WO2010020585A1 - Serotonin reuptake inhibitors for the treatment of rett syndrome - Google Patents

Abstract

The present invention relates to serotonin reuptake inhibitors for the treatment of the Rett syndrome.

Description

SEROTONIN REUPTAKE INHIBITORS FOR THE TREATMENT OF RETT

SYNDROME

FIELD OF THE INVENTION

The invention relates to methods for the treatment of Rett syndrome using serotonin reuptake inhibitors.

BACKGROUND OF THE INVENTION Rett syndrome (RTT) is a disabling neuropsychiatric condition with onset in early childhood (Hagberg et al., 1985; Rett, 1992). This pathology affects almost exclusively females. The incidence of RTT is estimated at 1/10,000-15,000 females, with 99.5% being sporadic cases.

This neurological disorder is characterized by a period of early normal growth and development followed by regression with loss of speech and acquired motor skills, stereotypical hand movements, and seizures. Slowing of brain growth and postnatal growth failure are frequently present (Hagberg et al. 1983; Trevathan et al. 1988).

The disease is caused by deleterious mutations within the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) (Amir et al., 1999). The ubiquitously expressed MeCP2 protein binds to methylated DNA on CpG dinucleotides present in gene promoters. It is therefore likely to mediate the biological role of DNA methylation, including transcriptional repression and chromatin condensation (Bird & Wolffe, 1999).

Missense and truncating mutations in the MECP2 gene were observed in 95% of RTT cases and are now considered as the main cause of the pathology. Loss of MeCP2 function ultimately leads to neuronal disease, and the neuropathology both of Rett patients and of MeCP2-null mutant mice is characterized by decreased brain weight, increased cell packing density, and neuronal dystrophy in the cerebral cortex and other brain regions (Armstrong, 1992; Baumann et al., 1995; Naidu, 1997; Chen et al., 2001 ). Interestingly, the expression of MeCP2 is significantly induced in normal adult rat brain after repeated injections of fluoxetine (Cassel et al, 2006).

At the present time, there is no cure for Rett Syndrome. Treatment for the disorder is symptomatic, focusing on the management of symptoms, and supportive.

Medication may be needed for breathing irregularities and motor difficulties, and antiepileptic drugs may be used to control seizures. Occupational therapy, physiotherapy, and hydrotherapy may prolong mobility. Some children may require special equipment and aids such as braces to arrest scoliosis, splints to modify hand movements, and nutritional programs to help them maintain adequate weight.

Special academic, social, vocational and support services may also be required in some cases. So, there is a real need of treatment for this pathology.

SUMMARY OF THE INVENTION The invention relates to a serotonin reuptake inhibitor for the treatment of the

Rett syndrome.

DETAILED DESCRIPTION OF THE INVENTION

A first object of the invention relates to serotonin reuptake inhibitors for the treatment of Rett syndrome.

The term "treating" or "treatment" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

Serotonin reuptake inhibitors (SRIs) are a class of antidepressants used in the treatment of depression, anxiety and panic disorders, and personality disorders. They act by inhibiting the reuptake of the neurotransmitter serotonin into the presynaptic terminal, therefore increasing the serotonin level within the synaptic cleft. They also display various degrees of selectivity towards the other monoamine reuptake systems, in particular the transporters for norepinephrine and dopamine. Such compounds include, but are not limited to: alaproclate, amoxapine, citalopram, clomipramine, duloxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, indalpine, milnacipran, paroxetine, sertraline, trazodone, venlafaxine, zimeldine. In a preferred embodiment, the invention relates to selective serotonin reuptake inhibitors for the treatment of Rett syndrome.

Selective serotonin reuptake inhibitors (SSRIs) are a sub-class of serotonin reuptake inhibitors which show a high degree of selectivity for the serotonin transporter, and negligible effects on other neurotransmitter reuptake systems.

Such compounds include, but are not limited to: citalopram (Celexa®, Cipramil®, Emocal®, Sepram®, Seropram®), dapoxetine (no trade name yet; not yet approved by the FDA), escitalopram oxalate (Lexapro®, Cipralex®, Esertia®, Seroplex®), fluoxetine (Prozac®, Fontex®, Seromex®, Seronil®, Sarafem®, Fluctin®, Fluox®, Depres®), fluvoxamine (Luvox®, Fevarin®, Dumyrox®, Movox®), paroxetine (Paxil®, Seroxat®, Sereupin®, Aropax®, Deroxat®, Rexetin®, Xetanor®, Paroxat®), sertraline (Zoloft®, Lustral®, Serlain®), zimelidine (Zelmid®, Normud®).

In a particular embodiment, the selective serotonin reuptake inhibitor can be Citalopram or 1 -[3-(dimethylamino)propyl]-1 -(4-fluorophenyl)-1 ,3- dihydro[3,4]benzofuran-5-carbonitrile, which is disclosed in U.S. Pat. No. 4,136, 193 and which has for formula:

In a particular embodiment, the selective serotonin reuptake inhibitor can be

Fluvoxamine or 2-[(5-methoxy-1 -[4-(trifluoromethyl)phenyl]- pentylidene)amino]oxyethanamine, which is taught by U.S. Pat. No. 4,085,225 and which has for formula:

In a particular embodiment, the selective serotonin reuptake inhibitor can be Paroxetine or (3S-trans)-3-((1 ,3-Benzodioxol-5-yloxy)methyl)-4-(4- fluorophenyl)-piperidine, which may be found in U.S. Pat. Nos. 3,912,743 and 4, 007,196 and which has for formula:

In a particular embodiment, the selective serotonin reuptake inhibitor can be Sertraline or (1 S)-cis-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1 - naphthalenamine, which is disclosed by U.S. Pat. No. 4,536,518 and which has for formula:

In a preferred embodiment, the selective serotonin reuptake inhibitor can be

Fluoxetine or N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]- propan-1 -amineheptane -4-carboxylique, which is marketed in the hydrochloride salt form, and as the racemic mixture of its two enantiomers. U.S. Pat. No. 4,314,081 provides an early reference to this compound. Robertson et al., J. Med. Chem. 31 ,

1412 (1988), taught the separation of the R and S enantiomers of fluoxetine and showed that their activity as serotonin uptake inhibitors is similar to each other. In this document, the word "fluoxetine" will be used to mean any acid addition salt or the free base, and to include either the racemic mixture or either of the R and S enantiomers. This compound has for formula:

A further object of the invention relates to methods and compositions for treatment of a subject affected by Rett syndrome. The term "subject" denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably, a subject according to the invention is a human.

According to the invention, the subject is affected by Rett syndrome. In a preferred embodiment the subject is a human affected by the Rett Syndrome. In a preferred embodiment, the subject is a human below 15. In a preferred embodiment, the subject is a human below 8.

The serotonin reuptake inhibitor may be administered in the form of a pharmaceutical composition. Preferably, said compound is administered in a therapeutically effective amount.

By a "therapeutically effective amount" is meant a sufficient amount of the serotonin reuptake inhibitor to treat and/or to prevent Rett syndrome at a reasonable benefit/risk ratio applicable to any medical treatment.

It is understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The serotonin reuptake inhibitor may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.

"Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.

Preferably, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The serotonin reuptake inhibitor of the invention can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.

For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCI solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The serotonin reuptake inhibitor of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.

In addition to the compounds of the invention formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations ; time release capsules ; and any other form currently used.

FIGURES

EXAMPLE

A one-case report concerns a 38-year old female diagnosed for RTT at age 30. Diagnosis was further confirmed by the demonstration of a mutation within the MeCP2 gene (nonsense mutation R270X). She was treated with fluoxetine (Prozac®), 20 mg/day. After a 10 to 12-day period, she showed an increased reactivity and an improved interaction with the environment, clearly associated with a better mood. An improvement in motor skills was also noticed (enhanced ability to walk). The treatment was then interrupted at day 32. Beginning day 42- 44, the improved signs vanished; a decrease in social reactivity was particularly manifest (noticed by nursing people and family members not aware of the treatment cessation). The same treatment was reinstated at day 56. A similar improvement was observed again, that did not quite reach the previous level though. After a treatment at the same dosage of about 3 years, she now shows a stabilized condition, with improved social communication, as evidenced by eye contact and sound emitting. Motor movements have improved (except for the hands).

REFERENCES

Amir, R. E.; Van den Veyver, I. B.; Wan, M.; Tran, C. Q.; Francke, U.; Zoghbi, H.Y. "Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2". Nature Genetics. 1999; 23:185-188.

Armstrong, D. D. "The neuropathology of the Rett syndrome". Brain Development.1992; 14(Suppl.), S89-S98.

Bauman, M L.; Kemper, T.L.; Arin, D. M.. "Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome". Neurology. 1995; 45: 1581-1586.

Bird, A. P.; Wolffe, A.P.. "Methylation-induced repression — Belts, braces, and chromatin". Cell. 1999; 99: 451-454. Cassel, S.; Carouge, D.; Gensburger, C; Anglard, P.; Burgun, C; Dietrich, J. B.; Aunis, D.; Zwiller, J.. Fluoxetine and Cocaine Induce the Epigenetic Factors MeCP2 and MBD1 in Adult Rat Brain. Molecular Pharmacology. 2006; 70:487-492.

Chen, R. Z.; Akbarian, S.; Tudor, M.; Jaenisch, R.. "Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice". Nature Genetics. 2001 ; 27: 327-331.

Hagberg, B.; Aicardi, J.; Dias, K.; Ramos O. "A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases". Ann Neurol. 1983; 14:471-479. Hagberg, B.; Goutieres, F.; Hanefeld, F.; Rett, A.; & Wilson, J.. "Rett syndrome: Criteria for inclusion and exclusion". Brain Development. 1985; 7: 372- 373.

Naidu, S. "Rett syndrome: A disorder affecting early brain growth". Ann. Neurol. 1997; 42: 3-10. Rett, A. "The mystery of the Rett syndrome". Brain Development. 1992;

14(Suppl.), S141-S142.

Trevathan, E.; Moser, H.W.; Opitz, J. M.; Percy A.K.; Naidu, S.; Holm, V.A.; Boring, CC; et al. "Diagnostic criteria for Rett syndrome". Ann Neurol. 1988; 23:425^128.

Claims

1. A serotonin reuptake inhibitor for the treatment of the Rett syndrome.

2. The inhibitor according to claim 1 wherein said inhibitor is a selective serotonin reuptake inhibitor.

3. The inhibitor according to any one of claims 1 -2, wherein said inhibitor is Fluoxetine.

4. A pharmaceutical composition for the treatment of the Rett syndrome comprising a serotonin reuptake inhibitor.