WO2023184031A1 - Method and use of bucillamine in the prevention and treatment of stroke - Google Patents
Method and use of bucillamine in the prevention and treatment of stroke Download PDFInfo
- Publication number
- WO2023184031A1 WO2023184031A1 PCT/CA2023/050425 CA2023050425W WO2023184031A1 WO 2023184031 A1 WO2023184031 A1 WO 2023184031A1 CA 2023050425 W CA2023050425 W CA 2023050425W WO 2023184031 A1 WO2023184031 A1 WO 2023184031A1
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- WO
- WIPO (PCT)
- Prior art keywords
- bucillamine
- stroke
- mammal
- therapeutically effective
- effective amount
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
Definitions
- the present invention relates to pharmaceutical compositions comprising bucillamine and their use for the treatment of stroke.
- Bucillamine N-(mercapto-2-methylpropionyl)-l-cysteine is a cysteine derivative with
- bucillamine 2 thiol groups.
- the structure of bucillamine is:
- Bucillamine is protective in the periphery.
- Bucillamine 125, 250, 500 pM
- bucillamine 22 mg/kg/h x 3 hr
- the effectiveness of Bucillamine (30-45 mg/kg, i.v., over 3 hours ) is similar to N-acetylcysteine at a dose of 300 mg/kg iv over 12 hours.
- Bucillamine is one log more potent than N-acetylcysteine in the peripheral organs.
- the present disclosure in one aspect, relates to a method for the treatment of stroke including administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
- compositions of the present disclosure can be administered to humans and other animals at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose.
- the daily dose is 300 mg per day.
- the daily does is 600 mg per day.
- the unit dose may be higher than 200 mg.
- the daily dose is 600 mg per day.
- the unit dose may be 200 mg to 300 mg.
- the daily dose may be higher than 600 mg per day.
- the daily dose is 600 mg to 800 mg per day.
- the daily dose is up to 1000 mg per day.
- the daily dose is up to 1500 mg per day, up to 2000 mg per day, up to 2500 mg per day, up to 3000 mg per day, 300-600 mg per day, 300-1000 mg per day, 300-1500 mg per day, 300-2000 mg per day, 300-2500 mg per day, 300-3000 mg per day, 600-1000 mg per day, 600-1500 mg per day, 600-2000 mg per day, 600-2500 mg per day, 600-3000 mg per day.
- the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
- the present disclosure in another aspect, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment of stroke.
- pharmaceutically acceptable compositions of the present disclosure can be used at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose.
- the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
- Fig. 1 includes photomicrographs and bar graphs for a timeline study
- Fig. 2 is a schematic timeline of an vivo experiment
- Fig. 3 are bar graphs body asymmetry and Bederson’s neurological scores
- Fig. 4 are typical TTC images from stroke rats receiving vehicle or Bucillamine.
- Fig. 5 is a graph of brain infarcation.
- a therapeutically effective amount of the bucillamine or pharmaceutically acceptable salts or solvates thereof may be presented as a pharmaceutical composition.
- the invention provides a pharmaceutical composition of bucillamine or pharmaceutically acceptable salts or solvates thereof in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients.
- the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- compositions of the present invention including bucillamine may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
- a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate.
- the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
- Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharinate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.
- Suitable salts may also be formed from bases, forming salts including ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium.
- Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, using conventional methods.
- compositions of the invention may be formulated for administration by any appropriate route, for example by the oral (including buccal or sublingual). Therefore, the pharmaceutical compositions of the invention may be formulated, for example, as tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral solutions or suspensions. Such pharmaceutical formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan,
- SUBSTITUTE SHEET (RULE 26) monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
- non-aqueous vehicles which may include edible oils
- almond oil oily esters such as glycerine, propylene glycol, or ethyl alcohol
- preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
- formulations may include other agents conventional in the art having regard to the type of formulation in question.
- compositions of the present invention may be suitable for the prevention or treatment of stroke in a human or animal patient.
- the patient is a mammal including a human, horse, dog, cat, sheep, cow, or primate.
- the patient is a human.
- the patient is not a human.
- the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
- the term also includes within its scope amounts effective to enhance normal physiological function.
- treatment refers to defending against or inhibiting a symptom, treating a symptom, delaying the appearance of a symptom, reducing the severity of the development of a symptom, and/or reducing the number or type of symptoms suffered by an individual, as compared to not administering a pharmaceutical composition of the invention.
- treatment encompasses the use in a palliative setting
- the present invention in one embodiment, relates to a method for the prevention or treatment of stroke in a mammal comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
- the present invention in another embodiment, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the prevention or treatment of stroke.
- H2O2 or glutamate were treated with H2O2 or glutamate to simulate free radical production and glutamate overflow in stroke. Both H2O2 and glutamate significantly reduced MAP-2 (microtubule-associated protein 2, a neuronal marker) immunoreactivity. These reactions were significantly antagonized by Bucillamine.
- MAP-2 microtubule-associated protein 2, a neuronal marker
- PCN rat cortical neurons
- SUBSTITUTE SHEET (RULE 26) After rinsing off trypsin with pre-warmed Dulbecco’s modified Eagle’s medium (Invitrogen), cells were dissociated by trituration, counted, and plated into 96-well (5.0x10 4 /well) cell culture plates precoated with poly-d-lysine (Sigma-Aldrich).
- the culture plating medium consisted of neurobasal medium supplemented with 2% heat-inactivated fetal bovine serum (FBS), 0.5 mM L-glutamine, 0.025mM L- glutamate and 2% B27 (Invitrogen). Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.
- the cultures were fed by exchanging 50% of media with feed media (Neurobasal medium, Invitrogen) with 0.5 mM L-glutamate and 2% B27 with antioxidants supplement on days in vitro (DIV) 3 and 5.
- feed media Neurorobasal medium, Invitrogen
- DIV 7 and 10 cultures were fed with media containing B27 supplement without antioxidants (Invitrogen).
- DIV 10 cultures were treated with reagents. After 48hrs, cells were fixed at 4% paraformaldehyde for 1 hour at room temperature (please see timeline in Fig 1 ).
- Cells were fixed 48 hours after treatment of reagents using 4% PFA. After removing 4% PFA solution, cells were washed with phosphate buffered saline (PBS). Fixed cells were treated with blocking solution [5% bovine serum albumin (BSA) and 0.1% Triton X-100 (Sigma, St. Louis, MO, USA) in PBS] for 1 hour. The cells were incubated for 1 day at 4°C with a mouse monoclonal antibody against MAP2 (1 :500, Millipore, Billerica, MA, USA) and then rinsed three times with PBS. The bound primary antibody was visualized using Alexa Fluor 488 goat anti-mouse secondary (Invitrogen).
- BSA bovine serum albumin
- Triton X-100 Triton X-100
- SUBSTITUTE SHEET (RULE 26) intracerebroventricular injections were: 0.8 mm posterior to the bregma; 1.5 mm lateral to the midline; 3.5 mm below the dura surface. The speed of injection was controlled by a syringe pump at a rate of 2.5 pl per min. The needle was retained in place for 5 min after injection. After injection, a piece of bone wax (W810, Ethicon) was applied to the skull defect to prevent leakage of the solution.
- W810, Ethicon bone wax
- MCA Right middle cerebral artery
- CCAs bilateral common carotids
- a craniotomy of about 2 x 2 mm 2 was made in the right squamosal bone.
- the right MCA was ligated with a 10-0 suture as previously described to generate focal infarction in the cerebral cortex.
- the ligature and clips were removed after 60 min ischemia to generate reperfusional injury.
- Core body temperature was monitored with a thermistor probe and maintained at 37 °C with a heating pad during anesthesia. After recovery from anesthesia, body temperature was maintained at 37 °C using a temperature-controlled incubator. Immediately after recovery from anesthesia, an elevated body swing test was used to evaluate the success of MCAo surgery.
- Rats keep the one forelimb to the breast and extend the other forelimb straight.
- Rats show decreased resistance to a lateral push in addition to the behavior in score 1 without circling.
- TTC Triphenyltetrazolium chloride
- PCNs Primary cortical neurons from rat embryos were prepared as previously described (1).
- the timeline of study is shown in Fig. 1.
- the MAP2ir was quantified and averaged to the mean of vehicle control group (Fig. 1-B1).
- Fig 3 are bar graphs of test results of treatment with Bucillamine reduced neurodegeneration in stroke rats.
- Adult rats received a 60-min MCAo.
- Bucillamine (Buc) or vehicle (veh) was given 15 min prior to the MCAo.
- Animals received neurological tests two days after MCAo.
- Bucillamine significantly reduced body asymmetry and Bederson’s neurological score. Data are represented as mean +/- SEM. *t-test.
- Raw data are listed in Table 3.
- Fig. 4. is a graph of test results showing Bucillamine reduced brain infarction in stroke rats. Animals received a 60-min middle cerebral artery occlusion (MCAo) on day 0. (A) Bucillamine or veh were given
- Table 2 Bodyweight and infarct area of each animal (raw data of Fig 5)
- Table 3 Neurological scores of each animal (raw data of Fig 3)
- the monitor contains 16 horizontal infrared sensors spaced 2.5 cm apart. Each animal was placed in a 42
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Abstract
Methods and uses for the treatment or prevention of stroke in a mammal including in a human, including administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof. The stroke can be ischemic stroke.
Description
METHOD AND USE OF BUCILLAMINE IN THE PREVENTION AND TREATMENT OF STROKE
FIELD
The present invention relates to pharmaceutical compositions comprising bucillamine and their use for the treatment of stroke.
BACKGROUND
Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine) is a cysteine derivative with
Previous studies have indicated that Bucillamine is protective in the periphery. Bucillamine (125, 250, 500 pM) reduced 100 uM H2O2 -mediated LDH production in cardiac cell culture. Bucillamine (22 mg/kg/h x 3 hr), given at the onset of reperfusion, reduced cardiac infarction after 90-min ischemia and repercussion. In heart failure patients, the effectiveness of Bucillamine (30-45 mg/kg, i.v., over 3 hours ) is similar to N-acetylcysteine at a dose of 300 mg/kg iv over 12 hours. Bucillamine is one log more potent than N-acetylcysteine in the peripheral organs.
Whether Bucillamine has a protective effect in central nervous system (CNS) has not been well documented.
SUMMARY OF THE INVENTION
The present disclosure, in one aspect, relates to a method for the treatment of stroke including administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
SUBSTITUTE SHEET (RULE 26)
In certain aspects of methods of the present disclosure, pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose. In another aspect, the daily dose is 300 mg per day. In another aspect, the daily does is 600 mg per day. In certain aspects, the unit dose may be higher than 200 mg. In another aspect, the daily dose is 600 mg per day. In certain aspects, the unit dose may be 200 mg to 300 mg. In certain other aspects, the daily dose may be higher than 600 mg per day. In another aspect, the daily dose is 600 mg to 800 mg per day. In another aspect, the daily dose is up to 1000 mg per day. In other aspects, the daily dose is up to 1500 mg per day, up to 2000 mg per day, up to 2500 mg per day, up to 3000 mg per day, 300-600 mg per day, 300-1000 mg per day, 300-1500 mg per day, 300-2000 mg per day, 300-2500 mg per day, 300-3000 mg per day, 600-1000 mg per day, 600-1500 mg per day, 600-2000 mg per day, 600-2500 mg per day, 600-3000 mg per day. However, the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
The present disclosure, in another aspect, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the treatment of stroke. In certain aspects of uses of the present disclosure, pharmaceutically acceptable compositions of the present disclosure can be used at a unit dose within range of about 10 mg to about 50 mg, the range of 100 mg to about 200 mg, 100mg, and 200 mg and this should provide a therapeutically effective dose. However, the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 includes photomicrographs and bar graphs for a timeline study;
Fig. 2 is a schematic timeline of an vivo experiment;
SUBSTITUTE SHEET (RULE 26)
Fig. 3 are bar graphs body asymmetry and Bederson’s neurological scores;
Fig. 4 are typical TTC images from stroke rats receiving vehicle or Bucillamine; and
Fig. 5 is a graph of brain infarcation.
DETAILED DESCRIPTION
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
For use in therapy a therapeutically effective amount of the bucillamine or pharmaceutically acceptable salts or solvates thereof, may be presented as a pharmaceutical composition. Thus, in a further embodiment the invention provides a pharmaceutical composition of bucillamine or pharmaceutically acceptable salts or solvates thereof in admixture with one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
When applicable, the compositions of the present invention, including bucillamine may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharinate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.
SUBSTITUTE SHEET (RULE 26)
Suitable salts may also be formed from bases, forming salts including ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium.
Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, using conventional methods.
Those skilled in the art of organic or coordination chemistry will appreciate that many organic and coordination compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of bucillamine are within the scope of the present invention.
Pharmaceutical compositions of the invention may be formulated for administration by any appropriate route, for example by the oral (including buccal or sublingual). Therefore, the pharmaceutical compositions of the invention may be formulated, for example, as tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral solutions or suspensions. Such pharmaceutical formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan,
SUBSTITUTE SHEET (RULE 26)
monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question.
The compositions of the present invention may be suitable for the prevention or treatment of stroke in a human or animal patient. In one embodiment, the patient is a mammal including a human, horse, dog, cat, sheep, cow, or primate. In one embodiment the patient is a human. In a further embodiment, the patient is not a human.
As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein the term “treatment” refers to defending against or inhibiting a symptom, treating a symptom, delaying the appearance of a symptom, reducing the severity of the development of a symptom, and/or reducing the number or type of symptoms suffered by an individual, as compared to not administering a pharmaceutical composition of the invention. The term treatment encompasses the use in a palliative setting
Accordingly, the present invention, in one embodiment, relates to a method for the prevention or treatment of stroke in a mammal comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.
SUBSTITUTE SHEET (RULE 26)
The present invention, in another embodiment, relates to a use of a pharmaceutical composition including bucillamine or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents and excipients for the prevention or treatment of stroke.
In vitro and in vivo experiments
In vitro and in vivo experiments were conducted to characterize the neuroprotective effect of Bucillamine in CNS.
(i) Neuroprotective effect of Bucillamine in primary cortical neuronal culture.
Cultured cells were treated with H2O2 or glutamate to simulate free radical production and glutamate overflow in stroke. Both H2O2 and glutamate significantly reduced MAP-2 (microtubule-associated protein 2, a neuronal marker) immunoreactivity. These reactions were significantly antagonized by Bucillamine.
(ii) Neuroprotective effect of Bucillamine in an animal model of stroke.
Adult rats were randomly assigned to two groups to receive intracerebroventricular injection (i.c.v) of Bucillamine or vehicle at 15 min prior to the middle cerebral artery occlusion (MCAo). The behavior test was conducted 2 days after MCAo. Animals were sacrificed for TTC (triphenultetrazolium chloride) staining after the behavior test. We found that Bucillamine significantly antagonized the neurological deficits and brain infarct in stroke rats.
These data support that Bucillamine is neuroprotective against ischemic stroke.
1. Objective: This study was designed to evaluate the protective effect of Bucillamine in neuronal culture and in an animal model of stroke.
2. Experimental study details:
3-1: Methods and material:
A. Primary cultures of rat cortical neurons (PCN)
Primary cultures were prepared from embryonic (E14-15) cortex tissues obtained from fetuses of timed pregnant Sprague-Dawley rats as we previously described (1). The olfactory bulbs, striatum, and hippocampus was removed aseptically; cortices were dissected. After removing the blood vessels and meninges, pooled cortices were trypsinized (0.05 %; Invitrogen, Carlsbad, CA) for 20 min at room temperature.
SUBSTITUTE SHEET (RULE 26)
After rinsing off trypsin with pre-warmed Dulbecco’s modified Eagle’s medium (Invitrogen), cells were dissociated by trituration, counted, and plated into 96-well (5.0x104/well) cell culture plates precoated with poly-d-lysine (Sigma-Aldrich). The culture plating medium consisted of neurobasal medium supplemented with 2% heat-inactivated fetal bovine serum (FBS), 0.5 mM L-glutamine, 0.025mM L- glutamate and 2% B27 (Invitrogen). Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air. The cultures were fed by exchanging 50% of media with feed media (Neurobasal medium, Invitrogen) with 0.5 mM L-glutamate and 2% B27 with antioxidants supplement on days in vitro (DIV) 3 and 5. On DIV 7 and 10, cultures were fed with media containing B27 supplement without antioxidants (Invitrogen). On DIV 10, cultures were treated with reagents. After 48hrs, cells were fixed at 4% paraformaldehyde for 1 hour at room temperature (please see timeline in Fig 1 ).
B. Immunocytochemistry
Cells were fixed 48 hours after treatment of reagents using 4% PFA. After removing 4% PFA solution, cells were washed with phosphate buffered saline (PBS). Fixed cells were treated with blocking solution [5% bovine serum albumin (BSA) and 0.1% Triton X-100 (Sigma, St. Louis, MO, USA) in PBS] for 1 hour. The cells were incubated for 1 day at 4°C with a mouse monoclonal antibody against MAP2 (1 :500, Millipore, Billerica, MA, USA) and then rinsed three times with PBS. The bound primary antibody was visualized using Alexa Fluor 488 goat anti-mouse secondary (Invitrogen). Images were acquired using a camera DS-Qi2 (Nikon, Melville, NY) attached to a NIKON ECLIPSE Ti2 (Nikon, Melville, NY). Data were analyzed using NIS Elements AR 5.11 Software (Nikon).
C. Animals:
Adult male Sprague-Dawley rats were used for the MCAo stroke model in this study. Animals were anesthetized with chloral hydrate (0.4 g/kg, i.p.). Bucillamine (Biosynth Carbosynth, UK; 107 mole in 20 pl saline per rat) or vehicle (20 pl saline per rat) was given intracerebroventricularly, contralateral to the ischemic hemisphere, through a 25 pl Hamilton syringe 15 min before MCAo. The coordinates for
7
SUBSTITUTE SHEET (RULE 26)
intracerebroventricular injections were: 0.8 mm posterior to the bregma; 1.5 mm lateral to the midline; 3.5 mm below the dura surface. The speed of injection was controlled by a syringe pump at a rate of 2.5 pl per min. The needle was retained in place for 5 min after injection. After injection, a piece of bone wax (W810, Ethicon) was applied to the skull defect to prevent leakage of the solution.
D. Stroke surgery
Right middle cerebral artery (MCA) was transiently occluded as previously described (2). In brief, the bilateral common carotids (CCAs) were ligated with nontraumatic arterial clips. A craniotomy of about 2 x 2 mm2 was made in the right squamosal bone. The right MCA was ligated with a 10-0 suture as previously described to generate focal infarction in the cerebral cortex. The ligature and clips were removed after 60 min ischemia to generate reperfusional injury. Core body temperature was monitored with a thermistor probe and maintained at 37 °C with a heating pad during anesthesia. After recovery from anesthesia, body temperature was maintained at 37 °C using a temperature-controlled incubator. Immediately after recovery from anesthesia, an elevated body swing test was used to evaluate the success of MCAo surgery.
E. Neurological tests
Two behavioral tests were used to examine stroke behavior, (a) Body asymmetry was analyzed using an elevated body asymmetry test (3, 4). Rats were examined for lateral movements/turning when their bodies were suspended 20 cm above the testing table by lifting their tails. The frequency of initial turning of the head or upper body contralateral to the ischemic side was counted in 20 consecutive trials. The maximum impairment in body asymmetry in stroke animals is 20 contralateral turns/20 trials. In non-stroke rats, the average body asymmetry is 10 contralateral turns/20 trials (i.e., the animals turn in each direction with equal frequency), (b) Neurological deficits were evaluated by the Bederson’s neurological test (5). In a postural reflex test, rats were examined for the degree of abnormal posture when suspended 20-30 cm above the testing table. They were scored according to the following criteria.
8
SUBSTITUTE SHEET (RULE 26)
0. Rats extend both forelimbs straight. No observable deficit.
1. Rats keep the one forelimb to the breast and extend the other forelimb straight.
2. Rats show decreased resistance to a lateral push in addition to the behavior in score 1 without circling.
3. Rats twist the upper half of their body in addition to behavior in score 2.
F: Triphenyltetrazolium chloride (TTC) staining (6, 7)
Two days after MCAo, animals were culled by decapitation. The brains were removed, immersed in cold saline for 5 minutes, and sliced into 2.0 mm thick sections. The brain slices were incubated in 2% triphenyltetrazolium chloride (Sigma- aldrich, MO, USA), dissolved in normal saline for 10 minutes at room temperature, and then transferred into a 5% formaldehyde solution for fixation. The area of infarction on each brain slice was measured double-blind using a digital scanner and the Image Tools program (University of Texas Health Sciences Center, San Antonio, TX).
G. Statistical Analysis
Data were presented as mean ± s.e.m. Student t-test, one or two-way ANOVA, and post-hoc Newman-Keuls tests (NK test) were used for statistical comparisons, with a significance level of p<0.05.
3-2: Results
A. Bucillamine induced neuroprotection in primary cortical neuronal culture
Primary cortical neurons (PCNs) from rat embryos were prepared as previously described (1). The timeline of study is shown in Fig. 1. Glutamate (Glu) or H2O2 - mediated neuronal loss was examined by MAP-2 immunostaining. Typical photomicrographs were shown in Fig. 1-A1. The MAP2ir was quantified and averaged to the mean of vehicle control group (Fig. 1-B1). Glu (100 pM) significantly reduced MAP2-ir (Fig. 1-B1, Glu vs. veh, p<0.001 , Fa,2i =29.926, one-way ANOVA+ post hoc NK test); this response was antagonized by Bucillamine (10 pM; Fig. 1-B2,
SUBSTITUTE SHEET (RULE 26)
Glu vs. Glu+Buc, p=0.005). Similarly, H2O2 (100 pM) also reduced MAP2-ir (Fig. 1- A2 and Fig. 1-B2, Glu vs. veh, p<0.001 , F2,14 =26.014, one-way ANOVA+ post hoc NK test), which was also antagonized by Bucillamine (Fig. 1- B2, p<0.001 , one-Way ANOVA+NK test). With reference to Figs. A1-C, Bucillamine (Buc) antagonized glutamate (Glu) and H2O2-mediated neuronal loss in primary cortical neuronal culture (PCN). (A) Glu or (B) H2O2 treatment reduced MAP2-ir, which was antagonized by Bucillamine. ‘Significant difference, one-way ANOVA + post-hoc NK test. Data are represented as mean +/- SEM, n=5-7 per each group. +AO: with antioxidants; -AO: without antioxidants.
B. The neuroprotective action of Bucillamine in stroke rats
A total of 10 rats were used for stroke study. Animals were randomly assigned to two groups (i.e. , Bucillamine and veh). Bucillamine (n=5) or veh (n=5) was given to the animals 15 min before the MCAo. The behavior test was conducted 2 days after MCAo. Animals were sacrificed forTTC staining after the behavior test (Fig. 2).
B1. Neurological tests:
Two neurological tests were used to examine behavioral improvement in 10 stroke rats. In an elevated body swing test, Bucillamine treatment significantly reduced body asymmetry in 20 trials (p= 0.014, t-test, Fig 3). Fig 3. are bar graphs of test results of treatment with Bucillamine reduced neurodegeneration in stroke rats. Adult rats received a 60-min MCAo. Bucillamine (Buc) or vehicle (veh) was given 15 min prior to the MCAo. Animals received neurological tests two days after MCAo. Bucillamine significantly reduced body asymmetry and Bederson’s neurological score. Data are represented as mean +/- SEM. *t-test. Bucillamine also significantly attenuated neurological deficits, examined by Bederson’s neurological test, in stroke rats (p=0.02, t-test, Fig 3). Raw data are listed in Table 3.
B2. Brain infarction:
All animals were sacrificed two days after MCAo. Brain tissues were collected and sliced for infarction analysis. Typical TTC staining from two rats receiving veh or Bucillamine is illustrated in Fig. 4. Fig 5. is a graph of test results showing Bucillamine reduced brain infarction in stroke rats. Animals received a 60-min middle cerebral artery occlusion (MCAo) on day 0. (A) Bucillamine or veh were given
10
SUBSTITUTE SHEET (RULE 26)
intracerebroventricularly before the MCAo. Brains were sliced into 2.0-mm thick sections on 2 days post stroke. The area of infarction in brain slices was analyzed after TTC staining. Bucillamine significantly reduced brain infarction at 2 days after the MCAo (* p=0.008, two-way ANOVA). Data are represented as mean +/- SEM.The area of infarction per each brain slice was further quantified. Using a two- way ANOVA, we found that Bucillamine significantly reduced brain infarction on day 2 (p=0.008, Fi, 56=7.531 , Fig 5). Raw data are listed in Table 2.
Buc: Bucillamine
Table 3: Neurological scores of each animal (raw data of Fig 3)
11
Buc: Bucillamine
3. Discussion:
In this study, we characterized the protective effect of Bucillamine in neuronal cultures and experimental animals. We demonstrate for the first time that Bucillamine reduced glutamate or H2O2 -mediated loss of MAP2-ir in primary cortical neurons from rats. Our data support that Bucillamine is neuroprotective against glutamate and H2O2 neurotoxicity in neuronal culture.
Using a rat model of ischemic stroke, we found that intracerebroventicular administration of Bucillamine antagonized the body assymmetry, reduced neurological scores, and mitigated infarction in stroke rats. Our data suggest that Bucillamine, given intracerebroventicularly, reduced neurodegeneration in stroke rats.
4. Supplementary data
Locomotor activity was examined two days after the MCAo. Animals (n=10) were placed in an Accuscan activity monitor (Columbus, OH) for 1 h at 2 days after MCAo for locomotor behavioral recording, as previously described (1). The monitor contains 16 horizontal infrared sensors spaced 2.5 cm apart. Each animal was placed in a 42
SUBSTITUTE SHEET (RULE 26)
x 42 x 31 cm plexiglass open box. Motor activity was calculated using the number of beams broken by the animals. As seen in Fig. 1 , there is a non-significant trend that Bucillamine may improve locomotor activity in stroke rats. The raw data is shown in Table 4.
References
1. Yu SJ, Wu KJ, Bae E, Wang YS, Chiang CW, Kuo LW, Harvey BK, Greig NH, Wang Y. Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain. iScience. 2020;23(2): 100866.
2. Luo Y, Kuo CC, Shen H, Chou J, Greig NH, Hoffer BJ, Wang Y. Delayed treatment with a p53 inhibitor enhances recovery in stroke brain. Ann Neurol. 2009;65(5):520-530.
3. Chang CF, Morales M, Chou J, Chen HL, Hoffer B, Wang Y. Bone morphogenetic proteins are involved in fetal kidney tissue transplantation -induced neuroprotection in stroke rats. Neuropharmacology. 2002;43(3):418-426.
4. Borlongan CV, Hida H, Nishino H. Early assessment of motor dysfunctions aids in successful occlusion of the middle cerebral artery. Neuroreport. 1998;9(16):3615-3621.
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SUBSTITUTE SHEET (RULE 26)
5. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17(3):472-476.
6. Shen H, Chen GJ, Harvey BK, Bickford PC, Wang Y. Inosine reduces ischemic brain injury in rats. Stroke. 2005;36(3):654-659.
7. Tomac AC, Agulnick AD, Haughey N, Chang CF, Zhang Y, Backman C, Morales M, Mattson MP, Wang Y, Westphal H, Hoffer BJ. Effects of cerebral ischemia in mice deficient in Persephin. Proc Natl Acad Sci U S A. 2002;99(14):9521-9526.
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SUBSTITUTE SHEET (RULE 26)
Claims
1. A method for the treatment or prevention of stroke in a mammal comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof.
2. The method of claim 1, wherein the stroke is ischemic stroke.
3. The method of claim 2, wherein the mammal is a human.
4. The method of claim 1 , wherein the therapeutically effective amount of bucillamine is a unit dose within range of about 10 mg to about 3000 mg per day.
5. A method for the treatment of brain infarction in a mammal that has suffered a stroke comprising administering a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof.
6. The method of claim 5, wherein the administration of the therapeutically effective amount reduces brain infarction in the mammal.
7. The method of claim 6, wherein the mammal is a human.
8. The method of claim 5, wherein the therapeutically effective amount of bucillamine is a unit dose within range of about 10 mg to about 3000 mg per day.
9. Use of a therapeutically effective amount of bucillamine or a pharmaceutically acceptable salt or solvate thereof for treating or preventing stroke in a mammal comprising administering to a mammal.
10. The use of claim 9, wherein the stroke is ischemic stroke.
11 . The use of claim 10, wherein the mammal is a human.
12. The use of claim 9, wherein the therapeutically effective amount of bucillamine is a unit dose within range of about 10 mg to about 3000 mg per day.
13. The use of claim 9, wherein the therapeutically effective amount of bucillamine is a unit dose is selected from the range consisting of 10 mg to about 50 mg, 100 mg to about 200 mg, 100mg, and 200 mg, and about 200 mg to about 300 mg.
14. The use of claim 9, wherein the therapeutically effective amount of bucillamine is a unit dose within range of 600 mg to about 800 mg.
SUBSTITUTE SHEET (RULE 26)
15. The use of claim 9, wherein the therapeutically effective amount of bucillamine is a unit dose is selected from the range consisting of up to 1000 mg per day, up to 2000 mg per day, and up to 2500 mg per day.
16
SUBSTITUTE SHEET (RULE 26)
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Non-Patent Citations (3)
Title |
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HORWITZ: "Bucillamine: A Potent Thiol Donor with Multiple Clinical Applications", CARDIOVASCULAR DRUG REVIEWS, vol. 21, no. 2, 2003, pages 77 - 90, XP055256998, DOI: 10.1111/j.1527-3466.2003.tb00107.x * |
KHAN MUSHFIQUDDIN, SEKHON BIPANJEET, JATANA MANU, GIRI SHAILENDRA, GILG ANNE G., SEKHON CHARANPAL, SINGH INDERJIT, SINGH AVTAR K.: "Administration of N‐acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke", JOURNAL OF NEUROSCIENCE RESEARCH, WILEY-LISS, US, vol. 76, no. 4, 15 May 2004 (2004-05-15), US , pages 519 - 527, XP093098634, ISSN: 0360-4012, DOI: 10.1002/jnr.20087 * |
SABETGHADAM MARYAM, MAZDEH MEHRDOKHT, ABOLFATHI PARNAZ, MOHAMMADI YOUNES, MEHRPOOYA MARYAM: "Evidence for a Beneficial Effect of Oral N-acetylcysteine on Functional Outcomes and Inflammatory Biomarkers in Patients with Acute Ischemic Stroke", NEUROPSYCHIATRIC DISEASE AND TREATMENT, vol. Volume 16, pages 1265 - 1278, XP093098631, DOI: 10.2147/NDT.S241497 * |
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