RESUMEN
BACKGROUND: Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown. METHODS: Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca(2+)]i, [ATP]i and [glucose]o uptake measurements. RESULTS: The cromakalim (10 nM to 10 µM)- and pinacidil (10 nM to 10 µM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 µM). Simvastatin (1, 3 and 10 µM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 µM)- and pinacidil (10 µM)-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 µM) and AICAR (1 mM) elicited a time-dependent, compound C (1 µM)-sensitive [(3)H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2-30 min)- and concentration (0.1-10 µM)-dependent increase by simvastatin of p-AMPKα-Thr(172) and p-PP2A-Tyr(307) expression was observed. The enhanced p-AMPKα-Thr(172) expression was inhibited by compound C, ryanodine (100 µM) and KN93 (10 µM). Simvastatin-induced p-PP2A-Tyr(307) expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 µM), and in [glucose]o-free or [Na(+)]o-free conditions. CONCLUSIONS: Simvastatin causes ryanodine-sensitive Ca(2+) release which is important for AMPKα-Thr(172) phosphorylation via Ca(2+)/CaMK II. AMPKα-Thr(172) phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKα-Thr(172) and PP2A-Tyr(307) resulted. Phosphorylation of PP2A-Tyr(307) occurs at a site downstream of AMPKα-Thr(172) phosphorylation.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Canales KATP/antagonistas & inhibidores , Músculo Liso Vascular/efectos de los fármacos , Simvastatina/farmacología , Adenilato Quinasa/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Células Cultivadas , Vasos Coronarios/citología , Vasos Coronarios/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Glucosa/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Técnicas de Placa-Clamp , Fosforilación , Proteína Fosfatasa 2/metabolismo , Ribonucleótidos/farmacología , PorcinosRESUMEN
AIM: The human hepatocellular carcinoma (HCC) cell line HepG2 can easily acquire resistance to doxorubicin. However, the mechanism of action is unclear. METHODS: In the present study, we used confocal microscopy, flow cytometry and other methods to reveal the mechanisms by which HepG2 cells acquire doxorubicin resistance. RESULTS: Our results showed that R-HepG2 cells, a doxorubicin-resistant sub-line of HepG2, exhibited decreased intracellular accumulation of doxorubicin and increased expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 when compared with HepG2 cells. R-HepG2 cells also harbored higher levels of glutathione and increased expression of glutathione peroxidase. Furthermore, we demonstrated that the phosphorylation of mitogen-activated protein kinases (p38 and c-jun-N-terminal kinases), IkBα and CREB were increased in R-HepG2 cells. Specific p38 inhibitor SB203580 decreased P-gp expression. The multi-kinase inhibitor sorafenib tosylate also significantly suppressed the phosphorylation of these proteins and inhibited the expression of P-gp. CONCLUSION: These findings reveal that the drug resistance could be acquired through mitogen-activated protein kinase-dependent upregulation of P-gp. This mechanism protects R-HepG2 cells from the anticancer action of doxorubicin.
RESUMEN
Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%-83% decrease in AUC(0-∞) and 38%-78% reduction in C(max). The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Citocromo P-450 CYP3A/fisiología , Interacciones de Hierba-Droga , Indinavir/farmacocinética , Preparaciones de Plantas/farmacocinética , Sophora , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Administración Oral , Animales , Citocromo P-450 CYP3A/genética , Medicina de Hierbas/métodos , Indinavir/administración & dosificación , Indinavir/sangre , Preparaciones de Plantas/sangre , ARN Mensajero/análisis , RatasRESUMEN
Danshen (Salvia miltiorrhiza Bunge) as a famous Traditional Chinese medicine is widely used in the treatment of cardiovascular and cerebrovascular diseases in the world. Danshen tincture (DT), extracted from Danshen root with a mixture of water and alcohol, is a commonly used preparation method for human consumption. The aim of this study was to investigate the effects of DT on the cytochrome P450 (CYP) 1A2 and 3A activities by human and rat liver microsomes. Effects of DT were assessed with use of Danshen ethanolic extract (DEE) and selective substrates, markers of CYP activities. DEE (0.5-10 µg/ml) competitively inhibited human and rat liver microsomal CYP1A2 activity with inhibition constant (K(i)) values at 3.40 and 5.16 µg/ml, respectively. At the same time, DEE (2.5-20 µg/ml) not only noncompetitively inhibited human liver microsomal CYP3A4/5 activity with a K(i) of 11.9 µg/ml, but also competitively inhibited rat liver microsomal CYP3A1/2 activity with a K(i) of 52.1 µg/ml. The data indicate that DEE inhibited the metabolism of CYP1A2 and 3A substrates in human and rat liver in vitro with different mode of inhibition. This study may be helpful for clinical application of Danshen tincture.
Asunto(s)
Inhibidores del Citocromo P-450 CYP1A2 , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/farmacología , Salvia miltiorrhiza/química , Animales , Biomarcadores/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Activación Enzimática , Etanol/química , Interacciones de Hierba-Droga , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Fenacetina/farmacología , Fenantrolinas/química , Fenantrolinas/farmacología , Raíces de Plantas/química , Ratas , Ratas Sprague-Dawley , Testosterona/farmacología , Agua/químicaRESUMEN
Doxorubicin is a chemotherapeutic drug widely used for the treatment of hepatocellular carcinoma but its efficacy is restricted by multidrug resistance. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2-selective inhibitors exhibit anti-cancer properties as well as abilities to overcome drug resistance. In the present study, indomethacin (a NSAID) and SC236 (a COX-2-selective inhibitor) enhanced the cytotoxicity of doxorubicin in the hepatocellular carcinoma cell line HepG2 and its drug-resistant sub-line R-HepG2. Both drugs increased the intracellular accumulation and retention of doxorubicin in vitro. The effects were not reversed by prostaglandin E(2), implicating a COX-independent mechanism. Indomethacin and SC236 partially reversed the increase in expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) induced by doxorubicin in R-HepG2 cells. In conclusion, indomethacin and SC236 increased the intracellular accumulation and retention of doxorubicin and thus its cytotoxicity in HepG2 and drug-resistant HepG2 cells. These effects, mediated through decrease in P-gp and MRP1 expression and/or direct inhibition of P-gp activity, may improve multidrug resistant-cancer chemotherapy.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/biosíntesis , Antibióticos Antineoplásicos/farmacología , Western Blotting , Línea Celular Tumoral , Separación Celular , Inhibidores de la Ciclooxigenasa 2/farmacología , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Citometría de Flujo , Humanos , Indometacina/farmacología , Microscopía Confocal , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/biosíntesis , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/efectos de los fármacos , Pirazoles/farmacología , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: We evaluated the role(s) of monoamine oxidase (MAO)-mediated H2O2 generation on 5-hydroxytryptamine (5-HT)-induced tension development of isolated basilar artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. EXPERIMENTAL APPROACH: Basilar artery (endothelium-denuded) was isolated for tension measurement and Western blots. Enzymically dissociated single myocytes from basilar arteries were used for patch-clamp electrophysiological and confocal microscopic studies. KEY RESULTS: Under resting tension, 5-HT elicited a concentration-dependent tension development with a greater sensitivity (with unchanged maximum tension development) in SHR compared with WKY (EC(50) : 28.4 ± 4.1 nM vs. 98.2 ± 9.4 nM). The exaggerated component of 5-HT-induced tension development in SHR was eradicated by polyethylene glycol-catalase, clorgyline and citalopram whereas exogenously applied H2O2 enhanced the 5-HT-elicited tension development in WKY. A greater protein expression of MAO-A was detected in basilar arteries from SHR than in those from WKY. In single myocytes and the entire basilar artery, 5-HT generated (clorgyline-sensitive) a greater amount of H2O2 in SHR compared with WKY. Whole-cell iberiotoxin-sensitive Ca(2+) -activated K(+) (BK(Ca) ) amplitude measured in myocytes of SHR was approximately threefold greater than that in WKY (at +60 mV: 7.61 ± 0.89 pA·pF(-1) vs. 2.61 ± 0.66 pA·pF(-1) ). In SHR myocytes, 5-HT caused a greater inhibition (clorgyline-, polyethylene glycol-catalase- and reduced glutathione-sensitive) of BK(Ca) amplitude than in those from WKY. CONCLUSIONS AND IMPLICATIONS: 5-HT caused an increased generation of mitochondrial H2O2 via MAO-A-mediated 5-HT metabolism, which caused a greater inhibition of BK(Ca) gating in basilar artery myocytes, leading to exaggerated basilar artery tension development in SHR.
Asunto(s)
Peróxido de Hidrógeno/metabolismo , Mitocondrias/efectos de los fármacos , Monoaminooxidasa/metabolismo , Serotonina/farmacología , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/metabolismo , Western Blotting , Relación Dosis-Respuesta a Droga , Hipertensión/fisiopatología , Masculino , Microscopía Confocal , Mitocondrias/metabolismo , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Técnicas de Placa-Clamp , Péptidos/farmacología , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Canales de Potasio Calcio-Activados/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Serotonina/administración & dosificación , Vasoconstricción/efectos de los fármacosRESUMEN
Folic acid supplementation provides beneficial effects on endothelial functions in patients with hyperhomocysteinemia. However, its effects on vascular functions under diabetic conditions are largely unknown. Therefore, the effect(s) of folic acid (5.7 and 71 microg/kg/day for 4 weeks) on aortic relaxation was investigated using obese/diabetic (+db/+db) mice and lean littermate (+db/+m) mice. Acetylcholine-induced relaxation in +db/+db mice was less than that observed in +db/+m mice. The reduced relaxation in +db/+db mice was restored by consumption of 71 microg/kg folic acid. Acetylcholine-induced relaxation (with and without folic acid treatment) was sensitive to N(G)-nitro-L-arginine methyl ester, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, geldanamycin and triciribine. In addition, acetylcholine-induced relaxation was attenuated by resistin. The plasma level of resistin in +db/+db mice was sevenfold higher than that measured in +db/+m mice, and the elevated plasma level of resistin in +db/+db mice was reduced by 25% after treatment with 71 microg/kg folic acid. Folic acid slightly increased the ratio of reduced glutathione to oxidized glutathione in +db/+db mice. Moreover, folic acid caused a reduction in PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression, an increase in the phosphorylation of endothelial nitric oxide synthase (eNOS(Ser1177)) and Akt(Ser473), and an enhanced interaction of heat shock protein 90 (HSP90) with eNOS in both strains, with greater magnitude observed in +db/+db mice. In conclusion, folic acid consumption improved blunted acetylcholine-induced relaxation in +db/+db mice. The mechanism may be, at least partly, attributed to enhancement of PI3K/HSP90/eNOS/Akt cascade, reduction in plasma resistin level, down-regulation of PTEN and slight modification of oxidative state.
Asunto(s)
Acetilcolina/farmacología , Diabetes Mellitus/metabolismo , Ácido Fólico/farmacología , Resistina/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Aorta/fisiopatología , Regulación hacia Abajo , Femenino , Ácido Fólico/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Obesidad/metabolismo , Fosfohidrolasa PTEN/metabolismoRESUMEN
In this study, we have investigated the actions of danshensu, an active, water-extractable component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the water-extractable fraction of the herb. Extraction of the water-soluble fraction from danshen (S. miltiorrhiza) provided yield of 17.5% (35 g/200 g). The amount of danshensu determined in the crude danshen herb and in its aqueous fraction was 0.45 mg/g (0.045%) and 3.28 mg/g (0.33%). The danshen aqueous extract was 13 times less potent than danshensu in relaxing 5-HT-precontracted coronary artery rings; IC50 values were 930.3+/-133.5 microg/ml and 71.5+/-11.0 microg/ml. Removal of the endothelium did not significantly affect their vasodilator potencies; IC50 values were 842.1+/-123.8 microg/ml and 84.8+/-8.8 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.2 folds. The possible involvement of Ca2+ channels was investigated in artery rings incubated with Ca2+-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to addition of CaCl2 to elicit contraction. In 5-HT-primed preparations, the CaCl2-induced vasoconstriction was abolished by 2 mg/ml danshen aqueous extract and 200 microg/ml danshensu, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 600 microg/ml danshensu were required to abrogate the vasoconstriction. These findings suggest the vasorelaxant actions of danshen aqueous extract and danshensu were produced by inhibition of Ca2+ influx in the vascular smooth muscle cells. The opening of K+ channels had a minor contribution to the response, but endothelium-dependent mechanisms were not involved.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Lactatos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Calcio/metabolismo , Vasos Coronarios/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/química , Técnicas In Vitro , Lactatos/aislamiento & purificación , Masculino , Músculo Liso Vascular/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Salvia miltiorrhiza , Tetraetilamonio/farmacologíaRESUMEN
In this study, we examined the effects of Salvia miltiorrhiza (Danshen) crude extract, some of its lipid-soluble components (tanshinone I, tanshinone II(A), cryptotanshinone, dihydroisotanshinone I) and the water-soluble compounds (danshensu and salvianolic acid B) on the K(+) channels such as the iberiotoxin-sensitive Ca(2+)-activated K(+) (BK(Ca)) channels and the glibenclamide-sensitive ATP-dependent K(+) (IK(ATP)) channels of the porcine left anterior descending coronary artery smooth muscle cells. Cumulative application of salvianolic acid B (30-300 microM) caused a l-NNA (100 microM)-insensitive, potentiation of the outward BK(Ca) current amplitude with no apparent effect on the IK(ATP) channels opening. Salvianolic acid B (300 microM) caused an ODQ (10 microM, a guanylate cyclase inhibitor)-sensitive enhancement of the outward BK(Ca) current amplitude. In contrast, none of the other isolated chemical constituents of S. miltiorrhiza modified the openings of the two types of K(+) channels studied. In conclusion, our results suggest that salvianolic acid B, a major hydrophilic constituent found in Radix S. miltiorrhiza, activated the opening of the BK(Ca) channels of the porcine coronary artery smooth muscle cells through the activation of guanylate cyclase without the involvement of the nitric oxide synthase activation.
Asunto(s)
Benzofuranos/farmacología , Músculo Liso Vascular/efectos de los fármacos , Péptidos/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Salvia miltiorrhiza , Animales , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Cromakalim/farmacología , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Gliburida/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/metabolismo , Técnicas In Vitro , Activación del Canal Iónico/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Oxadiazoles/farmacología , Técnicas de Placa-Clamp , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Quinoxalinas/farmacología , Receptores de Droga/efectos de los fármacos , Receptores de Droga/metabolismo , PorcinosRESUMEN
This study investigated the relaxant actions of danshen (Salvia miltiorrhiza) and its lipid-soluble- and water-soluble-fractions on endothelium-denuded rat isolated femoral artery rings. Danshen, its water-soluble fraction and its lipid-soluble fraction produced relaxation of the phenylephrine-precontracted artery rings with IC50 values of 149 +/- 20 microg/mL, 160 +/- 25 microg/mL, and 23 +/- 6 microg/mL, respectively. Pretreatment of the artery rings with a non-selective potassium channel inhibitor tetraethylammonium (TEA, 10 mM) produced a significant two-fold rightward shift of the concentration-response curve to danshen and a four-fold shift to its water-soluble fraction, but had no effect on the lipid-soluble fraction. A 3.3-fold shift was produced on the concentration-response curve of danshen when the artery rings were pretreated with a mixture of 10 mM TEA, 1 mM 4-aminopyridine (K(V) blocker), 1 microM glibenclamide (K(ATP) blocker), 100 nM iberiotoxin (BK(Ca) blocker), and 100 microM barium chloride (K(IR) blocker). Involvement of Ca2+ channels was investigated in endothelium-denuded artery rings incubated with Ca2+-free buffer and primed with 1 microM phenylephrine or 60 mM KCl for 5 minutes prior to adding CaCl2 to elicit contraction. In artery rings primed with phenylephrine, pretreatment with 1 mg/mL danshen, 1 mg/mL water-soluble fraction of danshen, 0.1 mg/mL lipid-soluble fraction of danshen, and 100 nM nifedipine abrogated the CaCl2-induced contraction. On the other hand, in artery rings primed with KCl, these agents produced 40%, 25%, 53%, and 92% inhibition on the maximum contraction induced by CaCl2, respectively. Increasing the concentrations of danshen and its water-soluble fraction to 3 mg/mL, and the lipid-soluble fraction to 0.3 mg/mL further reduced the maximum contraction to 92%, 93%, and 83%, respectively. Taken together, these findings suggested the vasorelaxant actions of danshen and its fractions were produced primarily by inhibition of Ca2+ influx in the vascular smooth muscle cells and a small component was mediated by the opening of K+ channels.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Arteria Femoral/efectos de los fármacos , Extractos Vegetales/farmacología , Salvia miltiorrhiza , Animales , Cloruro de Calcio/farmacología , Arteria Femoral/fisiología , Técnicas In Vitro , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Compuestos de Tetraetilamonio/farmacología , Vasoconstricción/efectos de los fármacosRESUMEN
OBJECTIVE: Zidovudine is one of the most common antiretroviral drugs used to prevent vertical transmission of human immunodeficiency virus. However, it is not recommended for use in the first trimester of pregnancy because of reservations about its potential teratogenicity during the organogenesis phase. The objective of this study was to investigate the placental transfer of zidovudine in the first trimester of human pregnancy. METHODS: Twenty-six pregnant women were given 2 oral doses of zidovudine (200 mg) before first trimester surgical termination of pregnancy. Maternal blood, fetal tissue, and coelomic and amniotic fluid were collected for drug analysis. RESULTS: Zidovudine was detected in all samples of maternal serum and fetal tissue but present in only 7 samples of amniotic and coelomic fluid. Zidovudine concentration in fetal tissue was similar to that of maternal serum. The median fetal/maternal ratio was 0.92 and was not associated with gestational age (r = 0.03, P = .89). CONCLUSION: Zidovudine crossed the first trimester human placenta readily and achieved the level of maternal serum rapidly. Patients who choose to take zidovudine in first trimester of pregnancy should be counseled about the potential fetal effects.
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Fármacos Anti-VIH/farmacocinética , Feto/metabolismo , Intercambio Materno-Fetal , Placenta/metabolismo , Primer Trimestre del Embarazo/metabolismo , Zidovudina/farmacocinética , Aborto Legal , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Embarazo no Deseado/metabolismoRESUMEN
This study investigates the actions of Danshen crude extract (Salvia miltiorrhiza) on rat isolated femoral artery rings precontracted with phenylephrine. Low concentrations of Danshen (10 to 30 microg/mL) enhanced the phenylephrine-precontracted tone by a maximum of 31.20+/-2.71%. At concentrations 100 microg/mL or above, Danshen relaxed the precontracted tone, with full relaxation obtained at 1 mg/mL. Involvement of endothelium-dependant mechanisms in the dilator effect of Danshen was investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on the Danshen-induced effect. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a histamine H2 receptor antagonist cimetidine (10 microM), a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 10 and 100 mM); only TEA was effective in partially inhibiting the Danshen-induced effect. These findings suggest the dilator action of Danshen on rat femoral artery was mediated in part by the opening of TEA-sensitive K+ channels in the smooth muscle cells. Muscarinic receptors, histamine receptors, beta-adrenoceptors, endothelium-derived relaxant factors, adenylyl cyclase, and guanylyl cyclase-dependent pathways did not play a role in its vasodilatory effect.
Asunto(s)
Arteria Femoral/efectos de los fármacos , Salvia miltiorrhiza/química , Vasodilatadores/farmacología , Inhibidores de Adenilato Ciclasa , Animales , Inhibidores de la Ciclooxigenasa/farmacología , Interacciones Farmacológicas , Endotelio Vascular/fisiología , Guanilato Ciclasa/antagonistas & inhibidores , Antagonistas de los Receptores H2 de la Histamina/farmacología , Técnicas In Vitro , Cinética , Masculino , Antagonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Vasoconstrictores/farmacologíaRESUMEN
OBJECTIVE: To determine the degree of placental transfer of rosiglitazone in early human pregnancy. DESIGN: Prospective observational study. SETTING: University teaching hospital. PATIENT(S): Thirty-one women undergoing surgical termination of pregnancy between 8 and 12 weeks' gestation. INTERVENTION(S): Each woman was given two doses of rosiglitazone (4 mg) before the procedure. MAIN OUTCOME MEASURE(S): Rosiglitazone concentration in fetal tissue and coelomic and amniotic fluids. RESULT(S): The mean maternal serum rosiglitazone concentration was 110.3 +/- 47.9 ng/mL. Rosiglitazone was detectable in 19 fetal samples (61.3%). The mean fetal tissue concentration was 52.7 +/- 26.3 ng/g. Rosiglitazone was more likely to be detected in fetal tissue if the gestation at termination was 10 weeks or more compared with earlier gestation. Coelomic fluid was obtained in 22 cases, and rosiglitazone was detected in 13 samples (59.1%). The mean concentration was 22.8 +/- 7.0 ng/mL. Rosiglitazone was detectable in only two of the 31 amniotic fluid samples, with concentrations of 10.3 and 12.6 ng/mL. CONCLUSION(S): The risk of placental transfer of rosiglitazone is much higher at or after 10 weeks of gestation. Absence of detectable rosiglitazone in amniotic fluid despite its presence in fetal tissue suggests that fetuses may have the ability to metabolize rosiglitazone, and little parent drug was excreted unchanged in urine.