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Established and potential therapeutic applications of cannabinoids
Abstracts of Minisymposium organized by Prof. M. Go¨thert / Pharmacological Reports 66 (2014) 330–333
from 123 to 72, from 13.8 to 5.3, and 143 to 87 mg/kg. However, the anticonvulsant action of clonazepam was not affected by ACEA. In no case, the evaluated combinations at the respective median anticonvulsive doses of antiepileptic drugs significantly modified the performance of mice in the tests for neurotoxicity when compared to the effects of antiepileptic drugs alone. Among potentiated antiepileptic drugs, only the total brain concentration of phenobarbital was not changed, those of ethosuximide and valproate being significantly elevated [Andres-Mach et al., Prog Neuropsychopharmacol Biol Psychiat, 2012]. As concerns WIN 55,212-2 mesylate, at 10 mg/kg it potentiated the anticonvulsant activity of carbamazepine, phenobarbital, phenytoin, and valproate against maximal electroshock, and at 15 mg/kg, that of ethosuximide, phenobarbital, and valproate, but not that of clonazepam, against pentetrazol clonic convulsions in mice. Co-administration of WIN 55,212-2 mesylate with antiepileptic drugs resulted in elevated total brain concentrations of ethosuximide and valproate. Moreover, combined treatment of WIN 55,212-2 mesylate with antiepileptic drugs resulted in profound neurotoxic effects [Luszczki et al., Prog Neuropsychopharmacol Biol Psychiat, 2011; Pharmacol Biochem Behav, 2011]. Synergistic interactions between WIN 55,212-2 and diazepam against electroconvulsions in mice were additionally reported by Naderi et al. [J Neural Transm, 2008]. The interaction of antiepileptic drugs with synthetic cannabinoid agonists seems more encouraging in case of the specific CB1 receptor agonist, ACEA. In no case neurotoxicity was reported. However, only a positive combination of ACEA with phenobarbital was of a pharmacodynamic nature. http://dx.doi.org/10.1016/j.pharep.2014.02.011 Established and potential therapeutic applications of cannabinoids Bela Szabo Institut fu¨r Pharmakologie, Albert-Ludwigs-Universita¨t, Albertstrasse 25, 79104 Freiburg i. Brsg., Germany The two G protein-coupled cannabinoid receptors (CB1 and CB2 receptors) are targets of phytocannabinoids, endocannabinoids and synthetic ligands. At the moment, two agonists of the CB1 receptor are used therapeutically: the phytocannabinoid D9tetrahydrocannabinol (international nonproprietary name: dronabinol) and the semisynthetic derivative of D9-tetrahydrocannabinol, nabilone. In one preparation (Sativex1), in addition to D9tetrahydrocannabinol the phytocannabinoid cannabidiol (which is an antagonist at CB1 receptors) is also included. D9-Tetrahydrocannabinol and nabilone are used therapeutically to inhibit emesis during cytostatic therapy and to increase body weight of patients with AIDS-induced wasting syndrome. Sativex is officially approved for treatment of spasticity in patients with multiple sclerosis. Clinical studies are under way to evaluate the effect of Sativex in spasticity due to cerebral palsy and traumatic central nervous injury.
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Numerous preclinical and clinical studies showed that cannabinoid agonists and antagonists possess therapeutic potential in other diseases and conditions: pain conditions, neurodegenerative diseases (Huntington’s disease and Parkinson’s disease), epilepsy, metabolic diseases (obesity, dyslipidemia and type 2 diabetes), gastrointestinal diseases (inflammatory bowel disease) and cancer. In animal experiments, cannabinoid agonists have remarkably strong analgesic effects against nociceptive pain, inflammatory pain and neuropathic pain. In humans, cannabinoids are effective against neuropathic pain. Surprisingly, the effects in other pain conditions are weak and/or the use of appropriate doses is limited by side effects (for example, sedation and psychotomimetic effects). With the aim to avoid central nervous side effects, CB1 receptor agonists are being developed which do not cross the blood brain barrier, but still cause analgesia with a peripheral mechanism. The other way to prevent central nervous side effects is to use CB2-selective agonists. CB2 agonists can also elicit analgesia, but only few central side effects are expected, because the CB2 receptor is only sparsely expressed in the central nervous system. Several phytocannabinoids slow down neurodegeneration in Parkinson’s disease and Huntington’s disease due to their antioxidative properties. Activation of CB2 receptors expressed in glial cells seems to have a neuroprotective effect in these disorders. Recently it has been shown that CB1 receptors are downregulated in several brain regions of patients with Huntington’s disease and that the loss of the CB1 receptors aggravates the motor symptoms of the disease. Because D9-tetrahydrocannabinol ameliorated the symptoms in these latter animal experiments, it is reasonable to hope for a similar therapeutic effect in humans with Huntington’s disease. The most intensive research to develop a cannabinoid receptor ligand for therapy was carried out on CB1 receptor antagonists. It was observed that the CB1 receptor antagonist/inverse agonist rimonabant lowers the body weight of animals and humans. The weight reduction is due a centrally mediated anorectic effect and peripheral metabolic effects in the fat tissue and the liver. Rimonabant was approved by the European Medicinal Agency for use in obesity. However, after a short period in clinical use, the antagonist was withdrawn from the market, mostly because it elicited unwanted psychiatric side effects. Despite this drawback, the idea of using a CB1 antagonist in obesity and type 2 diabetes has not been abandoned. One research initiative studies the effects on obesity of CB1 antagonists which do cross the blood brain barrier. The other research direction is to develop neutral CB1 antagonists, without inverse agonistic activity, in the hope that these antagonists will elicit less psychiatric side effects. In many of the above-mentioned studies, exogenous cannabinoids were administered to activate the cannabinoid receptors. These agonists expectedly elicit many side effects, because the cannabinoid receptors, especially the CB1 receptor, are broadly distributed in the nervous system. It is thought that inhibitors of the enzymes which inactivate the endocannabinoids will lead to a more restricted activation of the cannabinoid receptors and thus to a more favorable effect/side effect ratio. http://dx.doi.org/10.1016/j.pharep.2014.02.012
from 123 to 72, from 13.8 to 5.3, and 143 to 87 mg/kg. However, the anticonvulsant action of clonazepam was not affected by ACEA. In no case, the evaluated combinations at the respective median anticonvulsive doses of antiepileptic drugs significantly modified the performance of mice in the tests for neurotoxicity when compared to the effects of antiepileptic drugs alone. Among potentiated antiepileptic drugs, only the total brain concentration of phenobarbital was not changed, those of ethosuximide and valproate being significantly elevated [Andres-Mach et al., Prog Neuropsychopharmacol Biol Psychiat, 2012]. As concerns WIN 55,212-2 mesylate, at 10 mg/kg it potentiated the anticonvulsant activity of carbamazepine, phenobarbital, phenytoin, and valproate against maximal electroshock, and at 15 mg/kg, that of ethosuximide, phenobarbital, and valproate, but not that of clonazepam, against pentetrazol clonic convulsions in mice. Co-administration of WIN 55,212-2 mesylate with antiepileptic drugs resulted in elevated total brain concentrations of ethosuximide and valproate. Moreover, combined treatment of WIN 55,212-2 mesylate with antiepileptic drugs resulted in profound neurotoxic effects [Luszczki et al., Prog Neuropsychopharmacol Biol Psychiat, 2011; Pharmacol Biochem Behav, 2011]. Synergistic interactions between WIN 55,212-2 and diazepam against electroconvulsions in mice were additionally reported by Naderi et al. [J Neural Transm, 2008]. The interaction of antiepileptic drugs with synthetic cannabinoid agonists seems more encouraging in case of the specific CB1 receptor agonist, ACEA. In no case neurotoxicity was reported. However, only a positive combination of ACEA with phenobarbital was of a pharmacodynamic nature. http://dx.doi.org/10.1016/j.pharep.2014.02.011 Established and potential therapeutic applications of cannabinoids Bela Szabo Institut fu¨r Pharmakologie, Albert-Ludwigs-Universita¨t, Albertstrasse 25, 79104 Freiburg i. Brsg., Germany The two G protein-coupled cannabinoid receptors (CB1 and CB2 receptors) are targets of phytocannabinoids, endocannabinoids and synthetic ligands. At the moment, two agonists of the CB1 receptor are used therapeutically: the phytocannabinoid D9tetrahydrocannabinol (international nonproprietary name: dronabinol) and the semisynthetic derivative of D9-tetrahydrocannabinol, nabilone. In one preparation (Sativex1), in addition to D9tetrahydrocannabinol the phytocannabinoid cannabidiol (which is an antagonist at CB1 receptors) is also included. D9-Tetrahydrocannabinol and nabilone are used therapeutically to inhibit emesis during cytostatic therapy and to increase body weight of patients with AIDS-induced wasting syndrome. Sativex is officially approved for treatment of spasticity in patients with multiple sclerosis. Clinical studies are under way to evaluate the effect of Sativex in spasticity due to cerebral palsy and traumatic central nervous injury.
333
Numerous preclinical and clinical studies showed that cannabinoid agonists and antagonists possess therapeutic potential in other diseases and conditions: pain conditions, neurodegenerative diseases (Huntington’s disease and Parkinson’s disease), epilepsy, metabolic diseases (obesity, dyslipidemia and type 2 diabetes), gastrointestinal diseases (inflammatory bowel disease) and cancer. In animal experiments, cannabinoid agonists have remarkably strong analgesic effects against nociceptive pain, inflammatory pain and neuropathic pain. In humans, cannabinoids are effective against neuropathic pain. Surprisingly, the effects in other pain conditions are weak and/or the use of appropriate doses is limited by side effects (for example, sedation and psychotomimetic effects). With the aim to avoid central nervous side effects, CB1 receptor agonists are being developed which do not cross the blood brain barrier, but still cause analgesia with a peripheral mechanism. The other way to prevent central nervous side effects is to use CB2-selective agonists. CB2 agonists can also elicit analgesia, but only few central side effects are expected, because the CB2 receptor is only sparsely expressed in the central nervous system. Several phytocannabinoids slow down neurodegeneration in Parkinson’s disease and Huntington’s disease due to their antioxidative properties. Activation of CB2 receptors expressed in glial cells seems to have a neuroprotective effect in these disorders. Recently it has been shown that CB1 receptors are downregulated in several brain regions of patients with Huntington’s disease and that the loss of the CB1 receptors aggravates the motor symptoms of the disease. Because D9-tetrahydrocannabinol ameliorated the symptoms in these latter animal experiments, it is reasonable to hope for a similar therapeutic effect in humans with Huntington’s disease. The most intensive research to develop a cannabinoid receptor ligand for therapy was carried out on CB1 receptor antagonists. It was observed that the CB1 receptor antagonist/inverse agonist rimonabant lowers the body weight of animals and humans. The weight reduction is due a centrally mediated anorectic effect and peripheral metabolic effects in the fat tissue and the liver. Rimonabant was approved by the European Medicinal Agency for use in obesity. However, after a short period in clinical use, the antagonist was withdrawn from the market, mostly because it elicited unwanted psychiatric side effects. Despite this drawback, the idea of using a CB1 antagonist in obesity and type 2 diabetes has not been abandoned. One research initiative studies the effects on obesity of CB1 antagonists which do cross the blood brain barrier. The other research direction is to develop neutral CB1 antagonists, without inverse agonistic activity, in the hope that these antagonists will elicit less psychiatric side effects. In many of the above-mentioned studies, exogenous cannabinoids were administered to activate the cannabinoid receptors. These agonists expectedly elicit many side effects, because the cannabinoid receptors, especially the CB1 receptor, are broadly distributed in the nervous system. It is thought that inhibitors of the enzymes which inactivate the endocannabinoids will lead to a more restricted activation of the cannabinoid receptors and thus to a more favorable effect/side effect ratio. http://dx.doi.org/10.1016/j.pharep.2014.02.012