Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method

This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates.

The recent upsurge of antimony (Sb) resistance is a major impediment to successful chemotherapy of visceral leishmaniasis (VL). Mechanisms involved in antimony resistance have demonstrated an upregulation of drug efflux pumps; however, the biological role drug efflux pumps in clinical isolates remains to be substantiated. Thus, in this study, the functionality of drug efflux pumps was measured in promastigotes and axenic amastigotes isolated from VL patients, who were either Sb-sensitive (AG83, 2001 and MC9) or resistant (NS2, 41 and GE1) using rhodamine123 as a substrate for multidrug resistant (MDR) pumps and calcein as a substrate for multidrug resistance-associated proteins (MRP) respectively; their specificity was confirmed using established blockers. Sb-resistant (Sb-R) isolates accumulated higher amounts of R123, as compared to Sb-sensitive (Sb-S) isolates. Verapamil, a MDR inhibitor failed to alter R123 accumulation, suggesting absence of classical MDR activity. In Sb-R isolates, both promastigotes and axenic amastigotes accumulated significantly lower amounts of calcein than Sb-S isolates and probenecid, an established pan MRP blocker, marginally increased calcein accumulation. Depletion of ATP dramatically increased calcein accumulation primarily in Sb-R isolates, indicating existence of a MRP-like pump, which was more active in Sb-R isolates. In conclusion, our data suggested that overfunctioning of a MRP-like pump contributed towards generation of Sb-R phenotype in L. donovani field isolates.

Effect of probenecid on kinetics of enrofloxacin in lactating goats after subcutaneous administration.

A comparative pharmacokinetic study of enrofloxacin (5 mg/kg, sc) was conducted in probenecid-pretreated (70 mg/kg, orally 1.5 h prior to enrofloxacin administration) lactating goats to assess the effect of probenecid on the kinetics of enrofloxacin. Concentration of enrofloxacin in plasma, milk and urine was estimated by microbiological assay using Escherichia coli (ATCC 25922). Minimum detection level of enrofloxacin was 0.01 microg/ml. The plasma log concentration versus time curve showed monophasic pattern and followed one compartment open model. Plasma drug concentration was significantly higher during 1-2 h in probenecid-pretreated group. Significantly higher drug concentration in milk was noted at most of the time points, while significantly lower urine drug concentration (0.083-1 h and 5-12 h) were obtained in probenecid-pretreated group. The kinetic parameters (A, B and 3) were significantly higher, while t(1/2)beta, MRT and Vd(area) were significantly lower in probenecid-pretreated group. Probenecid pretreatment decreased the urinary excretion of enrofloxacin, whereas enhanced excretion in milk which could be useful in cases of affections of udder in goats.

Influence of cyclic guanosine 3', 5' monophosphate modulators on muscle contraction of rat aortas

The study examined the influence of probenecid [Pn], sildenafil [Sd] and oxidiazoloquinoxalin [ODQ] on contraction of phenylephrine [PhE] stimulated rat aortas. The study was performed at Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany, from 1st July to 30th September 2005. Thirty-five isolated rat aortas were stimulated with 10 micro M PhE or preincubated for 30 minutes with 10 micro M Pn, or 10 micro M ODQ, or 50 micro M Sd, and then incubated with 10 micro M PhE in the presence or absence of the substances. The phosphorylated myosin light chain 20 was detected by using an antibody against phosphomyosin light chain 2. The ratio of PhE stimulated phosphorylation of aortas [p<0.05] to the untreated was 16.7:1 at 30 seconds and 20.4:1 at 60 seconds. The stimulation decreased significantly at 120 seconds then during the following 10 minutes. Pre-incubation with 50 micro M Sd [p>0.05] or 10 micro M Pn [p<0.05] reduced the phosphorylation induced by PhE that was added to each for 30 seconds. But pre-incubation with 10 micro M ODQ increased the phosphorylation brought about by addition of PhE for 60 seconds, p>0.05. The washout-effect of these modulators was not significant after stimulation with PhE only. The study demonstrates the involvement of cyclic guanosine 3',5' monophosphate and its modulators on muscle contraction of rat aortas. Sildenafil and Pn reduced while oxidiazoloquinoxalin increased the contraction of rat aortas

Cambios en los niveles estriatales de glutamato y aspartato en un modelo de la corea de Huntington: prevención de la neurotoxicidad del ácido quinolínico por kinurenina y probenecid / Changes in the striatal levels of glutamate and aspartante in a Huntington chorea model: prevention of quinolinic acid induced neurotoxicity by kynurenine and probenecid

La kinurenina (KYN) es el metabolito precursor del antagonista de los receptores glutamatérgicos para N-metil-D-as-partato (NMDA), el ácido kinurénico (KYNA). Por su pate, el probenecid (PROB) bloquea la excreción del KYNA desde el fluido extracelular. El KYNA antagoniza la neurotoxicidad ácido quinolínico (QUIN), en el cerebro de mamíferos. En este trabajo evaluamos el efecto de la administración sistémica de KYN y del PROB por separado o en combinación, sobre el contenido estriatal de dos aminoácidos excitadores del sistema nervioso, los ácidos glutámico (Glu) y aspártico (Asp), después de la administración intraestriatal unilateral de QUIN (240 nmol/ml) a las ratas. Los contenidos estriales de Glu y Asp. Analizados por cromatografía de líquidos, se encontraron disminuidos en ratas lesionadas por QUIN al compararse contra valores control (-44 por ciento y -43 por ciento, respectivamente). Los cambios en las concentraciones de estos aminoácidos fueron parcial o totalmente prevenidos por la administración de los pretratamientos con KYN (150, 300 ó 450 mg/kg, i.p.) o PROB (100, 200 ó 300 mg/kg, i.p.) a las ratas 2 horas antes de la inyección del QUIN. La coadministración de ambos fármacos previno la pérdida estriatal de Glu y Asp mediada por QUIN. Por su parte, la administración de un conocido antagonista de los receptores para NMDA, la dizocilpina (MK-80 1, 10 mg/kg, i.p.) previno totalmente la disminución estriatal de ambos aminoácidos. Estos hallazgos sugieren un papel farmacológico de la KYN y del PROB como inductores del antagonismo del KYNA sobre los receptores para NMDA

Evidence in support of a chemiosmotic mechanism for stimulated prolactin release

Para comprobar la participación de un mecanismo quimiosmótico en la exocitosis de prolactina (PRL) se utilizaron células anterohipofisarias dispersas provenientes de ratas hembra. Luego de un cultivo primario éstas se incubaron en medios que contenían iones de bicarbonato o isetionato, probenecid y carboinlcianuro p-trifluorometoxi-fenilhidrazona (CCTP). Células incubadas sin estos aditivos o estimuladas con dibutiriladenosina 3:5 monofosfato cíclico se utilizaron como controles. Además se preparó una suspensión de gránulos secretorios aislados para estudiar el efecto de elevadas presiones osmóticas. La inhibición del transporte aniómico con probenecid siempre redujo significativamente la liberación de PRL; con el bicarbonato, en cambio, se obtuvo el efecto opuesto. El ionóforo de protones CCTP solamente inhibió la secreción estimulada de PRL y la substitución del cloro por el isetionato no produjo efectos significativos. Finalmente se pudo observar que elevadas presiones osmóticas suprimían la lisis de los gránulos prolactínicos cuando el medio de incubación contenía bicarbonato. Los resultados indicam que un mecanismo quimiosmótico, dependiente de protones e iones bicarbonato, , interviene en la liberación estimulada de PRL y que un mecanismo diferente, independiente de protones, devería considerarse para la secreción basal de PRL