WO2012149535A1

WO2012149535A1 - The use of angiotensin ii (at ii) type 1 receptor antagonist in the therapeutic treatment of autism

Info

Publication number: WO2012149535A1
Application number: PCT/US2012/035805
Authority: WO
Inventors: Jay Lombard
Original assignee: Genomind, Llc
Priority date: 2011-04-29
Filing date: 2012-04-30
Publication date: 2012-11-01

Abstract

Angiotensin II (AT II) type 1 receptor antagonist in the therapeutic treatment of autism. Described herein are compositions and methods of administering to the patient a therapeutically effective amount of an angiotensin II type 1 receptor antagonist.

Description

THE USE OF ANGIOTENSIN II (AT II) TYPE 1 RECEPTOR ANTAGONIST IN THE THERAPEUTIC TREATMENT OF AUTISM

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority to U.S. provisional patent application number 61/480487, titled "THE USE OF ANGIOTENSIN II (AT II) TYPE 1 RECEPTOR

ANTAGONIST IN THE THERAPEUTIC TREATMENT OF AUTISM," and filed on April 29, 2012.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. FIELD OF THE INVENTION

[0003] The present invention relates to the use of an angiotensin II (AT II) type 1 receptor antagonist in the therapeutic treatment of autism. Comprising administering to the patient a therapeutically effective amount of an angiotensin II type 1 receptor antagonist (e.g., angiotensin II receptors blockers, or ARB inhibitors). In particular, described herein are compositions and procedures (e.g., methods) for administering to these patients an angiotensin receptor binding inhibitor at a frequency and dosage sufficient to ameliorate the at least one behavioral aspect of the disorder. Accordingly, the present invention provides a new method for the treatment of persons with endogenous neural disorders such as autism, comprising the administration of one or more ARB in a therapeutic regimen that may parallel a regimen that would be used in those patients for the treatment of cardiovascular disease in which the ARB would be indicated.

BACKGROUND OF THE INVENTION

[0004] Autism spectrum disorder (AS) includes three separate diagnoses, which include autism, Asperger's syndrome and Pervasive Developmental Delay (PDD). PDD is characterized by developmental delays of sociability, communication and use of imagination. Asperger's syndrome is a more severe form of PDD but lacks the language and intelligence deficits normally associated with autism. Autism is exemplified by severe communication impairments, social interaction deficits and repetitive/stereotypic behaviors. Each of these disorders has specific diagnostic criteria as outlined by the American Psychiatric Association (APA) in its Diagnostic & Statistical Manual of Mental Disorders (DSM-IV-TR).

[0005] Autism impacts the normal development of the brain in the areas of social interaction and communication skills. Children and adults with autism typically have difficulties in verbal and non-verbal communication, social interactions, and leisure or play activities.

[0006] At times, aggressive and/or self-injurious behavior may exist.

[0007] Although there is no known single known cause for autism, it is generally accepted that it is caused by abnormalities in brain structure or function. The shape and structure of the brain in autistic versus non-autistic children show differences when brain scans are viewed. Currently the link between heredity, genetics and medical problems are being investigated by researchers, as well as a number of other theories.

[0008] Notwithstanding the foregoing, and to the best of Applicant's knowledge, there is no cure for autism. There are, however, a number of medications, developed for other conditions, which have been found to be somewhat helpful in treating a limited number of the symptoms and behaviors frequently found in individuals with autism, such as hyperactivity, impulsivity, attention difficulties, and anxiety. Examples of medications used to treat symptoms associated with autism include: Serotonin re-uptake inhibitors (e.g. clomipramine (Anafranil), fluvoxamine (Luvox) and fluoxetine (Prozac)) which have been effective in treating depression, obsessive- compulsive behaviors, and anxiety that are sometimes present in autism. Studies have shown that they may reduce the frequency and intensity of repetitive behaviors, and may decrease irritability, tantrums and aggressive behavior. Some children have shown improvements in eye contact and responsiveness. Other drugs, such as Elavil, Wellbutrin, Valium, Ativan and Xanax, require more studies to be done but may have a role in reducing behavioral symptoms.

[0009] Over the past 35 years, the most widely studied psychopharmacologic agents in autism have been anti-psychotic medications. Originally developed for treating schizophrenia, these drugs have been found to decrease hyperactivity, stereotypic behaviors, withdrawal and aggression in autistic children. Four that have been approved by the FDA are clozapine

(Clozaril), risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel). However, only risperidone has been investigated in a controlled study of adults with autism. Unfortunately, like the antidepressants, these drugs all have adverse side effects, including, but not limited to, sedation.

[00010] Stimulants, such as Ritalin, Adderall, and Dexedine, used to treat hyperactivity in children with ADHD have also been prescribed for children with autism. Although few studies have been done, they may increase focus, and decrease impulsivity and hyperactivity in autism, particularly in higher-functioning children. Unfortunately, adverse behavioral side effects are often observed. [00011] While many of the above-identified medications do appear to be somewhat helpful in treating a limited number of the symptoms and behaviors frequently found in individuals with autism, a wide variety of side effects are associated with such medications.

SUMMARY OF THE INVENTION

[00012] The present invention relates to compositions, compounds and therapies using these compounds to treat autism. In particular, described herein are compositions and compounds including one or more angiotensin II type 1 receptor antagonist (e.g., candesartan and candesartan cilexetil) for treating autism.

[00013] For example, described herein are methods for the treatment of autism, comprising administering an autistic patient a therapeutically effective amount of an angiotensin II type 1 receptor antagonist selected from the group consisting of candesartan and candesartan cilexetil.

[00014] In some variations the treatment is therapeutic or protective. In some variations, the angiotensin II type 1 receptor antagonist containing composition is provided to reduce, prevent and/or ameliorate the autism or autism-spectrum disorder.

[00015] For example, described herein are compositions (and methods of using them) of angiotensin II type 1 receptor antagonist compounded as a daily dose in the range of from about 0.01 mg to about 1000 mg of angiotensin II type 1 receptor antagonist (selected from the group consisting of candesartan and candesartan cilexetil). The composition may be compounded as a solid or liquid. For example, the composition may be compounded as a single dose (e.g., pill) to be taken once a day.

[00016] In some variations the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 0.1 mg to 750 mg; in the range of from 1 mg to 500 mg; in the range of from about 0.1 mg to about 100 mg; or in the range of from 0.2 mg to 50 mg. Thus, in general, the compound may be formulated for administration as a dosage unit form. The dosage unit form may be a tablet or capsule.

[00017] In some variations, the therapeutically effective amount comprises a dose of about O.lmg/kg; thus the daily dose may be formulated to provide at least 0.1 mg/kg to a patient, and the method of use may be configured to provide about 0.1 mg/kg of the compositions described herein to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

[00018] none DETAILED DESCRIPTION OF THE INVENTION

[00019] It has now been surprisingly discovered that administering an effective amount of an angiotensin-receptor antagonist or a pharmaceutically acceptable salt thereof appears to substantially improve autistic symptoms. Furthermore, administering such an Angiotensin receptor antagonist or a pharmaceutically acceptable salt thereof has not been shown to cause side effects associated with medications previously used to treat the symptoms of autism.

[00020] It is therefore an object of the present invention, to provide a method for treating autism via administering an effective amount of a angiotensin-receptor antagonist or a pharmaceutically acceptable salt thereof.

[00021] Oxytocin (OT) and arginine vasopressin (A VP) are synthesized in the brain's hypothalamic paraventricular and supraoptic nuclei, with AVP also synthesized in the suprachiasmatic nucleus. Both neuropeptides are transported via large neurosecretory axons to the posterior hypothalamus, hence their common designation as neurohypophyseal peptides, evidence support a role for oxytocin and vasopressin in complex social behaviors, including aggression.

[00022] OT is released from the posterior pituitary in response to sexual stimulation, uterine dilatation, nursing, and, in some situations, stress.

[00023] Oxtr(-/-) mice display certain phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism.

[00024] Modahl and colleagues reported a marked reduction in Oxytocin in children with autism relative to age matched controls. Oxytocin agents are currently being explored for autism. However, the route of administration and short half life have significantly limited their clinical applicability.

[00025] The neuropeptide arginine vasopressin (AVP) has also been hypothesized to play a role in the aetiology of autism based on a demonstrated involvement in social bonding and in the regulation of a variety of socially relevant behaviours in animal models. AVP is released in response to sexual stimulation, uterine dilatation, stress, and dehydration.. In non-human mammals, the variable expression of AVPR1 A is implicated in changes in social bonding, parental rearing behaviours and social recognition and memory.

[00026] AVP receptors have been classified into three subtypes: Via, Vlb, and V2 receptors. The Via receptor (VlaR) and Vlb receptor (VlbR) are widely distributed in the central nervous system, including the cortex and hippocampus. Research suggests that VlaR and VlbR may be involved in psychiatric disorders associated with impairments of sensorimotor gating and social behavior in autism.

[00027] Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1 A receptor (VIA), can stimulate aggressive behavior and increases in AVP have been associated with stressful or defensive circumstances. Intriguingly, social isolation increases aggression by increasing the number of Via vasopressin receptors in the hypothalamus.

[00028] Several studies have found AVP levels to be higher in plasma from individuals with autism than controls.

[00029] Various studies have linked different lengths of the AVPRl A polymorphisms to behavioral traits. Subjects with shorter length RS3 polymorphisms were found to be less altruistic and shorter variants in general were associated with lower levels of AVPRl A mRNA in postmortem hippocampus.

[00030] Pharmacological experiments which target vasopressin have included the following: AVP injected into the anterior hypothalamus (AH) stimulates aggression, while injection of a Via receptor antagonist inhibits the behavior.

[00031] Blockade of local vasopressin actions by bilateral administration of a selective vasopressin Via receptor antagonist into the central amygdala has been shown to reduce aggression. Pharmacological activation of AVP-Vla receptors (VlaR) in the AH induces selective aggression in animals, whereas VlaR blockade diminished selective aggression. Via receptor antagonists have been explored as agents to potentially treat interpersonal violence co- occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.

[00032] In the past decade, several potent and selective vasopressin peptide antagonists have been designed (Lazslo, et al., Pharmacological Reviews, 43, 73-108 (1991); Mah and Hofbauer, Drugs of the Future, 12, 1055-1070 (19871; Manning and Sawyer, Trends in Neuroscience, 7, 8- 9 (1984)). Their lack of oral bioavailability and short half-life, however, has severely limited their therapeutic potential. While novel structural classes of non-peptidyl vasopressin Via antagonists have been discovered (Yamamura, et al., Science, 275, 572-574 (1991); Serradiel-Le Gal, et al., Journal of Clinical Investigation, 92, 224-231 (1993); Serradiel-Le Gal, et al., Biochemical Pharmacology, 47(4), 633-641 (1994)), a clinically useful agent is yet to be identified. An alternative approach, relevant to this invention, is the ability to inhibit brain VI AR indirectly through the use of angiotensin receptor blockade.

[00033] Vasopressin and ANG II are known to play a major role in renal water and sodium reabsorption, and are mainly coupled to the cAMP/PKA pathways. There is evidence for cross talk between these two peptides through converging intracellular signaling pathways. In vitro studies showed that ANG II treatment is associated with increased hypothalamic cAMP levels, which are potentiated by cotreatment with ANG II and inhibited by ATI blockade.

[00034] Angiotensin II AT(1) antagonists prevent vasopressin release in response to isolation stress. Pretreatment with candesartan profoundly modifies the response to stress. The ARB prevents the peripheral and central sympathetic activation characteristic of isolation stress and abolishes the activation of the hypothalamic-pituitary-adrenal axis during isolation.

[00035] Oral administration of the ARB candesartan inhibits brain as well as peripheral ATI receptors, indicating transport across the blood brain barrier, and making it the preferred ARB for the clinical use of autism. Candesartan completely blocks the AVP release into the circulation induced by Ang II.

[00036] In the brain, ATI receptors are concentrated in areas belonging or related to the hypothalamic-pituitary-adrenal (HP A) axis. By stimulation of ATI receptors, circulating Ang II activates stress pathways in the brain.

[00037] The stress-mediated effects of circulating Ang II are associated with increased activity of the brain reticular activating system. Stress increases not only the local formation of Ang II in the hypothalamus but vasopressin levels as well.

[00038] Thus, there is strong rationale to direct pharmacological interventions which reduce brain angiotensin receptor activity in order to inhibit abnormal vasopressin effects in aggression, and in particular to aggression associated with autism.

Therapeutic interventions related to this invention.

[00039] The term angiotensin II (A-II) antagonist refers to a compound having the ability to inhibit the vasoactive effects of endogenous angiotensin II by competitive blockade at the angiotensin receptor sites in the central nervous system.

[00040] Angiotensin II AT(1) receptor blockers (ARBs) are commonly used in the clinical treatment of hypertension. Angiotensin II antagonists are understood to mean those active compounds which bind to the ATi receptor subtype. This category includes compounds having similar structural features.

[00041] For a detailed review of angiotensin II receptors and the various antagonists thereof see, for example, Pharmacol. Rev. 45, 206-242 (1993). A variety of A-II antagonists are, or will be, known to one skilled in the art.

[00042] Subcutaneous or oral administration of the ARB candesartan inhibits brain as well as peripheral AT(1) receptors, indicating transport across the blood-brain barrier, making it the prefered embodiment of this invention because this invention applies to a novel use of this agent to treat disorders of the CNS, particularly autism.

[00043] The preferred embodiment of this invention is the A-II antagonist candesartan: 1- (cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)biphen yl-4- yl]methyl]benzimidazole-7-carboxylate and the pharmaceutically acceptable salts thereof which are disclosed in U.S. Pat. No. 5,196,444, the disclosure of which is incorporated herein by reference.

[00044] The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

[00045] A preferred oral dosage form, such as tablets or capsules, will contain candesartan (the ARB or angiotensin II receptor antagonist) in an amount of from about 1 to about 500 mg, preferably from about 1 to about 100 mg, and more preferably from about 5 to about 50 mg, alone or with the neuroleptic, anti-psychotic or mood stabilizer.

[00046] The composition described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a higher dose . Extended release delivery systems or transdermal administrations can be applied by means known to those skilled in the art. A preferred embodiment would be a long acting agent.

Example of treatment with Candersartan in autism

[00047] A 16 year old boy with autism was evaluated for behavioral management. He was frequently aggressive, primarily directed to himself but to others as well. These episodes were usually unprovoked but would also occur when his parents attempted to re direct him. The child was essentially non verbal except for echolalia. His comprehension to verbal re direction was limited, making non pharmacological interventions to his aggression limited.

[00048] His neurological exam was otherwise normal.

[00049] An MRI, EEG were normal. Routine studies, including examination for fragile x and other metabolic disorders were negative.

[00050] Prior medication trials included anti convulsants which were without benefit and atypical neuroleptics, which resulted in weight gain and unsatisfactory effects on behavior.

[00051] After obtaining consent from his parents, Candesartan was started. An initial dose of 8 mg resulted in significant attenuation of aggressive behavior. Blood pressure remained stable. After 2 weeks, the dose was raised to 16 mg. Further improvement in aggression was noted with no adverse lowering of blood pressure.

[00052] The patient has remained on Candesartan with beneficial anti aggression effects being maintained over one year.

[00053] A preferred dose found by the inventor to treat autism is approximately O.lmg/kg. In children, a liquid form may be used.

Claims

What is claimed is:

A composition for the treatment of autism comprising sufficient angiotensin II type 1 receptor antagonist to provide a patient with a daily dose of the angiotensin II type 1 receptor antagonist of about 0.01 mg to about 1000 mg for the treatment of autism.

The composition of claim 1, wherein the angiotensin II type 1 receptor antagonist is selected from the group consisting of candesartan and candesartan cilexetil.

The composition of claim 2, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 0.1 mg to 750 mg.

The composition of claim 2, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 1 mg to 500 mg.

The composition of claim 2, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 0.2 mg to 50 mg.

A method for the treatment of autism, comprising administering an autistic patient a therapeutically effective amount of an angiotensin II type 1 receptor antagonist selected from the group consisting of candesartan and candesartan cilexetil.

The method of claim 6, wherein the treatment is therapeutic.

The method of claim 6, wherein a daily dose of the angiotensin II type 1 receptor antagonist is in the range of from about 0.01 mg to about 1000 mg.

The method of claim 6, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 0.1 mg to 750 mg.

The method of claim 6, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 1 mg to 500 mg.

The method of claim 6, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from about 0.1 mg to about 100 mg.

The method of claim 6, wherein the daily dose of the angiotensin II type 1 receptor antagonist is in the range of from 0.2 mg to 50 mg.

13. The method of claim 6, wherein the angiotensin II type 1 receptor antagonist is administered in a dosage unit form.

14. The method of claim 13, wherein the dosage unit form is a tablet or capsule.

15. The method of claim 6, wherein the therapeutically effective amount comprises a dose of about 0. lmg/kg.