TW201408293A - Use of (R)-phenylpiracetam for the treatment of disease-associated fatigue - Google Patents

Abstract

The present invention relates to the efficient treatment of an individual afflicted with fatigue, particularly mental fatigue, associated with certain diseases, particularly diseases of the central nervous system, including Parkinson's disease (PD), the instant treatment comprising administering to the individual an effective amount of (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof.

Description

Use of phenyl shawl for the treatment of fatigue-related diseases

The present invention relates to effective treatment of individuals suffering from fatigue, in particular to mental fatigue, which relates to certain diseases, in particular to central nervous system (CNS) diseases, including Parkinson's disease. Parkinson's disease (PD), this timely treatment comprises administering to the individual an effective dose of (R)-phenylpiracetam (R)-phenylpiracetam and its pharmaceutically acceptable salts.

The present invention relates to the treatment of patients suffering from certain forms of fatigue associated with diseases, particularly central nervous system diseases including Parkinson's disease.

Fatigue can include physical fatigue that affects muscle and/or mobility, as well as mental fatigue that affects concentration, willingness to move, and/or level of consciousness.

Among the many debilitating diseases, diseases including the development of the central nervous system and disease-related fatigue are particularly visible. For example: fatigue of Parkinson's disease, fatigue of cancer, fatigue of post-stroke, fatigue of burn-out syndrome, fatigue of multiple sclerosis, AIDS Fatigue of HIV/AIDS and other central nervous system infectious diseases, fatigue of fibromyalgia, fatigue of sarcoma sarkoid disease, fatigue of rheumatic disorders, muscle dystrophy (muscle dystrophies) fatigue, lupus erythematosus fatigue, Morbus Crohn fatigue, and spondylitis ankylosans (also known as Morbus Bechterew) Fatigue, fatigue of pulmonary arterial hypertension, depression of depression, fatigue of dementia, chronic fatigue syndrome, fatigue of chronic intoxication, traumatic Fatigue of traumatic brain injury, fatigue of hypoxic brain damage, fatigue of liver infection such as hepatitis C, cirrhosis such as primary biliary cirrhosis Fatigue, age-related or cancer-related cachexia fatigue, amyotrophic lateral sclerosis (AL) S) fatigue, post-polio fatigue, myasthenia gravis fatigue. Affected patients are persistently unable to have any relevant physical or mental activity, or have suffered from short-term or minor efforts. This pathological fatigue has significantly affected the quality of life of patients and requires treatment.

Disease-associated fatigue must be related to health The individual's fatigue symptoms are more defined as follows: The fatigue symptoms of healthy individuals are sustained and/or healthy burdens on the body and mind, work, mental stress, over-stimulation or irritation, jet lag, boredom, or lack of sleep. A normal result of a natural response. Physiological fatigue of healthy individuals is subject to physical exertion or stress Normal reaction, and its function is simply to protect the body, to prevent damage caused by excessive load. In general, this type of fatigue spontaneously disappears after a short recovery period. This type of fatigue is not pathological and does not require treatment. Therefore, this type of fatigue is excluded from the present invention which requires medical treatment.

Only pathological fatigue is the subject of the present invention, and unless otherwise defined, the term "fatigue" of the present invention is used only to refer to pathological forms of fatigue.

One type of fatigue that is widely accepted is the Fatigue Severity Scale (FSS), a self-managed one-dimensional universal 9-item fatigue assessment scale [Krupp et al., Arch Neurol. 46, 1121-23, 1989]. Each project is rated as a seven-graded Likert scale, ranging from 1 point of total disapproval to 7 points of total agreement, as shown in Table 1. The total fatigue score (total FSS score) is the average of the individual scores of the nine items. The Fatigue Severity Scale has a total score of 4 or higher and is acceptable for 2 weeks before the assessment and is defined as disease-directed fatigue, especially chronic diseases such as Parkinson's disease.

Cancer-related fatigue is defined as persistence Personal feeling that the feeling may be physical and/or emotional (or mental) fatigue or collapse, and related to cancer or cancer treatment, wherein the cancer treatment refers to disproportionate and serious disparity with recent activity The ground interferes with normal functions (National Comprehensive Cancer Network (NCCN) guidelines. Cancer-related fatigue is different from fatigue associated with daily life, which is usually temporary and can be relieved after a break.

Parkinson's disease is one of the most common chronic neurological diseases. Typical symptoms of Parkinson's disease are muscle stiffness, tremors, and bradykinesia. Today, especially in the early stages of illness, these operational impediments can be effectively treated with a variety of available Parkinson's disease drugs. However, in recent years, it has become increasingly recognized that the treatment of Parkinson's disease called non-motor symptoms is often unsatisfactory [Gallagher et al., Mov Disord. 2010 Nov 15; 25 ( 15): 2493-500]. Non-motor symptoms include cardiovascular, urinary and gastrointestinal autonomic dysfunctions, sleep problems, psychosis, pain, cognitive deficits And fatigue. Clinical studies have confirmed that the decline in quality of life in patients with Parkinson's disease has the strongest correlation with fatigue and depression [Beiske et al. Mov Disord. 2010 Oct 30; 25(14): 2456-60; Beiske and Svensson, Acta Neurol Scand Suppl. 2010; (190): 78-81].

The fatigue of Parkinson's disease is multi-faceted, including physical and mental Sexual and general aspects [Havlikova et al., Parkinsonism Relat Disord. 14, 187-92, 2008; Havlikova et al., Eur J Neurol.; 15(5): 475-80, 2008; Havlikova et al., J Neurol Sci .270,107-13, 2008]. The physical orientation of fatigue in Parkinson's disease is related to the mobility and activity of everyday life. The orientation of mental fatigue affects cognition, emotional happiness, and communication. In addition, general fatigue is related to the physical discomfort of the patient.

The choice of treatment for fatigue in Parkinson's disease is quite limited. Recent research And approved Parkinson's disease medication has been published, showing that in addition to the main effects on motor symptoms, the improvement in fatigue is moderate. These drugs are rasagiline inhibitors of monoamine oxidase [Rascol et al., Lancet Neurol. 10, 415-423, 2011] and pramipexole of dopamine agonist [Morita] Et al., Intern Med. 50, 2163-2168, 2011]. However, there are currently no specific drugs that provide good tolerance and strong anti-fatigue effects for patients with Parkinson's disease.

Karabanov et al. describe the effect of phenylpyrazine on patients with Parkinson's disease in an open-label trial [Karabanov et al., Atmosfera. Nervnye Bolezni 4, 29-32, 2009]. As mentioned in the test report, "Weary Labor is one of the parameters monitored in the trial, and it is shown in the figure that phenyl prajna has a positive effect on the combined parameters such as "general activity, physical and mental fatigue, and asthenization symptoms". Karabanov has neither published data on the effects of phenyl prajna alone on fatigue, nor on disease-related fatigue and physical fatigue. Similarly, Kalinskij and Nazarov describe the effect of phenyl prajna on the fatigue of the treatment of ashenic syndrome [Kalinskij and Nazarov, Zh Nevrol Psikhiatr Im SS Korsakova, 107, 61-63, 2007] And Akhapkina et al. provide additional data in a clinical trial of "Efficacy of Phenotropil in the treatment of asthenic syndrome and chronic fatigue syndrome" [Akhapkina Et al., Atmosfera. Nervnye Bolezni 3, 28-31, 2004]. Karabanov and others particularly emphasize "asthenization", which is what astronauts (healthy individuals) experience after a long space flight. Astronauts feel tired, irritated, lack of appetite and sleep after returning to Earth. Obstacles and other symptoms. Interestingly, phenylpyramid originated from the original use of compounds as "cosmic drugs" [Mendonca et al, Mov. Disord. 22, 2070-2076, 2007].

Conversely, the so-called "Parkinson's fatigue" is only happening in Parkin A specific embodiment of disease-related fatigue in patients with sensation. As the key assessments of Friedman JH et al. revealed, the use of a common fatigue scale in patients with Parkinson's disease would cause problems [Mov. Disorders, 25, 805-822, 2010]. Brown RG Et al. [Parkinsonism Related Disorders 2005, 11(1): 49-55] developed a Parkinson Fatigue Scale to rule out that it may occur in a part of the fatigue experience but may also occur independently in Parkinson's Emotional and cognitive characteristics in the disease. The 16 affected items of the Parkinson's Fatigue Scale were reported by the affected patients themselves, and these items were able to clearly distinguish between Parkinson's specific types of fatigue and other types of fatigue, including binary calculations. The resulting cut-off score is 7. However, it is not very suitable to analyze the mental fatigue associated with Parkinson's disease alone with the Parkinson's fatigue scale.

Thus, despite the fact that many attempts have been made to treat disease-related fatigue to develop agents, these attempts to date have not seen clinically meaningful success in patients.

Therefore, there is still a large demand for a drug that recognizes the treatment of disease-related fatigue, particularly the treatment of mental fatigue associated with the disease.

There is currently no method by which a person of ordinary skill can achieve or propose a solution to the problem provided by the present invention, that is, a method of using a specific compound.

The present invention relates to a method for treating disease-related fatigue, particularly in a disease-related mental fatigue individual, comprising administering an effective dose of (R)-phenyl prasal or its pharmaceutically acceptable salt.

In some embodiments of the methods of the invention, the (R)-phenyl prasal is (R)-phenylpyrazine hydrochloride ((R)-phenylpiracetam Hydrochloride).

In some embodiments, the disease-related fatigue system is fatigue of Parkinson's disease.

In some embodiments, the disease-related fatigue is mental fatigue of Parkinson's disease.

In some embodiments, the disease-related fatigue is fatigue of the cancer.

In some embodiments, the disease-related fatigue is mental fatigue of the cancer.

In some embodiments of the methods of the invention, the (R)-phenyl prasepide or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 1 mg/day to about 400 mg/day.

In a still further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered in a range from about 25 mg/day to about 350 mg/day.

In still a further embodiment of the method of the invention, the (R)-phenyl prasepamine or a pharmaceutically acceptable salt thereof is administered in a range of from about 50 mg/day to about 300 mg/day.

In a further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered once daily, in particular at a dose of about 200 mg once daily. Under the medicine.

In a further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered in multiple doses, for example twice daily. (b.i.d.) or 3 times a day, especially 2 times a day, especially at a dose of about 100 mg twice daily.

In a still further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered starting from about 50 mg and is increased from a dose of 50 mg until the desired treatment Efficacy was achieved, but the maximum was a dose of about 400 mg/day.

In still another embodiment of the method of the present invention, (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is administered in the form of an oral preparation.

In another aspect, the invention relates to a pharmaceutical composition comprising (R)-phenyl prasal or a pharmaceutically acceptable salt thereof for use in the treatment of disease-related fatigue.

In some embodiments of the pharmaceutical compositions of the present invention, the (R)-phenylpyrazine is phenylpyrazine hydrochloride.

In some embodiments of the pharmaceutical compositions of the present invention, (R)-phenyl prasal and its pharmaceutically acceptable salts are administered at a dose ranging from about 1 mg/day to about 400 mg/day.

In a still further embodiment of the pharmaceutical composition of the present invention, (R)-phenylpyrazine and a pharmaceutically acceptable salt thereof are administered in a range of from about 25 mg/day to about 350 mg/day. .

In still further embodiments, (R)-phenyl prasal and its pharmaceutically acceptable salts are administered in a range of from about 50 mg/day to about 300 mg/day, particularly in about Dosing is in the range of 50 mg/day to about 150 mg/day.

In still another embodiment of the pharmaceutical composition of the present invention, (R)-phenyl Prairie and its pharmaceutically acceptable salts (eg (R)-phenylpyrazine hydrochloride) are administered once a day, especially about 200 mg once daily. 2 times a day, especially about 100 mg, 2 times a day, or 3 times a day, especially once a day or twice a day.

In still further embodiments, (R)-phenyl prasal or its doctor The pharmaceutically acceptable salt is administered starting from about 50 mg and is increased from a dose of 50 mg until the desired therapeutic effect is achieved, but at a maximum of about 400 mg/day.

In still another embodiment of the pharmaceutical composition of the present invention, (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is administered in the form of an oral preparation.

Figure 1 shows that (R)-phenylpyrazine increases the degree of dopamine outside the rat striatum in microdialysis in the brain.

Figure 2 shows the concentration of (R)-phenylpyrazine, which was determined by microdialysis in the brain after intraperitoneal administration, wherein the dopamine transporter has an affinity of about 13 micromoles (μM).

Figure 3 shows that (R)-phenylpyrazine increases the rate of activity (horizontal activity) in rats (administered intraperitoneally 15 minutes prior to testing). ( ^* : p < 0.05 vs. vehicle, Kruskal-Wallis one-way ANOVA was performed on the ranks at each time period, followed by grade and Rank sum test)

Figure 4 shows an electroencephalogram scan of the (R)-phenyl pilosa in the central nervous system.

Figure 5 shows the results of the progressive ratio test to determine the effect of (R)-phenylpyrazine on the willingness to exercise compared to amphetamine.

Figure 6 shows the results of the progressive ratio test to determine the effect of (R)-phenylpyrazine on the willingness to exercise compared to methylphenidate.

Figure 7 shows the results of a cost benefit test to determine the effect of (R)-phenylpyrazine on the willingness to exercise compared to amphetamine.

Figure 8 shows the results of a cost benefit test to determine the effect of (R)-phenylpyrazine on the willingness to exercise compared to methylphenidate.

Figure 9 shows the effect of (R)-phenylpyrazine on rat rotation, in which the rat was subjected to unilateral substantia nigra (SNc) injury (experimental pattern of Parkinson's disease).

Figure 10 shows the efficacy of (R)-phenylpyrazine on sedation, in which the sedative is composed of respine (5 mg/kg) and α-methyltryptophan (α-methyl-). Produced by p-tyrosine, α-MT) (250 mg/kg).

Figure 11 shows the effect of (R)-phenyl prasal on sedation, in which sedation is produced by haloperidol (0.2 mg/kg).

Figure 12 shows the efficacy of (S)-phenylpyrazine on hypokinesia at doses of 50 mg/kg (Figure 12A) and 100 mg/kg (Figure 12B), with hypokinesia Produced by haloperidol (0.2 mg/kg) Health.

In contrast to previous treatments for disease-related fatigue, particularly treatments for disease-related mental fatigue, the present invention is characterized by the therapeutic efficacy of phenyl prajna, which is still unknown until now, which may be based, at least in part, on (R) ) - Phenylpyrazine as a newly discovered activity of dopamine reuptake inhibitors.

Accordingly, the present invention relates to the use of (R)-phenyl prasal and any salts, solvates, conjugates thereof, which possess at least dopamine re-uptake (dopamine re-uptake) Inhibitory activity of transporter).

Accordingly, a particular aspect of the present invention relates to a method of treating disease-related fatigue, particularly in a disease-related neurological fatigue, comprising administering an effective dose of (R)-phenyl prasal and its medicine. Acceptable salts to improve such disease-related fatigue, and pharmaceutical compositions including (R)-phenyl prasal and its pharmaceutically acceptable salts for such treatment.

It is common knowledge in the art that the term "phenyl prasal" refers to the compound 4-phenyl-2-pyrrolidone-1-acetamide (C ₁₂ H ₁₄ N ₂ O ₂ ; MW 218.3 g/mol). Phenyl pilosa is also known as fenotropil, phenotropyl, fenotropyl, carphedon or phenotropil, and is developed in Russia as a prescription drug that can be used under the name "Phenotropil®". As shown herein, phenylpyramid refers to the substance as well as its pharmaceutically acceptable salts.

Phenylpyrazine is optically active and is a racemate (racemate) of two enantiomers, which are (R)-phenyl pirate ((R)-phenylpiracetam) and (S)-phenyl prass Swing ((S)-phenylpiracetam). The International Nonproprietary Name (INN) has assigned "Fonturacetam" to the racemic phenyl pirate. The separation of the two palm-type isomers was first revealed in the international patent application on the priority date of 2006, and it was confirmed that the (R)-palm-isomer is mainly responsible for pharmacological activity (WO 2007/104780). (R)-Phenylpyrazine showed more pronounced activity in animal models that detected antidepressants, analgesics, muscle relaxants, and psychostimulants. This patent discloses the use of (R)-phenylpyrazine as an antidepressant, a stress-protective agent, a modulator of locomotor activity, a muscle relaxant, and an analgesic.

More detailed pharmacological data of (R)-Phenylpyrazine One author discloses (Zvejniece et al., Basic Clin Pharmacol Toxicol. 109, 407-12, 2011). In the open-field test, a significant increase in the activity rate (locomotor activity) was observed for phenyl prajna, while the effect of (R)-phenyl pilar was only better than that of (S)-phenyl. Laser is slightly stronger. In the forced swim test of the depression mode, the effect of (R)-phenyl pilosa is only slightly stronger than that of (S)-phenyl prajna. However, in the passive avoidance test, the (R)-phenyl prajna spurs more significantly enhances memory function than the (S)-phenyl pilosity. The authors conclude that these results may be important for the clinical use of optically simple isomers of phenyl prajna.

The inventor of the present invention for (R)-phenyl pilosa as a dopamine re-photograph Prior to the astounding discovery of transporter inhibitors, the clear pharmacological machine of phenyl prajna was still unclear. In pharmacological experiments, it was found that phenyl prasal can activate operational behavior, resist the psychological depressant effect of diazepam, inhibit post-rotational nystagmus, and prevent reverse amnesia ( The development of retrograde amnesia). Phenylpyrazine also exhibits anti-caries effects (Bobkov et al., Biull Eksp Biol Med. 95, 50-53, 1983) and some neuroprotective activity in cerebral ischemia experiments (Tiurenkov et al., Eksp Klin Farmakol., 70, 24-29, 2007). Therefore, phenyl prajna exhibits additional pharmacological effects that are not fully understood to date, and these effects show the difference between phenyl prajna and other simple dopamine reuptake transporter inhibitors.

Phenyl prasal is administered orally to humans and shows 3-5 small The half-life of the time. A small number of small-scale exploratory clinical trials have been published in German journals, suggesting that phenyl pilacetation may be linked to improvements in some conditions and diseases, including: debilitating, spontaneous trauma to brain trauma [Kalinskij and Nazarov] , Zh Nevrol Psikhiatr Im SS Korsakova 107, 61-63, 2007], brain organ damage [Savchenko et al. Zh Nevrol Psikhiatr Im SS Korsakova., 105, 22-26, 2005], epilepsy [Bel'skaia et al.Zh Nevrol Psikhiatr Im SS Korsakova 107, 40-43, 2007; Lybzikova et al., Zh Nevrol Psikhiatr Im SS Korsakova. 108, 69-70, 2008], oral problems [Novikova et al. Stomatologiia (Mosk). 87, 41- 45, 2008], vascular brain disease [Gustov et al. Zh Nevrol Psikhiatr Im SS Korsakova. 106, 52-53, 2006]. The effect of phenylpyrazine on immune outcomes in stroke has also been described [Gerasimova et al., Zh Nevrol Psikhiatr Im S S Korsakova, 105, 63-64, 2005].

According to the drug imitation approved by Russia, phenyl prasad is spurred The drug has a significant anti-forgetful effect, direct activation of the brain's integration activity, helps to consolidate memory, improves concentration and mental performance, helps the learning process, and increases the transmission of messages between the hemispheres. Increase brain tissue resistance to hypoxia and toxic effects, anti-spasmodic and anti-depressant effects, regulate central nervous system activation and inhibition processes, and improve mood. Phenylpyrazine has a positive effect on brain metabolism and blood circulation, stimulates the redox reaction process and increases the energy potential by using glucose to improve regional blood flow in the ischemic region of the brain. Phenylpyrazine increases the levels of norepinephrine, dopamine and serotonin in the brain without affecting the extent of gamma-aminobutyric acid (GABA), and is not associated with GABAA and GABAB receptors, and is spontaneous in the brain. Bioelectric activity also has no significant effect and does not affect the respiratory and cardiovascular systems. Phenylpyrazine has no significant diuretic effect and has no appetite loss during treatment. According to the Russian drug list, the stimulating effect of phenyl prajna shows that it has the proper function of providing a motor response and the ability to enhance athletic performance. The proper psychostimulant efficacy of the drug is accompanied by analgesic activity and can improve mood, has some analgesic effects and increases the threshold of pain. The adaptogenic effect of phenyl prajna shows that it can increase resistance to stress conditions: excessive mental and physical overload, fatigue, hypokinesia, immobilization, and hypothermia.

Therefore, although phenyl prajna has apparently become a health condition For prescription medications including pressure-related fatigue treatment, phenyl prajna has not been associated with treatment for fatigue in non-pathological or pathological categories.

The term "disease-related fatigue" as used in the present invention refers to pathological fatigue. Labor, which is independent of the type of fatigue (referred to as peripheral fatigue) of normal reactions due to physical exertion or stress. Peripheral fatigue refers to muscle fatigue and is caused by repeated muscle contractions (eg, sports) [Chaudhuri and Behan, J Neurol Sci. 179 (Suppl. 1-2), 34-42, 2000; Chaudhuri and Behan, Lancet .363, 978-988, 2004].

Disease-oriented fatigue is not caused by excessive muscle use or central nervous system Caused by physical discomfort outside. This important fatigue is an individual feeling of disease-related mental fatigue symptoms (inattention, memory loss, personal feelings with speech difficulties) and disease-related physical fatigue (exhaustion and lack of energy personal feeling). This personal disease-related fatigue originates from a particular embodiment of the dopamine-related system disorders in the central nervous system, particularly the lack of dopamine and potential constant changes in the body, resulting in abnormal levels of persistent fatigue, weakness, or collapse.

As noted above, the Fatigue Severity Scale is a widely accepted measure of fatigue for this type of fatigue.

In some particular embodiments, the fatigue severity scale has a score of at least 4.

In some particular embodiments, the fatigue severity scale has a score of at least 4 and is maintained for at least 2 weeks.

In some particular embodiments, disease-related fatigue is particularly lacking Fatigue of dopamine, which is related to or caused by a disorder in the dopamine-related system.

The term "individual" as used in the present invention is meant to include mammals such as animals and humans.

The term "treatment" as used in the present invention refers to alleviating or alleviating at least one symptom of a disease in an individual. The term "treatment" of the present invention also means preventing, delaying the onset of disease (i.e., the period before the disease manifests itself in clinical manifestation) and/or reducing the risk of developing or worsening the disease. Thus, "treatment" as used herein includes both modified, treated, and symptomatic treatments.

The term "therapeutically effective" as applied to a dose or amount means the amount of a compound or pharmaceutical composition sufficient to result in the desired activity when administered to a mammal in need thereof.

As used herein, the term "pharmaceutically acceptable" in connection with a composition means that the molecular entities and other components of such compositions are physically tolerable and produce no typical when administered to a mammal such as a human. Adverse reactions. The term "pharmaceutically acceptable" may also refer to a mammalian or state government regulatory agency or a US Pharmacopoeia or other recognized pharmacopeia listed for use in mammals, especially humans.

The term "salt" is defined as a chemical that contains different charge components. The term "salt" also includes hydrates or solvates.

(R)-Phenylpyrrole can be used in the form of any of the pharmaceutically acceptable salts, solvates and conjugates of the invention. References to any (R)-phenyl prasal of the present invention are also to be understood as such salts, solvates and conjugates.

In some embodiments, the (R)-phenyl prasal is fused to (R)-phenyl Larsing hydrochloride.

In some embodiments of the invention, the disease-related fatigue is selected from the group consisting of Column fatigue: fatigue of Parkinson's disease, fatigue of cancer, post-stroke fatigue, fatigue of burn-out syndrome, fatigue of multiple sclerosis, AIDS /AIDS) and other central nervous system infectious diseases fatigue, fibromyalgia fatigue, sarcoma sarkoidosis fatigue, rheumatic disorder fatigue, muscle dystrophies Fatigue, fatigue of lupus erythematosus, fatigue of Morbus Crohn, fatigue of spondylitis ankylosans (also known as Morbus Bechterew), pulmonary artery Fatigue of pulmonary arterial hypertension, depression of depression, fatigue of dementia, chronic fatigue syndrome, fatigue of chronic intoxication, traumatic brain injury ( Traumatic brain injury), fatigue of hypoxic brain damage, fatigue of liver infection such as hepatitis C, such as Fatigue of cirrhosis of biliary cirrhosis, aging or cancer-related cachexia, fatigue of amyotrophic lateral sclerosis (ALS), poliomyelitis Fatigue in post-polio and fatigue in myasthenia gravis.

In some embodiments, disease-related fatigue refers to Parkinson's disease fatigue.

In some embodiments, the invention relates to Parkinson's disease fatigue Treatment of associated symptoms, especially loss of vitality, lack of willingness to exercise, laziness, collapse, fatigue, and exhaustion.

As mentioned above, the Parkinson's Fatigue Scale is a widely accepted measure of fatigue for this type of fatigue.

In some embodiments, the disease-related fatigue is mental fatigue of Parkinson's disease.

In some embodiments, the Parkinson's Fatigue Scale has a score of at least 7.

In some embodiments, the Parkinson's Fatigue Scale scores at least 7 and is maintained for at least 2 weeks.

In some embodiments, the disease-related fatigue is fatigue of the cancer.

In some embodiments, the disease-related fatigue is mental fatigue of the cancer.

In some embodiments, the present invention relates to a method of treating sleep related problems in a patient with Parkinson's disease that has a significant impact on the quality of life of the patient, particularly general exhaustion and drowsiness.

In some embodiments of the methods of the invention, the (R)-phenyl prasepide or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 1 mg/day to about 400 mg/day.

The term "about" in the present invention means between 90% and 110%. A fixed value or range, in other words, "about 100" means "between 90 and 110". In the narrower embodiment, the term "about" means a given value or range between 95% and 105%, or a given value or range between 98% and 102%, or A given value or range between 99% and 101%.

In a still further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered in a range of from about 25 mg/day to about 350 mg/day.

In yet another embodiment, (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is administered in a range of from about 50 mg/day to about 300 mg/day, particularly at about 50 mg. Dosage in the range of approximately 150 mg/day.

In still another embodiment of the method of the present invention, (R)-phenyl prasal and its pharmaceutically acceptable salt (for example, (R)-phenylpyrazine hydrochloride) are daily 1 Sub-dosing, especially about 200 mg, once a day.

In a further embodiment of the method of the invention, the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered in multiple doses, for example twice daily (bid) or 3 times daily In particular, it is administered twice a day, especially at a dose of about 100 mg twice daily.

The method of the invention also provides a therapeutically effective amount of a pharmaceutical composition comprising (R)-phenyl prasal. The pharmaceutical composition further includes all pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be formulated to be administered once a day, twice a day, or three times a day.

The term "carrier" as applied to the pharmaceutical composition of the present invention means dilution A liquid, excipient, or carrier is administered with an active compound such as (R)-phenylpyrazine. Such pharmaceutical carriers may be sterile liquids such as water, physiological saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those derived from micro-oil, animal, vegetable or synthetic sources such as peanut oil, soybean oil, mineral oil, and Sesame oil and so on. Suitable pharmaceutical carriers are described in ""Remington's Pharmaceutical Sciences" by A.R. Gennaro, 20th Edition".

The active ingredient (e.g., (R)-phenyl prasal) or the composition of the invention may be used to treat at least one of the mentioned diseases, wherein the treatment is employed or suitably prepared for the particular administration disclosed herein. (eg 1 time a day, 2 times a day, or 3 times a day). To this end, the drug copy and/or patient instructions contain a corresponding message.

The active ingredient (e.g., (R)-phenyl prasal) or the composition of the present invention may be used as a pharmaceutical manufacturing to treat at least one of the diseases mentioned, wherein the drug is employed or suitably prepared as disclosed in the present invention. Specific administration (eg, once a day, twice a day, or three times a day). To this end, the drug copy and/or patient instructions contain a corresponding message.

According to the present invention, the dosage form of (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof may be a solid, semi-solid or liquid preparation.

(R)-Phenylpyrazine can be administered via different application routes. Oral and parenteral routes are preferred routes of administration. (R)-Phenylpyrazine can be adjusted to make a seasoned liquid, capsule or tablet.

For oral administration in the form of tablets or capsules, (R)-phenyl prasser The combination can be combined with non-toxic pharmaceutically acceptable excipients.

The optimal therapeutically effective dose can be determined experimentally to take into account the exact mode of administration, the form of administration, the indications for which the drug is administered, the individuals involved (eg, weight, health, age, sex, etc.) and the preferences of the physician or veterinarian responsible And experience.

A suitable daily therapeutic dose of the active ingredient of the present invention to humans is in the range of from about 1 mg/day to about 400 mg/day (based on free base (R)-phenyl prasal), such as From about 25 mg/day to about 350 mg/day, or from about 50 mg/day to about 300 mg/day, especially 200 mg/day. In another setting, the daily dose may be adjusted according to body weight, such as a dose of about 200 mg/day for a patient weighing up to 80 kg or a dose of about 240 mg/day for a patient weighing greater than or equal to 80 kg. . In yet another setting, the (R)-phenyl prasal and its pharmaceutically acceptable salts are administered at a dose starting from about 50 mg/day and are increased from a dose of 50 mg/day until The desired therapeutic effect is achieved, but the maximum is a dose of about 400 mg/day. Also, due to the reduced bioavailability, a higher total daily active ingredient administration can be administered in the modified release formulation, such as up to about 500 mg/day. (R)-Phenylpyrazine and its pharmaceutically acceptable salts, solvates, conjugates or derivatives, such as (R)-phenylpyrazine hydrochloride, the corresponding dose can be adjusted To use the amount of equimolar.

(R)-Phenylpyrazine may be administered in a single anti-fatigue formulation or in combination with one or more additional pharmaceutical preparations to treat fatigue, particularly mental fatigue.

In some particular embodiments, the one or more additional medicines The formulation is selected from the group consisting of rasagiline or pramipexole.

In another embodiment, a pharmaceutical composition comprising (R)-phenyl prasal may further comprise at least one additional active agent as defined herein, in particular an additional active agent for the treatment of fatigue related diseases. In some particular embodiments, the disease is Parkinson's disease.

In yet another embodiment, (R)-phenyl prasal is administered in combination with a drug to increase tolerance to (R)-phenyl prasal treatment, and/or to reduce (R)-benzene At least one side effect associated with the treatment of pilosia.

Example

The following examples are intended to describe the invention, but are not intended to limit the invention.

First Embodiment: Determining the (R)-phenyl shawl

Functional monoamine transporter assays were used to determine the potential drug targets for (R)-phenyl prasal.

Recombinant Chinese hamster ovary (CHO) cells CHO-K1 (ATCC® CCL-61 ^TM ) stably cultured with dopamine transporter were cultured. Cells (2 x 10 ⁵ /ml) were pre-incubated with test compounds and/or vehicles for 20 minutes at 25 ° C in adjusted pH 7.1 Tris-HEPES buffer. Then [氚]-dopamine ([ ³ H]-dopamine) was added for additional 15 minutes. Non-specific signals were determined at 10 micromolar (μM) nomifensine. The cells were then dissolved in 1% SDS lysis buffer. If the test compound group has a [氚]-dopamine uptake of 50% or more relative to the carrier control group ( 50%) indicates that the compound has significant inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 micromolar concentrations ([mu]M). These same concentrations of compounds were simultaneously added to individual groups of untreated cells to assess possible compound-induced cytotoxicity only when significant uptake inhibition was observed.

Ma expressed recombinant norepinephrine (norepinephrine) transporter - Darby Canine Kidney (Madin Darby canine kidney, MDCK) cells (NBL-2) (ATCC® CCL -34 TM) for 2 weeks. Cells (1 x 10 ⁵ /ml) were pre-incubated with test compounds and/or vehicles for 20 minutes at 25 ° C in adjusted pH 7.1 Tris-HEPES buffer. Then, [氚]-norrepinephrine ([ ³ H]-norepinephrine) at a concentration of 5 nmimo (nM) was further added for 15 minutes. The lysate was taken from the dissolved cells and calculated to confirm the uptake of [氚]-norrepinephrine ([ ³ H]-norepinephrine). If the compound with respect to 10 micromolar concentrations of desipramine off (of desipramine) which [tritium] - norepinephrine ^([3 H] -norepinephrine) is reduced by 50% or more indicates that it has a significant inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 micromolar concentrations (μM), and these same concentrations of compounds were simultaneously added to individual groups of untreated cells only when significant uptake inhibition was observed. To assess possible compound-induced cytotoxicity.

These medicinal experiments show 13 micromoles in the functional analysis. The affinity of the concentration (μM) of (R)-phenylpyrazine for the neurodamine dopamine re-uptake transporter.

In the microdialysis experiment, the behavioral (R)-phenyl prasser When the active dose is 100 mg/kg, the free concentration of dopamine in the extracellular fluid in the brain reaches 50 micromolar (μM); when the dose of (R)-phenyl pilosa is 50 mg/ At kilograms, the dopamine free concentration was 20 micromolar (μM).

These concentrations are quite high enough to presume that the dopamine reuptake transporter system is the corresponding target in the brain.

Second Example: Using microdialysis in the brain to measure the degree of extracellular dopamine in the striatum of rats (R)-phenylpyrazine - Figure 1 Test items

(R)-Phenylpyrazine was dissolved in physiological saline and intraperitoneally injected (i.p.).

animal

Sprague-Dawley adult male rats (n=5, approximately 300 g, Harlan, Netherlands) were used in the experiments. After the animals were operated, they were individually raised (cage 30 cm x 30 cm x 40 cm) in a standard environment with food and water and ad libitum. The recovery period after surgery is at least 48 hours.

surgery

The rats were anesthetized with isoflurane (2%, 800 ml/min of oxygen) and placed in a stereotaxic instrument (Kopf. Instruments, USA). An I-shaped probe (Hospal AN 69 membrane, exposed surface 3 mm, Brainlink, The Netherlands) was inserted into the striatum. The coordinates of the probe tip are: back end (AP) = +0.9 mm for the bregma, side (L) = +3.0 mm for the midline, ventral (V) = for the dura - 6.5 mm ( Paxinos, G., and Watson, C. (1982) The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego).

Microdialysis experiment

A 24-48 hour experiment was performed after surgery. On the day of the experiment, the probe was attached to a micro-perfusion pump (Syringe pump UV 8301501, Univentor, Malta) using a flexible polydiether ketone (PEEK) tube and using artificial cerebrospinal fluid (aCSF) at a flow rate of 1.5 μl/min (μl/ Min) under perfusion, the artificial cerebrospinal fluid includes 147 millimolar (mM) sodium chloride, 3.0 millimolar (mM) potassium chloride, 1.2 millimolar (mM) calcium chloride, and 1.2 millimolar Concentration (mM) magnesium chloride. Microdialysis samples from 20 minutes to 120 minutes were collected using an automated fraction collector (Univentor 820 Microsampler, Antec, The Netherlands) and stored in a -80 °C freezer for analysis. After the experiment, the rats were sacrificed and their brains removed. The brain was coronally sectioned and histologically confirmed for the position of each probe according to Paxinos and Watson as described above.

Determination of dopamine (DA) and 3,4-Dihydroxyphenylacetic acid (DOPAC) Separation of dopamine from 3,4-dihydroxyphenylacetic acid

The sample was injected into a high performance liquid chromatography (HPLC) column (reverse phase, particle size 3 micron (μm), C18, Thermo BDS Hypersil column, 150 x 2.1 mm, Thermo Scientific, USA) to refrigerate micro The sampling system was operated by a syringe pump (Gilson, model 402, France), a multi-column syringe (Gilson, model 233 XL, France), and a temperature regulator (Gilson, model 832, France). Chromatographic separation using a mobile phase consisting of sodium acetate buffer (6.15 g/L), methanol (2.5% v/v), Titriplex (250 mg/L), 1-octanesulfonic acid, OSA, 150 mg/L) and adjusted to pH 4.1 (equal strength) with glacial acetic acid. The flow rate of the mobile phase in the system was 0.35 ml/min by a high performance liquid chromatography pump (Shimadzu, model LC-10AD vp, Japan).

Detection

High performance liquid chromatography separation and electrochemical detection were used to determine the concentration of dopamine and 3,4-dihydroxyphenylacetic acid in the same sample. Electrochemical detection of dopamine with a potentiometer (potentiostate, Antec Leyden, model Intro, The Netherlands) with a glassy carbon electrode set to +500 millivolts (mV) for silver/silver chloride (Antec Leyden, The Netherlands) 3,4-dihydroxyphenylacetic acid. Software data system (Chromatography Data System, Shimadzu, class-vp, Japan) software Analysis of data. An external standard method was used to quantify the concentration.

Statistical Analysis

After the degree of the transmitter was stabilized, four consecutive pre-treatment microdialysis samples were used as the baseline, the difference between the four samples was less than 50% and the average was set to 100%. The transmitter concentration for each fraction is expressed as a percentage of the baseline ± standard error of the mean (% ± SEM).

result

The results showed that (R)-phenyl prasal increased the dopamine concentration in the striatum.

Third Embodiment: Measurement of the concentration of (R)-phenyl prasal in the brain using brain microdialysis - Fig. 2 theme

Adult male Sprague-Dawley rats in the study were housed in a standard environment. All experiments were performed on the light period of the rat during the day-night cycle.

surgery

Anesthetize animals with pentobarbital, according to the foregoing Paxinos and Watson atlas, in the caudate nucleus (caudatus putamen, CPu; relative to the bregma AP: +0.1, LM: ± 2.6, DV: -3.2 mm; -3.3 mm interaural) The side is implanted with a sputum catheter (MAB 6.14.IC) (MAB, Stockholm, Sweden). Rats were subjected to a microdialysis experiment at least 3 days after surgery.

Microdialysis

Microdialysis experiments were carried out in animal cages. Reduce the microdialysis probe (MAB 6.14.4.; exposed membrane length 4 mm, polyethersulfone (PES) membrane; MAB; Stockholm; Sweden) to pass through the catheter and into the caudate nucleocapsid (probe tip) The ventral position was at the reference position of the skull - 7.2 mm) and remained here throughout the test period, approximately 12 hours prior to sampling.

The probe was perfused with artificial cerebrospinal fluid and the flow rate was 2 μl/min (μl/min) using a CMA 102 perfusion pump (CMA, Solna, Sweden). The composition of the artificial cerebrospinal fluid is: 147 millimolar volume (mM) nano ions, 2.7 millimolar volume (mM) potassium ions, 1.2 millimolar volume (mM) calcium ions, 0.85 millimolar volume (mM) magnesium ions , 0.04 millimolar volume (mM) ascorbic acid. Animals were ligated with a dual channel liquid swivel 375/D/22QM (Instech, Plymouth Meeting, USA) using a head block tether system (Instech, Plymouth Meeting, USA). A fluorinated ethylene-propylene copolymer (FEP) tube and a tube connector (MAB, Stockholm, Sweden) were used. Charge 3 3 minute parts at the beginning of perfusion (fraction) was used as a baseline, and samples were collected one hour after the start. Thereafter, each rat received an intraperitoneal injection of (R)-phenylpyrazine and/or levodopa (L-DOPA, 25 mg/kg + benserazide, 15 mg/kg). Samples (40 microliters) were collected in an automated partial collector (CMA/142; CMA, Solna, Sweden) and stored at -20 °C for analysis.

Determination of recovery

To perform in vitro recovery, the probe was inserted into a beaker containing artificial cerebrospinal fluid (37 ° C) and a solution containing 100 nanomolar (nM) (R)-phenylpyrazine or levodopa. A total of 5 samples (40 microliters (μl)) were collected, of which only the last 2 samples were used to analyze the concentration of (R)-phenyl prajna or levodopa.

analysis

High performance liquid chromatography coupled to a gas pressure ionization tandem mass spectrometer (API-MS/MS instrument (Shimadzu Prominence, Duisburg, Germany) coupled to a tandem mass spectrometer API 4000 Q Trap equipped with TurboIonspray source (ESI) Grade, Applied Biosystems/MDS Sciex, Darmstadt, Germany)). The analytical column was Onyx Monolithic C1850 mm x 2 mm (Phenomenex, Aschaffenburg, Germany). The mobile phase consisted of a rinse A water containing 0.1% formic acid and a rinse solution B acetonitrile. The chromatography operation consisted of a gradient of more than 5 minutes starting with 5% acetonitrile in water until the mobile phase became 50% acetonitrile in water. The volume injected into the gas pressure ionization tandem mass spectrometer was 1 milliliter (ml). Using standard songs Lines were used to calculate the concentration of the drug samples in this study.

result

The results show that (R)-phenyl prasate reaches the brain to a degree sufficient to affect the primary target (dopamine carrier).

Fourth Example: Effect of (R)-Phenylpyrazine on Rat Activity Rate (Horizontal Activity) - Figure 3 animal

Experimental male Sprague-Dawley rats (230-300 g) were housed in the same cage every four animals, and the indoor temperature (21 ± 1 ° C) and humidity were controlled. Food and water were ad libitum, and animals were housed in alternate 12 hour/12 hour day/night cycles, allowing the animals to acclimate for at least 6 days prior to the start of the experiment. Each animal is used only once. Each experimental group consisted of 8 animals.

process

The activity rate is measured in 8 plexiglass boxes (ENV-515-16, 43.2 mm x 43.2 mm x 30 cm), Med-Associates Inc., equipped with 4 arrays of 16 infrared beams placed on the ground. The upper 3 cm is measured at the level of activity. Distance traveled is used for further analysis as a measure of activity.

deal with

(R)-Phenylpyrazine was dissolved in physiological test water in a volume of 2 ml/kg for intraperitoneal administration.

Statistical Analysis

The activity rate data is analyzed by the Kruskal-Wallis Variance Analysis (ANOVA) method if it is significant under the rank sum test.

result

Figure 3 shows that (R)-phenylpyrazine can increase the activity rate (horizontal activity) of rats starting from a dose of 100 mg/kg, indicating that (R)-phenyl prasal can stimulate activity.

Fifth Embodiment: (R)-Phenylpyrazine Spiral Test on Brain Wave Scan - Picture 4

(R)-Phenylpyrazine has 4 different test concentrations (1 mg/kg, 12.5 mg/kg, 25 mg/kg, and 50 mg/kg), scanned by an electroencephalograph, such as Dimpfel Description (Dimpfel, Neuropsychobiology, 58, 178-86, 2008).

animal

Eight adult Fisher 344 rats (age 8) were used in this series of experiments. Months were reared in an inverted light-dark cycle with a body weight of approximately 400 grams supplied by Charles River Laboratories, D-97633, Sulzfeld. The electrodes were implanted into the brain of the animal and a 2-week recovery period was given after surgery (see 6.4 for a detailed description). Then, insert the transmitter to adapt and control the experiment. Rats are unrestricted during the recording period and are free to move, but are not allowed to eat (chewing can cause too many human errors).

Domestication and breeding environment

Animals can be domesticated for at least 4 weeks before the study begins. The domesticated environment has an automatically controlled photoperiod, temperature and humidity. The hours of illumination are 18 hours in the evening and 6 hours in the morning. Daily monitoring can show that temperature and humidity are maintained within the target range of 22 ± 2 ° C and 44 ± 5%, respectively. The squirrel cage, litter, and water bottle are replaced at regular intervals, such as every 2-3 days. Animals can be fed a standard diet (Nohrlin H10, Altromin, D-32791 Lage, Germany) in any way. Animals can drink tap water at will.

surgery

Rats were anesthetized with K-death and received four bipolar concentric steel electrodes during stereotactic procedures. All four electrodes were placed 3 mm laterally in the left hemisphere of the brain, and the positions of the anterior cortex, striatum, hippocampus, and reticular (according to Paxinos and Watson Atlas, 1982) were respectively The abdominal coordinates are 4, 6, 4.2, and 8 mm, while the anterior coordinates are 3.7, 9.7, 5.7, and 12.2 mm. A pre-built bottom plate with four bipolar stainless steel semi-micro electrodes (neural electrode "SNF 100" comes from Rhodes Medical Instruments, Inc., Summerland, CA 93067, USA) and a five-pin plug are attached to the skull by a dental adhesive that interacts with three steel screws that are placed in the bone with a distance from each other. The distal recording point of the electrode is the active electrode and the near end points of the four electrodes are connected to each other as a reference value. The backplane with plug accepts a later transmitter (including a battery weight of 5.2 grams and a size of 26 mm x 12 mm x 6 mm).

experiment procedure

Brain wave signal recordings of the anterior cortex, hippocampus, striatum, and reticular body were performed on freely movable rats in a room that was completely shielded from copper. The signal is transmitted wirelessly using a radio telemetry system (carrier frequency 40 MHz (MHz), Rhema Labortechnik, Hofheim, Germany) and the signal is based on past research (Dimpfel et al. 1986; Dimpfel et al. 1988; Dimpfel et al. 1989; Dimpfel, 2003) Amplified and processed to obtain a power spectrum of 0.25 Hertz (Hz) resolution. In short, the automatic artifact rejection signals are collected after Hanning window collection in the range of 4 seconds. The sampling frequency is 512 Hz. The four values are averaged to obtain a final sampling frequency of 128 Hertz (Hz), which is much higher than the Nyquist frequency. The resulting electrical power spectrum results are divided into six specific frequency ranges (delta: 0.8-4.5 Hz); theta: 4.75-6.75 Hz (Hz); Alpha (alpha) 1: 7.00-9.50 Hz ( Hz); Alpha (alpha) 2: 9.75-12.50 Hz (Hz); beta (beta) 1.17.75-18.50 Hz (Hz); beta (beta) 2: 18.75 -35.00 Hertz (Hz)). The spectrum is averaged every 3 minutes and displayed on the line.

Test items

(R)-Phenylpyrazine dissolved in physiological saline was injected into the peritoneum of rats, and then recorded by the potential field of the brain "Tele-Stereo-EEG". An image tracking system was incorporated to detect changes in motion (GJB Datentechnik GmbH, D-98704 Langewiesen, Germany). The system recognizes movement and stereotype behavior by the black transmitter on the animal's head and the contrast between the environments.

Processing group

Animals were randomly assigned to the treatment group after surgery, so the treatment groups were evenly distributed in the system of the cage. The cross-design method was used to stop at least one week between the two administration periods. After the 45-minute period before the administration, the pre-dosing record was recorded, and the effect of the drug was continuously observed on the screen (human error control) for 300 minutes, wherein a delay of 5 minutes was given to allow the animal to be calmed after receiving the intraperitoneal administration. The time is then subdivided into periods of 15 minutes. The change in electrical power is expressed as a percentage (%) of the absolute pre-drug spectral power value (45 min) 45 minutes before administration.

Statistical Analysis

Data are expressed as percentage ± mean standard error (% ± S.E.M.). The results obtained by carrying out a vehicle injection at a special time period were calculated using Wilcoxon-Mann-Whitney's U test. To compare the data obtained from the reference compound test in the same environment earlier than the same environment, a differential analysis was performed according to Fischer. A total of 24 (6 frequency ranges multiplied by 4 brain regions) were analyzed for different variations. First, three spatial coordinates were used as the first three distinct axes to project spherical projections from 47 reference compounds with physiological sleep results. Next, the 4th to 6th differential analysis results are encoded into red, green, and blue, and color mixing is analogized to a so-called RGB mode (as used in television). Since further compound addition may alter the projection, this matrix of drug actions is maintained constant (frozen) in order to classify unknown formulations.

result

As the dose of (R)-phenyl prasal is reduced, fluctuations in alpha 2 and beta 1 are also slowed (see Figure 4). In the anterior cortex, the highest dose causes theta power to increase and produces a different pattern of change. Activity has increased. The fluctuation of Alpha (alpha) 2 is mainly under the control of dopamine (cited in Dimpfel's literature). Therefore, it can be expected that the direct or indirect effects of dopamine neurotransmission are derived from (R)-phenyl prasal. After administration of the therapeutic drugs used in Parkinson's disease (Dimpfel and Hoffmann, Neuropsychobiology, 62, 213-220, 2010), a slowing of the fluctuation of alpha 2 and beta 1 was observed. In summary, the (R)-phenyl prasal shows the contours in the stimulating drug area.

Sixth Embodiment: Effect of (R)-Phenylpyrazine on the exercise willingness test - Figures 5, 6, 7, and 8 Test items

Methylphenidate was dissolved in clean distilled water on a daily basis and purchased from Sigma (Taufkirchen, Germany). Modafinil was purchased from Sequoia Research Products Limited (Pangbourne, UK) and was tested daily in 1% w/v methylcellulose (Sigma, Taufkirchen, Germany) and 0.9% sodium chloride. Among the clean water.

animal

The experiment used 103 male Sprague-Dawley rats weighing 225-250 grams.

Domestication and breeding environment

Animals were housed in a standard laboratory environment with 4 rats per cage and any drinking water. A standard diet of rodents (Altromin) is given, and each animal can consume 15 grams of feed per day.

Processing group

Two experiments were performed using the same experimental plan. All animals were trained in continuous reinforcement training (CRF) and assigned to the treatment group so that the animals in all groups performed similarly. Treatment groups were evenly distributed among the cage systems.

experimental method

The following experimental schemes were used in both experiments: Overview: Three tests were performed in a continuous manner over the following days. On Days 1-2, the animals were individually adapted to the Skinner boxes. The adaptation period was divided into two phases, one for each phase and 30 minutes for each phase. Animals were given "free" food pellets (average 1 pellet per minute) at random times. On days 3-8, the animals were trained in akinner's box for a continuous intensive training session (one food pellet per press). On days 9-10, the animals received a progressive ratio test (first test) in the case of discontinuation and a test in the case of dosing on days 11-12. On the 13th day, the animal was subjected to a choice test (second test) in the case of administration, and on the 14th day, the animal was subjected to a consumption test (third test) in the case of administration. The following is a detailed experimental description.

The first test: progressive ratio (PR) task

Behavioral testing was performed in 12 operational test chambers (Med Associates, St. Albans, USA). Each operating box has a retractable pressure bar. The food supply container, the room light above the operating box, and two stimuli lights, above the pressure bar and above the other food containers. The infrared beam detects that the animal's nose is moving on the food container. The equipment used was controlled by a computer system (SmartControl®-Interface and MedPC-software, Med Associates, St. Albans, USA). Light above the food container is indicative of the transport of food particles in the container. During the 2 consecutive days, the rats were first conditioned in a two-stage (30 minutes per stage) in the operating box. Thereafter, the animals were subjected to 6 stages of training for 30 minutes each in a continuous intensive training session. Next, in each step, four stages are performed with an increase in the fixed ratio (FR) of 5 (two stages are discontinued, and two stages are medications), and each step is repeated three times (eg, 1). -1-1; 5-5-5; 10-10-10;...). When the fixed ratio required for each test is reached, the light on the container will indicate the delivery of a food pellet (45 mg, Bioserve, USA) and the light will continue to illuminate until the rat is on the container with the nose . Pressing the bar during light is considered a fixed bar press, although it can be counted but has no program results. One stage lasts until 90 minutes or when the rat does not press the pressure bar for 10 minutes. At each stage, the value of the final completion ratio (breakthrough point), the number of rewards, the number of fixed pressure strokes, the time of the phase, and the underlying factors of the response are recorded. Thirty minutes prior to testing, all treatment groups received vehicle/drug administration in the final 2 stages, including those under the Progressive Ratio (PR) stroke.

The second test: cost-effective (Cost-benefit) selection test

In this task, the rat has two options: to press the pressure bar in the aforementioned advancement ratio (PR) stroke to obtain a more preferred food (Bioserve The test food is freely available in the plate (about 15 grams) in the operating box. The food container and the pressure bar are placed on the same wall of the operation box, and the plate containing the experimental food is placed on the opposite side. One stage lasts until 90 minutes or when the rat does not press the pressure bar for 10 minutes. Thereafter, calculate the amount of food intake for the experiment. Animals in all treatment groups received vehicle/drug administration 30 minutes prior to testing.

The third test: consumption test (consumption test)

The animals were individually placed in separate cages (type 3) with a glass bowl containing 30 grams of food pellets. Animals are free to receive rewards (food pellets) within 20 minutes and measure the amount of reward consumed by measuring the weight of each glass bowl prior to testing minus the weight of each glass bowl after testing. Animals in all treatment groups received vehicle/drug administration 30 minutes prior to testing.

Statistical Analysis

Data were analyzed by one- or two-way ANOVA and then determined by Dunnett's post hoc test. All operations are using STATISTICA ^TM (StatSoft®, Tulsa, United States). The statistically significant (α-level) degree was set to p < 0.05.

result

The experimental data shows that (R)-phenyl prajna increases the willingness to exercise, such as workload, that is, animals will be willing to perform to get more reward food. with When you consume free food, you don't increase your willingness to exercise. In general, the results show that (R)-phenyl prasal can increase the willingness to exercise, and thus can be expected to have an effect on neurological fatigue. (R)-Phenylpyrazine is more potent than methylphenidate and amphetamine. In addition, (S)-Phenylpyrazine has a very low effect at 100 mg/kg, which is less than 2.5 times the effect of (R)-phenylpyrazine, and at 200 mg/kg. Not significant.

Seventh Example: (R)-Phenylpyrazine for unilateral substantia nigra (substantia nigra, SNc) Injury (Experimental Model of Parkinson's Disease) Efficacy of Rats - Figure 9

In the rat with unilateral substantia nigra injury (pre-clinical Parkinson's disease experimental mode), a test for (R)-phenyl pilosa was performed. In this experimental mode, ipsilateral rotation represents presynaptic mode action, consistent with inhibition of dopamine uptake, and is the primary mode of action.

animal

Male Sprague-Dawley rats were unilaterally treated with medial forebrain bundle damage using 6-hydroxydopamine and showed a clear ipsilateral rotational bias in the amphetamine rotation test. Every 4 rats were housed in the same cage, the 12-hour light-dark cycle was controlled in the animal room, and the temperature was controlled (21 ° C), and standard laboratory food (food pellets) was obtained, as well as any reference to tap water. All experiments were conducted between 9 and 16 o'clock.

chemical

(R)-Phenylpyrazine was dissolved in physiological saline and injected into the peritoneum.

Rotation test

The injected mice were placed in Perspex cylinders (30 cm diameter) and scored for rotation (360°) using a TSA rotation measurement system in a 20 minute interval for 360 minutes.

Statistical Analysis

Data are presented as mean ± mean standard error (means ± S. E. M.). Two-factor variance analysis was used to analyze the sum of all scores throughout the recording period. If significant, the two-factor variance analysis was followed by Dunnett's assay for pairwise multiple comparisons.

result

This study shows that (R)-phenylpyrazine can increase ipsilateral rotation in the Parkinson's disease animal model. The results indicate that (R)-phenyl prasal can improve fatigue-associated Parkinson's disease. In short, the results of the experiment show that (R)-phenyl prasal can provide effective and well-tolerated treatment for patients with Parkinson's disease with fatigue and fatigue-related symptoms, among which fatigue-related symptoms Including such as loss of vitality, Lack of willingness to move, indifference, laziness, collapse, fatigue, exhaustion, etc.

Based on these preliminary findings, (R)-phenylpyrazine is a drug candidate for the treatment of fatigue-related Parkinson's disease due to the efficacy of (R)-phenylpyrazine on the dopamine reuptake transporter.

Eighth Example: Effect of (R)-phenylpyrazine on sedation, in which sedation is induced by respine - Figure 10 animal

Male Sprague-Dawley rats weigh approximately 300 grams and are housed in a standard laboratory environment.

chemical

Animals were injected with reserpine (5 mg/kg) 24 hours before the test and α-methyltrycaramine (α-MT) (250 mg/kg) 3.5 hours before the test. (R)-Phenylpyrazine was administered intraperitoneally directly prior to testing.

Activity rate of rats treated with tongue base

The activity rate was measured in 4 plexiglass boxes (ENV-515-16, 43.2 cm x 43.2 cm x 30 cm, Med-Associates Inc. system), and 4 arrays of 16 infrared beams were placed in the box. Above the 3 cm of the ground in the box. The measurement of activity is further analyzed using Distance travelled (DT). Recording begins immediately after placing the animal in the open area.

Statistical Analysis

The sum of the scores obtained during all recording periods was analyzed by one-way ANOVA.

result

The data show that (R)-phenyl prasal can alleviate sedation and support anti-fatigue activity, which is produced by the base of the tongue.

Ninth Example: (R)-Phenylpyrazine for sedation, wherein the sedation is induced by haloperidol - Figure 11 animal

Male Sprague-Dawley rats weigh approximately 300 grams and are housed in a standard laboratory environment.

chemical

(R)-Phenylpyrazine (25 mg/kg, 50 mg/kg, and 100 mg/kg) was dissolved in physiological saline and injected into the peritoneum directly before the test. At 30 minutes before the start of the test, the 0.2 mg/kg dose of Hapod was also administered by intraperitoneal injection.

Activity rate of rats treated with Hapod

Activity rate measured in 4 plexiglass boxes (ENV-515-16, 43.2 The centimeters x 43.2 cm x 30 cm, Med-Associates Inc. system, has four arrays of 16 infrared beams placed above the 3 cm of the ground in the box. The measurement of activity is further analyzed using Distance travelled (DT). Recording begins immediately after placing the animal in the open area.

Statistical Analysis

One-way ANOVA was used to analyze the sum of the scores obtained during all recording periods. If significant, the Holm-Sidak test was used.

result

The data show that with the increase in the dose of (R)-phenyl prasal, the sedative effect of Harpert is also slowed down, ie (R)-phenyl prasal has anti-fatigue activity (see Figure 11). Additional experiments have shown that (S)-phenylpyrazine is less important, does not produce efficacy at doses of 50 mg/kg (see Figure 12A) or has almost only a dose of 100 mg/kg. Negotiable effects (see Figure 12B). It should be noted that (R)-phenylpyrazine can produce very robust effects at these doses.

references

Dimpfel, W. (2003). "Preclinical data base of pharmaco-specific rat EEG fingerprints (tele-stereo-EEG)." Eur J Med Res 8(5): 199-207.

Dimpfel, W., M. Spuler, et al. (1988). "Monitoring of the effects of antidepressant drugs in the freely moving rat by radioelectroencephalography (tele-stereo-EEG)." Neuropsychobiology 19(2): 116-120.

Dimpfel, W., M. Spuler, et al. (1989). "Hallucinogenic and stimulatory amphetamine derivatives: fingerprinting DOM, DOI, DOB, MDMA, and MBDB by spectral analysis of brain field potentials in the freely moving rat (Tele-Stereo -EEG)." Psychopharmacology (Berl) 98(3): 297-303.

Dimpfel, W., M. Spuler, et al. (1986). "Radioelectroencephalography (Tele-Stereo-EEG) in the rat as a pharmacological model to differentiate the central action of flupirtine from that of opiates, diazepam and phenobarbital." Neuropsychobiology 16(2-3): 163-168.

Krösser, S. and J. Tillner (2007). "Pharmacokinetics of sarizotan after oral administration of single and repeated doses in healthy subjects." International Journal of Clinical Pharmacology and Therapeutics 45: 271-280.

The specific embodiments described above are not intended to limit the scope of the invention. In fact, those skilled in the art, in light of the foregoing description, may be able to make various changes and modifications without departing from the spirit and scope of the invention. . These changes and refinements are within the scope of the patent application scope of the present invention.

All patents, applications, publications, test methods, documents, and other materials listed herein are incorporated herein by reference.

Claims (30)

A pharmaceutical composition comprising (R)-phenylpiracetam (R)-phenylpiracetam or a pharmaceutically acceptable salt thereof for the treatment of disease-related fatigue, particularly disease-related mental fatigue. The pharmaceutical composition according to claim 1, wherein the (R)-phenylpyrazine is (R)-phenylpiracetam hydrochloride. The pharmaceutical composition according to claim 1 or 2, wherein the fatigue severity scale (Fatigue Severity Scale) has a score of at least 4. The pharmaceutical composition according to claim 3, wherein the fatigue severity scale has a score of at least 4 and is maintained for at least 2 weeks. The pharmaceutical composition according to any one of claims 1 to 4, wherein the disease-related fatigue system is fatigue associated with Parkinson's disease. The pharmaceutical composition according to claim 5, wherein the disease-related fatigue system is mental fatigue associated with Parkinson's disease. The pharmaceutical composition according to claim 5 or 6, wherein the Parkinson Fatigue Scale has a score of at least 7. The pharmaceutical composition according to claim 7, wherein the Parkinson's fatigue scale has a score of at least 7 and is maintained for at least 2 weeks. The pharmaceutical composition according to any one of claims 1 to 8, wherein the (R)-phenylpyrazine is in the range of from about 1 mg/day to about 400 mg/day. Dosing, or (R)-phenylpyrazine, is administered at a dose of from about 25 mg/day to about 350 mg/day, or (R)-phenylpyrazine is about 50 mg. / Day to about 300 mg / day to administer. The pharmaceutical composition according to any one of the preceding claims, wherein (R)-phenyl prasal or its pharmaceutically acceptable salt is once daily, twice daily, or daily. Sub-dosing. The pharmaceutical composition according to any one of the preceding claims, wherein (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is administered as an oral preparation. A pharmaceutical composition according to any one of the preceding claims, wherein (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is co-administered with at least one additional pharmaceutical agent, the pharmaceutical agent It has been proven to have a therapeutic effect on disease-related fatigue. The pharmaceutical composition according to claim 12, wherein the disease-related fatigue is Parkinson's disease-associated fatigue. The pharmaceutical composition according to claim 13, wherein the disease-related fatigue is mental fatigue associated with Parkinson's disease. The pharmaceutical composition of claim 13 or claim 14, wherein the at least one additional pharmaceutical agent is selected from the group consisting of rasagiline and pramipexole. A method of treating disease-related fatigue, particularly in a subject associated with a disease-related neurological fatigue, comprising administering an effective amount of (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof. The method of claim 16, wherein the (R)-phenylpyrazine is (R)-phenylpyrazine hydrochloride. For example, the method described in claim 16 or 17 The Labor Severity Scale has a score of at least 4. The method of claim 18, wherein the fatigue severity scale has a score of at least 4 and is maintained for at least 2 weeks. The method of any one of claims 16 to 19, wherein the disease-related fatigue is fatigue associated with Parkinson's disease. The method of claim 20, wherein the disease-related fatigue is mental fatigue associated with Parkinson's disease. The method of claim 20, wherein the Parkinson's fatigue scale has a score of at least 7. The method of claim 22, wherein the Parkinson's fatigue scale has a score of at least 7 and is maintained for at least 2 weeks. The method of any one of claims 16 to 23, wherein the (R)-phenylpyrazine is administered in a range of from about 1 mg/day to about 400 mg/day, Or (R)-phenylpyrazine is administered at a dose of from about 25 mg/day to about 350 mg/day, or (R)-phenylpyrazine is applied at about 50 mg/day. Dosing in the range of about 300 mg / day. The method according to any one of the preceding claims, wherein the (R)-phenyl prasal or its pharmaceutically acceptable salt is administered once a day, twice a day, or three times a day. . A method according to any one of the preceding claims, wherein (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is administered as an oral preparation. A method according to any one of the preceding claims, wherein (R)-phenylpyrazine or a pharmaceutically acceptable salt thereof is co-administered with at least one additional pharmaceutical agent, the pharmaceutical agent has been confirmed Therapeutic effect of disease-related fatigue. The method of claim 27, wherein the disease-related fatigue is fatigue associated with Parkinson's disease. The method of claim 28, wherein the disease-related fatigue is mental fatigue associated with Parkinson's disease. The method of claim 28, wherein the at least one additional pharmaceutical agent is selected from the group consisting of rasagiline and pramipexole.