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1.
Anesth Prog ; 70(1): 31-33, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36995958

RESUMO

Nasal intubation is often required during oral surgery; however, nasal intubation can cause various complications including bleeding associated with nasal mucosal trauma during intubation and obstruction of the endotracheal tube. Two days before surgery, a nasal septal perforation was identified using computed tomography during a preoperative otorhinolaryngology consultation for a patient planned to undergo a nasally intubated general anesthetic. Subsequently, nasotracheal intubation was successfully performed after confirming the size and location of the nasal septal perforation. We used a flexible fiber optic bronchoscope to safely perform the nasal intubation while assessing for inadvertent migration of the endotracheal tube or soft-tissue damage around the perforation site. Careful preoperative planning in cooperation with the otorhinolaryngology department and use of computed tomography is recommended when a nasal abnormality is suspected.


Assuntos
Anestésicos Gerais , Perfuração do Septo Nasal , Humanos , Septo Nasal/cirurgia , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Hemorragia
2.
ACS Med Chem Lett ; 13(12): 1885-1891, 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36518702

RESUMO

Internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3) (FLT3-ITD) is the most frequently observed mutation in acute myeloid leukemia (AML). Currently approved FLT3 kinase inhibitors have high efficacy, but drug resistance caused by reactivation of FLT3 kinase activity is often clinically observed. In this study, we developed novel FLT3 degraders by introducing gilteritinib, an FDA-approved FLT3 inhibitor, into targeted protein degradation technology. The most active compound, CRBN(FLT3)-8, potently degraded FLT3-ITD via the ubiquitin-proteasome system and inhibited the proliferation of FLT3-ITD mutant AML cells more effectively than gilteritinib. These findings provide a new lead compound for degradation-based drugs targeting FLT3-ITD-positive cancers.

3.
Cancer Sci ; 113(8): 2828-2838, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35579105

RESUMO

BRAF mutations are frequently observed in melanoma and hairy-cell leukemia. Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization-dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras (PROTACs), that target BRAFV600E protein for degradation. CRBN(BRAF)-24, the most effective chimera, potently degraded BRAFV600E in a ubiquitin-proteasome system (UPS)-dependent manner and inhibited the proliferation of BRAFV600E -driven cancer cells. In BRAF wild-type cells, CRBN(BRAF)-24 induced neither BRAFWT degradation nor paradoxical activation of the MAPK pathway. Biochemical analysis revealed that CRBN(BRAF)-24 showed more potent and sustained suppression of MAPK signaling than a BRAFV600E inhibitor, PLX-8394, in BRAFV600E -driven cancer cells. Targeted degradation of BRAFV600E by CRBN(BRAF)-24 could be a promising strategy to evade paradoxical activation of the RAF-MAPK pathway.


Assuntos
Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo
4.
Anesth Prog ; 68(4): 235-237, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34911063

RESUMO

We describe a case of massive epistaxis that occurred after removal of a nasal endotracheal tube, prompting emergent reintubation. Mask ventilation could not be performed because the nasal cavity was packed with gauze and the airway was being evacuated with a suction catheter. Therefore, instead of inhalational anesthetics and muscle relaxants, boluses of midazolam and remifentanil were administered, and reintubation was promptly performed. Sedation was maintained with dexmedetomidine infusion and midazolam. Nasal cautery was performed near the left sphenopalatine foramen. The patient was extubated without agitation or additional hemorrhage. Immediate recognition of the potential for airway loss, sufficient control of active bleeding, and drug selection in accordance with the emergent circumstances enabled prompt resecuring of the airway without pulmonary aspiration of blood.


Assuntos
Extubação , Epistaxe , Extubação/efeitos adversos , Cauterização/efeitos adversos , Epistaxe/etiologia , Epistaxe/terapia , Humanos , Intubação Intratraqueal/efeitos adversos , Mucosa Nasal , Sucção/efeitos adversos
5.
Gan To Kagaku Ryoho ; 46(12): 1903-1905, 2019 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-31879413

RESUMO

We report the case ofa 76-year-old man who had bacteremia due to Edwardsiella tarda during the course ofchemotherapy, including ponatinib, for the treatment of recurrent Philadelphia-positive acute lymphoblastic leukemia. Treatment with cefepime improved his general condition. The number ofreported cases ofbacteremia due to Edwardsiella tarda is limited. Further accumulation ofcases is necessary to obtain accurate data such as the risk factors of Edwardsiella tarda bacteremia.


Assuntos
Bacteriemia , Infecções por Enterobacteriaceae , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Idoso , Edwardsiella tarda , Humanos , Masculino
6.
Micromachines (Basel) ; 10(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262078

RESUMO

We propose a method to print four-dimensional (4D) stimuli-responsive hydrogel structures with internal gaps. Our 4D structures are fabricated by printing an N-isopropylacrylamide-based stimuli-responsive pre-gel solution (NIPAM-based ink) and an acrylamide-based non-responsive pre-gel solution (AAM-based ink) in a supporting viscous liquid (carboxymethyl cellulose solution) and by polymerizing the printed structures using ultraviolet (UV) light irradiation. First, the printed ink position and width were investigated by varying various parameters. The position of the printed ink changed according to physical characteristics of the ink and supporting liquid and printing conditions including the flow rates of the ink and the nozzle diameter, position, and speed. The width of the printed ink was mainly influenced by the ink flow rate and the nozzle speed. Next, we confirmed the polymerization of the printed ink in the supporting viscous liquid, as well as its responsivity to thermal stimulation. The degree of polymerization became smaller, as the interval time was longer after printing. The polymerized ink shrunk or swelled repeatedly according to thermal stimulation. In addition, printing multi-hydrogels was demonstrated by using a nozzle attached to a Y shape connector, and the responsivity of the multi-hydrogels to thermal-stimulation was investigated. The pattern of the multi-hydrogels structure and its responsivity to thermal-stimulation were controlled by the flow ratio of the inks. Finally, various 4D structures including a rounded pattern, a spiral shape pattern, a cross point, and a multi-hydrogel pattern were fabricated, and their deformations in response to the stimuli were demonstrated.

7.
Rinsho Ketsueki ; 59(5): 492-494, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29877236

RESUMO

Here, we report a case of a 67-year-old man who had septic shock due to Citrobacter braakii infection during the course of chemotherapy with high-dose cytosine arabinoside for acute myeloid leukemia. Treatment with cefepime rapidly improved his condition. The number of reported cases of sepsis due to Citrobacter braakii is limited. Further accumulation of cases is necessary to obtain accurate data such as the risk factors for Citrobacter braakii infections.


Assuntos
Infecções por Enterobacteriaceae/complicações , Leucemia Mieloide Aguda , Choque Séptico , Idoso , Citrobacter , Citarabina , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Choque Séptico/etiologia
8.
Behav Pharmacol ; 26(1-2): 73-80, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25438092

RESUMO

Intra-accumbal infusion of the α1-adrenergic agonist methoxamine, which has comparable affinity for α1A-, α1B- and α1D-adrenoceptor subtypes, fails to alter noradrenaline efflux but reduces dopamine efflux in the nucleus accumbens of rats. In-vivo microdialysis experiments were carried out to analyse the putative contribution of α1A-, α1B- and α1D-adrenoceptor subtypes to the methoxamine-induced decrease in accumbal dopamine efflux in freely moving rats. The drugs used were dissolved in the infusion medium and administered locally through a dialysis membrane. Intra-accumbal infusions of the α1A-adrenoceptor antagonist 5-methylurapidil (6 pmol), the α1B-adrenoceptor antagonist cyclazosin (0.6 and 6 pmol) and the α1D-adrenoceptor antagonist BMY 7378 (0.6 pmol) did not alter accumbal efflux of noradrenaline or dopamine: pretreatment with each of these α1-adrenoceptor subtype-selective antagonists counteracted the methoxamine (24 pmol)-induced decrease in accumbal dopamine efflux. Doses indicated are the total amount of drug administered over a 60-min infusion period. These results clearly suggest that the α1A-, α1B- and α1D-adrenoceptor subtypes in the nucleus accumbens mediate the α1-adrenergic agonist methoxamine-induced decrease in accumbal dopamine efflux. The present study also provides in-vivo neurochemical evidence indicating that concomitant, but not separate, activation of the α1A-, α1B- and α1D-adrenoceptors in the nucleus accumbens is required for α1-adrenergic inhibition of accumbal dopaminergic activity.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Metoxamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Microdiálise , Núcleo Accumbens/metabolismo , Piperazinas/farmacologia , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo
9.
Eur J Pharmacol ; 715(1-3): 363-9, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-23665498

RESUMO

The effects of intra-accumbal infusion of selective agonists for the ß-adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither ß1-(dobutamine: 0.06 and 0.12 pmol) nor ß2-adrenoceptor agonist (salbutamol: 0.36 and 3.6 pmol) altered the basal noradrenaline and dopamine efflux in the nucleus accumbens. Co-administration of 0.06 pmol of dobutamine with salbutamol (3.6 pmol) did not affect the noradrenaline levels, but it increased the dopamine efflux to approximately 120%. Co-administration of 0.12 pmol of dobutamine with salbutamol (0.36 or 3.6pmol) also increased DA efflux to approximately 120% without affecting noradrenaline levels. The non-selective ß-adrenoceptor antagonist l-propranolol (1200 pmol) that did not alter the basal noradrenaline and dopamine levels, suppressed the dopamine efflux, induced by co-administration of dobutamine (0.12 pmol) and salbutamol (3.6 pmol). The doses mentioned are the total amount of drug over the 60-min infusion period. The present results support our previously reported conclusion that stimulation of accumbal ß-adrenoceptors which are suggested to be postsynaptically located on accumbal dopaminergic terminals, can enhance the dopamine efflux in the nucleus accumbens. The present study also provides in vivo neurochemical evidence that concomitant, but not separate, activation of accumbal ß1- and ß2-adrenoceptors synergistically increases the accumbal dopamine efflux.


Assuntos
Albuterol/farmacologia , Dobutamina/farmacologia , Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Masculino , Movimento , Norepinefrina/metabolismo , Núcleo Accumbens/citologia , Ratos , Ratos Sprague-Dawley
10.
Eur J Pharmacol ; 688(1-3): 35-41, 2012 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-22617026

RESUMO

In vivo microdialysis was used to analyse the role of the α(1)- and α(2)-adrenoceptor subtypes in the regulation of noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. Intra-accumbal infusion of α(1)-adrenoceptor agonist methoxamine (24pmol) failed to alter the noradrenaline efflux, but decreased the dopamine efflux. The intra-accumbal infusion of α(1)-adrenoceptor antagonist prazosin (6, 600 and 6000pmol) produced a dose-related increase and decrease of the noradrenaline and dopamine efflux, respectively. An ineffective dose of prazosin (6pmol) counteracted the methoxamine (24pmol)-induced decrease of dopamine efflux. The prazosin (6000pmol)-induced increase of noradrenaline efflux, but not the decrease of dopamine efflux, was suppressed by the co-administration of an ineffective dose of methoxamine (0.024pmol). Neither the α(2)-adrenoceptor agonist clonidine (300pmol) and UK 14,304 (300pmol) nor the α(2)-adrenoceptor antagonist RX 821002 (0.6, 3, 600 and 6000pmol) significantly affected the accumbal noradrenaline and dopamine efflux. The doses mentioned are the total amount of drug over the 60-min infusion period. The present results show that (1) accumbal α(1)-adrenoceptors which are presynaptically located on noradrenergic nerve terminals inhibit the accumbal noradrenaline efflux, increasing thereby the accumbal dopamine efflux, (2) accumbal α(1)-adrenoceptors which are postsynaptically located on dopaminergic nerve terminals inhibit the accumbal dopamine efflux, and (3) accumbal α(2)-adrenoceptors play no major role in the regulation of accumbal efflux of noradrenaline and dopamine.


Assuntos
Dopamina/metabolismo , Movimento , Norepinefrina/metabolismo , Núcleo Accumbens/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Tartarato de Brimonidina , Clonidina/farmacologia , Relação Dose-Resposta a Droga , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Masculino , Metoxamina/antagonistas & inibidores , Metoxamina/farmacologia , Movimento/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Prazosina/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Neuropharmacology ; 62(2): 907-13, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21964521

RESUMO

GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GABA released from the neuron. Therefore, we hypothesised that glutamic acid decarboxylase (GAD) which generates GABA in accumbal GABAergic neurons, at least partly determines the GABA receptor subtype-mediated GABAergic tonus. To (in)validate this hypothesis, in vivo microdialysis was used to study the effects of an intra-accumbal infusion of the GAD inhibitor l-allylglycine (allylglycine) on the accumbal dopamine efflux of freely moving rats. The intra-accumbal infusion of allylglycine (50.0, 250.0 and 500.0 nmol) dose-dependently increased the accumbal dopamine levels. The co-administration of tetrodotoxin (720 pmol) suppressed the allylglycine (500.0 nmol)-induced dopamine efflux. The intra-accumbal infusion of GABA(B) receptor agonist baclofen (2.5 and 5.0 nmol) inhibited the allylglycine (500.0 nmol)-induced dopamine efflux. The baclofen's effects were counteracted by GABA(B) receptor antagonist saclofen (10.0 nmol). Neither GABA(A) receptor agonist (muscimol: 25.0 and 250.0 pmol) nor antagonist (bicuculline: 50.0 pmol) altered the allylglycine (250.0 and 500.0 nmol)-induced dopamine efflux. The present study provides in vivo neurochemical evidence that newly synthesised GABA that exerts an inhibitory tonus on the accumbal dopaminergic activity, acts at the level of GABA(B) receptors, but not GABA(A) receptors. The present study also shows that there is an allylglycine-insensitive GABA pool that release GABA exerting an inhibitory control of the accumbal dopaminergic activity, at the level of GABA(A) receptors. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Terminações Nervosas/metabolismo , Núcleo Accumbens/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Ácido gama-Aminobutírico/metabolismo , Alilglicina/farmacologia , Animais , Baclofeno/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Masculino , Microdiálise , Muscimol/farmacologia , Terminações Nervosas/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
12.
Eur J Pharmacol ; 648(1-3): 80-6, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20816815

RESUMO

We studied the effects of the intra-striatal infusion of Ca(2+)-free medium on the intra-striatal injection of 0.5 µg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca(2+)-insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca(2+)-sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D1-like receptors play only a very limited role in these processes. The present study underlines our previous notion that the effects of SKF38393 cannot simply be ascribed to the dopamine D1-like receptor stimulation (Saigusa et al., 2009): in fact, the present study clearly reveals that SKF38393 is not at all selective in that respect.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Dopamina/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Receptores de Dopamina D1/metabolismo , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Arteríolas/fisiologia , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Felipressina/farmacologia , Técnicas In Vitro , Injeções , Soluções Isotônicas/administração & dosagem , Soluções Isotônicas/farmacologia , Masculino , Neostriado/irrigação sanguínea , Neostriado/citologia , Oximetazolina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/metabolismo , Solução de Ringer , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vênulas/efeitos dos fármacos , Vênulas/metabolismo , Vênulas/fisiologia
13.
Eur J Pharmacol ; 624(1-3): 10-5, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19836368

RESUMO

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular dopamine pool and the alpha-methyl-para-tyrosine-sensitive cytosolic dopamine pool. Given the similarities between dexamphetamine and SKF38393, we hypothesized that both types of pool also contribute to the striatally applied SKF38393-induced dopamine efflux. Using in vivo microdialysis technique, we analysed the contribution of these pools to the SKF38393-induced striatal dopamine efflux in freely moving rats. The increase of dopamine efflux induced by 1.5 microg SKF38393 was largely prevented by either reserpine (5mg/kg i.p., given 24h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2h earlier), showing that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the SKF38393-induced increase in striatal dopamine efflux. The sum of the amounts of dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was greater than 100%, namely 137.6% of the basal dopamine level and 143.9% of the SKF38393-induced dopamine level, suggesting that striatally applied SKF38393 promotes the redistribution of dopamine from vesicles to the cytosol, and vice versa. The finding that the combined treatment of reserpine and alpha-methyl-para-tyrosine only inhibited the SKF38393-induced striatal dopamine efflux till 86.0% of the control, is ascribed to the notion that SKF38393 can also inhibit the re-uptake of dopamine. The latter conclusion has far-reaching consequences for studies in which the effects of SKF38393 are simply ascribed to its dopamine D1 receptor stimulation capacity.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Citosol/metabolismo , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Receptores de Dopamina D1/metabolismo , Vesículas Transportadoras/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , Animais , Citosol/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Reserpina/administração & dosagem , Reserpina/farmacologia , Vesículas Transportadoras/efeitos dos fármacos , alfa-Metiltirosina/administração & dosagem , alfa-Metiltirosina/farmacologia
14.
Bioorg Med Chem Lett ; 19(7): 2013-7, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19269821

RESUMO

A new series of triazole compounds possessing an amide-part were efficiently synthesized and their in vitro antifungal activities were investigated. The amide analogs showed excellent in vitro activity against Candida, Cryptococcus and Aspergillus species. The MICs of compound 23d against C. albicans ATCC24433, C. neoformans TIMM1855 and A. fumigatus ATCC26430 were 0.008, 0.031 and 0.031 microg/mL, respectively, (MICs of fluconazole: 0.5, >4 and >4 microg/mL; MICs of itraconazole: 0.125, 0.25, 0.25 microg/mL). Furthermore, compound 23d was stable under acidic conditions.


Assuntos
Amidas/síntese química , Antifúngicos/síntese química , Benzamidas/síntese química , Dioxanos/química , Dioxanos/síntese química , Triazóis/química , Triazóis/síntese química , Amidas/química , Amidas/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Candida/efeitos dos fármacos , Dioxanos/farmacologia , Testes de Sensibilidade Microbiana , Triazóis/farmacologia
15.
Org Lett ; 11(7): 1559-62, 2009 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-19275223

RESUMO

Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skeletally diverse small molecules. The synthetic pathway yields products having 12 different skeletons using only three steps and has the potential to enable substantial stereochemical diversification in the future.


Assuntos
Compostos Heterocíclicos/síntese química , Catálise , Cristalografia por Raios X , Ciclização , Compostos Heterocíclicos/química , Conformação Molecular , Estrutura Molecular
16.
Bioorg Med Chem Lett ; 18(24): 6538-41, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18974000

RESUMO

A new series of triazole compounds possessing a carbon atom in place of a sulfur atom were efficiently synthesized and their in vitro antifungal activities were investigated. The carbon analogs showed excellent in vitro activity against Candida, Cryptococcus, and Aspergillus species. The MICs of compound 1c against C. albicans ATCC24433, C. neoformans TIMM1855, and A. fumigatus ATCC26430 were 0.016, 0.016, and 0.125 microg/mL, respectively (MICs of fluconazole: 0.5, >4, and >4 microg/mL; MICs of itraconazole: 0.125, 0.25, and 0.25 microg/mL).


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Carbono/química , Dioxanos/química , Triazóis/química , Química Farmacêutica/métodos , Desenho de Fármacos , Compostos de Epóxi/química , Fluconazol/síntese química , Fluconazol/farmacologia , Humanos , Técnicas In Vitro , Itraconazol/síntese química , Itraconazol/farmacologia , Testes de Sensibilidade Microbiana , Modelos Químicos , Estereoisomerismo
17.
Eur J Pharmacol ; 538(1-3): 94-100, 2006 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-16682023

RESUMO

This study examined the effects on orofacial movement topography of SK&F 83822 ([R/S]-6-chloro-7,8-dihydroxy-3-allyl-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates dopamine D(1)-like receptors coupled to stimulation of adenylyl cyclase (AC) but not phosphoinositide (PI) hydrolysis, in comparison with SK&F 83959 ([R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), which stimulates PI hydrolysis but not AC. SK&F 83822 alone induced chattering, while SK&F 83959 alone exerted little effect. SK&F 83822 and SK&F 83959 each in combination with the dopamine D(2)-like agonist quinpirole resulted in synergistic induction of non-chattering movements with tongue protrusions. These effects were blocked by the dopamine D(1)-like receptor antagonist SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). However, the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) exerted a biphasic effect on synergism with SK&F 83822: chattering was initially released but antagonised thereafter. Only antagonism was seen for synergism with SK&F 83959. While both AC- and PI-coupled dopamine D(1)-like receptors participate in synergistic dopamine D(1)-like:D(2)-like receptor interactions, topographically specific synergistic and oppositional dopamine D(1)-like:D(2)-like interactions evident with SK&F 83822 reflect the involvement primarily of D(1)-like receptors coupled to AC rather than PI.


Assuntos
Adenilil Ciclases/metabolismo , Benzazepinas/farmacologia , Arcada Osseodentária/fisiologia , Receptores de Dopamina D1/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Análise de Variância , Animais , Benzamidas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Movimento/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Fatores de Tempo
18.
Eur J Pharmacol ; 510(1-2): 39-47, 2005 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-15740723

RESUMO

The role of gamma-aminobutyric acid (GABA)(A) receptors in the retrorubral field in the production of rat repetitive jaw movements was examined, as this nucleus receives a GABAergic, inhibitory input from the nucleus accumbens and is connected with the parvicellular reticular formation, a region that is directly connected with the orofacial motor nuclei. The GABA(A) receptor antagonist bicuculline (150 ng/0.2 microl per side) significantly produced repetitive jaw movements when injected bilaterally into the retrorubral field, but not the ventral pallidum. The effects of bicuculline were GABA(A) receptor specific, because the effects were abolished by muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline-induced jaw movements differed qualitatively from those elicited by injection of a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist at dopamine D1 and D2 receptors respectively, into the nucleus accumbens shell. Nevertheless, bilateral injections of muscimol (10 ng, 25 ng and 50 ng/0.2 microl per side) into the retrorubral field significantly inhibited jaw movements evoked by the dopamine D1/D2 receptor stimulation in the nucleus accumbens shell. Bilateral injections of bicuculline (50 ng and 150 ng/0.2 microl per side) also reduced the dopamine D1/D2 receptor-mediated jaw movements. Essentially similar effects were obtained when muscimol and bicuculline were given into the ventral pallidum, a region that is also known to receive GABAergic inhibitory inputs from the nucleus accumbens. In conclusion, GABA(A) receptor blockade in the retrorubral field elicits characteristic repetitive jaw movements, and the GABA(A) receptors in that region as well as in the ventral pallidum modulate the accumbens-specific, dopamine D1/D2 receptor-mediated jaw movements.


Assuntos
Dopaminérgicos/farmacologia , Globo Pálido/fisiologia , Arcada Osseodentária/fisiologia , Núcleo Accumbens/fisiologia , Receptores de GABA-A/fisiologia , Núcleo Rubro/fisiologia , Animais , Benzazepinas/farmacologia , Bicuculina/farmacologia , Agonistas de Dopamina/farmacologia , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Agonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-A , Arcada Osseodentária/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
19.
Eur J Pharmacol ; 484(1): 75-82, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14729384

RESUMO

Dopamine and acetylcholine receptor functions in spontaneously hypertensive rats (SHR) and in control progenitor Wistar-Kyoto (WKY) rats were assessed, using dopamine D1-like/D2-like receptor-mediated and acetylcholine receptor-mediated jaw movements as readout parameters. Spontaneous behaviours such as locomotor activity, vacuous chewing, grooming, sniffing and rearing occurred significantly more in SHR than in WKY rats. In the anaesthetised rats, a mixture of SKF 38393 (5 micrograms), a dopamine D1-like receptor agonist, and quinpirole (10 micrograms), a dopamine D2-like receptor agonist, readily produced repetitive jaw movements in WKY rats, but not SHR, when bilaterally injected into the ventrolateral striatum; such injections into the nucleus accumbens shell were ineffective in each strain. Bilateral injections of carbachol (2.5 micrograms each side), an acetylcholine receptor agonist, into the ventrolateral striatum elicited repetitive jaw movements in both SHR and WKY rats, but to a far less degree in SHR. The present study demonstrates that spontaneous behaviours are enhanced in SHR, and that postsynaptic dopamine D1-like/D2-like receptors and acetylcholine receptors in the ventrolateral striatum of SHR are hyposensitive when compared to those of WKY rats.


Assuntos
Corpo Estriado/fisiologia , Hipertensão/fisiopatologia , Receptores Colinérgicos/fisiologia , Receptores Dopaminérgicos/fisiologia , Sinapses/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Arcada Osseodentária/efeitos dos fármacos , Arcada Osseodentária/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Movimento/efeitos dos fármacos , Movimento/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Especificidade da Espécie , Sinapses/efeitos dos fármacos
20.
Bioorg Med Chem Lett ; 12(13): 1705-8, 2002 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12067542

RESUMO

Sordaricin analogues possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biological activity. In particular, N-(2-methylpropenyl) derivative 12p exhibited potent in vitro antifungal activity. Furthermore, 12p maintained significant activity (MIC 0.25 microg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Fator 2 de Elongação de Peptídeos/antagonistas & inibidores , Antifúngicos/química , Candida albicans/classificação , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Diterpenos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
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