RESUMO
BACKGROUND: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. METHODS: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. RESULTS: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. CONCLUSIONS: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.
Assuntos
Diester Fosfórico Hidrolases , Síndrome de Tourette , Adulto , Animais , Cães , Feminino , Humanos , Masculino , Ratos , Transtornos dos Movimentos/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Tomografia por Emissão de Pósitrons , Ratos Sprague-Dawley , Síndrome de Tourette/tratamento farmacológico , HaplorrinosRESUMO
While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.
Assuntos
Anti-Inflamatórios/uso terapêutico , Tratamento Farmacológico da COVID-19 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Anti-Inflamatórios/farmacologia , COVID-19/epidemiologia , COVID-19/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Sistema de Sinalização das MAP Quinases/fisiologia , Pneumonia/epidemiologia , Pneumonia/imunologia , Inibidores de Proteínas Quinases/farmacologia , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/imunologiaRESUMO
BACKGROUND: Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages. METHODS: We used monocyte-derived macrophages (MDMs) from healthy donors (n = 15), MDMs with CFTR inhibited with C-172 (n = 5) and MDMs from patients with CF (n = 4). Monocytes were differentiated to macrophages and polarized into classically activated (M1) macrophages by LPS or alternatively activated (M2) macrophages by IL-13 in presence or absence of lenabasum. RESULTS: Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious. CONCLUSION: In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.
Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Fibrose Cística/patologia , Dronabinol/análogos & derivados , Macrófagos/efeitos dos fármacos , Estudos de Casos e Controles , Técnicas de Cultura de Células , Diferenciação Celular , Regulador de Condutância Transmembrana em Fibrose Cística , Citocinas/metabolismo , Dronabinol/farmacologia , Humanos , Macrófagos/fisiologiaRESUMO
Anabasum is a synthetic analog of Δ8 -tetrahydrocannabinol (THC)-11-oic acid that in preclinical models of experimental inflammation exerts potent anti-inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV-killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB4 , while the inhibition of antiphagocytic prostanoids (PGE2 , TxB2 , and PGF2 α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro-resolving lipid mediators including LXA4 , LXB4 , RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti-inflammatory and pro-resolution effects of a synthetic analog of THC in healthy humans.
Assuntos
Anti-Inflamatórios/administração & dosagem , Canabinol/análogos & derivados , Dermatite/tratamento farmacológico , Dronabinol/administração & dosagem , Infecções por Escherichia coli/tratamento farmacológico , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Dermatopatias Bacterianas/tratamento farmacológico , Pele/efeitos dos fármacos , Adolescente , Adulto , Anti-Inflamatórios/efeitos adversos , Canabinol/administração & dosagem , Canabinol/efeitos adversos , Citocinas/imunologia , Citocinas/metabolismo , Dermatite/imunologia , Dermatite/metabolismo , Dermatite/microbiologia , Relação Dose-Resposta a Droga , Dronabinol/efeitos adversos , Dronabinol/análogos & derivados , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Fagocitose/efeitos dos fármacos , Prednisolona/farmacologia , Pele/imunologia , Pele/metabolismo , Pele/microbiologia , Dermatopatias Bacterianas/imunologia , Dermatopatias Bacterianas/metabolismo , Dermatopatias Bacterianas/microbiologia , Adulto JovemRESUMO
Ajulemic acid, a side-chain analog of Δ(8)-THC-11-oic acid, was designed as a potent therapeutic agent free of the psychotropic adverse effects typical of most cannabinoids. Subsequent studies of ajulemic acid have yielded widely divergent findings on the occurrence of these adverse effects. To help resolve these discrepancies, we have prepared highly purified ajulemic acid using a different synthetic method than previously reported in the literature and compared its cannabinoid receptor binding constants with those obtained using several other preparations from different sources. Whereas CB2 binding did not vary greatly among all of the samples, the CB1 binding showed a wide range of affinities. The highly purified product (JBT-101) reported here had the weakest affinity for CB1 while the original preparation (HU-239) showed the strongest affinity for CB1. The CB1/CB2 ratio of affinities was 12.3 for JBT-101 whereas that for HU-239 was 0.19, a 65-fold difference. Functional responses such as catalepsy and hypothermia using JBT-101 versus HU-239 displayed reduced CB1 activity in keeping with the receptor binding data. Thus, earlier conclusions on the limited therapeutic index for ajulemic acid need to be reconsidered in the light of the data now obtained using JBT-101.
Assuntos
Dronabinol/análogos & derivados , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/química , Dronabinol/farmacologia , Feminino , Células HL-60 , Humanos , Camundongos , Conformação Molecular , Medição da Dor/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
Ajulemic acid is a synthetic analog of Δ(8)-THC-11-oic acid, the terminal metabolite of Δ(8)-THC. Unlike Δ(9)-THC, the psychoactive principle of Cannabis, it shows potent anti-inflammatory action and has minimal CNS cannabimimetic activity. Its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. Five metabolites, M1 to M5, were observed in human hepatocyte incubations. One metabolite, M5, a glucuronide, was observed in the chromatogram of canine hepatocyte incubations. In monkey hepatocyte incubations, M5 was observed in the chromatograms of both the 120 and 240 min samples, trace metabolite M1 (side-chain hydroxyl) was observed in the 120 min samples, and trace metabolite M4 (side-chain dehydrogenation) was observed in the 240 min samples. No metabolites were found in the rat hepatocyte incubations. Unchanged amounts of ajulemic acid detected after the 2-h incubation were 103%, 90%, 86%, and 83% for rat, dog, monkey, and human hepatocytes, respectively. Additional studies were done to ascertain if ajulemic acid can inhibit the activities of five principal human cytochrome P450 isozymes; CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. In contrast to the phytocannabinoids Δ(9)-THC and CBD, no significant inhibition of cytochrome activity was observed. These data further support the conclusions reached in earlier reports on ajulemic acid's high margin of safety and suggest that it undergoes minimal metabolism and is not likely to interfere with the normal metabolism of drugs or endogenous substances.
Assuntos
DNA Viral/genética , Imunidade Inata/genética , Doenças das Plantas/genética , Doenças das Plantas/virologia , Vírus de Plantas/genética , Vírus de Plantas/fisiologia , Transgenes/genética , Sequências Repetitivas de Ácido Nucleico , Nicotiana/genética , Nicotiana/virologia , Integração ViralRESUMO
Interferon-beta (IFN-beta) is biologically unstable under physiologic conditions in vitro and is cleared rapidly from the bloodstream on administration in vivo. In the present study, we demonstrate that a soluble recombinant form of the type I IFN receptor subunit, sIFNAR-2, can neutralize the bioactivity of type I IFNs at high concentrations and, at lower concentrations, causes an enhancement of IFN-beta-mediated antiviral activity. The in vitro enhancement is due to the specific interaction of IFN-beta with sIFNAR-2, followed by dissociation of IFN-beta from the complex over time in culture. In vivo, the serum half-life of IFN-beta is extended from minutes to hours when administered intravenously in mice as a sIFNAR-2-associated complex. Moreover, the antitumor effect of IFN-beta is increased by between 9-fold and 27-fold when injected as an sIFNAR-2-associated complex, as demonstrated by an increase in the mean survival time of immunodeficient mice challenged with human Burkitt lymphoma cell (Daudi) xenografts (sIFNAR-2-complexed vs. free IFN-beta treatment). These results show that on association with sIFNAR-2, IFN-beta is more stable in vitro and exhibits increased efficacy when administered in vivo. Administration as a complex with sIFNAR-2 may, therefore, provide a method of enhancing the delivery and effectiveness of type I IFNs.
Assuntos
Interferon Tipo I/uso terapêutico , Interferon beta/farmacologia , Receptores de Interferon/uso terapêutico , Animais , Linfoma de Burkitt/imunologia , Células CHO , Linhagem Celular Tumoral , Cricetinae , Feminino , Meia-Vida , Humanos , Imunoterapia , Injeções Intravenosas , Interferon Tipo I/farmacocinética , Interferon Tipo I/farmacologia , Interferon beta/farmacocinética , Interferon beta/uso terapêutico , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos , Camundongos SCID , Transplante de Neoplasias/imunologia , Receptor de Interferon alfa e beta , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transplante Heterólogo/imunologiaRESUMO
All living organisms produce heat as a by-product of metabolism. For centuries, clinicians and scientists have been interested in measuring heat output (thermogenesis) as an indicator of metabolic state. This paper briefly reviews current methods for metabolic measurements and describes recent results in diabetes research with a novel infrared thermal imaging technology, Thermal Signature Analysis (TSA). TSA measures unique thermal signatures in cells and animals that are indicative of disease, genetic variations, or drug function.