RESUMO
Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.
Assuntos
Acetamidas/farmacologia , Acetamidas/uso terapêutico , Estimulação Acústica/efeitos adversos , Cóclea/patologia , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Perda Auditiva Provocada por Ruído/patologia , Perda Auditiva Provocada por Ruído/prevenção & controle , Caracteres Sexuais , Sinapses/patologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/fisiologia , Animais , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Células Ciliadas Auditivas , Perda Auditiva Provocada por Ruído/etiologia , Perda Auditiva Provocada por Ruído/terapia , Masculino , Camundongos Endogâmicos CBA , Percepção da Fala , ZumbidoRESUMO
Adult Tcell leukemia/lymphoma (ATLL) constitutes an aggressive malignancy caused by human Tcell leukemia virus type 1 (HTLV1) that is resistant to available chemotherapeutics. The constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is an important feature of ATLL, and spleen tyrosine kinase (SYK) is overexpressed in HTLV1-transformed Tcell lines. In this study, we evaluated the effects of SYK- (PRT060318) or JAK- (JAK inhibitor 1) selective inhibitors and the dual SYK/JAK inhibitor, cerdulatinib, on the viability of HTLV1-transformed and ATLL-derived Tcell lines. Cell proliferation, viability, cell cycle, apoptosis and intracellular signaling cascades were analyzed by the water-soluble tetrazolium-8 assay, flow cytometry and western blot analysis. HTLV1-infected Tcell lines were sensitive to both SYK-selective and pan-JAK inhibitors, whereas cerdulatinib more potently suppressed cell proliferation and reduced cell viability than either of these agents alone. By contrast, the cytotoxic effects of cerdulatinib on uninfected Tcell lines and peripheral blood mononuclear cells from a healthy donor were less pronounced. Cerdulatinib induced cell cycle arrest in the G2/M phase, which was associated with a decreased cyclin-dependent kinase 1 and cyclin B1, and an increased p21 and p27 expression. Hoechst staining revealed chromatin condensation and nuclear fragmentation in the cells treated with cerdulatinib, and an increased fraction of apoptotic APO2.7-stained cells was detected by flow cytometry. This corresponded to the activation of caspase-8, -9 and -3, and decreased levels of the anti-apoptotic factors, Bcl-xL, survivin, X-linked inhibitor of apoptosis (XIAP) and cFLIP. The cerdulatinib-induced decrease in cell viability was partly reversed by the caspase inhibitor, zVADFMK. These anti-ATLL effects were associated with the suppression of SYK and JAK/STAT signaling, along with that of the downstream factors, AKT, ERK, activator protein1 and nuclear factor-κB. Finally, oral dosing with cerdulatinib lowered the tumor burden in a murine model of ATLL. Thus, our findings indicate that the simultaneous inhibition of therapeutically relevant targets, such as SYK and JAK is a more effective approach than single-agent therapy for the treatment of ATLL.
Assuntos
Janus Quinases/antagonistas & inibidores , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacocinética , Sulfonas/farmacocinética , Quinase Syk/antagonistas & inibidores , Animais , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Leucemia-Linfoma de Células T do Adulto/virologia , Camundongos Endogâmicos ICR , Camundongos SCID , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Linfócitos T , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain comprehensive insights into the impacts of AS events on cancer biology and therapeutic developments, this paper highlights recent findings regarding the therapeutic routes of targeting alternative-spliced isoforms and splicing regulators to treatment strategies for distinct cancers.
Assuntos
Processamento Alternativo/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/terapia , Fatores de Processamento de RNA/antagonistas & inibidores , RNA Mensageiro/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Caspase 9/genética , Caspase 9/metabolismo , Ciclina D1/antagonistas & inibidores , Ciclina D1/genética , Ciclina D1/metabolismo , Cicloexilaminas/uso terapêutico , Compostos de Epóxi/uso terapêutico , Humanos , Macrolídeos/uso terapêutico , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligonucleotídeos/genética , Oligonucleotídeos/metabolismo , Oligonucleotídeos/uso terapêutico , Piranos/uso terapêutico , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Compostos de Espiro/uso terapêutico , Spliceossomos/efeitos dos fármacos , Spliceossomos/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several models. Therefore, the present study examined the effect of SYK inhibition with the selective spleen tyrosine kinase inhibitor P505-15 in experimental rheumatoid arthritis (RA) using a murine model of collagen-induced arthritis (CIA). Treatment with the selective SYK inhibitor P505-15, a small molecule kinase inhibitor selective for SYK, led to a reduction in arthritis score and attenuated histological damage. P505-15 reduced cartilage destruction and macrophage infiltration in CIA mice. In addition, P505-15-treated mice showed lower circulating levels of type II-collagen immunoglobulin (Ig)G1 and IgG2 and pro-inflammatory cytokines. Importantly, P505-15 treatment markedly reduced the interleukin 1ß-stimulated inflammatory response in human RA synovial cells. Given these encouraging results, a key function for SYK in the development of RA was identified, highlighting that SYK may be a potential therapeutic target for human RA.
Assuntos
Artrite Experimental/tratamento farmacológico , Cicloexilaminas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/uso terapêutico , Animais , Articulação do Tornozelo/patologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Células Cultivadas , Colágeno Tipo II/imunologia , Cicloexilaminas/farmacologia , Citocinas/sangue , Modelos Animais de Doenças , Humanos , Imunoglobulina G/sangue , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Quinase Syk , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to legal high and online-based research chemical vendors. Starting with the first dissociative research chemical, 4-MeO-PCP in 2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half of which were unknown in the scientific literature prior to their introduction. Several of these, including methoxetamine, have reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled from a diverse collection of sources. The first complete portrait of this underground market is presented along with the relevant legal, technological, and scientific developments which have driven its evolution.
Assuntos
Anestésicos Dissociativos/farmacologia , Drogas Ilícitas/farmacologia , Anestésicos Dissociativos/química , Anestésicos Dissociativos/uso terapêutico , Cicloexanonas/química , Cicloexanonas/farmacologia , Cicloexanonas/uso terapêutico , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Humanos , Drogas Ilícitas/química , Internet , Fenciclidina/química , Fenciclidina/farmacologia , Fenciclidina/uso terapêuticoRESUMO
The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM-1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM-1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed.
Assuntos
Cicloexilaminas/uso terapêutico , Epilepsia Reflexa/tratamento farmacológico , Memantina/uso terapêutico , Receptores de AMPA/antagonistas & inibidores , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estimulação Acústica , Adamantano/administração & dosagem , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Animais , Cicloexilaminas/administração & dosagem , Diaminas/administração & dosagem , Diaminas/uso terapêutico , Esquema de Medicação , Epilepsia Reflexa/metabolismo , Epilepsia Reflexa/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Injeções Intramusculares , Masculino , Memantina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/uso terapêutico , Ratos , Receptores de AMPA/metabolismo , Receptores de Ácido Caínico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/prevenção & controleRESUMO
Despite their widespread Internet availability and use, many of the new drugs of abuse remain unfamiliar to health care providers. The herbal marijuana alternatives, like K2 or Spice, are a group of herbal blends that contain a mixture of plant matter in addition to chemical grade synthetic cannabinoids. The synthetic cathinones, commonly called "bath salts," have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. Kratom, a plant product derived from Mitragyna speciosa Korth, has opioid-like effects, and has been used for the treatment of chronic pain and amelioration of opioid-withdrawal symptoms. Salvia divinorum is a hallucinogen with unique pharmacology that has therapeutic potential but has been banned in many states due to concerns regarding its psychiatric effects. Methoxetamine has recently become available via the Internet and is marked as "legal ketamine." Moreover, the piperazine derivatives, a class of amphetamine-like compounds that includes BZP and TMFPP, are making a resurgence as "legal Ecstasy." These psychoactives are available via the Internet, frequently legal, and often perceived as safe by the public. Unfortunately, these drugs often have adverse effects, which range from minimal to life-threatening. Health care providers must be familiar with these important new classes of drugs. This paper discusses the background, pharmacology, clinical effects, detection, and management of synthetic cannabinoid, synthetic cathinone, methoxetamine, and piperazine exposures.
Assuntos
Alcaloides/toxicidade , Canabinoides/toxicidade , Cicloexanonas/toxicidade , Cicloexilaminas/toxicidade , Mitragyna/toxicidade , Piperazinas/toxicidade , Psicotrópicos/toxicidade , Salvia/toxicidade , Alcaloides/análise , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Canabinoides/análise , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Cicloexanonas/análise , Cicloexanonas/farmacologia , Cicloexanonas/uso terapêutico , Cicloexilaminas/análise , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Humanos , Piperazinas/análise , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Psicotrópicos/análise , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêuticoRESUMO
Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 µM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 µM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 µM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by â¼67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.
Assuntos
Artrite Experimental/prevenção & controle , Cicloexilaminas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Sinovite/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Artrite Experimental/complicações , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Biocatálise/efeitos dos fármacos , Sangue/efeitos dos fármacos , Sangue/imunologia , Sangue/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloexilaminas/administração & dosagem , Cicloexilaminas/farmacocinética , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Edema/complicações , Edema/patologia , Edema/prevenção & controle , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Pé/patologia , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucócitos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/imunologia , Células Precursoras de Linfócitos B/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Endogâmicos LewRESUMO
Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas Tirosina Quinases/fisiologia , Lesões do Sistema Vascular/fisiopatologia , Cicatrização/genética , Animais , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Suínos , Quinase Syk , Trombose/tratamento farmacológico , Trombose/genética , Trombose/patologia , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/reabilitaçãoRESUMO
In Oriental medicine, roots of Polygala tenuifolia Willdenow have been known to be an important herb that exhibits sedative effects in insomnia, palpitation with anxiety, restlessness, and disorientation in humans. We previously reported that BT-11, extracted from those roots, improved scopolamine-induced amnesia in rats and inhibited acetylcholinesterase activities in vitro. Therefore, we proposed that BT-11 could remedy stress-induced memory deficits in rats. In this study, the stress-induced memory impairments in rats were significantly reversed almost to the control level by BT-11 treatment. To seek an active component of BT-11 that plays an important role in antipsychotic effects, we compared BT-11 with 3,4,5-trimethoxycinnamic acid (TMCA), which is a constituent of those root extracts. However, the effects of TMCA were less or were not consistent with those of BT-11 in some of tests. In particular, BT-11 reversed the stress-induced reduction of glucose utilization by [(18)fluorodeoxyglucose]FDG-PET and the levels of neural cell adhesion molecule (NCAM) in rat brains to the control levels, whereas TMCA did not. Therefore, BT-11 improved stress-induced memory impairments through increment of glucose utilization and total NCAM levels in rat brains. In conclusion, BT-11 may be strongly effective against stress-induced amnesia in rats, through the combined effects of TMCA and other active components of BT-11.
Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Transtornos da Memória/tratamento farmacológico , Moléculas de Adesão de Célula Nervosa/metabolismo , Fitoterapia/métodos , Polygala/química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Fluordesoxiglucose F18/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Wistar , Estresse Psicológico/complicaçõesRESUMO
Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.
Assuntos
Adenina/análogos & derivados , Antimaláricos/farmacologia , Cicloexilaminas/farmacologia , Regulação Enzimológica da Expressão Gênica/genética , Malária/parasitologia , Plasmodium falciparum/enzimologia , Proteínas Quinases/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas de Protozoários/antagonistas & inibidores , Adenina/química , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Células CHO , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Cicloexilaminas/química , Cicloexilaminas/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Movimento/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Testes de Sensibilidade Parasitária , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas Quinases/fisiologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/fisiologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Bibliotecas de Moléculas Pequenas , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
As new compounds are being evaluated for use in clinical trials involving antiangiogenic therapies, two important factors must be considered. Independent of clinical efficacy, the potential drug must be cost-effective and have reasonable ease of production. The compound endostatin (Entremed, Inc.) has recently completed two Phase I trials with minimal toxicity to the patients treated [1,2]. However, due to the difficulty and expense of producing large quantities of a recombinant protein, Entremed Inc. has experienced financial difficulties [3]. As this company's fate indicates, a drug must not only be clinically effective, but must also possess reasonable production economics. Another interesting component of compound development is selectivity. Highly selective antiangiogenic compounds such as the tyrosine kinase inhibitor SU-5416 are being replaced by less selective compounds such as SU-6668, which acts on a broader spectrum of tyrosine kinase receptors [4]. This move towards using less selective antiangiogenic compounds is based on preclinical models that demonstrate both better clinical efficacy when using less specific molecules and low response rates from the more selective compounds. With the aim of further examining broadly-acting antiangiogenic agents, the authors are currently evaluating new classes of agents that preferentially bind copper and inhibit angiogenesis. Copper has been known to be a significant target for antiangiogenic therapy for a number of years [5]. Recently, through the use of molecular techniques, the target enzymes that utilise copper as a cofactor are being elucidated. This review will describe the historical use of anticopper therapy for the treatment of Wilson's disease and evaluate some of the new anticopper compounds currently under consideration for use in antiangiogenic therapy.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Quelantes/uso terapêutico , Terapia por Quelação , Cobre , Inibidores da Angiogênese/farmacologia , Animais , Quelantes/farmacologia , Neovascularização da Córnea/tratamento farmacológico , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Molibdênio/farmacologia , Molibdênio/uso terapêutico , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Penicilamina/farmacologia , Penicilamina/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Coelhos , Trientina/farmacologia , Trientina/uso terapêuticoRESUMO
We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of T. brucei by >90% at concentrations of 1 microM. The most active derivative (1-adamantyl-4-amino-cyclohexane) was about 20 to 25 times more effective than rimantadine. We observed a correlation between structural features of the derivatives and their trypanocidal properties; hydrophobic substitutions to the adamantane or cyclohexane rings generally enhanced activity. As with rimantadine, the activity in vitro varied with the pH. T. brucei was more sensitive in an alkaline environment (including a normal bloodstream pH of 7.4) and less sensitive under acidic conditions. Tests for activity in vivo were carried out with a mouse model of infection with a virulent strain of T. brucei. Although the parasitemia was not eliminated, it could be transiently suppressed by >98% with the most active compounds tested. These results suggest that aminoadamantane derivatives could have potential as a new class of trypanocidal agents.
Assuntos
Adamantano/análogos & derivados , Cicloexilaminas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Adamantano/química , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Cicloexilaminas/química , Cicloexilaminas/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/crescimento & desenvolvimento , Tripanossomíase/tratamento farmacológicoRESUMO
Experiments on arrhythmia models showed a high antiarrhythmic activity of new derivatives of dicyclohexylamides of N-replaced alpha-aminocarbonic acids. The new compounds surpassed in intensity and duration of the antiarrhythmic effect the standard agents with classes I and III antiarrhythmic activity. In doing so they raise myocardial electrical stability and prevent sudden development of ventricular fibrillation. According to the mechanism of the antiarrhythmic activity, the new compounds may be related to antiarrhythmic agents possessing the properties of classes I and III.
Assuntos
Antiarrítmicos/uso terapêutico , Cicloexilaminas/uso terapêutico , Aconitina , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Compostos de Bário , Gatos , Cloretos , Cicloexilaminas/farmacologia , Cicloexilaminas/toxicidade , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Coração/efeitos dos fármacos , Coração/fisiologia , Dose Letal Mediana , Masculino , Potenciais da Membrana/efeitos dos fármacos , Cloreto de Potássio , Coelhos , Rana temporaria , Ratos , Relação Estrutura-AtividadeRESUMO
The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.
Assuntos
Proteínas Sanguíneas/análise , Cicloexilaminas/uso terapêutico , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Indóis/uso terapêutico , Peroxidase/metabolismo , Proctocolite/tratamento farmacológico , Receptores de Taquicininas/antagonistas & inibidores , Ácido Acético/efeitos adversos , Doença Aguda , Administração Retal , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Animais de Doenças , Interações Medicamentosas , Cobaias , Masculino , Mesalamina/farmacologia , Proctocolite/induzido quimicamente , Fatores de TempoRESUMO
The Institute of Pharmacology, Academy of Medical Sciences, jointly with AWD (Germany) has synthesized and tested a novel class III antiarrhythmic coded AWD-160-275, a derivative of dicyclohexylamides of aminocarboxylic acids. The compound was shown to prolong cardiac repolarization, to increase atrial and ventricular refractory periods, to decrease sinus nodal automatism, and to unchange intraventricular conduction. The compound proved to be superior to the reference drugs in the rate and duration of antiarrhythmic and antifibrillatory action. In therapeutical doses it has no antiarrhythmic effect. The specific feature of the agent is that there is no relation of longer effective refractory periods to the frequency of stimulation. This property may be useful in treating tachyarrhythmias.
Assuntos
Antiarrítmicos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Aminoácidos/toxicidade , Animais , Antiarrítmicos/uso terapêutico , Antiarrítmicos/toxicidade , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Gatos , Cicloexilaminas/farmacologia , Cicloexilaminas/uso terapêutico , Cicloexilaminas/toxicidade , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Cobaias , Técnicas In Vitro , Dose Letal Mediana , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somatodendritic autoreceptor antagonists) enhance the increase in extracellular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reuptake inhibitors, it was of interest to determine if these antagonists also enhance the anticonvulsant effect of fluoxetine in Genetically Epilepsy-Prone Rats (GEPRs). The 5-HT1A receptor antagonists (-)-pindolol and LY 206130 (1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) were examined in the present study and both enhanced the anticonvulsant action of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose- and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT1A receptor antagonist is physiologically important and that the anticonvulsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT.
Assuntos
Anticonvulsivantes/uso terapêutico , Fluoxetina/uso terapêutico , Receptores de Serotonina/efeitos dos fármacos , Convulsões/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Estimulação Acústica , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cicloexilaminas/uso terapêutico , Interações Medicamentosas , Feminino , Fenclonina/farmacologia , Norepinefrina/metabolismo , Pindolol/uso terapêutico , Ratos , Receptores 5-HT1 de Serotonina , Serotonina/metabolismoRESUMO
Water-miscible platinum(II) complexes with 1,2-diaminocyclohexane as the carrier ligand and bile acids as the leaving ligands were synthesized and tested for antitumor activity against intraperitoneally implanted leukemia L1210 cells in mice. These complexes were water-miscible after appropriate sonication due to the presence of hydrophilic hydroxyl groups in the molecule, even though the complexes were essentially lipophilic. The complexes had high antitumor activity, but their optimal dose levels differed, and the administration route and form affected the antitumor activity. More lipophilic complexes showed higher activity when administered with Lipiodol than in water suspension, while the hydrophilic complexes showed significant activity when administered in water suspension. Intravenous administration of DACHP(cheno)2 in water suspension resulted in potent antitumor activity, while other complexes showed moderate activity via this route.
Assuntos
Antineoplásicos/uso terapêutico , Cicloexilaminas/administração & dosagem , Leucemia L1210/tratamento farmacológico , Platina/uso terapêutico , Animais , Antineoplásicos/síntese química , Ácidos e Sais Biliares/uso terapêutico , Cicloexilaminas/uso terapêutico , Óleo Iodado/uso terapêutico , Ligantes , CamundongosRESUMO
There is a great need for clinical trial of new second-generation platinum coordination compounds that might demonstrate greater clinical activity in a broader spectrum of tumors, decreased renal toxicity and emesis, improved solubility, synergism in combination therapy, and lack of cross-resistance to cis-dichlorodiammineplatinum(II) (cis-platinum). Lack of cross-resistance to cis-platinum is shown by certain 1,2-diamino-saturated cyclic platinum derivatives which also have a high degree of activity against transplanted mouse leukemias. cis-Platinum and these cyclic compounds combine synergistically with derivatives of cytosine arabinoside, VP-16-213, and Adriamycin. These 1,2-diamino cyclic compounds appear to have less renal toxicity than cis-platinum. The toxic and therapeutic effects of both cis-platinum and the diamino cyclic compounds can be blocked by massive doses of thiourea. Varying doses and time intervals of thiourea rescue are being studied in the hope of improving the therapeutic index of the platinum derivatives.