Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • 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
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• MCI memory and generally other cognitive domains that are more impaired in dementia.
• ADL daily living
• MCI-amnestic and MCI-other depending on the presence or absence of amnesic components. Numerous studies have demonstrated that the presence of MCI, in particular the amnestic subtype, may be a risk state for the development of dementia.
• AD Alzheimer's disease
• Viral infections are often associated with cognitive impairment (Cl), human immunodeficiency virus (HIV), herpes simplex virus (HSN), hepatitis C virus (HCV) and cytomegalovirus (CMV) being the most often reported infective agents that correlate with cognitive impairment.
• Cl cognitive impairment
• HCN herpes simplex virus
• HCV hepatitis C virus
• CMV cytomegalovirus
• At least 20% of patients newly diagnosed for CMN suffer from Cl, and this figure only rise with disease progression.
• An estimated 30% of persons diagnosed with HIN develop cognitive changes and an additional 15-20% develop more profound debilitating dementia.
• the worldwide prevalence of these viral infections is significant with about 170 million people for HCN, over 50 million people infected with HIN, 15-50% for HSN and over 50% for CMN.
• Even with a conservative estimate of 20% of virally infected person who will develop Cl, virally induced Cl represent an important challenge for the medical community.
• These compounds are derivatives and analogues of essentially pure stereospecific (+) enantiomers, having the (3S,4S) configuration, of ⁇ 6 -tetrahydrocannabinol (THC) type compounds, devoid of any undesirable cannabimimetic psychotropic side-effects.
• THC ⁇ 6 -tetrahydrocannabinol
• the compounds serving as active ingredient in the compositions of the present invention may operate via diverse mechanisms to provide the combined neuroprotective and anti-inflammatory properties.
• compositions of the present invention will be useful in the prevention of post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment.
• the pharmaceutical compositions of the present invention will be useful in prophylactic treatment of populations at risk for neurodegenerative disorders, including patients suffering from mild cognitive impairment.
• compositions for preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, and neonatal cognitive impairment comprising as an active ingredient a compound of general formula (I):
• each ring optionally is further substituted with one or more groups selected from i)-viii) as defined above, b) an amine or an amide substituted with at least one substituent as defined in R' above, c) a thiol, a sulfide, a sulfoxide, a sulfone, a thioester or a thioamide optionally substituted with one substituent as defined in R' above, and d) a hydroxyl or an ether -OR' wherein R' is as defined above; R 2 is selected from the group consisting of a) a halogen, b) a linear, branched or cyclic, saturated or unsaturated Ci-C 6 alkyl, and c) -OR wherein R is selected from the group consisting of
• R 3 is selected from the group consisting of a) a linear, branched or cyclic, saturated or unsaturated C 1 -C 1 2 alkyl, b) -OR a , in which R a is a linear, branched or cyclic, saturated or unsaturated C 2 -C 9 alkyl which may be substituted at the terminal carbon atom by a phenyl group, and c) a linear, branched or cyclic, saturated or unsaturated C 1 -C 7 alkyl-OR'" wherein R'" is as previously defined; and pharmaceutically acceptable salts, esters or solvates thereof.
• the present invention further provides pharmaceutical compositions for preventing, reducing or delaying the onset of neurodegenerative disorders in populations at risk exhibiting mild cognitive impairment comprising as an active ingredient a compound of general formula I as previously defined.
• compositions can be administered by any conventional and appropriate route including oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, intrathecal, rectal or intranasal.
• a further aspect of the present invention provides a method of preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment, by administering to a patient in need thereof a prophylactically and/or therapeutically effective amount of a pharmaceutical composition containing as an active ingredient a compound of general formula I as previously defined.
• a further aspect of the present invention provides a method for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders, by administering to a patient in need thereof a prophylactically and/or therapeutically effective amount of a pharmaceutical composition containing as an active ingredient a compound of general formula I as previously defined.
• a further aspect of the present invention relates to the use for the manufacture of a medicament for preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment, of a compound of general formula I as previously defined.
• a further aspect of the present invention relates to the use for the manufacture of a medicament for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders, of a compound of general formula I as previously defined.
• Figure 1 shows the effect of dexanabinol administered prior to surgery on learning capacity (panel A) and on memory (panel B) in animals subjected to four- vessel occlusion as measured using the Morris water maze model.
• the present invention provides pharmaceutical compositions effective in prophylactic treatment of patients who suffer from medical conditions that may result in cognitive impairment, including but not limited to surgical operations, certain diseases or viral infections, certain therapeutic procedures or medications, abnormal peri-natal conditions and of patients at risk for the development of neurodegenerative disorders.
• the advantageous mechanisms of action are now disclosed to be the combined neuroprotective and anti-inflammatory activities of the therapeutic agents.
• Increasing knowledge about the pathophysiology of ischemic or hypoxic brain injury gained from research and clinical trials has demonstrated that pretreatment, prior to the ischemic insult improves the efficacy of neuroprotective agents. Numerous studies have shown lengthening the period between insult and neuroprotective administration diminishes treatment benefits.
• the quantitative criterion of the minimum acceptable degree of optical purity of an intended therapeutic enantiomer is dictated by the pharmacological potency of the opposite enantiomer. The higher the psychotropic activity of the opposite enantiomer, the stricter the requirement for optical purity.
• the enantiomeric pair HU-210 and HU-211, of (3R,4R) and (3S,4S) configuration, respectively, is an extreme example of such a situation, HU-210 being a synthetic cannabinoid at least one hundred times more psychoactive than natural ⁇ 9 -THC, the major active constituent in marijuana (Mechoulam R. et al., Tetrahedron Asymmetry 1(5): 315-8, 1990).
• prodrug represents compounds which are rapidly transformed in vivo to the parent compounds of formula (I), for example by hydrolysis in blood.
• Some of the compounds of formula (I) are capable of further forming pharmaceutically acceptable salts and esters.
• “Pharmaceutically acceptable salts and esters” means any salt and ester that is pharmaceutically acceptable and has the desired pharmacological properties. Such salts include salts that may be derived from an inorganic or organic acid, or an inorganic or organic base, including amino acids, which is not toxic or undesirable in any way.
• the present invention also includes within its scope solvates of compounds of formula (I) and salts thereof, for example, hydrates. All of these pharmaceutical forms are intended to be included within the scope of the present invention.
• compositions of the present invention will be useful in the prevention of disease induced cognitive impairment that may occur in disorders including but not limited to cardiovascular diseases, haemodynamic shock, atherosclerosis, ischemic events, traumatic brain injury (TBI), demyelinating disorders, Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), cancer, autoimmune diseases, multiple sclerosis (MS), mood disorders, epilepsy, chronic infection and viral infections by HCV, HIV, HSV, or CMV.
• cardiovascular diseases haemodynamic shock, atherosclerosis, ischemic events, traumatic brain injury (TBI), demyelinating disorders, Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), cancer, autoimmune diseases, multiple sclerosis (MS), mood disorders, epilepsy, chronic infection and viral infections by HCV, HIV, HSV, or CMV.
• alkyl substituents can be saturated or unsaturated, linear branched or cyclic, the latter only when the number of carbon atoms in the alkyl chain is equal or superior to 3.
• Ri is selected from the group consisting of a) R' where R' is selected from the group consisting of A) a linear or branched, saturated or unsaturated, carbon side chain comprising 1-8 carbon atoms optionally interrupted by 1-3 heteroatoms, and
• R 2 is selected from the group consisting of a) a halogen, b) a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 6 alkyl, and c) -OR wherein R is selected from the group consisting of
• R 3 is selected from the group consisting of a) a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 12 alkyl, b) -OR a , in which R a is a linear, branched or cyclic, saturated or unsaturated C 2 -C 9 alkyl which may be substituted at the terminal carbon atom by a phenyl group, and c) a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 7 alkyl-OR'" wherein R'" is as previously defined; and pharmaceutically acceptable salts, esters or solvates thereof.
• a pharmaceutical composition for preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment comprising as an active ingredient a compound of the general formula I wherein Ri is 2- sulfanyl-lH-imidazole, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• the compound of said pharmaceutical composition is designated hereinafter as PRS-211,092.
• compositions of the present invention for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders, comprise as an active ingredient a compound of general formula (I):
• Ri is selected from the group consisting of a) R' where R' is selected from the group consisting of
• -C 6 alkoxy iii) a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 6 alkylthio, iv) a halogen, v) carboxyl, vi) -CO 2 -C 1 -C 6 alkyl, wherein the alkyl can be linear, branched or cyclic, saturated or unsaturated, vii) keto, viii) nitro, ix) a saturated or unsaturated cyclic moiety, or an aromatic or a heterocyclic moiety comprising one or two ringed structures, wherein each ring comprises 3-8 carbons optionally interrupted by
• a pharmaceutical composition for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders comprising as an active ingredient a compound of the general formula I wherein Ri is 2-sulfanyl-lH-imidazole, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• the compound of said pharmaceutical composition is designated hereinafter as PRS-211,092.
• a pharmaceutical composition for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders comprising as an active ingredient a compound of the general formula I wherein Ri is imidazole, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• the compound of said pharmaceutical composition is designated hereinafter as PRS-211,095.
• a pharmaceutical composition for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders comprising as an active ingredient a compound of the general formula I wherein Ri is pyrazole, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• the compound of said pharmaceutical composition is designated hereinafter as PRS-211,220.
• Specific pharmaceutical compositions of particular interest comprise as an active ingredient compounds of Formula I previously disclosed as HU-211, also known as dexanabinol, US Patent No. 4,876,276, and PRS-211,092, PRS-211,095, PRS-211,220 in US Patent No. 6,610,737.
• Solid compositions for oral administration such as tablets, pills, capsules, softgels or the like may be prepared by mixing the active ingredient with conventional, pharmaceutically acceptable ingredients such as corn starch, lactose, sucrose, mannitol, sorbitol, talc, polyvinylpyrrolidone, polyethyleneglycol, cyclodextrins, dextrans, glycerol, poly- glycolized glycerides, tocopheryl polyethyleneglycol succinate, sodium lauryl sulfate, polyethoxylated castor oils, non-ionic surfactants, stearic acid, magnesium stearate, dicalcium phosphate and gums as pharmaceutically acceptable diluents.
• conventional, pharmaceutically acceptable ingredients such as corn starch, lactose, sucrose, mannitol, sorbitol, talc, polyvinylpyrrolidone, polyethyleneglycol, cyclodextrins, dextrans, gly
• a further aspect of the present invention provides a method of preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment in a patient, by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition containing as an active ingredient a compound of general formula (I):
• a method for preventing, alleviating or diminishing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment in a patient by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition comprising as an active ingredient a compound of the general formula I wherein Ri is OH, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• a method for preventing, alleviating or dimimshing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment in a patient by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition comprising as an active ingredient a compound of the general formula I wherein Ri is imidazole, R ⁇ is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl.
• a further aspect of the present invention provides a method of preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders in a patient, by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition containing as an active ingredient a compound of general formula (I): Formula I
• R 2 is selected from the group consisting of a) a halogen, b) a linear, branched or cyclic, saturated or unsaturated -C ⁇ alkyl, and c) -OR wherein R is selected from the group consisting of A) -R", wherein R" is hydrogen or a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 6 alkyl optionally containing a terminal -OR'" or -OC(O)R'" moiety wherein R'" is hydrogen or a linear, branched or cyclic, saturated or unsaturated C ⁇ -C 6 alkyl, and B) -C(O)R'" wherein R'" is as previously defined; and R 3 is selected from the group consisting of a) a linear, branched or cyclic, saturated or unsaturated C 1 -C 12 alkyl, b) -OR a , in which R a is a linear, branched or cyclic, saturated
• a method for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition comprising as an active ingredient a compound of the general formula I wherein Ri is OH, R 2 is OH, R 3 is 1,1 -dimethylheptyl and there is a double bond between C6 and Cl .
• a method for preventing, reducing or delaying the deterioration of mild cognitive impairment to chronic neurodegenerative disorders by administering a prophylactically and/or therapeutically effective amount of a pharmaceutical composition comprising as an active ingredient a compound of the general formula I wherein Ri is pyrazole, R 2 is OH, R 3 is 1,1- dimethylheptyl and there is a double bond between C6 and Cl.
• a further aspect of the present invention relates to the use for the manufacture of a medicament for preventing, alleviating or dimimshing post-operative, disease induced, virally induced, therapy induced, neonatal cognitive impairment, of a compound of general formula I as previously defined.
• Sprague Dawley rats (140-250 g body weight, Charles River Laboratory, MI, USA) were maintained under controlled environmental conditions, with 12:12 hour light dark cycle, and had free access to food and water. The animals were acclimated for at least seven days prior to study day 1. Animals were randomly assigned to the following treatment groups: saline (negative control), CREMOPHOR EL ® :ethanol (70:30 w/w respectively supplemented with 0.5% w/v dl- -tocopherol and 0.01% w/v edetic acid; vehicle) and 50 mg/kg dexanabinol. For all groups the volume dosage was 10 ml/kg and the treatments were administered via bolus intravenous injection into the lateral tail vein of animals.
• CREMOPHOR EL ® ethanol and dexanabinol 50 mg/ml were diluted 1:10 into saline prior to injection.
• Each treatment group consisted of six males and six females, which were at first analyzed separately to assess gender influence.
• Clinical observations including observations for mortality or moribundity, were recorded pretest, once daily, and when a change was noted during the twice-daily observations.
• Body weights were recorded pretest and predose on study day 1.
• Six animals per sex per group per time point were submitted for necropsy at approximately 4 and 12 hours post-dose, and 1, 3, and 7 days post-dose. At the predetermined time points, the animals were humanely euthanized via intraperitoneal injection of 100 mg/kg sodium pentobarbital to achieve deep anesthesia.
• Table 1 Average number of vacuoles and necrotic foci per treatment group at predetermined time points post-dosing.
• dexanabinol is much safer than the NMDA antagonist MK-801 with no formation of vacuoles during the first 12 hours post-dosing, at an absolute dose 10 times higher than MK-801.
• the foci observed in vehicle or dexanabinol treated animals differed from the foci observed in the MK-801 or saline treated controls.
• the results expressed as number of animals showing necrotic foci in the cingulated gyrus are presented in table 2. The results obtained with male and female animals were combined for the preparation of this table.
• Table 2 Number of animals with necrotic foci per treatment group at predetermined time points post-dosing.
• necrosis of cingulated gyrus neurons was not noted in any of the dexanabinol treated animals.
• Dexanabinol has totally prevented the occurrence of necrotic foci in the cingulated gyrus one of the area of the brain that could be involved in cognitive functions.
• rats treated with compounds devoid of neuronal vacuolization side effects in the cingulated cortex performed as normal animals in the Morris water maze model for cognitive assessment, as opposed to animals treated with MK-801.
• This model was used to test the ability of dexanabinol or related compounds to act as neuroprotectant when administered prior to surgery.
• the blood supply to the rat brain arrives via the two vertebral and two common carotid arteries.
• Transient occlusion of all four vessels results in global ischemia, as would occur during cardiac arrest in humans.
• Global ischemia results in neurological deficits, including short-term memory deficits, and a selective loss of neurons, including pyramidal cells, in the CA1 field of the hippocampus, similarly to the situation observed in MCI.
• the ability of compounds to reduce the neurological deficits and increase neuronal survival in this model is considered indicative of their potential in preventing brain damage related to cardiac arrest, and is also predictive for ischemic damages and MCI caused by surgery, for instance cardiac surgery performed or not under cardiopulmonary bypass.
• the 4-vessel occlusion (4 VO) rat model is relatively easy to produce and shows good reproducibility. Transient ischemia causes irreversible injury to a few, specific populations of highly vulnerable neurons.
• test compound dexanabinol was dissolved in a minimum volume of absolute ethanol and the solution was added dropwise to hydroxypropyl- ⁇ -cyclodextrin (HPCD) powder.
• HPCD hydroxypropyl- ⁇ -cyclodextrin
• the ethanol was allowed to evaporate (1 hour at 45°C) and water was added to produce a solution of 2 mg/ml dexanabinol in 45% HPCD (weight per volume) that was mixed by stirring, sonicated and filtered.
• Test compound or vehicle control 45% HPCD were administered i.v. 15 minutes before the onset of CCA occlusion, at dose volume of 4 ml/kg.
• Each treatment group was composed of at least 10 animals, randomly assigned.
• the total neurological score was calculated by adding the results of all tests for each animal and the maximal score obtainable for normal animals is 16 points. Then the average total score was calculated for each treatment group as well as the standard error. The differences between the various treatment groups were statistically analyzed using ANOVA followed by post-hoc Kruskal-Wallis test. A value of p ⁇ 0.05 was considered to be statistically significant. It was observed that operated non-treated animals and animals treated with vehicle only displayed a similar drastic drop of about 5 points in neurological score five hours after occlusion and a partial recovery in the following days which stabilized with an average neurological score of about 13 points with no significant trend of further improvement. The vehicle treated group still displayed 35% reduction in neurological score as compared to sham operated animals 72 hours post-occlusion.
• dexanabinol treated animals have not only improved learning capacity, but also better memory over vehicle treated animals with almost 22% reduction in average time for platform localization.
• the animals treated with 8 mg/kg dexanabinol behaved as well as sham operated animals, or even slightly better though this difference is not statistically significant.
• the sham operated animals needed 34.8 seconds to localize the hidden platform while dexanabinol treated animals performed the same task in 4 seconds less with an average of 30.8 seconds.
• Sprague-Dawley male rats (200-300 g body weight, Harlan, Israel) are anesthetized using 4% halothane for induction and 1% halothane for maintenance, in a mixture of 70% N 2 O and 30% 0 2 .
• the embolization procedure is according to Lapchak et al. (Lapchak P.A. et al., Stroke 33: 1411, 2002).
• the animals are anesthetized, the bifurcation of one carotid artery is exposed, and the external carotid is ligated just distal to the bifurcation.
• a catheter is then inserted anteretrograde into the common carotid and secured with ligatures.
• the incision around the catheter is closed so that the distal ends are accessible outside the animal's neck.
• the catheter is filed with heparanized saline and plugged with an injection cap.
• the animals are allowed to recover from anesthesia for a minimum of 3 hours so that they are awake and behave normally.
• To prepare small clots blood was drawn from a donor rat and allowed to clot at 37°C. The clot is resuspended in PBS solution containing 0.1 % bovine serum albumin and is fragmented with a Polytron (setting 6, 3 seconds).
• the fragments are sized by sequential filtration down to 100 ⁇ m 2 and resuspended in PBS at a predetermined weight of particles per ml that will cause damage in the hippocampal region of the brain.
• the clot particles are rapidly injected through the catheter, and the syringe and catheter system are flushed with 5 ml of saline.
• Test compounds or vehicle control are administered i.v. 15 minutes before embolization, at dose volume of 5 ml/kg.
• Each treatment group is composed of at least 8 animals, randomly assigned.
• the study comprises the following control groups: “sham”, animals that undergo surgical procedure for catheter insertion but receive only saline; “untreated”, animals injected with microemboli that receive no treatment at all; “vehicle”, animals injected with microemboli that are only treated with vehicle 15 minutes before embolization.
• body sham
• untreated animals injected with microemboli that receive no treatment at all
• vehicle animals injected with microemboli that are only treated with vehicle 15 minutes before embolization.
• the purpose of this study is to check the effect of one of the preferred compounds on the incidence and severity of post-surgical cognitive impairment.
• the clinical trial is performed on patients undergoing elective Coronary Artery Bypass Surgery (CABS), where there is a significant risk to develop post-operative CL
• CABS elective Coronary Artery Bypass Surgery
• This prospective, double blind, placebo controlled, randomized, parallel group Phase Ila trial assesses in 200 patients undergoing CABS, the efficacy, and the safety, of dexanabinol given as a single intravenous fast infusion. An interim analysis is performed following enrolment of the first 100 subjects.
• Subjects who meet the inclusion criteria of age 60 and over, undergoing non- emergency CABS, and language proficient, are eligible for the study.
• the subjects must not suffer at the time of enrolment from neurological disorders, psychiatric diseases, drug abuse, dementia, or being enrolled in another study.
• Patients who signed informed consent and who fulfill inclusion criteria are randomized in a 1:1 ratio to receive dexanabinol (150 mg) or placebo (vehicle only).
• Dexanabinol is supplied in its vehicle, comprising CREMOPHOR EL ® :ethanol (70:30 w/w), supplemented with 0.5% w/v dl- ⁇ -tocopherol and 0.01% w/v edetic acid.
• Dexanabinol and placebo are diluted in sterile saline to generate the administered dosage form.
• the medication is administered during initiation of the first thoracic incision, by fast drip intravenous infusion or peristaltic pump over a period of 15 minutes. Fifteen minutes prior to the administration of the study medication, patients are given intravenously a mixture of HI and H2 blockers, to prevent possible supersensitivity reaction to the CREMOPHOR EL ® component of the vehicle.
• the primary efficacy endpoint of the trial is the reduction in the incidence of post- surgical Cl at 6 weeks and 3 months following surgery compared to pre-surgery baseline.
• Patients are tested by a battery of computerized neuropsychological tests assessing the following parameters: power of attention, speed and quality of working memory, quality of episodic secondary memory and continuity of attention.
• the primary efficacy analysis is a multiple regression analysis of the mean change scores from baseline to 6 weeks and 3 months on the Power of Attention Factor test scores.
• patients are submitted to a clinical neurological examination leading to a Neurological Assessment Score (NAS) according to NIH guidelines.
• NAS Neurological Assessment Score
• a series of questionnaires are administered and also considered as secondary end-points including the Hospital Anxiety and Depression Scale (HADS; adapted from Zigmond A.S. et al, Acta Psychiatr. Scand.
• HADS Hospital Anxiety and Depression Scale
• Safety is assessed by comparing the rate of adverse events, classified according to body system, severity, consequent dropout if any, and relation to treatment, between the two groups. Comparison of adverse event rates between the two groups is done using Fisher's Exact test. The clinical laboratory tests (Blood Chemistry, Hematology, Urinalysis) as well as the cardiovascular functions (Heart Rate, Mean Arterial Blood Pressure and Electrocardiogram) are taken into account. Mean Change scores are compared between the two groups using a t-test or Wilcoxon-Mann- Whitney test as appropriate.

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• 2003
  • 2003-09-04 JP JP2004534012A patent/JP2006502159A/ja not_active Abandoned
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