WO2007012154A1

WO2007012154A1 - Pharmaceutical preparation containing an acetylcholinesterase ihibitor and an antidepressant with 5-ht and alpha-2-adrenoceptor blocking properties.

Info

Publication number: WO2007012154A1
Application number: PCT/BR2005/000140
Authority: WO
Inventors: Carlos Henrique Horta Lima
Original assignee: Carlos Henrique Horta Lima
Priority date: 2005-07-27
Filing date: 2005-07-27
Publication date: 2007-02-01
Also published as: CA2616858A1

Abstract

The present invention relates to a pharmaceutical combination consisting of an acetylcholinesterase inhibitor drug (rivastigmine, donepezil or galantamine) and a serotoninergic (5-HT) and alpha-2 adrenergic (mirtazapine or mianserin) receptors blocker antidepressant. The preparation is useful for the treatment of painful syndromes with increased efficacy and better tolerability than the drugs alone. It is useful for the treatment of dementia with better tolerability than the anticholinesterase drug alone and for the treatment of dementia associated with depression or depressive symptoms.

Description

Pharmaceutical preparation containing an acetylcholinesterase inhibitor and an antidepressant with 5-HT and alpha-2-adrenoceptor blocking properties.

Invention introduction - Painful syndromes The International Association for the Study of Pain (IASP) defines pain as an "Unpleasant sensorial and emotional experience associated with a current or potential tissue injury or described in terms of such an injury" . The most usual classifications for pain are based in its inferred neurophysiological mechanisms, its length, etiology or affected region. In the neurophysiological classification, pain may be nociceptive or non-nociceptive; and nociceptive pain may be somatic or visceral; and non-nociceptive pain may be neuropathic or psychogenic. Nociceptive pain results from the activation of nociceptors by stimuli that can be mechanic, thermal or chemical. Here, the nervous system is intact and properly detects the painful stimuli. Neuropathic pain results from an injury or irritation of the nerve. This classification according to the physiopathology is inferred, since there are no definite evidences that a certain mechanism is contributing, within the clinical context, to keep a chronic painful syndrome. The physiopathologic classification is based on the pain as described by the patient during the physical exam and complementary exams. Patients commonly show more than one pain generation mechanism. This classification became widely accepted by clinicians due to its usefulness when definition the type of required evaluation, required therapy and the prognosis.

The physician suspects of neuropathic pain when patients use terms to characterize their compatible pains with dysesthesia, that is, an abnormal painful complaint that may be described as burning, electric shock or pulsation. Neuropathic pain is usually different from any previous painful complaint. The physical exam may show allodynia, that is, pain to a slight touch, hypoesthesia or hyperesthesia (decrease or increase in the perception of a non-painful stimulus) . There may be other focal neurological deficits, such as, paresis and focal autonomic disorders. Supplementary exams, such as electromyography and nervous conduction studies, may be useful to confirm the neurological injury.

The neuropathic pain is an important clinical condition due to its high incidence, no response to conventional or opiate analgesics, thus generating an extensive search for new drugs for its treatment . The present invention is intended for the treatment of several chronic painful syndromes, that is, for more than three months in length, such as, the neuropathic pain, migraine, fibromyalgia, myofascial pain, painful syndromes in cancer patients, and others. Analgesic mechanisms of action

Anticholinesterase drugs

In several animal models, cholinergic agonists caused potent antinociception after the systemic or intracerebroventricular administration, by the action on muscarinic and nicotinic cholinergic receptors ^1,2,3,4,5,6 _ Acetylcholine may cause analgesia through the direct action on muscarinic cholinergic spinal receptors Ml and M3 , nicotinic receptors and by the release of the second nitric oxide messenger .

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in the spinal cord ⁷. It is believed that anticholinesterase drugs promote their therapeutic effects optimizing the cholinergic function. It occurs by increasing the concentration of acetylcholine through the inhibition of the acetylcholinesterase hydrolysis, an enzyme responsible for acetylcholine metabolism.

The anticholinesterase drug donepezil, primarily used in the treatment of the Alzheimer's disease, also showed analgesic efficacy in animal models of pain ⁸ (United States Patent 6,608,088 Nicolodi et al . August 19, 2003). In humans, donepezil was more effective in the prophylactic treatment of migraine than propranolol in a clinical trial involving 147 patients; it also showed benefits in the extension of this clinical trial with 346 patients ⁸. In clinical studies, the anticholinesterase drug and the cholinergic agonist neostigmine, by intrathecal route in combination with intrathecal morphine or with transdermal nitroglycerine, was effective in gynecological postoperative analgesia ⁷'⁹.

As with donepezil, galantamine and rivastigmine are anticholinesterase drugs primarily used in the treatment of the Alzheimer's disease. Galantamine is a cholinergic agent with double mechanism of action, acetylcholinesterase (AchE) inhibition and allosteric modulation of nicotinic cholinergic receptors (nAchR) . The nicotinic modulation potentiates the acetylcholine effects in nicotinic receptors . Galantamine also modulates the release of glutamate, dopamine and gamma-aminobutyric acid (GABA) , neurotransmitters also involved in the neuronal transmission of pain ¹⁰. Rivastigmine is a pseudo-irreversible inhibitor of acetylcholinesterase, mainly in its Gl form, having selective action on the central nervous system. Rivastigmine also inhibits butyrylcholinesterase ^lλ'¹². Donepezil is a reversible inhibitor of acetylcholinesterase, having selective action on the central nervous system ¹³-¹⁴.

The main pharmacokinetic aspects of such drugs are showed in the table below:

Table 1 : Pharmacokinetic data of anticho1inesterase drugs :

* There was an increase in bioavailability (AUC)

10 for galantamine in 30-40% with the co-administration of paroxetine and ketoconazole; and the clearance of galantamine decreased in 25-33% with the co-administration of amitriptyline, fluoxetine, fluvoxamine and quinidine, known as CYP 450 2D6 inhibitors ¹⁹.

The most frequent adverse reactions of

15 galantamine are nausea, vomiting, diarrhea, anorexia, weight loss and sleeping disorders ²⁰.

The use of rivastigmine is associated with significant GI effects, including nausea, vomiting, anorexia and weight loss. Other frequent adverse reactions include fatigue, 0 asthenia, dizziness, headache, diarrhea, dyspepsia, insomnia and confusion ²¹. Predominant adverse effects of donepezil are nausea, vomiting, diarrhea, muscular cramps, insomnia, fatigue and anorexia ²².

The antidepressants mirtazapine and mianserin Antidepressants are usually used in the treatment of chronic pain. Antidepressants have analgesic effects both on neuropathic and nociceptive pain and such effects are not dependent on their antidepressive effects ²³. The analgesic action of the antidepressants, among other mechanisms, is attributed to the neurotransmission optimization in serotoninergic and noradrenergic pain inhibitory descending pathways ^24~2S.

Mianserin is a tetracyclic antidepressant.

Mirtazapine is an analog tetracyclic piperazinoazepine of mianserin. Both act by blocking the serotoninergic (5HT-2 and 5HT- 3) and adrenergic (alpha-2) receptors ²⁶'²⁷'²⁸. Mianserin is a more potent 5HT-2 blocker than mirtazapine ²⁹. Both have low or absent anticholinergic activity ³⁰'³¹, and antihistamine action ²⁹'³⁰. The antidepressive action of these agents is associated with the affinity for 5HT-2 and α-2 adrenergic receptors. Mirtazapine is metabolized by the cytochrome CYP

450, isoenzymes 2D6, 1A2 and 3A; it binds 85% to plasmatic proteins, is predominantly excreted by the kidneys, does not inhibit nor induces cytochrome CYP 450; its half-life ranges from 20 to 40 hours ^32>33'³⁴. Mianserin is metabolized by cytochrome CYP 450, isoenzyme 2D6; it binds 90% to plasmatic proteins and has a half-life from 10 to 40.8 hours; it is excreted in 14 to 28% in the feces, 4 to 7% by the kidneys ^3S'³⁶. in animal models of pain, mianserin increased the antinociceptive effects of indomethacin and metamizole ^3? when administered with opiates, potentiated analgesia in mu, kappa 1 and kappa 2 receptors ^3a; and decreased morphine tolerability ³⁹. Mianserin was effective in the treatment of pain in a study involving 16 patients with chronic idiopathic pain at a dose from 30 to 60 mg a day ⁴⁰. It also showed benefits in a randomized double-blind study on chronic tension-type headache ⁴¹.

In a double-blind placebo-controlled study with 47 patients receiving a dose of 120 mg a day, mianserin was also effective in reducing abdominal pain, abdominal discomfort symptoms, functional capacity in patients with irritable bowel syndrome or non-ulcerous dyspepsia ⁴².

In animal models of pain, mirtazapine showed antinociceptive effects through noradrenergic, serotoninergic and opiate (kappa 3) receptors. ⁴³

Mirtazapine showed efficacy in a randomized comparative clinical study using amitriptyline in 60 patients for the treatment of chronic tension-type headache ⁴⁴. Mirtazapine was beneficial in an open-label trial involving patients with cancer and pain ⁴⁵. Mirtazapine showed to be effective in a chronic pain report referring to a 47-year-old male patient with backache resulting from a neck and back injury after a fall, treated with amitriptyline 50 mg for several years. Previously started associated depressive symptoms did not respond to fluoxetine and bupropion. With the introduction of mirtazapine (15 mg a day) , pain decrease from ten to three points in a ten-point scale ^4S. In a study with oncologic patients, mirtazapine significantly improved appetite and decreased weight loss, in addition to improve the quality of life ⁴⁵. The antiemetic effects of mianserin and mirtazapine may be related to the 5HT-3 receptor blockage.

Ondasentron, a drug having beneficial effects on emesis from different etiologies, acts by blocking the 5HT-3 receptor ⁴⁷.

The invention: the pharmaceutical preparation A pharmaceutical combination consisting of an acetylcholinesterase inhibitor drug (rivastigmine, donepezil or galantamine, or another acetylcholinesterase inhibitor) and an antidepressant that blocks serotoninergic (5-HT-2 and 5HT-3) receptors and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) . Said combination has synergic analgesic effects and has antagonistic effects on the production of adverse events, promoting better tolerability than the treatment with one of the drugs alone.

The analgesic effects, as described above, occur through the 5HT-2, alpha-2 adrenergic receptors, and muscarinic cholinergic Ml and M3 receptors (and nicotinic receptors, in case of galantamine) . Additionally, the 5HT-2 receptors may be also involved in the release of acetylcholine in generating analgesia

48

The combination has antagonistic effects on the production of the most common adverse events of both drug classes .

Nausea and vomiting caused by anticholinesterase drugs are treated with mianserin or mirtazapine through the 5HT-3 receptors. Weight loss and anorexia caused by anticholinesterase drugs are treated with mianserin or mirtazapine through the histamine receptors

(Hl) . Sedation caused by mianserin or mirtazapine may be antagonized by the action of anticholinesterase drugs.

Electroencephalograph^ measurements in animals showed that, contrary to other antidepressants with relevant anticholinergic activity, mianserin did not interfere with the electroencephalograph^ activation promoted by galantamine ⁴⁹.

Synergism in the analgesic action and antagonism in the generation of adverse reactions allow a more efficient treatment .

Further, the prevalence of Major Depression in patients with chronic lumbar pain may be 3 to 4 times higher than in the general population ^so, thus making the use of a drug with antidepressive and analgesic effects especially appropriate in chronic pain patients .

Dementia A general description of dementia, according to the Classification of Mental and Behavior Disorders of ICD-10 (international classification of diseases - 10^th revision) , is as follows :

Dementia is a syndrome resulting from a cerebral disease, usually of chronic or progressive nature, in which there is a disorder of multiple upper cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgment. There is no conscience disturbance. Dementia causes significant reduction of the intellectual functioning and may interfere with routine personal activities, such as cleaning, dressing, feeding and personal care, physiologic and restroom activities. The manifestation of such decrease widely depends on the social and cultural environment the patient lives in. The primary diagnosis requirement, as per the ICD-IO classification, is the evidence of a memory and thinking reduction, being sufficient to impair routine personal activities as described above. Memory impairment typically affects recording, storage and retrieving of new information, however family and previously learned materials may also be lost, particularly in later phases . Thinking and reasoning capacity are also impaired and the flow of ideas is also reduced. Since processing of received information is impaired, the individual progressively has more difficulties in responding to more than one stimulus each time, for example, joining a conversation with several persons and change the attention focus from one topic to another.

Dementia syndrome occurs in Alzheimer's disease, Lewy body dementia, cerebrovascular disease, mixed dementia (Alzheimer and vascular) and in a number of other conditions that, primarily or secondarily, affect the brain. The Alzheimer's disease is the most common form of dementia, consisting in almost 60% of the cases of dementia; its prevalence in persons over 65 years old is approximately 5%. It is estimated that the Alzheimer's disease affects 15 million people worldwide ⁵¹. Lewy body dementia was recognized in the last decade as a common form of dementia, representing 15 to 25 % of all cases of dementia ⁵².

In dementia physiology, especially the Alzheimer- type dementia and Lewy body dementia, the cholinergic neuronal pathways involved in cognitive processes, such as memory, attention, learning, and others, are impaired. Although the precise mechanism of action of anticholinesterase drugs on such dementias is unknown, it is believed that they perform their therapeutic effects by optimizing the cholinergic function. It occurs by increasing the acetylcholine concentration through the inhibition of acetylcholinesterase hydrolysis, an enzyme responsible for metabolizing acetylcholine. Depression is a psychiatric co-morbidity more frequently observed in Alzheimer's disease, affecting up to 50% of the cases ^S3. Depression in elderly is many times sub-syndromic ⁵⁴ (26) and has a complex diagnosis when associated with Alzheimer ^5S.

The pharmaceutical preparation in dementia A pharmaceutical combination consisting in an acetylcholinesterase inhibitor drug (rivastigmine, donepezil or galantamine, or another acetylcholinesterase inhibitor) and an antidepressant that blocks serotoninergic receptors (5-HT-2 and 5HT-3) and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) , improves cognitive symptoms and has antagonistic effects on the generation of adverse events, promoting improved tolerability than the treatment with one of the drugs alone; this is a very relevant aspect, for example, in the treatment of Alzheimer's disease where the dose of anticholinesterase drug usually recommended is the highest tolerated dose in the drug's therapeutic range. Here, as with the chronic pain treatment, the pharmaceutical combination has antagonistic effects on the generation of the most common adverse events of both drug classes. Nausea and vomiting caused by anticholinesterase drugs are treated with mianserin or mirtazapine through 5HT-3 receptors; and weight loss and anorexia are treated through Hl receptors . Sedation caused by mianserin or mirtazapine is treated by the action of anticholinesterase drugs. Electroencephalograph^ measurements in animals showed that, contrary to other antidepressants with relevant anticholinergic activity, mianserin did not interfere with the electroencephalograph^ activation promoted by galantamine ⁴⁹. Mirtazapine shows an even lower tendency to anticholinergic effects ^5S

Antagonism in the generation of adverse reactions allows a more efficient treatment. The patient with Alzheimer's disease associated with depression or sub-syndromic depressive symptoms may also have a better treatment with this combination.

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Claims

1. "Pharmaceutical preparation for the treatment of painful syndromes and dementia", characterized by the use of an acetylcholinesterase inhibitor drug (rivastigmine, donepezil, or

5 galantamine, or another acetylcholinesterase inhibitor) in combination with an antidepressant that blocks 5HT and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) .

2. "Pharmaceutical preparation for the treatment ,10 of painful syndromes and dementia", characterized by a composition comprising a pharmaceutical combination with pharmacologically acceptable excipients .

3. "Pharmaceutical preparation for the treatment of painful syndromes and dementia", according to claims 1 and 2,

15 wherein the preparation is administered to the patient at an equivalent dose of 7.5 mg to 45 mg of mirtazapine, OR 15 mg to 120 mg of mianserin, OR a therapeutically effective and safe dose of another 5HT and alpha-2 adrenergic receptors blocker antidepressant; AND an equivalent dose of 1.5 to 12 mg of

20 rivastigmine, OR 2.5 to 15 mg of donepezil, OR 4 to 24 mg of galantamine OR a therapeutically effective and safe dose of another acetylcholinesterase inhibitor.

4. The preparation is administered to the patient using a route selected from the following group: oral (for

25 example, capsule, tablet, oral solution, slow-release preparations) , transdermal (for example, patches) , intramuscular

(for example, depot slow-release preparations) , transmucosal , buccal, intrathecal, intravenous, intraperitoneal, vaginal, anal or pulmonary.

5. A package containing separate units of an anticholinesterase drug (rivastigmine, donepezil, galantamine, or another acetylcholinesterase inhibitor) AND an antidepressant that blocks 5HT and alpha-2 adrenergic receptors (mirtazapine or mianserin, or another antidepressant with these properties) , with the respective doses according to claim 3.