HK1079688B - Statin product for enhancing cognitive maintenance - Google Patents

Description

Statin products for enhancing cognitive maintenance

Technical Field

The present invention relates to a method for the treatment of dementia or memory disorders comprising administering an effective amount of galantamine (I) and a statin (II). The invention further relates to products containing galantamine (I) as the first active ingredient and a statin (II) as the second active ingredient as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from Alzheimer's disease or related dementias; the invention also relates to a related pharmaceutical composition and application thereof.

Background

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and dementia. Non-alzheimer's disease dementia is associated with memory loss and dementia as in the case of AD. Both AD and non-AD dementia are often accompanied by behavioral, psychiatric and/or psychological symptoms including psychosis, depression, anxiety and agitation, and other mood changes and social withdrawal. In fact, the behavioral, psychiatric and/or psychological symptoms of dementia can occur in 60-90% of patients with Alzheimer's Disease (AD) or other dementing illnesses, and are of critical importance since they are a significant source of caregiver stress and contribute to the caregiver anxiety syndrome.

Behavioral, psychiatric and/or psychological clinical manifestations associated with dementia or memory disorders, more particularly with Alzheimer's Disease (AD), can be assessed by clinically accepted scales such as the brief psychotic scale, the Alzheimer's disease assessment scale-non-cognitive, general syndrome's associated assessment, the dementia behavior disorder scale, the neuropsychiatric list, the Kannel dementia depression scale, the Cohen-Mansfield anxiety list, the geriatric depression scale, the behavior grade scale, the disability assessment of dementia, caregiver time and the dementia mood assessment scale.

In primary care hospitals and home care, the treatment of behavioral, psychiatric and/or psychological manifestations in patients with dementia or memory disorders involved the use of antipsychotics, antidepressants, anxiolytics and antiepileptics/anticonvulsants such as carbamazepine and valproic acid.

Acetylcholinesterase (AChE) is an enzyme that plays a key role in cholinergic (acetylcholine) neurotransmission. Physiologically, the hydrolysis of acetylcholine to acetate and choline serves to inactivate acetylcholine molecules released at synaptic terminals and thus to terminate the synaptic signaling initiation initiated by acetylcholine (ACh) release from the nerve endings. Ac hE inhibitors are a class of compounds that inhibit the enzyme that degrades acetylcholine. Thus, by inhibiting AchE, the retention time of acetylcholine in the synapse is prolonged, and thus the activity of acetylcholine is enhanced. Acetylcholinesterase inhibitors include galanthamine, rivastigmine polynaphthapine and tacrine.

Galanthamine, also known aS galanthamine antamine or (4aS, 6R, 8aS) -4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuran [3a, 3, 2-ef)][2]Benzazepine compounds-6-ol is a naturally occurring organic substance that can be derived from the bulb of common snowdrop and many plants of the Amaryllidaceae family, and can also be synthetically prepared. More recently, galantamine has become the subject of clinical evaluation for the combined treatment of neurological and behavioral symptoms associated with Alzheimer's disease, and is acquiring or awaiting market approval in many world markets, under the trade name REMINYL。

The known pharmacology of galantamine includes the ability to inhibit AchE. The therapeutic evaluation for an AChE-inhibitor such as galantamine is based on the fact that: in the brain of AD patients, neurons that release some Ach as a synaptic signalling messenger (neurotransmitter) are dysfunctional or anorgonic due to cell death or synaptic degeneration. In this pathological environment, AchE inhibitors enhance Ach-mediated synaptic activity by extending the time over which Ach molecules released by the remaining functional synaptic terminals are available to activate Ach receptors in the membrane of postsynaptic neurons. Galantamine is a reversible cholinesterase inhibitor. Galantamine interacts competitively with the enzyme acetylcholinesterase and shows a 10 to 50 fold selectivity for acetyl over butyrylcholinesterase.

Recently, new pharmacological properties of galantamine have been discovered, which suggest that galantamine can enhance the activity of Ach through mechanisms independent of its ability to inhibit AchE, such as allosteric modulation of nicotinic receptors. Galantamine has also been reported to have an effect on the behavioral and psychiatric symptoms of AD.

Galantamine has been used in the treatment of many chronic diseases that must be treated for life. Galantamine has been shown to be effective in the treatment of joint inflammation, fatigue syndrome, mania, schizophrenia, memory dysfunction, including alzheimer's disease (US 4663318), alcoholism, nicotine dependence, attention disorders (WO 99/21561). Jetlag inhibits 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase, rate-limiting enzyme in cholesterol biosynthesis, and is useful for preventing and treating hypercholesterolemia, hyperlipidemia, atherosclerosis and the like.

There is a hypothetical relationship between the production of cholesterol and beta-amyloid, a protein collected in the brain of a patient suffering from Alzheimer's disease; inhibin reduces the production of beta-amyloid. The suggestive survey results are:

patients taking inhibin (HMG-CoA reductase inhibitor) have a lower probability of developing Alzheimer's disease and dementia

Cholesterol increased the production of beta-amyloid peptide in rabbit and mouse brains

Inhibin decreases the production of beta-amyloid peptide in brain neurons of brain in cultures and live animals (Guinean pigs)

Patients with high levels of ldl cholesterol show a decrease in serum β -amyloid when treated with randomized clinical trials with lovastatin 40 or 60mg, using placebo as control.

Brief description of the invention

The present invention relates to a method for the treatment of dementia or memory disorders comprising administering an effective amount of galantamine (I) and a statin (II). Typically, the dementia is dementia resulting from Alzheimer's Disease (AD). The effect of statins on cognitive maintenance in alzheimer's disease patients and the safety of co-administration of statins and galantamine were studied in randomized clinical trials of galantamine for 5 to 6 months. The combined administration of statins and galantamine demonstrated enhanced cognitive effects compared to the effects obtained with galantamine alone.

Inhibin (II) is selected from: simvastatin (simvastatin), pravastatin (lovastatin), lovastatin (lovastatin), fluorostatin (flustatin), atorvastatin (atorvastatin), or rosuvastatin (rosuvastatin), or any of the foregoing therapeutically active acid addition salt forms. Such salts include forms in which the active ingredient (II) is capable of forming a salt with a suitable acid, such as an inorganic acid, for example, a hydrohalic acid, e.g., hydrochloric or hydrobromic acid; sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Galanthamine is conveniently used as the (1: 1) hydrobromide salt.

Preferably, the amount of statin (II) is equal to or less than the amount approved for monotherapy with said statin (II).

Most preferred are products wherein galantamine (I) as base is 8, 16 or 24mg in each dosage form.

The invention also relates to products containing as first active ingredient galantamine (I) and as second active ingredient a statin (II) as combined preparations for simultaneous, separate or sequential use in the treatment of patients suffering from dementia or memory disorders.

The invention also relates to pharmaceutical compositions comprising a carrier and galantamine (I) as a first active ingredient and a statin (II) as a second active ingredient, preferably each in an amount that produces a therapeutic effect in patients suffering from dementia or memory disorders. The invention also relates to a method for preparing the pharmaceutical composition.

Furthermore, the invention relates to the use of a statin (II) for the preparation of a medicament for enhancing the therapeutic effect of galantamine (I) in patients suffering from dementia or memory disorders.

Detailed Description

As used herein, the term "dementia" includes mental deterioration and other mental disorders, regardless of the cause of impairment of daily activities, and as a result of defects in previously successful behavior. Suitable examples of dementia include, but are not limited to, dementia due to Alzheimer's disease, vascular-related dementia, dementia associated with multiple infarcts, dementia due to brain trauma, dementia due to diffuse brain injury, dementia pugilistica, dementia due to Huntington's disease, dementia due to alcoholism, dementia due to diffuse white matter lesions, dementia associated with Parkinson's disease, dementia due to Lewy body lesions, dementia due to pick's disease, dementia due to multiple system degeneration, dementia due to progressive supranuclear palsy, dementia associated with the ALS-Parkinson's dementia complex of Guiam, dementia anterior lobe and dementia due to cortical basal degeneration.

As used herein, the term "memory disorder" will include memory loss, mental deterioration, diminished mental capacity, and loss of cognition.

As used herein, a "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder or disease being treated. More particularly, in the present invention directed to combination therapies comprising the administration of galantamine and one or more statins, "therapeutically effective amount" refers to the combined amount of the drugs that are co-administered such that the combined effect elicits the desired biological or pharmaceutical response. For example, a therapeutically effective amount of galantamine and simvastatin would be the amount of galantamine and the amount of simvastatin which when taken together or sequentially have a combined effect, i.e., a therapeutic effect. Furthermore, those skilled in the art will recognize that in the case of co-treatment with therapeutically effective amounts, as shown in the above examples, the amount of galantamine and/or the amount of simvastatin individually may or may not be therapeutically effective.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The individual components of the compositions may be administered simultaneously, sequentially, separately or in separate pharmaceutical formulations in any suitable manner according to the methods of the invention. When galantamine and a statin are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different. Galantamine and statins can be administered by the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal and rectal modes of administration. The compounds may also be administered directly to the nervous system, including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peripheral spinal routes of administration via intracranial or intraspinal needles and/or catheters with or without pumping devices. Galantamine and statins can be administered in divided or single dosage forms concurrently, according to a simultaneous or alternating regimen, at the same or different times during the course of treatment. It is therefore to be understood that the invention may encompass all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

Preferred dosages and dosage regimens for administration can be determined by one skilled in the art and will vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including the patient's sex, age, weight, diet, physical activity, time of administration, and concomitant diseases, will create a need to adjust the dosage and/or administration regimen.

Examples

The objective was to evaluate the effect of statins on cognitive maintenance in patients with Alzheimer's disease during randomized clinical trials of galantamine at 5 and 6 months.

Design of research

Data were combined from 3 double-blind, placebo-controlled clinical trials, limited to patients treated with either 24mg of galantamine or placebo per day.

-classifying the patients according to grade of galantamine and use of any statin.

Efficacy results

Evaluation of the changes in the Alzheimer's disease evaluation Scale-cognitive subscale by last Observation extrapolation (LOCF) Using Standard 11 items (ADAS-cog/11)

-performing comparisons between patient subgroups to control the associated confusion factor.

Safety results

The incidence of adverse side effects commonly associated with acetylcholinesterase inhibitors, including nausea, diarrhea, anorexia and vomiting, as well as any of these gastrointestinal symptoms, was calculated and the relative risk of galantamine with statins versus galantamine alone was compared.

The incidence of adverse events commonly associated with statins, including back pain, leg cramps, skeletal pain, muscle atrophy, muscle weakness and myalgia, as well as any of these musculoskeletal symptoms, was calculated and the relative risk of using galantamine with statins versus statin alone was compared.

The incidence of adverse events, including abdominal pain or headache, normally associated with acetylcholinesterase inhibitors or statins was calculated and the relative risk of galantamine with a statin versus galantamine alone and a statin alone was compared.

Limiting

As concomitant therapy, the mode of using statins varies in dosage, type and duration. The study is not very powerful for testing the effect of statins.

Results

Characteristics of the drug treatment groups

Baseline statistics and patient characteristics for each treatment group are summarized in table 1.

TABLE 1 characteristics of the drug treatment groups

	Mean value (SD)	Mean value (SD)	Mean value (SD)	Mean value (SD)
						Age in yearsADAS-Cog Baseline Total CholesterolMMSE Baseline	72.4(8.4)26.8(11.3)218.0(47.2)18.2(4.1)	74.0(7.8)25.7(8.9)219.3(38.1)18.4(3.8)	75.7(7.9)26.5(10.1)228.3(43.6)18.7(3.8)	75.2(8.2)26.8(10.6)224.6(43.8)18.7(4.0)	0.0450.8520.1770.784

	Percentage of	Percentage of	Percentage of	Percentage of
						Severity,% mild of AD	61.9％	66.0％	64.8％	64.9％	0.98

All values are mean values (SD) unless otherwise noted.

¹P-value is based on analysis of variance of continuous variables and chi-square test of absolute variables

²Pairwise comparison of differential significance (P ≦ 0.05): statin + galantamine as compared to galantamine alone; inhibin + galantamine were not compared to either.

³Since data N is lost 1311.

⁴Mini mental state test (MMSE): slight (MMSE. gtoreq.18) as compared to moderate (MMSE < 18).

The proportion of patients taking inhibin was 6.9% (n 92).

Inhibin subgroup has a lower proportion of women (p ═ 0.06)

The inhibin + galantamine group is 3 years younger (p ═ 0.05) than the non-inhibin group

Each group was similar in cognitive score and total cholesterol at baseline levels.

The distribution of inhibin types divided by group is shown in Table 2.

Table 2: distribution of statin type in clinical laboratory patients with galantamine treated with statins (n-92)

¹Patients treated with galantamine and statins at 24 mg/day as concomitant medication

²Patients treated with placebo and statin as concomitant therapeutics

³Chi-square test based P-value

⁴Of the 10 patients treated with 2 statins, only the first statin employed was encoded.

Patients were treated with 5 different statins (simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin) grouped according to statin with no significant difference in distribution (p ═ 0.135).

Simvastatin had the highest frequency of use (38.1% in the statin + galantamine group and 34% in the statin only group).

In the group with statins only, statins (simvastatin and atorvastatin) which resulted in the greatest reduction of low density lipoprotein cholesterol in the serum were administered in a higher proportion of patients (40.5% in the statin + galantamine group and 52% in the statin only group).

Statins (simvastatin and lovastatin) which were able to cross the central nervous system in both statin-treated groups were administered in similar proportions of patients (59.5% in the statin + galantamine group and 58% in the statin-only group).

Effect of treatment with statins and galantamine (intent-to-treat analysis)

Cognitive status was improved in the group with galantamine (-0.88, SE 0.25) alone and with inhibin + galantamine (-2.85, SE 0.91).

Decline in cognitive status occurred in the group with placebo only (2.24, SE 0.24) and with statin only (1.98, SE 0.85).

The effect with galantamine alone was very significant (p < 0.001), the effect of statin was not significant (p ═ 0.083), and the interaction of statin and galantamine was not significant (p ═ 0.183).

In the case of no multiple comparison correction, the effect of statin + galantamine appears to be better in the pair-wise comparison than in the group with galantamine alone (p ═ 037).

These results are based on ANOVA as a study control and the severity of AD with MMSE; similar results were also found when limiting the analysis to the observed case data (table 3).

Table 3: inhibin therapeutic effect as reflected by changes in ADAS-Cog in combination experimental data

¹Least squares mean (LS) and Standard Error (SE)

²Four-way ANOVA based on the inclusion of inhibin (Y/N), drug (galantamine/PBO), study, MMSE-based AD severity terminology, and inhibin-drug

³Also as a control for studies (p 0.037) and severity of AD (p 001)

⁴Also as a control for studies (p 0.065) and severity of AD (p 001)

Conclusion

Although the use of statins did not result in significant improvement when administered alone or in combination with galantamine, galantamine improved cognitive function in patients with alzheimer's disease in 5 and 6 month clinical trials. However, the combined use of statins and galantamine did increase the cognitive effect compared to treatment with galantamine alone. The results further show that: when administered in combination with galantamine to the elderly, high statin doses are not necessary to obtain a positive result. Adverse event data was inconclusive due to the smaller number of treatment groups. The combination of statins and galantamine increases the risk of diarrhea, abdominal pain, and muscle or skeletal pain relative to treatment with statins or galantamine alone.

Claims (14)

1. A product containing as a first active ingredient galantamine and as a second active ingredient a statin as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from dementia or a memory disorder, wherein the statin is selected from: simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin or lovastatin, or a therapeutically active acid addition salt form of any of the foregoing.

2. The product of claim 1, wherein galantamine is present as galantamine hydrobromide.

3. The product of claim 1 wherein the amount of statin is equal to or less than the amount approved for monotherapy with said statin.

4. The product of claim 1, wherein the amount of galantamine as base is 8, 16 or 24mg per dosage form.

5. A pharmaceutical composition comprising a carrier and galantamine as a first active ingredient and a statin as a second active ingredient, wherein the statin is selected from the group consisting of: simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin or lovastatin, or a therapeutically active acid addition salt form of any of the foregoing.

6. A composition according to claim 5, comprising a carrier and galantamine as a first active ingredient and a statin as a second active ingredient, wherein each active ingredient is present in an amount to produce a therapeutic effect in patients suffering from dementia or memory disorders.

7. The composition of claim 5, wherein galantamine is present as galantamine hydrobromide.

8. The composition of claim 5, wherein the amount of statin is equal to or less than the amount approved for monotherapy with the statin.

9. The composition of claim 5, wherein the amount of galantamine as base is 8, 16 or 24mg per dosage form.

10. Use of a statin in the manufacture of a medicament for enhancing the therapeutic effect of galantamine in patients suffering from dementia or a memory disorder, wherein the statin is selected from the group consisting of: simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin or lovastatin, or a therapeutically active acid addition salt form of any of the foregoing.

11. Use according to claim 10, wherein galantamine is present in the form of galantamine hydrobromide.

12. The use of claim 10, wherein the amount of statin is equal to or less than the amount approved for monotherapy with said statin.

13. Use according to claim 10, wherein the amount of galantamine as base is 8, 16 or 24mg per dosage form.

14. A process for the preparation of a pharmaceutical composition as defined in any one of claims 5 to 9, comprising the step of admixing galantamine, a statin and a pharmaceutically acceptable carrier, wherein the statin is selected from the group consisting of: simvastatin, pravastatin, lovastatin, fluvastatin, atorvastatin or lovastatin, or a therapeutically active acid addition salt form of any of the foregoing.