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1.
Am J Physiol Gastrointest Liver Physiol ; 318(5): G980-G987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308039

RESUMO

Glucagon-like peptide (GLP)-1 and -2-secreting L cells have been shown to express the bile acid receptor Takeda G protein-receptor-5 (TGR5) and increase secretion upon receptor activation. Previous studies have explored GLP-1 secretion following acute TGR5 activation, but chronic activation and GLP-2 responses have not been characterized. In this study, we aimed to investigate the consequences of pharmacological TGR5 receptor activation on L cell hormone production in vivo using the specific TGR5 agonist RO5527239 and the GLP-2 receptor knockout mouse. Here, we show that 1) TGR5 receptor activation led to increased GLP-1 and GLP-2 content in the colon, which 2) was associated with an increased small intestinal weight that 3) was GLP-2 dependent. Additionally, we report that TGR5-mediated gallbladder filling occurred independently of GLP-2 signaling. In conclusion, we demonstrate that pharmacological TGR5 receptor activation stimulates L cells, triggering GLP-2-dependent intestinal adaption in mice.NEW & NOTEWORTHY Using the specific Takeda G protein-receptor-5 (TGR5) agonist RO5527239 and GLP-2 receptor knockout mice, we show that activation of TGR5 led to the increase in colonic GLP-1 and GLP-2 concomitant with a GLP-2 dependent growth response in the proximal portion of the small intestine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Enteroendócrinas/efeitos dos fármacos , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Intestino Delgado/efeitos dos fármacos , Ácidos Isonipecóticos/farmacologia , Oximas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Colo/efeitos dos fármacos , Colo/crescimento & desenvolvimento , Colo/metabolismo , Células Enteroendócrinas/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Intestino Delgado/crescimento & desenvolvimento , Intestino Delgado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais
2.
Gut ; 69(1): 146-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723104

RESUMO

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.


Assuntos
Sistema Biliar/fisiopatologia , Colestase Intra-Hepática/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Colestase Intra-Hepática/metabolismo , Impedância Elétrica , Epitélio/fisiopatologia , Ácidos Isonipecóticos/farmacologia , Ácidos Isonipecóticos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oximas/farmacologia , Oximas/uso terapêutico , Permeabilidade , Fosforilação/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/fisiologia , Proteínas de Junções Íntimas/metabolismo
3.
Int J Parasitol Drugs Drug Resist ; 6(1): 60-73, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27054065

RESUMO

Soil-transmitted helminth infections in humans and livestock cause significant debility, reduced productivity and economic losses globally. There are a limited number of effective anthelmintic drugs available for treating helminths infections, and their frequent use has led to the development of resistance in many parasite species. There is an urgent need for novel therapeutic drugs for treating these parasites. We have chosen the ACR-16 nicotinic acetylcholine receptor of Ascaris suum (Asu-ACR-16), as a drug target and have developed three-dimensional models of this transmembrane protein receptor to facilitate the search for new bioactive compounds. Using the human α7 nAChR chimeras and Torpedo marmorata nAChR for homology modeling, we defined orthosteric and allosteric binding sites on the Asu-ACR-16 receptor for virtual screening. We identified four ligands that bind to sites on Asu-ACR-16 and tested their activity using electrophysiological recording from Asu-ACR-16 receptors expressed in Xenopus oocytes. The four ligands were acetylcholine inhibitors (SB-277011-A, IC50, 3.12 ± 1.29 µM; (+)-butaclamol Cl, IC50, 9.85 ± 2.37 µM; fmoc-1, IC50, 10.00 ± 1.38 µM; fmoc-2, IC50, 16.67 ± 1.95 µM) that behaved like negative allosteric modulators. Our work illustrates a structure-based in silico screening method for seeking anthelmintic hits, which can then be tested electrophysiologically for further characterization.


Assuntos
Ascaris suum/anatomia & histologia , Ascaris suum/efeitos dos fármacos , Ascaris suum/metabolismo , Descoberta de Drogas/métodos , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Regulação Alostérica , Sítio Alostérico/genética , Animais , Ascaris suum/genética , Sítios de Ligação/genética , Butaclamol/farmacologia , Simulação por Computador , Sistemas de Liberação de Medicamentos , Fluorenos/metabolismo , Fluorenos/farmacologia , Humanos , Concentração Inibidora 50 , Ácidos Isonipecóticos/metabolismo , Ácidos Isonipecóticos/farmacologia , Ligantes , Modelos Moleculares , Agonistas Nicotínicos/química , Nitrilos/farmacologia , Oócitos , Técnicas de Patch-Clamp , Tetra-Hidroisoquinolinas/farmacologia , Torpedo/genética , Torpedo/fisiologia , Xenopus/genética
4.
Clin Chim Acta ; 440: 108-12, 2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25447702

RESUMO

Pipecolic acid (PA) is an important biochemical marker for the diagnosis of peroxisomal disorders. PA is also a factor responsible for hepatic encephalopathy and a possible biomarker for pyridoxine-dependent seizures. We developed an easy and rapid PA quantification method, by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), requiring no derivatization and applicable to small sample volumes. Plasma (100 µl) is extracted with 500 µl acetonitrile (ACN) containing 2 µmol/l [(2)H5]-phenylalanine as internal standard, vortexed and centrifuged. The supernatant is analyzed by HPLC-MS/MS in positive-ion mode using multiple reaction monitoring scan type. HPLC column is a Luna HILIC (150×3.0mm; 3 µ 200A): Buffer A: ammonium formate 5 mmol/l; Buffer B: ACN/H20 90:10 containing ammonium formate 5 mmol/l. PA retention time is 4.86 min. Recovery was 93.8%, linearity was assessed between 0.05 and 50 µmol/l (R(2)=0.998), lower limit of detection was 0.010 µmol/l and lower limit of quantification was 0.050 µmol/l. Coefficient of variation was 3.2% intra-assay and 3.4% inter-assay, respectively. Clinical validation was obtained by comparing PA plasma values from 5 patients affected by peroxisomal disorders (mean, 23.38 µmol/l; range, 11.20-37.1 µmol/l) to 24 ages related healthy subjects (mean, 1.711 µmol/l; range, 0.517-3.580 µmol/l).


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ácidos Pipecólicos/sangue , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Biomarcadores/sangue , Calibragem , Criança , Pré-Escolar , Epilepsia/sangue , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Ácidos Isonipecóticos/isolamento & purificação , Limite de Detecção , Masculino , Ácidos Nipecóticos/isolamento & purificação , Transtornos Peroxissômicos/sangue , Transtornos Peroxissômicos/diagnóstico , Ácidos Pipecólicos/isolamento & purificação , Valores de Referência , Reprodutibilidade dos Testes , Adulto Jovem
5.
Xenobiotica ; 44(7): 591-605, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24380613

RESUMO

1. Elaborate studies of cholesteryl ester transfer protein (CETP) polymorphisms and genetic deficiency in humans suggest direct links between CETP, high-density lipoprotein cholesterol (HDL-c) levels and coronary heart diseases. The hypothesis that CETP inhibition by small molecule inhibitors raises HDL-c has been validated clinically with structurally-diverse CETP inhibitors such as torcetrapib, anacetrapib, dalcetrapib and evacetrapib. 2. Despite promising phase 2 results with respect to HDL-c elevation, torcetrapib was discontinued in phase 3 trials due to increased mortality rates in the cardiovascular outcomes study. Emerging evidence for the adverse effects hints at off-target chemotype-specific cardiovascular toxicity, possibly related to the pressor effects of torcetrapib, since structurally diverse CETP inhibitors such as anacetrapib, evacetrapib and dalcetrapib are not associated with blood pressure increases in humans. Nonclinical follow-up studies showed that torcetrapib induces aldosterone biosynthesis and secretion in vivo and in vitro, an effect which is not observed with other CETP inhibitors in clinical development. 3. As part of ongoing efforts to identify novel CETP inhibitors devoid of pressor effects, strategies were implemented towards the design of compounds, which lack the 1,2,3,4-tetrahydroquinoline (THQ) scaffold present in torcetrapib. In this article, we disclose results of structure-activity relationship studies for a series of novel non-THQ CETP inhibitors, which resulted in the identification of a novel isonipecotic acid derivative 10 (also referred to as PF-04445597) with vastly improved oral pharmacokinetic properties mainly as a result of improved aqueous solubility. This feature is attractive in that, it bypasses significant investments needed to develop compatible solubilizing formulation(s) for oral drug delivery of highly lipophilic and poorly soluble compounds; attributes, which are usually associated with small molecule CETP inhibitors. PF-04445597 was also devoid of aldosterone secretion in human H295R adrenal carcinoma cells.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Quinolinas/química , Administração Oral , Aldosterona/metabolismo , Animais , Anticolesterolemiantes/farmacocinética , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Desenho de Fármacos , Feminino , Humanos , Injeções Intravenosas , Ácidos Isonipecóticos/química , Ácidos Isonipecóticos/farmacologia , Macaca fascicularis , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Quinolinas/farmacologia , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 23(24): 6598-603, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24239017

RESUMO

The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Ácidos Isonipecóticos/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Benzotiazóis/síntese química , DNA Girase/química , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Ativação Enzimática/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacocinética
7.
Prostaglandins Other Lipid Mediat ; 107: 26-34, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24045148

RESUMO

Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE2 production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids.


Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Ácidos Isonipecóticos/farmacologia , Animais , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Concentração Inibidora 50 , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Prostaglandina H2/metabolismo , Prostaglandina-E Sintases , Ratos , Tromboxano B2/metabolismo
8.
Br J Pharmacol ; 169(3): 671-84, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23488746

RESUMO

BACKGROUND AND PURPOSE: Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the BA receptor G protein-coupled bile acid receptor 1 (GPBAR1). EXPERIMENTAL APPROACH: A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration. KEY RESULTS: GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys. CONCLUSION AND IMPLICATIONS: Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Enteroendócrinas/efeitos dos fármacos , Fármacos Gastrointestinais/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Ácidos Isonipecóticos/uso terapêutico , Oximas/uso terapêutico , Peptídeo YY/metabolismo , Piperidinas/uso terapêutico , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Linhagem Celular , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Células Enteroendócrinas/metabolismo , Fármacos Gastrointestinais/metabolismo , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/farmacologia , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Ácidos Isonipecóticos/metabolismo , Ácidos Isonipecóticos/farmacocinética , Ácidos Isonipecóticos/farmacologia , Macaca fascicularis , Masculino , Desintoxicação Metabólica Fase II , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Oximas/metabolismo , Oximas/farmacocinética , Oximas/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/farmacologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Taurina/metabolismo
9.
J Mass Spectrom ; 45(10): 1121-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20690157

RESUMO

Metopimazine (MPZ) is a phenothiazine derivative used to prevent emesis during chemotherapy where few structural analysis of the aforementioned compound have been described in the literature. Thus, this work reports, for the first time, the detailed study of fragmentation pathways of MPZ and its metabolite (AMPZ) using electrospray ionization (EI) with multistage mass spectrometry (ESI-MS(n)) in positive-ion mode. The structures of 21 product ions were identified and their accurate masses were determined using high resolution mass spectrometry (HRMS) experiments. Characteristic product ions of these two phenothiazine derivatives are more particularly displayed along with differences between their relative abundances and their structures checked by H/D exchange experiments.


Assuntos
Medição da Troca de Deutério/métodos , Antagonistas de Dopamina/química , Ácidos Isonipecóticos/química , Fenotiazinas/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Ácidos Isonipecóticos/análise , Estrutura Molecular , Fenotiazinas/análise
11.
Bioorg Med Chem Lett ; 19(9): 2392-5, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19356931

RESUMO

A series of 1-substituted-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl) piperidine-4-carboxamides has been synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit-heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 1-(2-fluorobenzyl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)piperidine-4-carboxamide 6a was the most potent, increasing stroke volume by 11.92+/-0.35% (milrinone: 6.36+/-0.13%) at 1x10(-4)M.


Assuntos
Química Orgânica/métodos , Coração/efeitos dos fármacos , Piperidinas/química , Quinolinas/química , Animais , Cardiotônicos/síntese química , Cardiotônicos/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Ácidos Isonipecóticos/química , Milrinona/síntese química , Milrinona/farmacologia , Modelos Químicos , Miocárdio/metabolismo , Coelhos
12.
J Aquat Anim Health ; 21(3): 133-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20043397

RESUMO

During shipping, ornamental fish can be stressed due to handling, high stocking densities, and deteriorating water quality. Adding sedatives, such as metomidate hydrochloride, to shipping water may improve fish survival rates and the percentage of fish in saleable condition. Although the effects of metomidate hydrochloride on the stress response in fish have been studied, its application as a shipping additive has not been well investigated, particularly for tropical ornamental fishes shipped under industry conditions. Convict cichlids Cichlasoma nigrofasciatum and black mollies Poecilia sphenops were evaluated for 7 d after a 24-h period of exposure (including ground and air transport) to one of four metomidate hydrochloride concentrations: 0.0, 0.2, 0.5, and 1.0 mg/L. Immediate posttransport and cumulative mortality data, as well as 12-h and 7-d posttransport appearance and behavior scores, were generated. In convict cichlids, the highest dose of metomidate hydrochloride (1.0 mg/L) reduced mortality (0% compared with cumulative means of 5.5-9.2% in other groups) and increased the percentage of saleable fish (91.7% were immediately saleable compared with 12.5-50% in other groups). No effect was detected in black mollies at any concentration tested. Metomidate hydrochloride showed promise as a shipping additive for convict cichlids, but further studies are warranted to evaluate species-specific responses in other ornamental species.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ciclídeos/fisiologia , Hipnóticos e Sedativos/farmacologia , Ácidos Isonipecóticos/farmacologia , Poecilia/fisiologia , Animais , Estresse Fisiológico/efeitos dos fármacos , Transportes
14.
Curr Opin Support Palliat Care ; 2(1): 28-34, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18685391

RESUMO

PURPOSE OF REVIEW: Only a few studies have investigated the effect of antiemetic therapy in patients treated with multiple-day or multiple cycles of chemotherapy. The present review will assess the available data, highlight the current recommendations and draw attention towards the remaining problems in this field of antiemetic treatment. RECENT FINDINGS: Evidence-based guidelines recommend a combination of a 5-HT3-receptor antagonist and dexamethasone in the prophylaxis of nausea and vomiting in multiple-day cisplatin-based chemotherapy. In patients treated with multiple cycles of chemotherapy the addition of a NK1-receptor antagonist aprepitant to standard antiemetic therapy has increased the antiemetic effect, and multiple cycle extension studies have demonstrated that this increment in effect is sustained during multiple cycles of chemotherapy. A recent study indicated that the dopamine D2-receptor antagonist metopimazine has some additive effect on delayed symptoms induced by multiple-day chemotherapy. SUMMARY: The development of the NK1-receptor antagonist aprepitant has significantly improved the antiemetic control in patients treated with multiple cycles of chemotherapy. Far too many patients still experience considerable emetic side effects. The effect of aprepitant in multiple-day chemotherapy has yet to be defined. The effect of new antiemetic agents such as palonosetron and olanzapine also needs to be investigated in randomized trials.


Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Aprepitanto , Benzodiazepinas/uso terapêutico , Cisplatino/efeitos adversos , Dexametasona/uso terapêutico , Antagonistas dos Receptores de Dopamina D2 , Esquema de Medicação , Humanos , Ácidos Isonipecóticos/uso terapêutico , Isoquinolinas/uso terapêutico , Morfolinas/uso terapêutico , Náusea/etiologia , Antagonistas do Receptor de Neuroquinina-1 , Olanzapina , Palonossetrom , Quinuclidinas/uso terapêutico , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/uso terapêutico , Vômito/etiologia
15.
J Dermatol Sci ; 52(3): 170-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18678472

RESUMO

BACKGROUND: Metopimazine is an antiemetic drug already used by oral and rectal administration. It would be interesting to develop a new formulation for a transdermal administration. OBJECTIVE: The objective of this study was to determine the influence of iontophoresis on the metopimazine transdermal absorption and the possible synergistic enhancement with chemical enhancers. METHODS: Transdermal transport of metopimazine was studied in vitro in a Franz cell with pig skin according to the following protocol: 1h of iontophoresis followed by 7h of passive diffusion. Different current densities were applied: 0, 0.125, 0.25 and 0.5 mA/cm(2). Chemical enhancers used as solvent dilution were ethanol, propylene glycol and isopropyl myristate. Metopimazine was assayed by HPLC. Fourier transform infrared spectroscopy was used to determinate the interaction between chemical enhancers and stratum corneum. RESULTS: The iontophoresis has increased the percutaneous absorption of metopimazine and has decreased the lag time with 3.85+/-0.90 microg/(cm(2)h) and 1.9h for 0.5 mA/cm(2) and with 0.27+/-0.20 microg/(cm(2)h) and >8h for passive diffusion. Transdermal transport has been increased with current density and with isopropyl myristate and was not modified by ethanol or propylene glycol. CONCLUSION: Results indicated that iontophoresis is an effective method for transdermal administration of metopimazine.


Assuntos
Antieméticos/farmacocinética , Iontoforese , Ácidos Isonipecóticos/farmacocinética , Absorção Cutânea , Animais , Etanol/farmacologia , Propilenoglicol/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos
16.
Drug Dev Ind Pharm ; 34(5): 478-84, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18473229

RESUMO

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl beta cyclodextrin (HPbetaCD) and partially methylated beta cyclodextrin (PMbetaCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 +/- 0.054 microg/h/cm(2) and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 +/- 0.032 microg/h/cm(2) and 0.566 +/- 0.057 mug/h/cm(2) for HPbetaCD and PMbetaCD, respectively, with a concentration of 20%. This study has shown that HPbetaCD and PMbetaCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMbetaCD was also able to extract cutaneous fatty acids.


Assuntos
Antieméticos/farmacocinética , Ácidos Isonipecóticos/farmacocinética , Absorção Cutânea , 2-Hidroxipropil-beta-Ciclodextrina , Adjuvantes Farmacêuticos/farmacologia , Administração Cutânea , Animais , Antieméticos/administração & dosagem , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Sistemas de Liberação de Medicamentos , Orelha Externa , Técnicas In Vitro , Ácidos Isonipecóticos/administração & dosagem , Permeabilidade , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Suínos , beta-Ciclodextrinas/farmacologia
17.
J Chromatogr A ; 1189(1-2): 514-22, 2008 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-18355831

RESUMO

Direct analysis, with minimal sample pretreatment, of antidepressant drugs, fluoxetine, imipramine, desipramine, amitriptyline, and nortriptyline in biofluids was developed with a total run time of 8 min. The setup consists of two HPLC pumps, injection valve, capillary RAM-ADS-C18 pre-column and a capillary analytical C18 column connected by means of a six-port valve in backflush mode. Detection was performed with ESI-MS/MS and only 1 microm of sample was injected. Validation was adequately carried out using FLU-d(5) as internal standard. Calibration curves were constructed under a linear range of 1-250 ng mL(-1) in plasma, being the limit of quantification (LOQ), determined as 1 ng mL(-1), for all the analytes. With the described approach it was possible to reach a quantified mass sensitivity of 0.3 pg for each analyte (equivalent to 1.1-1.3 fmol), translating to a lower sample consumption (in the order of 10(3) less sample than using conventional methods).


Assuntos
Antidepressivos/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Antidepressivos/química , Ácidos Isonipecóticos/análise , Ácidos Isonipecóticos/química , Meperidina/análogos & derivados , Meperidina/análise , Meperidina/química , Fenóis/análise , Fenóis/química , Reprodutibilidade dos Testes
18.
Proc Natl Acad Sci U S A ; 105(5): 1448-53, 2008 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-18245389

RESUMO

Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) (37 nM) against LmPTR1, and the structure of this complex was also determined. Biological evaluation of selected inhibitors was performed against the extracellular forms of T. cruzi and L. major, both wild-type and overexpressing PTR1 lines, as a model for PTR1-driven antifolate drug resistance and the intracellular form of T. cruzi. An additive profile was observed when PTR1 inhibitors were used in combination with known DHFR inhibitors, and a reduction in toxicity of treatment was observed with respect to administration of a DHFR inhibitor alone. The successful combination of antifolates targeting two enzymes indicates high potential for such an approach in the development of previously undescribed antiparasitic drugs.


Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Isonipecóticos/farmacologia , Leishmania major/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Pteridinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Ácido Fólico/química , Ácidos Isonipecóticos/química , Leishmania major/enzimologia , Oxirredutases/química , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/química , Pteridinas/química , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos , Timidilato Sintase/antagonistas & inibidores , Tripanossomicidas/química , Trypanosoma cruzi/enzimologia
19.
Pathol Biol (Paris) ; 56(1): 21-8, 2008 Feb.
Artigo em Francês | MEDLINE | ID: mdl-18178023

RESUMO

INTRODUCTION: Given the national therapeutic guidelines in France, halofantrine represents the first line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria in children. But several disadvantages exist using halofantrine in paediatrics. OBJECTIVES: The primary objective of this study is to evaluate the tolerance and the efficacy of mefloquine as the first line treatment of uncomplicated P. falciparum malaria in a paediatric emergency department. The secondary objective of the study is to evaluate whether symptomatic measures may improve the gastrointestinal tolerance of mefloquine. PATIENTS AND METHODS: This retrospective observational cohort study includes all the patients who have been treated for acute uncomplicated P. falciparum malaria in the paediatric emergency department of the Hospital Trousseau (Paris, France) in 2003. RESULTS: First line treatment was mefloquine in 35 children. Early vomiting occurred in 22 (63%) cases. All children responded to mefloquine therapy except two children who had persistent vomiting early after mefloquine therapy and required intravenous quinine. Those two children had initial vomiting. Light meal and metopimazine prophylaxis did not precede mefloquine intake in those two children. CONCLUSION: This study suggests that mefloquine treatment of uncomplicated P. falciparum malaria is effective and well tolerated in children. Furthermore, a light meal and metopimazine prophylaxis preceding mefloquine intake may improve its gastrointestinal tolerance.


Assuntos
Malária Falciparum/tratamento farmacológico , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Adolescente , Antieméticos/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Alimentos , Humanos , Lactente , Ácidos Isonipecóticos/administração & dosagem , Estudos Retrospectivos , Vômito/induzido quimicamente , Vômito/prevenção & controle
20.
Pharmacol Res ; 56(1): 11-7, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17572097

RESUMO

PURPOSE: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood-brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). METHODS: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. RESULTS: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. CONCLUSIONS: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile.


Assuntos
Antieméticos/farmacocinética , Barreira Hematoencefálica/metabolismo , Clorpromazina/farmacocinética , Domperidona/farmacocinética , Ácidos Isonipecóticos/farmacocinética , Metoclopramida/farmacocinética , Animais , Animais Recém-Nascidos , Antieméticos/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Permeabilidade Capilar , Células Cultivadas , Clorpromazina/metabolismo , Claudina-1 , Técnicas de Cocultura/métodos , Domperidona/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Ácidos Isonipecóticos/metabolismo , Proteínas de Membrana/análise , Metoclopramida/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Ocludina , Fosfoproteínas/análise , Ratos , Sacarose/metabolismo , Junções Íntimas/química , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1
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