Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Alverine alone or in combination with a tricyclic antidepressant or an antidepressant specific inhibitor of serotonin reuptake for the treatment of depression
• Depression is one of the most common psychological disorders. In France, the depressive rate is 14.9%, of which almost a third is not treated medically. The prevalence of reported depression has increased six-fold since 1970. The risk of developing major depression during life varies, according to studies, from 10 to 25% for women and from 5 to 12% for men.
• Depressive syndrome combines mood disorders (feelings of sadness, abandonment, humiliation, worthlessness), psychomotor inhibition (fatigue, helplessness in daily life, concentration disorders), manifest anxiety (often foreground) with almost constant somatic disorders (oppression, spasm, sleep disorders, appetite disorders, sexuality disorder).
• antidepressants are capable, within two to three weeks, of improving depressed mood and relieving mental distress. If the primary indication for antidepressants obviously remains endogenous unipolar depression, it is necessary to know the extensions of indication which now concern other psychiatric entities such as depressive episodes of bipolar psychosis, certain anxiety states, obsessive compulsive disorders, disorders of behavior, eating disorders but also other nosographic contexts such as the therapeutic management of certain pains.
• Tricyclic antidepressants with Pamitriptyline (Laroxyl®) and imipramine (Tofranil®) were the first to be discovered, followed by irreversible and non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine (hydrazine) pargyline (class of acetylenics) and iproniazude (Marsilid).
• MAOIs monoamine oxidase inhibitors
• Serotonin syndrome often overlooked, is linked to certain overdoses or interactions and justifies immediate discontinuation of treatment. It can lead to hospitalization, or even exceptionally jeopardize the vital prognosis. It combines a set of digestive symptoms (diarrhea), vegetative (sweating, thermal dysregulation, hypo or hypertension), motor (myoclonus, tremors), neuropsychic (confusion, agitation or even coma).
• the pharmacopoeia has effective antidepressant products but not without side effects.
• the current problem is the existence of an effective treatment for depression which has the least possible number of undesirable effects and zero or almost zero toxicity.
• One of the aims of the present invention is to provide products which make it possible to treat depression but which are largely devoid of the side effects mentioned above.
• Alverine is a medication conventionally used as an antispasmodic for the treatment of abdominal functional manifestations, particularly with meteorism.
• the present invention is based on the unexpected demonstration of the antidepressant properties of Alverine.
• Alverine The mode of action of Alverine is different from that of tricyclic antidepressants and that of specific or non-specific inhibitors of serotoriin reuptake, because Alverine interacts marginally with serotonin or norepinephrine reuptake systems .
• the advantage of Alverine is that this product, on the market for over 50 years, has very low toxicity compared to the conventional antidepressants described above and side effects which are very limited with a decline of more than one half century.
• the present invention describes the anti-depressive properties in animals of Alverine.
• the subject of the present invention is the use of Alverine or its metabolites, as well as esters and pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for treating depression.
• Alverine N-Ethyl-3,3'-diphenyldipropylamine
• Alverine metabolites means, inter alia, the mono or poly hydroxylated derivatives on the phenyl nuclei and the mono or poly hydroxylated or mono or poly carboxylated nuclei on the aliphatic chains.
• Three of the main metabolites identified in As an example after incubating Alverine with human liver microsomes are:
• pharmaceutically acceptable salts means the addition salts of Alverine which can be obtained by reaction of this compound with a mineral or organic acid according to a method known per se.
• acids which can be used for this purpose are hydrochloric, hydrobromic, sulfuric, phosphoric, 4-toluene sulfonic, methane sulfonic, cyclohexyl sulfamic, oxalic, succinic, formic, umaric, maleic, citric, aspartic, cinnamic, lactic, glutamic acids.
• N-acetylaspartic, N-acetylglutamic, ascorbic, malic, benzoic, nicotinic and acetic, citrate and Alverine tartar have been widely used in pharmaceutical spasmolytic preparations.
• esters on the hydroxy function mention may be made of carboxylic acid esters having from 1 to 6 carbon atoms.
• Alverine is known for its antispasmodic activity and is used for the treatment of abdominal functional manifestations, particularly with meteorism, its action as an antidepressant agent has never been described or suggested.
• Alverine, its metabolites, its salts, and in particular citrate and esters can be administered in a pharmaceutically acceptable form by one of the various routes known for this type of active principle.
• the invention relates to the use of Alverine or its metabolites in which the pharmaceutical composition is administered by oral, sublingual, buccal, subcutaneous, transdermal, local, rectal, infranasal, or injectable route. , especially intraperitoneally, intravenously or intramuscularly.
• the invention relates to the use of Alverine or its metabolites for the preparation of a pharmaceutical composition which can be administered orally, in particular in the form of capsules or tablets.
• the active substance can be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the process of encapsulation.
• various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the process of encapsulation.
• Magnesium stearate as an additive, provides a useful lubricant function if necessary. It may in certain cases be advantageous to provide forms with controlled release, in particular sustained release by known galenical forms.
• the subject of the invention is the use of Alverine or its metabolites for the preparation of a pharmaceutical composition which can be administered by injectable route.
• the active substances of the pharmaceutical compositions according to the invention can be dissolved or suspended in a sterile injectable liquid pharmaceutically acceptable, such as sterile water, a sterile organic solvent or a mixture of these two liquids for intravenous administration.
• a sterile injectable liquid pharmaceutically acceptable such as sterile water, a sterile organic solvent or a mixture of these two liquids for intravenous administration.
• Other routes of administration may include, but are not limited to, subcutaneous implants, as well as oral, sublingual, fransdermal, topical, infranasal or rectal administration.
• Biodegradable and non-biodegradable delivery systems can also be used.
• the usable daily dose is between 0.01 and 100 mg per kg.
• Alverine, or its metabolites, salts or esters can also be used according to the object of the present invention in combination with a tricyclic antidepressant compound.
• the tricyclic antidepressant compound is imipramine.
• Alverine, or its metabolites, salts or esters can also be used according to the object of the present invention in combination with an antidepressant compound specific for inhibiting the reuptake of serotonin.
• an antidepressant compound specific for inhibiting the reuptake of serotonin is fluoxetine.
• the administration will be in the form of co-prescription.
• the products may be administered simultaneously or separately over time to take account of their particularities and in particular their bioavailability.
• the dose ratios of the different products obviously depend on the products used, but preliminary tests have shown that the 1/1 combinations of Alverine and antidepressant made it possible to substantially divide by three the doses administered to obtain the same antidepressant effect.
• the present invention also relates to a pharmaceutical composition characterized in that it is a combination product comprising at least the Alverine compound or its metabolites, salts or esters and at least one tricyclic antidepressant compound for simultaneous use , separated or spread over time to treat depression.
• the pharmaceutical composition according to the present invention is characterized in that it comprises dose ratios by weight of Alverine and of tricyclic antidepressant understood as 1/10 and 10/1. More preferably, the dose ratios by weight are understood as 1/4 and 4/1.
• the tricyclic antidepressant compound is imipramine.
• tricyclic antidepressants can be used, including clomipramine, Pamitriptyline, maprotiline, Pamoxapine, desipramine, nortriptyline, demexiptiline, dibenzepine, dosulepine, doxepine, metapramine, noxiptiline, opipramol , quinupramine, and trimipramine.
• the present invention also relates to a pharmaceutical composition, characterized in that it is a combination product comprising at least the compound Alverine or its metabolites, salts or esters and at least one antidepressant compound specific inhibitor of reuptake of serotonin for simultaneous, separate or spread over time intended for treating depression.
• the pharmaceutical composition according to the present invention is characterized in that it comprises dose ratios by weight of Alverine and of antidepressant specific inhibitor of the reuptake of serotonin of between 1/10 and 10/1. More preferably, the dose ratios by weight are understood as 1/4 and 4/1.
• the specific antidepressant inhibitor compound for serotonin reuptake is fluoxetine.
• Other serotonin reuptake inhibitors may be used, including paroxetine, citalopram, fluvoxamine, serfralin.
• treatment of depression is meant the treatment of all phenomena of the depressive type, as well the treatment of single depressive episodes as recurrent depressive episodes or major depressions, but also the treatment of depressive episodes of bipolar or cyclothymic disorders. and related disorders.
• the present invention also relates to a method of treating depression comprising administering a composition according to the present invention to a patient in need of such treatment.
• Said composition comprises Alverine or its metabolites, alone or in combination with a tricyclic antidepressant or an antidepressant specific inhibitor of serotonin reuptake.
• Antidepressant specific reuptake inhibitor of serotonin the weight ratios in doses are from 1/10 to 10/1 and preferably from 1/4 to 4/1.
• the processes for the preparation of Alverine from phenylpropyl chloride and ethylamine in an alkaline medium are described in Kûlz et al., Ber. 72.2165 (1939) and its galenics is also known.
• Figure 1 Histogram of presentation of the results obtained by an antidepressant activity test of Alverine administered intraperitoneally on a batch of mice, presented in Table 1 and described in Example 1.
• Figure 2 Histogram of presentation of the results obtained by an antidepressant activity test of Alverine administered orally on a batch of mice, presented in Table 2 and described in Example 2.
• Figure 3 Histogram of presentation of the results obtained by an antidepressant activity test of Alverine and imipramine administered by the intraperitoneal route on a batch of mice, presented in Table 3 and described in Example 3
• Figure 4 Histogram of presentation of the results obtained by an antidepressant activity test of Alverine and fluoxetine administered intraperitoneally on a batch of mice, presented in table 4 and described in example 3 EXAMPLES
• Example 1 Antidepressant activity test of Alverine administered intraperitoneally on a batch of mice.
• mice were divided into 5 groups of 10 mice each. These are Swiss CD1 (CD-1® (ICR) IGS (Charles River France) mice weighing 25 and 35 g. They were placed in a room at a temperature between 19.5 and 24.5 ° C and a relative humidity 45 to 65% with a 12h light / dark cycle, ad libitum access to filtered water and standard laboratory food pellets. They are placed 15 to 20 per cage, during an acclimatization period of at least 5 days before the tests They are identified by marking on the fur.
• Swiss CD1 CD-1® (ICR) IGS (Charles River France) mice weighing 25 and 35 g. They were placed in a room at a temperature between 19.5 and 24.5 ° C and a relative humidity 45 to 65% with a 12h light / dark cycle, ad libitum access to filtered water and standard laboratory food pellets. They are placed 15 to 20 per cage, during an acclimatization period of at least 5 days before the tests They are identified by marking on
• test substance is Alverine citrate (Sigma, in dry powder form, with a salt / base ratio of 1.68) compared to imipramine hydrochloride (Sigma, in the form of dry powder, with a salt / base ratio of 1 J 3).
• the first group is the control group: it is only treated with an excipient.
• the second group is treated with Alverine at a dose of 3 mg / kg
• the third group is treated with Alverine at a dose of 10 mg / kg
• the fourth group is treated with Alverine at a dose of 30 mg / kg
• the fifth group is treated with imipramine (tricyclic antidepressant) at a dose of 10 mg / kg
• the doses are expressed in terms of free active substances.
• the substances are prepared extemporaneously in the excipient.
• the treatments are administered thirty minutes before the test in a coded and random order by the intraperitoneal route with a volume of 10 ml / kg.
• Thirty minutes after administration the five groups of mice are subjected to the forced swimming test, in a vertical plexiglass cylinder (height: 24 cm, diameter 9 cm) containing water (height 6 cm, temperature: 18-22 ° C).
• the total duration of immobility is measured during the last four minutes of the test, lasting a total of six minutes.
• a mouse is considered immobile when it stops fighting and floats in the water without movements that are superfluous to those allowing it to keep its head above water.
• a reduction in downtime is a reflection of an antidepressant effect.
• the forced swimming test is a pre-clinical behavioral model that has good predictive validity and is widely used to determine the effectiveness of antidepressant drugs (Borsini and Meli, 1988).
• the results are expressed in total duration of immobility in seconds and as a percentage change in the total duration of immobility calculated from the mean value of the control group.
• Table 1 results obtained by an antidepressant activity test of Alverine administered intraperitoneally on a batch of mice.
• n 10 animals per group * indicates a significant difference for p ⁇ 0.05 (Dunnett test) ns indicates a non-significant result It is observed that the higher the dose of Alverine administered, the more the immobility time of the mice decreases, indicating an antidepressant effect proportional to the dose ( Figure 1).
• mice of the third group treated with 10 mg / kg of Alverine exhibit a time of immobility comparable to that of the mice of the fifth group treated with 10 mg / kg of Imipramine.
• Alverine, injected intraperitoneally has a significant antidepressant effect in mice and as important as imipramine, at comparable doses.
• Example 2 Antidepressant activity test of Alverine administered orally on a batch of mice.
• mice were divided into 5 groups of 10 mice each. These are Swiss CD1 mice (CD-1® (ICR) IGS (Charles River France) weighing 25 and 35 g. They were placed in a room at a temperature between 19.5 and 24.5 ° C and relative humidity 45 to 65% with a 12h light / dark cycle, ad libitum access to filtered water and standard laboratory food pellets.
• CD-1® ICR
• IGS Charles River France
• test substance is Alverine citrate (Sigma, in the form of dry powder, with a salt / base ratio of 1.68), compared to imipramine hydrochloride (Sigma, in the form of dry powder, with a salt / base ratio of 1J3).
• the first group is the control group: it is only treated with the excipient.
• the second group is treated with Alverine at a dose of 10 mg / kg
• the third group is treated with Alverine at a dose of 30 mg / kg
• the fourth group is treated with Alverine at a dose of 100 mg / kg
• the fifth group is treated with imipramine (tricyclic antidepressant) at a dose of 30 mg / kg
• the doses are expressed in terms of free active substances.
• the substances are prepared extemporaneously in the excipient.
• the treatments are administered one hour before the test in a coded and random order orally with a volume of 10 ml / kg.
• mice are subjected to the forced swimming test, in a vertical plexiglass cylinder (height: 24 cm, diameter 9 cm) containing water (height 6 cm, temperature: 18-22 ° C).
• the total duration of immobility is measured during the last four minutes of the test, lasting in total six minutes.
• a mouse is considered immobile when it stops fighting and floats in the water without movements that are superfluous to those allowing it to keep its head above water.
• a reduction in downtime is a reflection of an antidepressant effect.
• the forced swimming test is a pre-clinical behavioral model that has good predictive validity and is widely used to determine the effectiveness of antidepressant drugs (Borsini and Meli, 1988).
• the results are expressed in total duration of immobility in seconds and as a percentage change in the total duration of immobility calculated from the mean value of the control group.
• results obtained are presented in the form of a table below, and in the form of a histogram, in FIG. 2.
• Table 2 results obtained by an antidepressant activity test of Alverine administered orally on a batch of mice.
• n 10 animals per group * indicates a significant difference for p ⁇ 0.05 (Dunnett test) ns indicates a non-significant result
• Example 3 Antidepressant activity test of Alverine combined with imipramine or fluoxetine administered intraperitoneally on a batch of mice.
• the substances to be tested are Alverine citrate (Sigma, in the form of dry powder, with a salt / base ratio of 1.68), imipramine hydrochloride (Sigma, in the form of dry powder, with a salt / base ratio of 1J3 ), and fluoxetine hydrochloride (Sigma, in the form of dry powder, with a salt / base ratio of 1J2).
• mice were divided into two trials comprising six groups of 10 mice: For the first trial:
• the first group is the control group: it is only treated with the excipient.
• the second group is treated with imipramine at a dose of 3 mg / kg
• the third group is spawned with Alverine at a dose of 3 mg / kg
• the fourth group is treated with Alverine at a dose of 3 mg / kg and imipramine at a dose of 3 mg / kg
• the fifth group is milled with imipramine at a dose of 10 mg / kg
• the sixth group is treated with Alverine 10 mg / kg
• the first group is the control group: it is only spoiled by the excipient.
• the second group is treated with fluoxetine at a dose of 3 mg / kg.
• the third group is milled with Alverine at a dose of 3 mg / kg.
• the fourth group is milled with Alverine at a dose of 3 mg / kg and fluoxetine at a dose of 3 mg / kg
• the doses are expressed in terms of free active substances.
• the test substances are prepared extemporaneously in a saline solution.
• the treatments are co-administered thirty minutes before the test in a coded and random order by the intraperitoneal route with a volume of 10 ml / kg (5 ml / kg for each administration).
• mice Thirty minutes after administration, the six groups of mice are subjected to the forced swimming test, in a vertical plexiglass cylinder (height: 24 cm, diameter 9 cm) containing water (height 6 cm, temperature: 18-22 ° C). The total duration of immobility is measured during the last four minutes of the test, lasting a total of six minutes.
• a mouse is considered immobile when it stops fighting and floats in the water without movements that are superfluous to those allowing it to keep its head above water.
• a reduction in downtime is a reflection of an antidepressant effect.
• the forced swimming test is a pre-clinical behavioral model that has good predictive validity and is widely used to determine the effectiveness of antidepressant drugs (Borsini and Meli, 1988).
• Table 3 results obtained by an antidepressant activity test of Alverine and imipramine administered intraperitoneally on a batch of mice.
• the doses of each product used makes it possible, with similar results, to greatly reduce the doses administered and thus to reduce the side effect or side effects of the compounds used.

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