acceptable anion. Alkali metal (e.g. sodium, potassium or lithium) or alkaline earth metal (e.g. calcium) salts of carboxylic acids can also be made.

The compounds of formulas I, II, III and IV may be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, via intramuscular routes. Solutions of the active compound or its salts may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under common 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 and / or IV are formulated with a buffer, for example a citrate, for example sodium citrate.

Suitable pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient (s) which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. . In all cases, the final dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The carrier or liquid carrier may be a liquid dispersing solvent or medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols and the like), vegetable oils, esters non-toxic glyceryl compounds and their appropriate mixtures. Appropriate flowability may be maintained, for example, by the formation of liposomes, by maintaining the required particle size in the case of dispersions or by using surfactants. The prevention of the action of microorganisms can be accomplished by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example sugars, buffers (e.g. sodium citrate) or sodium chloride. Prolonged absorption of the injectable compositions may be accomplished by use in the delayed absorption agent compositions, for example aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the active compound (s) in an appropriate solvent with the other optional ingredients, for example, listed above, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze drying techniques, which give a powder of the active ingredient plus any additional desired ingredient present in the filtered solutions. previous sterile

As used herein, the terms "treating", "treating" and "treating" include administering a compound prior to the onset of clinical symptoms of a disease state / condition to prevent the development of any symptoms. as well as administering a compound after the onset of one or more clinical symptoms of a disease state / condition in order to reduce or eliminate such symptom, aspect or feature of the disease state / condition. Such treatment need not be absolute to be useful. As illustrated below, active compounds may be administered prior to exposure to the virus. Agents may also be administered subsequent (for example, within 1, 2, 3, 4 or 5 days) to exposure to the virus.

As used herein, the term "unit dosage form" refers to an intramuscular formulation containing a specific amount of a drug (for example, from about 10 mg to about 500 mg, for example, about 150 mg), the whole of which is to be administered as a single dose. It is distinguished from a supply of an indefinite amount of a drug, for example a medicine bottle, from which a dose has to be withdrawn according to a measure.

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 influenza mouse model was evaluated. In short, peramivir has been found to be effective when administered intramuscularly in a mouse influenza virus infection model. Peramivir potently inhibited the H1N9 virus neuraminidase N9 enzyme in vitro with a 50% inhibitory concentration (IC50) of 1.3 ± 0.4 nM. Site dissociation studies indicated that peramivir remains tightly bound to neuraminidase Ν9 (t1 / 2> 24 hours), while zenamivir and oseltamivir carboxylate rapidly dissociate from the enzyme (t1 / 2 = 1.25 hours). A single intramuscular injection of peramivir (10 mg / kg) significantly reduced weight and mortality in mice infected with influenza A / H1N1, while osel- tamivir showed no efficacy through the same treatment regimen. Additional efficacy studies indicated that a single injection of peramivir (2-20 mg / kg) was comparable to an oral course q.d. oseltamivir orally administered (2-20 mg / kg / day) x5 in the prevention of etiology in H3N2 and H1N1 influenza models. Thus, a single intramuscular injection of peramivir can be used to treat influenza infections and provide an alternative option for oseltamivir during an influenza outbreak. Results

The ability of peramivir to inhibit H1N9 virus N9 neuraminidase activity 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 enzyme N9 was not significantly different. ICg0 values were: to peramivir 5.0 +/- 1.1 nM; for oseltamivir carboxylate 10.4 +/- 0.7 nM; and for zanamivir 10.0 +/- 1.2 nM.

In the mouse influenza model, viral infection leads to body weight loss and high mortality, and this decrease in body weight is related to pulmonary viral titer and lung injury score. Thus, the peramivir, oseltamivir and zanamivir efficacy administered orally and intramuscularly administered was assessed based on weight loss, average days to death and survival rate, measured at 16 or 21 days post-infection for infected, treated animals. , regarding infected, untreated animals (control).

In the prophylaxis model, a single intramuscular injection of perivival given 4 hours before viral challenge with H1N1 virus was compared with an oral peramivir treatment once daily for 5 days at doses of 1 and 10 mg / kg / day. Complete protection against mortality was observed in mice treated at 10 mg / kg with both treatment regimens. However at a dose of 1 mg / kg / dose, 60% of mice survived in the oral treatment group versus 40% survival in the intramuscular treatment group. Mice treated with a single intramuscular injection of peramivir (10 mg / kg) showed no weight loss around day 5, while mice given orally peramivir for 5 days at the same dose lost 0.22 g.

Peramivir was also administered at 2, 10 and 20 mg / kg as a single intramuscular injection 4 hours before viral infection with the H1N1 virus. Complete protection against etality was observed in all doses. However, none of the five control mice treated with saline survived. By comparison, complete protection against ketalide was also observed in mice treated orally with oselamivir at both 2 and 10 mg / kg / day (q.d. x5 days). Any signs of drug-related toxicity were observed when peramivir was administered intramuscularly at the highest dose (20 mg / kg).

Peramivir and oseltamivir showed a dose response relationship when the weight loss of time-infected mice was followed. At day 8, the maximum mean weight loss in the groups treated with perivir at 2, 10 and 20 mg / kg was 3.3, 0.98 and Og, respectively. Additionally, oseltamivir provided a similar effect with the greater average weight loss of 1.34 and 0 g occurring on day 8 for the 2 and 10 mg / kg groups, respectively. Day 5 weight loss shows a similar inclination. In general, a lower dose resulted in greater weight loss compared to a higher dose.

Single intramuscular injections of 10 mg / kg peramivir and oseltamivir were evaluated when administered 4 hours before H1N1 virus inoculation. Oseltamivir provided only 30% protection, which is not significantly different from the control group where 90% of mice died. In the peramivir-treated group, complete protection against mortality was observed. The peramivir group showed no substantial weight loss (about 1.7% initial weight). In contrast, the oseltamivir group lost significant weight, about 4 g (25% of initial weight), and only 3 out of 10 mice survived. In the same model, a comparison of single oral treatments at a dose of 10 mg / kg or peramivir or oseltamivir was evaluated. Peramivir provided better oral protection with a 50% survival rate, while only 10% of mice survived in the oseltamivir group.

To determine whether similar protective effects are observed using different viruses, the efficacy of a single iramammiral injection of peramivir was compared with oral oseltamivir treatment (q.d. x5 days) in H3N2 virus infected mice. In this study the drug was administered 1 hour before viral inoculation. Single intramuscular treatment of peramivir at a dose of 20 mg / kg provided almost complete protection against mortality (9/10 survived). Oseltamivir also demonstrated similar protective effects (9/10 survived). The average weight loss was almost identical in both treatment groups because oseltamivir-treated mice lost 28% of their weight (about 5.1 g) compared to 25% (4.5 g) of weight loss in the treatment group. peramivir group around day 8. In the delayed treatment model, intramuscular administration of a single dose of 10 mg / kg peramivir 24 hours or 48 hours post-infection gave complete protection against lethality, whereas in the solution group saline, 70% lethality was observed. There was no significant weight loss around day 5 in both 24- and 48-hour peramivir-treated groups given either orally (qd x5 days) and by single intramuscular injection while the saline-treated group lost 2.1 g.

Materials and methods

The influenza A viruses used in this study were obtained from the American Type Culture Collection, Manassas, VA, USA (A / NWS / 33; H1N1) and Dr. Robert Sidwell, Utah State University, Logan, UT, USA (A / Victoria / 3/75; H3N2) and were adapted to mouse. Purified N9 crystals from bird A / H1N9 virus (NWS / G70) were obtained from Dr. Graeme Laver, Australian National University, Canberra, Australia.

Pathogen-free female BALB / c mice (10-19 g) were obtained from Charles River Laboratories (Raleigh, NC, USA). They were quarantined for 24 hours prior to infection and kept on Harlan Teklad's rodent diet and tap water.

Peramivir, oseltamivir, oseltamivir carboxylate and zanamivir were synthesized by BioCryst Pharmaceuticals, Inc. (Birmingham, AL, UAS). Each compound was prepared in sterile 0.9% sodium chloride for in vivo experiments. A 5% isoflurane / 95% oxygen mixture was administered as anesthesia.

A standard fluorometric assay was used to measure influenza virus neuraminidase activity (Potier et al., Anal. Biochem., 94, 287-296 (1979)). The (2 '- (4-methylumbelliferyl) -α-D-acetylneuraminic acid substrate, MuNANA) is cleaved by neuraminidase to give a fluorescent product that can be quantified. The assay mixture contained inhibitor at varying concentrations and neuraminidase enzyme in 32.5 mM MES buffer (2- (N-morpholino) ethanesulfonic acid), 4 mM calcium chloride at pH 6.5 and incubated for 10-30 minutes The reaction was initiated by the addition of substrate. After incubation for 30-120 minutes fluorescence was recorded (excitation: 360 nm and emission: 450 nm) and unimpressive substrates were subtracted from the sample readings. IC50 was calculated by plotting percent inhibition of neuraminidase activity versus inhibitory concentration. Results are reported as the average of the three experiments.

Mice were anesthetized with isoflurane and exposed to 100 μL of virus by intranasal instillation. In the prophylaxis model, drug was administered 1 or 4 hours before viral infection; In the treatment model, drug was given at indicated times after viral infection. Each infected group treated with drug or saline contained 5-10 mice. All mice were observed daily for changes in weight and for any deaths. Parameters for assessing antiviral activity included weight loss, reduction in mortality and / or increase in average days of death determined by 16 or 21 days.

Mice were infected intranasally with an approximately 70-90% lethal dose of influenza A / NWS / 33 (Η1N1) or A / Victoria / 3/75 (H3N2). Oral treatment with peramivir or oseltamivir (prepared in injection grade saline) began 1 to 4 hours before virus exposure (prophylaxis model) and continued once daily for 5 days unless indicated. A single intramuscular treatment was administered 1 or 4 hours before virus exposure or at designated times (treatment model). Normal and saline-treated control mice were included in the same treatment program. The studied parameters were reduction in mortality and / or increase in average days to death.

Data were analyzed using Sigma Plot (Windows Version 4.01, SPSS, Chicago, IL, USA) and Sigma Stat (Windows Version 2.0, Jandel Corporation, San Rafael, CA, USA). The t-test was used to assess differences in mean days to death. Analysis of variance (ANOVA) was performed using the Holm-Sidak test for multiple pairwise comparisons to assess differences in weight loss. Kaplan-Meier survival analyzes (Iog rank test or Gehan-Breslow) were applied to differences in survival number.

These findings, including methods, results, and discussion, are provided in Bantia et al., Antiviral Research, 69, 39-45 (2006).

All publications, patents and patent applications mentioned herein are incorporated herein by reference. Although in the above report the present invention has been described with respect to certain embodiments thereof, and many details have been shown for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

The use of the terms "one" and "one" and "o / a" and similar referents in the context of describing the invention should be considered to understand both the singular and the plural, unless otherwise indicated or clearly contradicted herein. context. The terms "comprising", "having", "including" and "containing" shall be deemed to be open terms (ie meaning "including, but not limited to") unless otherwise indicated. Mention of value ranges herein is only intended to serve as a stenographic method of reference individually to each separate value being within the range, unless otherwise indicated herein, and each separate value is incorporated into the report as if they were individually here. mentioned. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all of the examples, or exemplary language (e.g., "as"), provided herein is only intended to further illuminate the invention and not to impose a limitation on the scope of the invention unless otherwise claimed.

Claims (61)

A method for treating a viral infection in a human being comprising administering an effective antiviral amount of a compound of formula I, II, III or IV: <formula> formula see original document page 18 </formula> or a salt pharmaceutically acceptable to man via an intramuscular route. The method of claim 1, wherein the compound; of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa: or a pharmaceutically acceptable salt thereof. A method according to claim 1 or 2, wherein the viral infection is an influenza infection. The method of claim 3, wherein the viral infection is a type A or type B influenza infection. The method of claim 3, wherein the influenza is an avian or seasonal influenza H3N2, H1N1, H5N1. A method according to any one of claims 1-5, wherein the antiviral effective amount is up to about 500 mg. A method according to any one of claims 1-5, wherein the antiviral effective amount is up to about 150 mg. A method according to any one of claims 1-5, wherein the antiviral effective amount is about 150 mg. A method according to any one of claims 1-8, wherein the full effective dose is administered in an intramuscular administration. A method according to any one of claims 2-9, wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered. A method for inhibiting a neuraminidase in a human being comprising administering an inhibitory effective amount of a compound of formula I, II, III or IV: <formula> formula see original document page 19 </formula> <formula> formula see original document page 20 </formula> or a pharmaceutically acceptable salt thereof to a human via an intramuscular route. The method of claim 11, wherein the compound of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa: or a pharmaceutically acceptable salt thereof. The method of claim 11 or 12, wherein the effective inhibitory amount is up to about 500 mg. The method of claim 11 or 12, wherein the effective inhibitory amount is up to about 150 mg. The method of claim 11 or 12, wherein the effective inhibitory amount is about 150 mg. A method according to any one of claims 11-15, wherein the full effective inhibitory dose is administered in an intramuscular administration. A method according to any one of claims 11-16, wherein a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered. A method according to any one of claims 1-17 further comprising orally administering a neuraminide inhibitor to humans. The method of claim 18, wherein the orally administered neuraminidase inhibitor is oseltamivir carboxylate. The method of claim 18, wherein the orally administered neuraminidase inhibitor is a compound of formula I, II, III or IV: or a pharmaceutically salt acceptable of it. The method according to claim 18, wherein the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa or IVa: <formula> formula see original document page 21 </formula> <formula> formula see original document page 22 </formula> or a pharmaceutically acceptable salt thereof. The method of claim 21, wherein the orally administered neuraminidase inhibitor is a compound of formula 1a or a pharmaceutically acceptable salt thereof. A method according to any one of claims 18-22, wherein the orally administered neuraminidase inhibitor is administered for up to 20 days. A method according to any one of claims 18-22, wherein the orally administered neuraminidase inhibitor is administered for up to 10 days. A method according to any one of claims 18-22, wherein the orally administered neuraminidase inhibitor is administered for up to 5 days. 26. Unit dosage form which is suitable for intramuscular administration to a human comprising up to about 500 mg of a compound of formula I, II, III or IV: <formula> formula see original document page 22 </formula> <formula> formula see original document page 23 </formula> or a pharmaceutically acceptable salt thereof. A unit dosage form according to claim -26, wherein the compound of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa: <formula> see original document page 23 </ formula> or a pharmaceutically acceptable salt thereof. A unit dosage form according to claim 26 or 27 comprising up to about 500 mg of the compound or salt. A unit dosage form according to claim 26 or 27 comprising about 150 mg of the compound or salt. A kit comprising packaging materials, a compound of formula I, II, III or IV: <formula> formula see original document page 24 </formula> or a pharmaceutically acceptable salt thereof and instructions for administering the compound to a human being via intramuscular route. The kit of claim 30, wherein the compound is provided in a formulation suitable for intramuscular administration. A kit according to claim 30 or 31 comprising up to about 500 mg of the compound or salt. A kit according to claim 30 or 31 comprising up to about 150 mg of the compound or salt. The kit of claim 30 or 31 comprising about 150 mg of the compound or salt. A kit comprising a packaging material, a unit dosage form as described in any one of claims -26-34 and instructions for administering the compound to a human via intramuscular route. 36. Use of a compound of formula I, II, III or IV: <formula> formula or original pharmaceutically acceptable salt thereof, in the manufacture of an intramuscular injection drug to increase life expectancy or reduce mortality in a group of mammals exposed to an influenza virus source by intramuscular injection of a dose of the drug into each group member. presenting clinical symptoms of infection. Use according to claim 36, wherein the compound of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa: <formula> formula see original document page 25 </formula> or a pharmaceutically acceptable salt thereof. Use according to claim 36 or 37, wherein the influenza virus is an avian influenza virus. Use according to claim 38, wherein the bird influenza virus is H5N1 or a mutant strain thereof. Use according to any one of claims 36-39, wherein each member of the group exhibiting symptoms of infection receives only one intramuscular dose of the medicament. Use according to any one of claims 36-40 for increasing life expectancy or reducing mortality in a mammalian group, wherein members of the group exhibiting clinical symptoms of infection are treated orally with an inhibitor. of neuraminidase. Use according to claim 41, wherein the neuraminidase inhibitor is oseltamivir carboxylate. Use according to claim 41, wherein the neuraminidase inhibitor is a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof. Use according to claim 41, wherein the neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa or IVa: <formula> formula see original document page 26 </formula> <formula> formula see original document page </formula> or a pharmaceutically acceptable salt thereof. Use according to claim 41, wherein the neuraminidase inhibitor is a compound of formula Ia or a pharmaceutically acceptable salt thereof. Use according to any one of claims 36-45, wherein the source of the virus is an infected bird. Use according to any one of claims 36-45, wherein the source of the virus is a mammal showing symptoms of infection. Use according to any one of claims 36-47 which is for reducing mortality. 49. Use of a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof, in the manufacture of an intramuscular injection drug for increasing life expectancy or reducing mortality in a group of exposed mammals. to a source of an influenza virus by intramuscular injection of a dose of the drug into each member of the group. Use according to claim 49, wherein the compound of formula I, II, III or IV is a compound of formula Ia, IIa, IIIa or IVa: a pharmaceutically acceptable salt thereof. Use according to claim 49 or 50, wherein the influenza virus is an avian influenza virus. Use according to claim 51, wherein the avian influenza virus is H5N1 or a mutant strain thereof. Use according to any one of claims 49-52, wherein each member of the group receives only one intramuscular dose of the medicament. Use according to any one of claims 49-53 for increasing life expectancy or reducing mortality in a mammalian group, wherein members of the group are orally treated with a neuraminidase inhibitor. Use according to claim 54, wherein the neuraminidase inhibitor is oseltamivir carboxylate. Use according to claim 54, wherein the neuraminidase inhibitor is a compound of formula I, II, III or IV: or a pharmaceutically acceptable salt thereof. Use according to claim 54, wherein the neuraminidase inhibitor is a compound of formula Ia, IIa1 Illa or IVa: or a pharmaceutically acceptable salt thereof. Use according to claim 54, wherein the neuraminidase inhibitor is a compound of formula Ia or a pharmaceutically acceptable salt thereof. Use according to any one of claims 49-58, wherein the source of the virus is an infected bird. Use according to any one of claims 49-58, wherein the source of the virus is a mammal showing symptoms of infection. Use according to any one of claims 49-60, which is for reducing mortality.