ES2354791B1 - DOMPERIDONE AT A LOW DAILY DOSE FOR USE IN THE TREATMENT OR PREVENTION OF AN ILLNESS ASSOCIATED WITH AN ALTERATION OF THE IMMUNE RESPONSE. - Google Patents

Abstract

The invention relates to the use of domperidone or a pharmaceutically acceptable salt thereof at low doses for the preparation of a medicament for preventing and / or treating a disease associated with an alteration of the immune response such as leishmaniosis.

Description

Domperidone at a low daily dose for use in the treatment or prevention of a disease associated with an impaired immune response.

Background of the invention

Field of the Invention

The invention relates to the use of domperidone or a pharmaceutically acceptable salt thereof at low doses to prevent and / or treat a disease associated with an alteration of the immune response such as leishmaniasis.

Description of the related technique

Canine leishmaniasis is a parasitosis that is endemic in the countries of the Mediterranean basin where seroprevalence can reach a value of 48.4% (Alvar et al. 2004, Paradies et al 2006).

Leishmania parasites, similar to what has been described for other intracellular pathogens, can survive and reproduce in the body of infected dogs thanks to their ability to divert the cellular-type immune response (Th1) to the immune-type response. humoral (Th2). In reality, the clinical evolution of the disease depends mainly on the immune response developed by the animal once it has been infected. Therefore, an infected animal will resist the evolution of the disease while maintaining a predominance of the cellular immune response (Th1), with a marked production of Th1 type cytokines, such as gamma interferon or IL-2 interleukin, which are responsible for the activation of macrophages and, through it, their leishmanicidal potential. On the contrary, when the humoral response (Th2) becomes predominant, which can happen immediately after infection or after a period of resistance to the evolution of the disease more or less prolonged, the animal succumbs to the disease and begins to present clinical signs that may even lead to death (Chamizo et al. 2005, Brachelente et al. 2005).

In dogs, disease resistance appears to be associated with a certain balance between Th1 and Th2 responses although the cellular response (Th1) seems to predominate. In species such as the mouse, the evolution of the disease or the resistance of the animal to the disease depends on a complete polarization of the immune response towards the humoral (Th2) or the cellular (Th1), respectively. (Chamizo et al. 2005, Brachelente et al. 2005).

Therefore, the evolution of the disease seems to be due to an alteration of the balance between the cellular-type immune response (Th1) and the humoral-type immune response (Th2).

Document ES 2246142 describes the effect of domperidone in the treatment of leishmaniasis, administered at a dose of 2 mg / kg / day in dogs infected with L. Infantum, by restoring the balance between the cellular-type immune response (Th1 ) and the humoral-type immune response (Th2) through an increase in blood levels of prolactin. It shows that, at this dose, domperidone can reduce the clinical signs of leishmaniasis and / or reduce the level of antibodies in infected animals.

To the best of our knowledge, there has been no attempt in the prior art to treat or prevent leishmaniasis in healthy or infected mammals using domperidone at a dose regimen of less than 2 mg / kg / day. Nor is any known method of prevention or treatment using domperidone at a dose regimen lower than 2 mg / kg / day during the latent phase of the disease or during outbreaks or secondary events of the disease.

In Merck 1997, a recommended dose of domperidone of 1 mg / kg / day is described, however, this dose regimen is restricted to a different indication, specifically as an antiemetic agent in dogs and not for the treatment of leishmaniasis.

The review article on Canine Leishmaniasis and its therapeutic approaches, recently published by a group of experts in this disease worldwide (Solano-Gallego et al. 2009. Vet Parasitol, 165: 1-18) mentions, when referring to employment of serology (titration of antibodies against Leishmania) in the monitoring of conventional treatments (including Alopurinol) of the disease, that the decrease in antibody titre is usually not observed until after 6 months (180 days) of the start of treatment .

“Recent studies have shown a slow and progressive decrease in the levels of IgG and IgA anti bodies that is associated with clinical improvement. Therefore, we recommend repeating a quantitative serological test in the same laboratory 6 months after the initial treatment due to the relatively long measured life of the IgG ”(page 12).

“Some dogs would have a significant decrease in the levels of anti-bodies associated with clinical improvement within 6 months to 1 year of treatment, while others may not have a decrease in antibody titres despite clinical improvement” (page 12).

It would be of great interest to develop an improved use of domperidone for the treatment of leishmaniasis or a method of treatment of leishmaniosis that would allow to reduce the unnecessary toxicity of the active substance, maintaining the same efficacy of the drug observed at the highest dose regimens described in the prior art and / or allowing a faster decrease in antibody titre in treated mammals.

Summary of the invention

The present invention is based on the finding that domperidone or a pharmaceutically acceptable salt thereof can be used in a dosage regimen or dose regimen, which implies total daily amounts well below those suggested so far in the art for prevent and / or treat a disease associated with a decrease in the immune response. The use of lower dosage levels may allow minimization of the occurrence of adverse effects.

Furthermore, it has also been found that, surprisingly, the dosing regimens according to the present invention allow a faster decrease in antibody titers in the treated subjects than that achieved by the treatments described in the prior art.

Therefore, the present invention is directed to a method of treatment or prevention of leishmaniasis in healthy or infected mammals using domperidone with a dosage regimen of 0.2-1 mg / kg / day that has an efficacy equal to or greater than that achieved. with the dose regimens known in the existing methods of treatment or prevention of the prior art.

The present invention is also directed to preparing domperidone formulations for the treatment or prevention of leishmaniasis in healthy or infected mammals adapted to a dose regimen of 0.2-1 mg / kg / day that provides an efficacy equal to or greater than the achieved with the dose regimens known in the existing methods of treatment or prevention of the prior art.

The present invention also relates to the use of domperidone in combination with other drugs that are known to be useful for the treatment or prevention of leishmaniasis in healthy or infected mammals (such as leishmanicidal agents such as N-methylglucamine or miltephosin antimoniate, or such as leishmaniostatic agents such as allopurinol) in which the new domperidone dosing regimen provides the same or greater efficacy than that achieved with the domperidone dose regimens known in the existing treatment or prevention methods of the prior art.

Detailed description of the invention

An aspect of the present invention is the use of domperidone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for administration of a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred that the medicament be prepared for the administration of a daily dose of domperidone of from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0 , 55 mg / kg / day and most preferably 0.5 mg / kg / day.

In one embodiment of the present invention, the medicament is an oral dosage form intended for administration once a day. This embodiment facilitates patient adherence to the therapeutic regimen and therefore compliance with this regimen.

In an alternative embodiment of the present invention, the medicament is an oral dosage form intended for administration twice a day.

In a preferred embodiment of the present invention, the medicament is intended for use in the treatment of dogs.

In yet another embodiment of the present invention, domperidone is used in the form of its free base for the formulation of the medicament.

In one embodiment of the present invention, the medicament is for the treatment or prevention in a mammal of a disease associated with an alteration in cellular immunity mediated by CD4 + Th1 lymphocytes. Examples of such diseases are:

-

leishmaniasis

-

parasitosis such as: malaria, other trypanosomiasis, ehrliquiosis, toxoplasmosis and coccidiosis,

-

immune diseases that evolve with an increase in Th2 lymphocytes and a decrease in Th1 such as asthma, atopias, allergic hypersensitivity reactions, and

-

viral diseases that evolve with immunosuppression such as AIDS, herpesvirosis, adenovirosis, cytomegalovirosis.

In a preferred embodiment of the present invention, the medicament is for the treatment of leishmaniasis in a mammal or to prevent its symptoms after infection has occurred.

In one embodiment of the present invention, the medicament is prepared for administration over a period of at least 10 days, preferably at least 15 days, more preferably at least 30 days.

Beneficial use of domperidone or a pharmaceutically acceptable salt thereof in the treatment or prevention of leishmaniasis in mammals (such as dogs) could be of high value when combined with a conventional treatment with a leishmanicidal agent such as N- antimoniate. methylglucamine or miltefosine and / or a leishmaniostatic agent such as allopurinol.

In one embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for combined administration of allopurinol and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

Combined use can be facilitated by including all active ingredients in a single pharmaceutical dosage form, although it is also possible to use them in separate dosage forms.

In one embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for combined administration of N-methylglucamine antimoniate and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferably 0.5 mg / kg / day.

In one embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is used for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for combined administration of miltefosine and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

An embodiment of the invention is the use of domperidone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for combined administration of allopurinol and N-methylglucamine antimonate, and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferably 0.5 mg / kg / day.

An embodiment of the invention is the use of domperidone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, the medicament being prepared for combined administration of allopurinol and miltefosine, and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day , more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferably 0.5 mg / kg / day.

Domperidone or its pharmaceutically acceptable salts and the leishmaniostatic agent or the leishmanicidal agent can be administered either in a single dosage form or in separate dosage forms.

Another aspect of the present invention is a method for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, which comprises the step of administering to said mammal a daily dose of domperidone or a pharmaceutically acceptable salt of the same from 0.2 mg / kg / day to 1 mg / kg / day. It is particularly preferred to administer a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

In one embodiment of the present invention, the method is characterized in that domperidone or a pharmaceutically acceptable salt thereof is administered as an oral dosage form intended for administration once a day, which facilitates the patient's adherence to the therapeutic regimen and by both compliance with the regime.

In an alternative embodiment of the present invention, the method is characterized in that domperidone or a pharmaceutically acceptable salt thereof is administered as an oral dosage form intended for administration twice a day.

In a preferred embodiment of the present invention, the method is used to treat dogs.

In yet another embodiment of the present invention, the method is characterized in that domperidone or a pharmaceutically acceptable salt thereof is used in the form of its free base for incorporation into a medicament before administration to the mammal.

In one embodiment of the present invention, the method of treatment is used to treat or prevent a disease associated with an alteration in cellular immunity mediated by CD4 + Th1 lymphocytes. In a preferred embodiment the disease is selected from the group comprising:

-

leishmaniasis

-

parasitosis such as: malaria, other trypanosomiasis, ehrliquiosis, toxoplasmosis and coccidiosis,

-

immune diseases that evolve with an increase in Th2 lymphocytes and a decrease in Th1 such as asthma, atopias, allergic hypersensitivity reactions, and

-

viral diseases that evolve with immunosuppression such as AIDS, herpesvirosis, adenovirosis, cytomegalovirosis.

In a preferred embodiment of the present invention, the method of treatment is used to treat leishmaniasis or to prevent its symptoms after infection has occurred.

In one embodiment of the present invention, the treatment is maintained over a period of at least 10 days, preferably at least 15 days, more preferably at least 30 days.

In one embodiment of the invention, the beneficial use of domperidone or a pharmaceutically acceptable salt thereof in the treatment or prevention of leishmaniasis in mammals (such as dogs) could be of high value when carried out after conventional treatment with a leishmanicidal agent such as N-methylglucamine or miltefosine antimoniate and / or a leishmaniostatic agent such as allopurinol once the parasite load in the infected animal has been reduced, thereby helping the animal to recover an effective immune response to the disease.

In a preferred embodiment, domperidone or a pharmaceutically acceptable salt thereof is administered in combination with a leishmanicidal agent such as N-methylglucamine or miltephosine antimony, both agents being administered in a single dosage form or in separate dosage forms.

In another preferred embodiment, domperidone or a pharmaceutically acceptable salt thereof is administered in combination with a leishmaniostatic agent such as allopurinol, both agents being administered in a single dosage form or in separate dosage forms.

An embodiment of the invention is a method of treating a mammal so that prolactin levels in said mammal are increased by preventing and / or thereby treating a disease associated with an alteration of the immune response, a combination being administered to said mammal which comprises allopurinol and a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred to administer a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

An embodiment of the invention is a method of treating a mammal so that prolactin levels in said mammal are increased by preventing and / or thereby treating a disease associated with an alteration of the immune response, a combination being administered to said mammal which comprises N-methylglucamine antimoniate and a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred to administer a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

An embodiment of the invention is a method of treating a mammal so that prolactin levels in said mammal are increased by preventing and / or thereby treating a disease associated with an alteration of the immune response, a combination being administered to said mammal comprising miltefosine and a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred to administer a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

An embodiment of the invention is a method of treating a mammal so that prolactin levels in said mammal are increased by preventing and / or thereby treating a disease associated with an alteration of the immune response, a combination being administered to said mammal comprising allopurinol and N-methylglucamine antimonate and a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred to administer a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

An embodiment of the invention is a method of treating a mammal so that prolactin levels in said mammal are increased by preventing and / or thereby treating a disease associated with an alteration of the immune response, a combination being administered to said mammal which comprises allopurinol and miltefosine and a daily dose of domperidone or a pharmaceutically acceptable salt thereof from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred to administer a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day and most preferably 0.5 mg / kg / day.

Domperidone or a pharmaceutically acceptable salt thereof and the leishmaniostatic agent or the leishmanicidal agent can be administered either in a single dosage form or in separate dosage forms.

An aspect of the present invention is a composition comprising domperidone or a pharmaceutically acceptable salt thereof for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which the composition is prepared for administration of a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day. It is further preferred that the composition be prepared for administration of a daily dose of domperidone of from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0 , 55 mg / kg / day, and most preferably 0.50 mg / kg / day.

In one embodiment of the present invention the composition is prepared as an oral dosage form for once daily administration. This embodiment facilitates patient adherence to the therapeutic regimen and therefore compliance with this regimen.

In an alternative embodiment of the present invention it is characterized in that the composition is administered as an oral dosage form intended for administration twice a day.

In one embodiment the composition is for the treatment or prevention of a disease associated with an alteration of the immune response in a dog.

In yet another embodiment the composition comprises domperidone in the form of a free base.

In another embodiment of the present invention the composition is for use in the treatment or prevention of a disease associated with an alteration of the immune response, preferably the disease is selected from the group of diseases associated with an alteration in cellular immunity mediated by CD4 lymphocytes. + Th1. It is further preferred that the disease be selected from the group comprising:

-

leishmaniasis

-

parasitosis such as: malaria, other trypanosomiasis, ehrliquiosis, toxoplasmosis and coccidiosis,

-

immune diseases that evolve with an increase in Th2 lymphocytes and a decrease in Th1 such as asthma, atopias, allergic hypersensitivity reactions, and

-

viral diseases that evolve with immunosuppression such as AIDS, herpesvirosis, adenovirosis, cytomegalovirosis.

In a more preferred embodiment the composition is for use in the treatment of leishmaniasis or in the prevention of its symptoms after the infection has occurred.

In yet another embodiment the composition is prepared for administration for a period of at least 10 days, preferably 15 days, more preferably 30 days.

The composition is beneficially used in the treatment or prevention of Leishmaniosis in mammals (such as dogs) and could have a high value when combined with a conventional treatment with a leishmanicidal agent such as N-methylglucamine or miltefosine antimoniate and / or a Leishmaniostatic agent such as allopurinol.

In one embodiment of the invention the composition is prepared for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which the composition is prepared for the combined administration of allopurinol and a daily dose of Domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention the composition is prepared for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which the composition is prepared for the combined administration of N-methylglucamine antimoniate and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention the composition is prepared for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which the composition is prepared for the combined administration of miltefosine and a daily dose of Domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention the composition is prepared for use for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response and is prepared for the combined administration of allopurinol and N-methylglucamine antimonate, and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention the composition is prepared for use for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response and is prepared for the combined administration of allopurinol and miltefosine, and a daily dose of domperidone. from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In yet another embodiment of the invention the composition is prepared for the combined administration of domperidone or a pharmaceutically salt thereof and a leishmanicidal agent such as N-methylglucamine antimoniate.

or miltefosine, preferably the composition comprises both agents in a single dosage form or in separate dosage forms.

In yet another embodiment of the invention the composition is prepared for the combined administration of domperidone or a pharmaceutically salt thereof and a leishmaniostatic agent such as allopurinol, preferably the composition comprises both agents in a single dosage form or in separate dosage forms.

The domperidone composition or a pharmaceutically acceptable salt thereof and the leishmaniostatic agent or the leishmanicidal agent can be administered either in a single dosage form or in separate dosage forms.

In one aspect of the present invention domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response at a daily dose of domperidone of from 0.2. mg / kg / day up to 1 mg / kg / day. It is further preferred to use it at a daily dose of domperidone from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day , and most preferably 0.50 mg / kg / day.

In one embodiment of the present invention domperidone or a pharmaceutically acceptable salt thereof is for use in the form of an oral dosage form for once daily administration. This embodiment facilitates patient adherence to the therapeutic regimen and therefore compliance with this regimen.

In an alternative embodiment of the present invention domperidone or a pharmaceutically acceptable salt thereof is for use as an oral dosage form intended for administration twice daily.

In one embodiment, domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a disease associated with an alteration of the immune response in a dog.

In yet another embodiment, domperidone or a pharmaceutically acceptable salt thereof is for use as a free base.

In another embodiment of the present invention domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention of a disease associated with an alteration of the immune response, preferably the disease is selected from the group of diseases associated with a alteration in cellular immunity mediated by CD4 + Th1 lymphocytes. It is further preferred that the disease be selected from the group comprising:

-

leishmaniasis

-

parasitosis such as: malaria, other trypanosomiasis, ehrliquiosis, toxoplasmosis and coccidiosis,

-

immune diseases that evolve with an increase in Th2 lymphocytes and a decrease in Th1 such as asthma, atopias, allergic hypersensitivity reactions, and

-

viral diseases that evolve with immunosuppression such as AIDS, herpesvirosis, adenovirosis, cytomegalovirosis.

In a more preferred embodiment, domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment of leishmaniasis or in the prevention of its symptoms after infection has occurred.

In yet another embodiment, domperidone or a pharmaceutically acceptable salt thereof is for use in administration for a period of at least 10 days, preferably 15 days, more preferably 30 days.

Domperidone or a pharmaceutically acceptable salt thereof is beneficially used in the treatment.

or prevention of Leishmaniosis in mammals (such as dogs) and could have a high value when combined with a conventional treatment with a leishmanicidal agent such as N-methylglucamine or miltefosine antimoniate and / or a leishmaniostatic agent such as allopurinol.

In one embodiment of the invention domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which it is prepared for the combined administration of allopurinol and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which it is prepared for the combined administration of antimoniate. of N-methylglucamine and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response in which it is prepared for the combined administration of miltefosine. and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In one embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an impaired immune response and is prepared for the combined administration of allopurinol and antimoniate. of N-methylglucamine, and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0.45 mg / kg / day to 0.55 mg / kg / day, most preferably 0.5 mg / kg / day.

In one embodiment of the invention domperidone or a pharmaceutically acceptable salt thereof is for use in the treatment or prevention in a mammal of a disease associated with an alteration of the immune response and is prepared for the combined administration of allopurinol and miltefosine. , and a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day, preferably from 0.3 mg / kg / day to 0.7 mg / kg / day, more preferably from 0, 45 mg / kg / day up to 0.55 mg / kg / day, most preferred 0.5 mg / kg / day.

In yet another embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is for use in administration in combination with a leishmanicidal agent such as N-methylglucamine or miltephosine antimoniate, preferably by combined administration with both agents in a single dosage form.

or in separate dosage forms.

In yet another embodiment of the invention, domperidone or a pharmaceutically acceptable salt thereof is for use in administration in combination with a leishmaniostatic agent such as allopurinol, preferably by combined administration with both agents in a single dosage form or in separate dosage forms. .

Domperidone or a pharmaceutically acceptable salt thereof and the leishmaniostatic agent or the leishmanicidal agent can be administered either in a single dosage form or in separate dosage forms.

The active compounds can be administered orally in any suitable dosage form such as syrups, tablets, capsules, lozenges, controlled release preparations, quick dissolving preparations, sucking pills, etc.) or by injection (subcutaneous, intradermal , intramuscular, intravenous, etc.).

Formulations for administration by injection include suspensions, solutions, emulsions in oily or aqueous vehicles, pastes and biodegradable or sustained release formulations that can be implanted. Such formulations may further comprise one or more additional components including suspending, stabilizing or dispersing agents. In an embodiment of a formulation for parenteral administration, the active ingredient is provided in dry form (i.e., in powder or granular form) for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before parenteral administration. of the reconstituted composition.

The pharmaceutical compositions can be prepared, packaged or sold in the form of a sterile injectable aqueous or oily solution or suspension. This solution or suspension may be formulated according to the known technique, and may comprise, in addition to the active ingredient, additional components such as dispersing agents, wetting agents or suspending agents described herein. Such sterile injectable formulations can be prepared using a non-toxic solvent or diluent acceptable parenterally.

Other formulations that can be administered parenterally that are useful include those that comprise the active ingredient in microcrystalline form, in a liposomal preparation or as a component of a biodegradable polymer system. Compositions for sustained release or implant may comprise pharmaceutically acceptable hydrophobic or polymeric materials such as an emulsion, an ion exchange resin, a soluble polymer in moderation or a soluble salt in moderation.

Pharmaceutical formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the stage of associating the active principle (s) with the vehicle. In general, the formulations are prepared by uniformly and intimately associating the active substance with liquid vehicles or finely divided solid vehicles.

or both and then, if necessary, forming the product in the desired formulation.

The formulations of the present invention suitable for oral administration may be presented as differentiated units such as capsules, seals or tablets each containing a predetermined amount of the active substance; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid emulsion of oil in water or a liquid emulsion of water in oil. The active substance can also be presented as a bolus injection, an electuary or a paste.

A syrup formulation will generally consist of a suspension or dissolution of the compound or salt in a liquid vehicle, for example natural, synthetic or semisynthetic oils or water with flavoring, sweetening and / or coloring agents. When the composition is in the form of a tablet, any pharmaceutical carrier commonly used to prepare solid formulations can be used.

A tablet can be prepared by compression or molding, optionally with one or more additional components. Compressed tablets can be prepared by compression in a suitable machine of the active ingredient in a freely flowing form such as a powder or granules, optionally mixed with binders, lubricants, inert diluents, lubricating agents, surfactants or dispersion. Molded tablets can be prepared by molding in a suitable machine a mixture of the powder combination comprising the active compounds moistened with an inert diluent and optionally dried and sieved. The tablets may be optionally coated or grooved and may be formulated so as to provide a modified (i.e., slow or controlled) release of the active ingredient therein.

When the composition is in the form of a capsule, any usual encapsulation is suitable, for example using the vehicles mentioned above in a hard gelatin capsule. When the composition is in the form of a soft gelatin capsule, any pharmaceutical vehicle commonly used to prepare dispersions or suspensions can be considered.

De fi nitions and Conventions

The definitions and explanations below are for the terms as they are used throughout this document including both the specification and the claims.

Pharmaceutically acceptable refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and to the pharmaceutical chemist who manufactures it from a physical / chemical point of view regarding the composition, formulation, stability , patient acceptance and bioavailability.

The term "pharmaceutically acceptable salt" encompasses salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulfuric, phosphoric, diphosphoric, bromhydric, iodhydric and nitric acids, and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric acid. , benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic (cyclamic) or p-toluenesulfonic. Pharmaceutically acceptable bases include alkali metal (for example, sodium or potassium) and alkaline earth metal (for example, calcium or magnesium) hydroxides and organic bases, for example alkylamines, arylalkylamines and heterocyclic amines.

In the context of infectious diseases, the term prevention is not used to designate the avoidance of inoculation of the patient with the infectious agent but the avoidance of the appearance of infection or of the clinical signs associated with the evolution of the disease after the disease has occurred. infection.

When the amounts or doses of domperidone or pharmaceutically stable salts thereof are mentioned in this application, they refer to the amounts or doses expressed as domperidone free base.

The term treatment is used to designate the control of the evolution of the disease once the clinical signs have appeared.

The present invention shows the advantages of reducing the unnecessary toxicological effects of the drug when administered at higher doses to the mammal.

In the event that the dosing regimen is administered once a day, this has the additional advantage of facilitating compliance with the therapeutic dosing regimen (it is easier and more convenient to administer the medication once a day).

A leishmanicidal agent refers to an agent that can kill the parasite that produces leishmaniosis. A leshmaniostatic agent refers to an agent that does not kill the parasite that produces leishmaniosis but instead can prevent its reproduction.

By "combined administration", it is to be understood that domperidone can be administered separately, concurrently, concurrently or sequentially or together with a leishmanicidal agent as an N-methylglucamine antimonate

or miltefosine and / or a leishmaniostatic agent such as allopurinol in any order, for example the administration of domperidone may be performed first, followed by the administration of the leishmanicidal agent and / or the leishmaniostatic agent, or the administration of domperidone may be performed last. , preceded by the administration of the leishmaniostatic agent and / or the leishmanicidal agent; or the administration of domperidone can be performed concomitantly with the leishmaniostatic agent and / or the leishmanicidal agent.

Synergistic effect between domperidone and allopurinol means the effect observed on the clinical improvement of the disease, when both drugs are co-administered. Specifically, it is observed that the decrease in antibody titre against Leishmania decreases faster when both drugs are administered combined than when each of them is administered separately.

Examples

The advantages of the invention are more fully illustrated with reference to the following examples.

Example 1

Study of the prolactin hormone kinetic profile after oral administration of domperidone in a male beagle dog

The present study was conducted in order to determine the kinetic profile of the hormone prolactin in a male dog after oral administration of domperidone at different dosage levels. Ten animals were used, which received a single oral administration of domperidone at six different dosage levels (0.125 mg / kg, 0.250 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg) as well as a placebo, following a cross-test in 7 phases separated by a minimum washing period of 6 days. During each of the 7 phases blood samples were taken at different times (t = 0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 18 h, 36 and 48 h) to determine serum concentrations of prolactin using a commercial immunoenzymatic assay kit.

Although all dosages produced a rapid increase in average blood prolactin concentrations, this increase was lower at two lower dosage levels (0.125 and 0.250 mg / kg). With higher dosage levels (0.5 mg / kg, 1 mg / kg, 2 mg / kg and 4 mg / kg), the increase was more pronounced but similar among them, not being possible to observe a dose-effect correlation. In all cases, the average prolactin concentrations in the first 36 hours after domperidone administration remained above the prolactin concentration in the placebo group.

Higher values were obtained for the area under the prolactin curve calculated between 0h12h (AUC) after domperidone administration at levels of 0.5 mg / kg and higher. However, the values obtained after administration at 1 mg / kg, 2 mg / kg and 4 mg / kg were not significantly higher than those obtained with the dosage of 0.5 mg / kg.

In addition, higher values of maximum prolactin concentration (Cmax) were also obtained after domperidone administration at dosing levels of 0.5 mg / kg and higher. Once again, the values obtained after administration at 1 mg / kg, 2 mg / kg and 4 mg / kg were not significantly higher than those obtained with the dosage of 0.5 mg / kg.

Finally, the time required to reach the maximum prolactin concentration (Tmax) when domperidone was administered at levels of 0.5 mg / kg and above was less than the time required after administration at lower dosages (0.125 mg / kg and 0, 250 mg / kg) In this case, no statistically significant differences were observed between the 6 dosages studied.

Table 1 summarizes the average values of AUC-12 h obtained in the 6 treatment groups. The last column of each group indicates the groups against which statistically significant differences were observed (p <0.05).

TABLE 1

Table 2 summarizes the average Cmax values obtained in the 6 treatment groups. The last column of each group indicates the groups against which statistically significant differences were observed (p <0.05).

TABLE 2

Table 3 summarizes the average Tmax values obtained in the 6 treatment groups. The last column of each group indicates the groups against which statistically significant differences were observed (p <0.05).

TABLE 3

The results show surprisingly that it is possible to administer dosage levels of domperidone to dogs below those described in the art (administration of 1 mg / kg /) while prolactin production is induced at levels comparable with those produced at dosing more high described in the art. This effect is con fi rmed at dosages of only 0.5 mg / kg.

Example 2

Study of the effect of domperidone administration on the cellular immune response in healthy dogs

The present study was conducted to demonstrate the effect of domperidone administration on the cellular immune response in healthy dogs through a controlled trial. 20 dogs of different breed, sex and age were randomly distributed in two groups of 10. The animals of one of the two groups acted as a negative control and received no treatment. Animals from the other group received 0.5 mg domperidone / kg / day, orally, for 30 consecutive days. During the study, several visits were attended (days 0, 15, 30, 60 and 90) during which some clinical tests were performed and blood samples were collected for biochemical, hematological and serological analysis (DAT). The percentages of monocytes and activated neutrophils in whole blood samples were determined through the tetrazolium nitro-blue reduction (NBT) test.

Table 4 summarizes the average values of monocyte activation percentages in the two groups, compared by Student's t.

TABLE 4

Table 5 summarizes the average values of the neutrophil activation percentages in the two groups, compared by Student's t.

TABLE 5

The results showed that in the group that did not receive any treatment, the percentage of activated neutrophils and monocytes remained low and stable during the 90 days monitored. However, animals treated with domperidone suffered a statistically significant increase during treatment, remaining high for at least 30 days after the end of treatment.

The results showed surprisingly that the administration of domperidone at a dosage of 0.5 mg / kg / day in healthy dogs for 30 consecutive days, produced a stimulation effect of the cellular immune response that persists at least one month after the end of treatment.

Example 3

Study of the response of macrophages derived from circulating monocytes of a healthy dog treated with domperidone, against in vitro infection with Leishmania infantum

The objective of this study is to evaluate the effect of domperidone on the susceptibility to infection and the in vitro leishmanicidal capacity of macrophages derived from circulating monocytes exposed to promastigotes of Leishmania infantum.

It is designed as a prospective monocentric study. A total of 10 dogs have been included, each of them acting as their own control, which is why the use of a negative control has not been considered necessary. All animals received domperidone orally at a dosage of 0.5 mg / kg / day for 30 consecutive days. During the study, several visits were attended on days 0 (baseline), 15 and 30 of treatment, and days 60 and 90 (one and two months after the end of treatment, respectively). During each visit, blood was collected from the animals and processed to isolate and grow monocyte-macrophages, which are then grown in conjunction with Leishmania promastigotes. After 48 hours the tetrazolium nitro-blue (NBT) reduction test was carried out in the cultures and the percentage of parasitized macrophages and the number of amastigotes per macrophage were measured. Blood samples are also collected on days 0 and 90 to assess the health of the animal by biochemical and hematological analysis.

Table 6 summarizes the percentage of infected macrophages after 48 hours of in vitro culture with promastigotes of Leishmania infantum.

TABLE 6

Table 7 shows the percentage of positive NBT macrophages after 48 hours of co-culture with promastigotes of Leishmania infantum.

TABLE 7

Table 8 summarizes the number of amastigotes per macrophage after 48 hours of in vitro culture with promastigotes of Leishmania infantum.

TABLE 8

These results show a significant increase in phagocytic activity (NBT positive macrophages, Table 7) in macrophages in samples collected on days 15 and 30, although the percentages of activated macrophages returned to their normal basic values in samples collected in days 60 and 90. In parallel, and in accordance with the present results, the average percentage of infected macrophages, which in the cell culture of samples collected on day 0 was approximately 90%, decreased significantly to approximately 25% in the samples collected on days 15 and 30, thereby returning to values close to the basic ones on the samples collected on days 60 and 90 (Table 6). Finally, the number of amastigotes per infected macrophage followed a dynamic similar to that described for the other two parameters (Table 8).

According to the results obtained, it can be concluded that the daily administration of 0.5 mg / kg of domperidone in dogs prepares the main cells involved in non-specific immunity (monocytes / macrophages) for an effective activation against a Leishmania infection, in experimental conditions in vitro.

Example 4

Study of the clinical efficacy of a domperidone treatment plan against canine leishmaniasis in its early stages

The objective of this study is to evaluate the effectiveness of an oral treatment plan with domperidone against canine leishmaniasis in its early stages, evaluating its effect on the incidence of clinical disease in a population of healthy animals resident in a highly endemic area. .

It is designed as a controlled clinical trial in practice (treated group versus untreated group) with 100 initially healthy (uninfected) animals residing in a highly endemic area, therefore with high chances of becoming infected. Half of the animals have received domperidone at a dosage of 0.5 mg / kg / day according to a treatment plan consisting of repeatedly administering domperidone for periods of 30 days, guaranteeing every four months that the treatment covers the onset and the end of the period of activity of the transmitting insect to guarantee a double objective: firstly to strengthen the dog's primary cellular response, so that when the insect infects the animal its primary defense barrier is prepared to overcome the resistance of the parasites, destroy them and develop a specific immune response appropriate for disease control / elimination. Second, to balance the immune response of animals that, having been infected during periods of least protection, are still in the initial phase of the disease.

Table 9 shows the cumulative percentage of animals with signs of canine Leishmaniosis at the end of the study (second year of follow-up).

TABLE 9

As shown in the table, after 2 years 50% of the animals in the untreated group presented signs indicative of the disease progression while in the treated group this percentage was statistically lower (only 11% of the animals that also they only presented positive serology against Leishmania but no clinical sign, unlike those of the untreated group).

From the results, it is concluded that the treatment program applied in the present study to healthy animals resident in a highly endemic area entails a statistically significant decrease in the number of sick animals at 2 years, thus confirming their clinical efficacy in the prevention of canine leishmaniasis.

Example 5

Study of the clinical efficacy and safety of a domperidone treatment program for the control of canine leishmaniasis in low incidence areas

In order to assess the effectiveness of a domperidone-based oral treatment program for the control of canine Leishmaniasis, a controlled study was carried out with 240 seronegative animals against Leishmania residing in an endemic geographic area.

The study lasted 9 months, beginning at the beginning of the activity period of the insect vector of the disease in the geographical area in which the animals were and ending three months after the end of that period. The presence of the vector was confirmed before starting treatment.

Half of the animals (n = 120) received two 30-day treatments at a rate of 0.5 mg / kg / day of domperidone orally, one at the beginning and the other at the end of the activity period of the vector.

The other 120 animals received a placebo under an equivalent pattern.

Throughout the study, most of the dogs presented a normal clinical status with the exception of some animals from both treatment groups, which suffered superficial wounds accompanied by mild lymphadenopathy as a result of fights, and 7 animals from the untreated group in Those who observed the appearance of lymphadenopathy and alopecia during the last month of follow-up. In the control carried out at the end of the study, the same 7 animals in which lymphadenopathy and alopecia have been observed, showed seropositivity against Leishmania (DAT≥1 / 400) while all the animals in the treated group remained negative. The differences observed (5.83% vs. 0%) were statistically significant. In the 7 seropositive cases the disease was confirmed by direct observation of Leishmania amastigotes inside macrophages in any of the lymph node or bone marrow samples obtained by fine needle puncture (FAP). None of the animals in the treated group presented clinical symptoms indicative of adverse reactions attributable to the administration of the medication during the study.

Table 10 summarizes the cumulative percentage of animals with signs of canine Leishmaniosis at the end of the study (9th month of follow-up).

TABLE 10

The results obtained confirm the efficacy and safety of the treatment regimen used in the present study, for the control of canine leishmaniasis in animals resident in an endemic geographic area.

Example 6

Study of the clinical efficacy of domperidone alone in the treatment of canine leishmaniasis

A clinical study was carried out in which a group of 70 dogs with an initial stage of Leishmaniosis (titration of antibodies against Leishmania between 1/800 and 1/1600 -dintel of positivity 1 / 800- and oligosymptomatic) were included. . All animals were treated with domperidone, orally and for 30 consecutive days, at a rate of 1 mg / kg / 12 h (animals weighing less than 30 kg) or 0.7 mg / kg / 12 h (the other animals).

In addition to a baseline control, all animals underwent several clinical controls 30, 90 and 180 days after the start of treatment. During these controls, different immunological parameters were evaluated (antibody titre against Leishmania-DAT, intradermoreaction test -Leishmanin), clinical (clinical symptomatology, body weight) and analytical (biochemical profile, blood hematology, proteinogram and urine analysis for determination of the UPC ratio).

The evaluation of the effectiveness of the treatment was carried out based on the global evaluation of all the parameters, although paying special attention to the evolution of the antibody titre (Ac) against Leishmania as well as to the evolution of clinical symptomatology and specifically of lymphadenopathy, a symptom that all animals presented to a greater or lesser extent at the time of inclusion in the study. Table 11 summarizes the percentage of dogs that show an antibody titer less than the titer of antibodies at day 0.

TABLE 11

The results show that the treatment was effective in slowing the evolution of the disease. In 47% of the animals, the antibody titer decreased after 90 days from the start of the treatment while in no case there was an increase in it. At 180 days said percentage speaks up to 57%.

These observations show that when domperidone alone is administered, the decrease in antibodies against Leishmania takes place faster than the decrease described in the literature with treatments with other drugs such as allopurinol (180 days in the case of allopurinol) .

In addition, clinical symptomatology (mainly lymphadenopathy) progressively decreased until its total disappearance in 100% of the animals over the 12 months following the start of treatment.

In general, the treatment entails a clear decrease and / or stabilization of both the antibody titre and the clinical symptomatology associated with Leishmaniosis, and this phenomenon can be attributed to an indirect immunomodulatory effect of the molecule whose final result consists of a turnaround of the response. immune Th2 to Th1.

Experimental data from animals treated with domperidone show that although at day 180, 57% of treated animals experienced a decrease in antibody titre against Leishmania, at day 90, 47% of animals experienced such decline, indicating that Domperidone administration entails a clear advantage over the administration of conventional treatments, accelerating the decrease in antibody titre against Leishmania.

Example 7

Study of the synergistic effect of domperidone and allopurinol in the treatment of canine leishmaniasis

Seven dogs with clinical signs compatible with leishmaniasis (lymphadenomegaly, weight loss, alopecia ...), positive antibody titer in the Direct Agglutination test (DAT) (cut off ≥ 1/400), and identification were included in the study. direct by means of fine needle puncture of popliteal or bone marrow lymph node. All of them were given domperidone at a dose of 0.5 mg / kg / 24 h for a consecutive month, and allopurinol at 10 mg / kg / 12 h for three months. For the evaluation of the efficacy, a clinical follow-up was carried out during the three months, monitoring the main symptoms related to the disease (skin lesions, lymphadenomegaly, progressive weight loss, muscular atrophy, exercise intolerance, epistaxis, lameness, onychogryphosis), thus as a DAT serology on days 30 and 90.

The results obtained regarding clinical follow-up and antibody level were:

-

The seven dogs had a significant improvement over the baseline visit both on the 30th and the 90th.

-

In the seven animals a significant decrease in antibody titration was observed on day 90 with respect to baseline.

-

Four of the seven dogs had negative serologies at the end of the study.

Table 12 summarizes the percentage of dogs that show an antibody titer less than day 0 to days 30, 90 and 180 determined by the Direct Agglutination test (DAT).

TABLE 12

On day 30, 42.8% of dogs show a titre of Ac less than day 0. On day 90 this percentage increased to 100%.

The prognosis of a dog suffering from leishmaniosis is determined by its immune response. Any treatment capable of correcting the imbalance in this response affects the key point of the disease.

Two drugs have been used for this study. These drugs achieve good results separately, by immunostimulation (domperidone) and reducing the activity of the parasite (allopurinol. By their association, this combination is very effective in the treatment of canine leishmaniasis producing a clinical improvement and a rapid decrease in the level of antibodies The resulting synergy provides a more efficient and faster response.

Experimental data from animals treated with domperidone and allopurinol show that at day 90, 100% of the treated animals experienced a decrease in antibody titre against Leishmania (unlike the previous study in which at day 90 only 47% of the animals experienced this decrease), which demonstrates a clear synergistic effect of the combination of both drugs on the evolution of the disease.

It has been surprisingly observed that the combination of allopurinol and domperidone can reduce the antibody titer well before the 180-day period mentioned in the prior art (Solano-Galician) when domperidone is used alone at conventional doses.

Claims (18)

one.

Use of domperidone or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention in a mammal of a disease associated with an alteration of the immune response, where the medicament is prepared for the administration of a daily dose of domperidone from 0.2 mg / kg / day to 1 mg / kg / day.

2.

Use according to claim 1, characterized in that the medicament is prepared for the administration of a daily dose of from 0.3 mg / kg / day to 0.7 mg / kg / day.

3.

Use according to claim 2, characterized in that the medicament is prepared for the administration of a daily dose of from 0.45 mg / kg / day to 0.55 mg / kg / day.

Four.

Use according to claim 3, characterized in that the medicament is prepared for the administration of a daily dose of 0.50 mg / kg / day.

5.

Use according to any preceding claim, wherein the medicament is prepared as an oral dosage form for administration once a day.

6. Use according to any preceding claim, characterized in that the mammal is a dog.

7.

Use according to any preceding claim, characterized in that domperidone is used in the form of the free base.

8.

Use according to any preceding claim, characterized in that the disease is selected from the group of diseases associated with an alteration in cellular immunity mediated by CD4 + Th1 lymphocytes.

9.

Use according to claim 8, characterized in that the disease is leishmaniosis.

10.

Use according to claim 8, characterized in that the disease is selected from the group comprising:

-

parasitosis such as: malaria, other trypanosomiasis, ehrliquiosis, toxoplasmosis and coccidiosis,

-

immune diseases that evolve with an increase in Th2 lymphocytes and a decrease in Th1, such as asthma, atopias, allergic hypersensitivity reactions, and

-

viral diseases that evolve with immunosuppression, such as AIDS, herpesvirosis, adenovirosis, cytomegalovirosis.

eleven.

Use according to any preceding claim, characterized in that the medicament is prepared for administration over a period of at least 10 days.

12.

Use according to claim 11, characterized in that the medicament is prepared for administration over a period of at least 15 days.

13.

Use according to claim 12, characterized in that the medicament is prepared for administration over a period of at least 30 days.

14.

Use according to any preceding claim, the medicament being prepared for the combined administration of domperidone and a leishmanicidal agent such as N-methylglucamine antimoniate or miltefosine.

fifteen.

Use according to claim 14, wherein the medicament comprises both domperidone and a leishmanicidal agent such as N-methylglucamine or miltephosine antimonate either in a single dosage form or in separate dosage forms.

16.

Use according to any preceding claim, the medicament being prepared for the combined administration of domperidone and a leishmaniostatic agent such as allopurinol.

17.

Use according to claim 16, wherein the medicament comprises both domperidone and a leishmaniostatic agent such as allopurinol either in a single dosage form or in separate dosage forms.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201030477 SPAIN Date of submission of the application: 30.03.2010 Priority Date: 03-31-2009 REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

X

EN 2246142 A1 (HIGHER SCIENTIFIC RESEARCH COUNCIL) 01.02.2006, examples 1,2; page 7, line 26; claims. 1-3,5-17

TO

EP 0848954 A1 (CLEMSON UNIVERSITY) 24.06.1998, page 5, lines 13-17; claims 17,19. 1-3,5-13

TO

US 5372818 A (CROSS et al.) 13.12.1994, example 7. 1-3,5-13

TO

US 20030216355 A1 (ENGEL) 20.11.2003, paragraphs 23,24,26. 14-17

TO

BRYCESON, A. &quot; A policy for leishmaniasis with respect to the prevention and control of drug resistance &quot;. Tropical medicine and international health. 2001. vol. 6, No. 11, pages 928-934, table 2, conclusions. 14-17

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 14.02.2011

Examiner H. Aylagas Cancio Page 1/5

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201030477 CLASSIFICATION OBJECT OF THE APPLICATION A61K31 / 454 (01.01.2006) A61P33 / 02 (01.01.2006) A61P37 / 02 (01.01.2006) Minimum documentation sought (classification system followed by classification symbols) A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, MEDLINE, BIOSIS, NPL, EMBASE, XPESP, HCAPLUS State of the Art Report Page 2/5  WRITTEN OPINION Application number: 201030477 Date of Completion of Written Opinion: 02.22.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims 1-17 Claims IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims 4 Claims 1-3,5-17 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/5  WRITTEN OPINION Application number: 201030477 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

ES 2246142 A1 01.02.2006

D02

EP 0848954 A1 24.06.1998

D03

US 5372818 A 13.12.1994

D04

US 20030216355 A1 11/20/2003

D05

BRYCESON, A. &quot; A policy for leishmaniasis with respect to the prevention and control of drug resistance &quot;. Tropical medicine and international health. 2001. vol. 6, No. 11, pages 928-934, table 2, conclusions.

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The present application refers to the use of domperidone or a salt thereof for the preparation of a medicament for the treatment or prevention of a disease associated with an alteration of the immune response where the medicament is prepared for the administration of a daily dose of Domperidone from 0.2 mg / kg / day to 1 mg / kg / day. Its use is specifically claimed in leishmaniasis in dogs. A study of the kinetic profile of the hormone prolactin is performed (example 1). It also refers to the use of the medicament prepared for the combined administration of domperidone and a leishmanicidal agent such as N-methylglucamine antimonate (miltefosine) or allopurinol. Document D1 refers to a pharmaceutical composition containing domperidone or a pharmaceutically acceptable salt for the treatment or prevention in a mammal, preferably human or a dog, of a disease due to a decrease in the immune response by increasing the level of prolactin in this animal (see examples 1 and 2), by oral administration for 1 month of a dose of 1mg / kg / 12 hours (page 7, line 26), for the treatment of diseases associated with altered cellular immunity mediated by CD4 + Th1 lymphocytes (claim 6), for the treatment of leishmaniasis (example 2, claim 5) and parasitic diseases such as malaria, toxoplasmosis, trypanosomiasis, etc. (claim 6). This document is considered the state of the art closest to the invention as set forth in claim 1 of the application. The difference between said document and the technical object of claim 1 of the application lies in the dose used in the range of 0.2 to 1 mg / kg / day. There is no surprising or unexpected effect associated with this difference. The technical problem that therefore underlies the present invention can be considered as the provision of an alternative dose of domperidone for the treatment or prevention of a disease associated with an alteration of the immune response. The solution consists in the use of alternative doses. In the clinical trial described in document D1 (example 2), the effect of domperidone in vivo in dogs on the prevention or treatment of leishmaniasis is evaluated, and only one dose is used. The person skilled in the art could look for an appropriate dose as the next step without making an inventive effort in order to solve the problem. The use of domperidone in a dose of 0.08 to 3.3 mg / kg is already known in the state of the art (see document D2, claim 19), achieving the same effects as in the present application, that is, stimulating breastfeeding (document D2 reiv 17) and increasing the level of prolactin (page 5, lines 13-17). The choice of a sub-range between 0.2 to 1 mg / kg / day cannot be considered to imply inventive activity in the absence of a particular technical effect. Document D3 refers to the use of domperidone in steers with an average weight of 340 kg, 75 mg of domperidone is administered, which corresponds to a dose of 0.22 mg / kg / day (example 7). Therefore, the selection of the range 0.2 to 1 mg / kg / day cannot be considered to involve inventive activity. With regard to dependent claims 2,3,5-13, they do not contain any additional features that confer inventive activity in view of the cited documents. Claims 14-17 refer to a combination of domperidone with miltefosine (Reiv. 14 and 15) or with allopurinol (Reiv. 16 and 17) in a single dose and in separate doses. State of the Art Report Page 4/5  WRITTEN OPINION Application number: 201030477 These combinations have already been used for the same purpose, that is to say in the treatment of Leishmaniasis (see document D4 paragraphs 23, 24 and 26) and document D5 refers to the use of two known compounds in the treatment of Leishmaniasis (Table 2 and conclusions). It would be obvious to the person skilled in the art to use these compounds with the doses mentioned in document D1, in order to arrive at the content of claims 14-17. Therefore, in view of documents D1-D5, claims 1-3, 5-17 lack inventive activity in accordance with Article 8.1 of the L.P. As for claim 4, which refers to the use of a dose of 0.5 mg / kg / day, the use of said dose in the treatment of a disease associated with an alteration of the response is not mentioned in any of the cited documents immune in and in view of a proven effect of its use in the present application, said claim presents novelty and inventive activity in accordance with articles 6.1 and 8.1 of the LP State of the Art Report Page 5/5