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CA2515991C - Use of ace inhibitors for treatment of patients suffering from behavioral disorders - Google Patents

Use of ace inhibitors for treatment of patients suffering from behavioral disorders Download PDF

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CA2515991C
CA2515991C CA2515991A CA2515991A CA2515991C CA 2515991 C CA2515991 C CA 2515991C CA 2515991 A CA2515991 A CA 2515991A CA 2515991 A CA2515991 A CA 2515991A CA 2515991 C CA2515991 C CA 2515991C
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disorder
ace
patient
inhibitor
behavioral
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CA2515991A1 (en
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Robert C. Kevorkian
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Abstract

A method for the treatment of a patient suffering from an endogenous behavioral disorder in order to ameliorate at least some behavioral aspects of the disorder, the method comprising administering to the patient a therapeutic quantity of at least one ACE inhibitor. Behavioral aspects of endogenous disorders such as attention deficit disorder (ADD), obsessive- compulsive disorder (OCD), oppositional explosive defiant disorder (OEDD), anxiety and panic disorders (APD) and temper, rage and outburst behavior disorder (TROBD), are ameliorated by a regimen of ACE inhibitor.

Description

USE OF ACE INHIBITORS FOR TREATMENT OF
PATIENTS SUFFERING FROM BEHAVIORAL DISORDERS
BACKGROUND OF THE INVENTION
Field of the Invention [0001] Angiotensin converting enzyme inhibitors (ACE inhibitors) are known to be useful for treatment of a variety of cardiovascular ailments such as hypertension, heart failure, myocardial infarction, left ventricular dysfunction and diabetic nephropathy. ACE
inhibitors are believed to inhibit the action of angiotensin-converting enzyme (ACE) in the body in its conversion of angio-tensin I, a relatively inactive peptide, to angiotensin II, a powerful vasoconstrictor and stimulant of the adrenal cortex for the secretion of aldosterone, which is normally associated with fluid reten-tion. Angiotensin I is the product of the action of renin, which is produced by the kidneys, on an-giotensinogen (a globulin of plasma). The action of an ACE inhibitor, by reducing conversion of angiotensin I, relieves vasoconstriction and reduces aldosterone secretion. It also provides negative feedback on renin release, which is also believed to decrease aldosterone secretion. ACE inhibitors also include angiotensin II antagonists.
[0002] Another possible basis for the effectiveness for ACE inhibitors is that ACE is identical to bradykininase (kininase II), which acts on bradykinin. Bradykinin stimulates prostaglandin bio-synthesis and it is believed that ACE inhibitors also inhibit bradykininase and thereby increase bra-dykinin levels. ACE inhibitors thus stimulate the biosynthesis of prostaglandin, which is a vasodi-lator and which may contribute to the pharmaceutical effects of ACE
inhibitors.
[0003] The physiological effects associated with ACE inhibitors include increases in serum po-tassium and sodium and fluid loss, a reduction of peripheral arterial resistance in hypertensive pa-bents and an increase in cardio output with little or no change in heart rate.
There is also an in-crease in renal blood flow, reduction in blood pressure and an improvement in maximal exercise tolerance in patients with heart failure.
[0004] ACE inhibitors are characterized as peptides that fall into three groups: sulfhydryl-containing (e.g., captopril), dicarbocyl-containing (e.g., enalapril, lisinopril, benazepril, quinapril, moexipril, trandolapril, and ramipril), and phosporous-containing (e.g., fosinopril). Other known V80167CA1\VAN LAw~ 201518\1 [0005] ACE inhibitors are enalaprilat, irbesartan, losartan potassium, valsartan, zofenapril and ceranapril. The pharmaceutical dosages and administration of the various ACE
inhibitors are known to those of ordinary skill in the art. Typically, the compositions are administered orally.
Related Art [0006] In Drug Facts and Comparisons, January 2000, published by Facts and Comparisons, St. Louis, Missouri, certain "adverse reactions" of various ACE inhibitors are shown, including re-actions pertaining to the central nervous system. Some of these include confusion, depression, malaise, nervousness and anxiety. When the incidence of these reactions were given, they almost all were reported in less than one percent of the persons treated. In addition, the following reac-tions were reported at incidences of less than one percent of the persons treated: dream abnormal-ity (in connection with enalapril); memory disturbance, mood change and behavior change (in con-nection with fosinopril); irritability (in connection with lisinopril) and mood changes (in connec-tion with moexipril).
1 S [0007] U.S. Patent 5,049,553 entitled "Method For Preventing or Treating Symptoms Resulting From Closed Head Injuries Employing an ACE Inhibitor" issued on September 17, 1991 to A.
Sudilovsky. The '553 Patent discloses the administration of an ACE inhibitor to treat symptoms brought on by head trauma which causes unconsciousness for twenty minutes or more. The stated symptoms include rages as well as memory loss, headache, dissociation of thought and depression, among others. See column 1, lines 60-64 and column 1, line 65 to column 2, line 17. The'S53 Patent also notes that ACE inhibitors are useful for treating hypertension;
see the art cited at col-umn 1, lines 27 to 59 and column 2, lines 18-20.
SUMMARY OF THE INVENTION
[0008] Generally, the present invention provides a method for the treatment of patients suffer-ing from an endogenous behavioral disorder by administering to the patient a therapeutic quantity of at least one ACE inhibitor, such as a dicarbocyl-containing ACE inhibitor, e.g., lisinopril. As used herein and in the claims, "endogenous" behavioral disorders are disorders not associated with or resulting from traumatic head injury or other trauma, but rather those which find their etiology solely in non-trauma induced conditions such as psychological conditions or illnesses, hormonal imbalances, or the like.
V80167CA1\VAN LAW\ 201518\1 [0009] Specifically, in accordance with the present invention there is provided a method for the treatment of a patient who suffers from an endogenous behavioral disorder in order to ameliorate at least some behavioral aspects of the disorder, comprising administering to the patient at least one ACE inhibitor at a frequency and dosage sufficient to ameliorate at least some behavioral aspects of the disorder.
[0010] The endogenous behavioral disorder may be one which is associated with the elevation of blood pressure. For example, the endogenous behavioral disorder may be one selected from the group consisting of attention deficit disorder (ADD), obsessive-compulsive disorder (OCD), op-positional explosive defiant disorder (OEDD), anxiety and panic disorders (APD) and temper, rage and outburst behavior disorder (TROBD).
[0011] In accordance with one aspect of the present invention, the method comprises adminis-tering a dicarbocyl-containing ACE inhibitor, e.g., lisinopril.
[0012] In another aspect of the present invention, the at least one ACE
inhibitor is administered to the patient by oral ingestion, e.g., by oral ingestion of at least one orally-ingestable, pre-measured unit dosage.
[0013] A particular aspect of the present invention provides a method for the treatment of a pa-tient who suffers from temper, rage and outburst behavior disorder (TROBD), the method compris-ing administering to the patient at least one ACE inhibitor as described above, e.g., administering a dicarbocyl-containing ACE inhibitor, e.g., lisinopril.
DETAILED DESCRIPTION OF THE
INVENTION AND PREFERRED EMBODIMENTS THEREOF
[0014] The present invention is based on the observation that beneficial behavioral modifica-tion effects are produced by ACE inhibitors in patients suffering from endogenous behavioral dis-orders, making ACE inhibitors useful for certain patients for whom they might not otherwise be prescribed. These beneficial effects may be manifested as behavioral improvements in people, both children and adults, who suffer from endogenous disorders including attention deficit disorder (ADD), obsessive compulsive disorder (OCD), oppositional explosive defiant disorder (OED), anxiety and panic disorders (APD), and impulsive temper, rage and outburst behavior disorder (TROBD). Accordingly, the present invention provides a new method for the treatment of persons with such endogenous disorders, comprising the administration of one or more ACE inhibitors in a V80167CA1\VAN LAW\ 201518\1 therapeutic regimen that may parallel a regimen that would be used in those patients for the treat-ment of cardiovascular disease in which the ACE inhibitor would be indicated.
Without wishing to be bound by any particular theory, it is believed that certain endogenous physiological conditions which are controllable through the use of ACE inhibitors are related to certain behavioral prob-lems. For example, the production of angiotensin II and its associated elevation of blood pressure appear to be correlated with outbursts of rage, anger and even violence. In two patients who volun-teered to be studied, it was found that significantly elevated blood pressure accompanied temper outbursts. It is therefore believed that controlling these phenomena can help the patient control the undesired behavior.
[0015] This invention is expected to be useful not only for human patients but also for non-human mammalian patients whose cardiovascular systems are known to be affected by ACE in-hibitors in a manner analogous to the reactions of humans to ACE inhibitors.
Example 1 [0016] A twelve-year old human male had an eight-year history of uncontrollable temper, rage and violent outburst behavior, i.e., was a patient suffering from TROBD. The TROBD was an en-dogenous behavioral disorder. The patient was placed on a regimen of the dicarbocyl-containing ACE inhibitor lisinopril, 10 mg per day, oral administration. Prior to medication, the patient dis-played two to four episodes of fit or rage and/or violent behavior per week, each lasting approxi-mately twenty minutes per episode. When confined to his room, the patient would act out with banging and stomping. Episodes were accompanied by physiological changes including dilation of pupils, expressionless face and a rise in blood pressure. Prior treatments with methylphenidate (e.g., Ritalir.), dextroamphetamine (e.g., Dexedrine) and counseling were ineffective to provide adequate relief.
[0017] With lisinopril medication as noted above over a period of about four weeks, definite changes in behavior were evident. Episodes were reduced in duration and frequency to episodes of approximately five to ten minutes with a frequency of approximately one per week, without violent outburst. At home, he retreated from a situation triggering the event to his room, where he re-mained quiet.
[0018] The patient exhibited improved behavior throughout a therapeutic regimen extending for a period of approximately two and one-half months. Under treatment, there was no noticeable V80167CA1\VAN LAW\ 201518\1 dilation of pupils and blood pressure did not go over 128/64 during the three most marked temper-related episodes in that period. Each of the three episodes occurred at school. In one episode, the patient was working on a computer and refused to give up his work station when his allotted time had been used up. The teacher reported that the patient was verbally resistive and spilled his milk, but did not act out violently and, when so instructed, walked to the principal's office without being physically coerced. A second episode was triggered when the patient was asked to make up a class he had missed. He refused to go to the class but voluntarily moved himself to a "cooling room" to allow his temper to subside. He again, when so instructed, walked to the school office without be-ing physically coerced. In a third episode, the patient was asked to leave the classroom because he would not stop talking during a quiet time. In this case, there was a limited degree of acting out in that, while sitting in a chair, he kicked a desk which was knocked over. He then allowed himself to be escorted by police officers to the school office without being physically coerced. In the office, he kicked another desk and was taken by ambulance to a children's hospital for evaluation. The degree of violence in all of these episodes, including the third episode, was significantly reduced compared to the patient's behavior prior to treatment with the ACE inhibitor.
Example 2 [0019] The grandfather of the subject of Example 1 also had a long history of endogenous tem-per, rage and outburst behavior disorder (TROBD). After receiving an ACE
inhibitor for treatment of his high blood pressure, his outbursts were markedly reduced.
V80167CAI\VAN LAW\ 201518\1

Claims (14)

1. A use of at least one angiotensin converting enzyme ("ACE") inhibitor for the treatment of a patient who suffers from an endogenous behavioral disorder selected from the group consisting of attention deficit disorder (ADD), oppositional explosive defiant disorder (OEDD) and temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
2. A use of at least one angiotensin converting enzyme ("ACE") inhibitor in the manufacture of a medicament for the treatment of a patient who suffers from an endogenous behavioral disorder selected from the group consisting of attention deficit disorder (ADD), oppositional explosive defiant disorder (OEDD) and temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
3. A use of at least one angiotensin converting enzyme ("ACE") inhibitor for the treatment of a patient who suffers from endogenous temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
4. A use of at least one angiotensin converting enzyme ("ACE") inhibitor in the manufacture of a medicament for the treatment of a patient who suffers from endogenous temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
5. The use of any one of claims 1 to 4, wherein the at least one ACE inhibitor comprises a dicarbocyl-containing ACE
inhibitor.
6. The use of any one of claims 1 to 4, wherein the at least one ACE inhibitor comprises lisinopril.
7. The use of any one of claims 1 to 6, wherein the at least one ACE inhibitor is administerable to the patient by oral ingestion of at least one orally-ingestable, pre-measured unit dosage.
8. The use of any one of claims 1 to 7, wherein the patient is a human being.
9. An angiotensin converting enzyme ("ACE") inhibitor for use in the treatment of a patient who suffers from an endogenous behavioral disorder selected from the group consisting of attention deficit disorder (ADD), oppositional explosive defiant disorder (OEDD) and temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
10. An angiotensin converting enzyme ("ACE") inhibitor for use in the treatment of a patient who suffers from endogenous temper, rage and outburst behavior disorder (TROBD) in order to ameliorate at least one behavioral aspect of the disorder.
11. The ACE inhibitor of claim 9 or 10, wherein the ACE
inhibitor comprises a dicarbocyl-containing ACE inhibitor.
12. The ACE inhibitor of claim 9 or 10, wherein the ACE
inhibitor comprises lisinopril.
13. The ACE inhibitor of any one of claims 9 to 12, wherein the ACE inhibitor is administerable to the patient by oral ingestion of at least one orally-ingestable, pre-measured unit dosage.
14. The ACE inhibitor of any one of claims 9 to 13, wherein the patient is a human being.
CA2515991A 2005-01-18 2005-08-15 Use of ace inhibitors for treatment of patients suffering from behavioral disorders Expired - Lifetime CA2515991C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/037,564 US7276492B2 (en) 2000-06-01 2005-01-18 Use of ACE inhibitors for treatment of patients suffering from behavioral disorders
US11/037,564 2005-01-18

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CA2515991A1 CA2515991A1 (en) 2006-07-18
CA2515991C true CA2515991C (en) 2012-07-10

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