Biomedical subjects

Julio G Prieto

Publications and source records attributed to Julio G Prieto.

11 recordsLinked to original sources

PubMed2006

Inhibitory effects of different antioxidants on hyaluronan depolymerization.

Hyaluronan (HA) was depolymerized by hydroxyl radicals generated from hydrogen peroxide and cupric ions. Inhibition of HA degradation by four well-known antioxidants was investigated, as HA can scavenge reactive oxygen species (ROS). Change in hyaluronan molecular weight was observed by size-exclusion chromatography. Inhibition of HA degradation was estimated from the retention times observed. It was found that HA degradation was inhibited in a clearly concentration-dependent manner by mannitol, thiourea and vinpocetine. Propofol also inhibited the depolymerization, but its concentration-dependent effect was not so clear. The antioxidant concentrations at which HA degradation was decreased by 50% were 42 microM for thiourea; 1.35 microM for vinpocetine; and 0.39 microM for propofol. A concentration of 26.51 mM of mannitol was needed to attain the same inhibitory effect. Although many factors are involved in a therapeutic response, the results obtained in this study support the idea that HA may be protected from ROS attack by the concomitant use of well-known antioxidants.

Antioxidants↗

PubMed2006

Effects of ischemia-reperfusion on the absorption and esterase metabolism of diltiazem in rat intestine.

Intestinal ischemia-reperfusion (I/R) is a serious clinical condition that triggers a complex inflammatory response. Inflammatory processes affect some enzymatic systems related to intestinal drug metabolism and bioavailability. Diltiazem (DTZ) is a calcium channel blocker, which is extensively metabolised in the intestine by esterases and different CYP450 isoforms. The main biotransformation pathway of DTZ in rats is desacetylation by esterases. This study analysed the effect of I/R on intestinal absorption and metabolism of DTZ, focusing on esterase activity, through different methodologies, after 60 min of superior mesenteric artery occlusion and 30 min of reperfusion or sham surgical procedures. The rate of DTZ appearance in blood during in situ studies increased significantly in the I/R group (0.094+/-0.014 10(-5) cm/s vs 0.271+/-0.110 10(-5) cm/s) and the calculated metabolised fraction of DTZ decreased significantly, showing an important reduction in the desacetylase activity in the I/R group. These results were supported by microsomal incubations, where desacetylase activity was related to esterases by specific inhibition, using paraoxon and bis-nitrophenylphosphate, and also by studies in everted rings. DTZ metabolism was higher in the jejunum than in the ileum, the esterase activity being affected by I/R in both regions. The present findings suggest that I/R injury clearly affects the esterases' activity and modifies the amount of DTZ and its metabolites in blood during in situ perfusion. This modification of intestinal esterase activity could be important for the pharmacokinetic behaviour of other drugs and prodrugs after intestinal pathologies involving inflammation and oxidative stress.

Animals↗

PubMed2006

Breast cancer resistance protein (BCRP/ABCG2) transports fluoroquinolone antibiotics and affects their oral availability, pharmacokinetics, and milk secretion.

The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette drug efflux transporter that extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds, including their secretion into the milk. The purpose of this study was to determine whether three widely used fluoroquinolone antibiotics (ciprofloxacin, ofloxacin, and norfloxacin) are substrates of Bcrp1/BCRP and to investigate the possible role of this transporter in the in vivo pharmacokinetic profile of these compounds and their secretion into the milk. Using polarized cell lines, we found that ciprofloxacin, ofloxacin, and norfloxacin are transported by mouse Bcrp1 and human BCRP. In vivo pharmacokinetic studies showed that the ciprofloxacin plasma concentration was more than 2-fold increased in Bcrp1(-/-) compared with wild-type mice (1.77 +/- 0.73 versus 0.85 +/- 0.39 microg/ml, p < 0.01) after oral administration of ciprofloxacin (10 mg/kg). The area under the plasma concentration-time curve in Bcrp1(-/-) mice was 1.5-fold higher than that in wild-type mice (48.63 +/- 5.66 versus 33.10 +/- 4.68 min x microg/ml, p < 0.05) after i.v. administration (10 mg/kg). The milk concentration and milk/plasma ratio of ciprofloxacin were 2-fold higher in wild-type than in Bcrp1(-/-) lactating mice. We conclude that Bcrp1 is one of the determinants for the bioavailability of fluoroquinolones and their secretion into the milk.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Interaction of enrofloxacin with breast cancer resistance protein (BCRP/ABCG2): influence of flavonoids and role in milk secretion in sheep.

The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP)/ABCG2 is a high-capacity efflux transporter with wide substrate specificity located in apical membranes of epithelia, which is involved in drug availability. BCRP is responsible for the active secretion of clinically and toxicologically important substrates to milk. The present study shows BCRP expression in sheep and cow by immunoblotting with MAb (BXP-53). Vanadate-sensitive ATPase activity with specific BCRP substrates and inhibitors was measured in bovine mammary gland homogenates. To assess the role of BCRP in ruminant mammary gland we tested the fluoroquinolone enrofloxacin (ENRO). In polarized cell lines, ENRO was transported by Bcrp1/BCRP with secretory/absorptive ratios of 6.5 and 2 respectively. The efflux was blocked by the BCRP inhibitor Ko143. ENRO pharmacokinetics in plasma and milk was studied in sheep after co-administration of drug (2.5 mg/kg, i.v.) and genistein (0.8 mg/kg, i.m.) or albendazole sulfoxide (2 mg/kg, i.v) as BCRP inhibitors. Concomitant administration of BCRP inhibitors with ENRO had no significant effect on the plasma disposition kinetics of ENRO but decreased ENRO concentrations in milk.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Role of ABC transporters in veterinary drug research and parasite resistance.

A considerable body of research has been carried out in order to throw light on the pharmacological and toxicological impact of ATP-binding cassette (ABC) drug efflux transporters such as P-glycoprotein and Breast Cancer Resistance Protein (BCRP/ABCG2/MXR). Most studies focus on their role in rendering cancer cells resistant to anticancer drugs. Drug transporters are expressed in many tissues and they are strongly involved in the oral bioavailability, and the hepatobiliary, direct intestinal and renal excretion of many drugs. In veterinary therapy, some anti parasitic drugs and/or their metabolites, such as ivermectin, moxidectin, albendazole sulfoxide, which are widely used, have been shown to be actively transported by efflux pumps. This interaction plays an important role in drug disposition since its inhibition has been shown to increase the drug bioavailability in some domestic species. Moreover, some authors have reported that parasite resistance to anthelmintic drugs may be mediated by parasite P-glycoprotein efflux. In addition, the importance of milk residues for human nutrition has aroused increasing concern about the inadvertent transfer of drugs and other substances into mammary milk of domestic animals, potentially posing a health risk to consumers. Recently, the important role of BCRP in the secretion of its substrates in milk has been demonstrated.

ATP-Binding Cassette Transporters↗

PubMed2005

Apoptosis and nitric oxide in an experimental model of osteoarthritis in rabbit after hyaluronic acid treatment.

OBJECTIVE: this study determine the effect of hyaluronic acid on chondrocyte apoptosis, as well as variations in nitric oxide levels in an experimental model of osteoarthritis elicited anterior cruciate ligament section (ACL) in a rabbit model with two differentiated developmental periods. METHODS: apoptosis and the quantification of nitric oxide (NO) were studied in two groups of 16 animals each. All animals had both knees operated, but only the right knees were treated with hyaluronic acid (HA). In the first group hyaluronic treatment was performed five weeks after osteoarthritis induction (short term group, ST) and in the second group, 10 weeks after induction (long term group, LT). The animals in both series were sacrificed two weeks after the last dose of HA. Flow cytometry by means of Annexin labelling and the TUNEL method were used for the study of apoptosis, NO levels were measured in cultured cartilage and in the supernatant of the enzymatic digestion of the cartilage. RESULTS: regarding apoptosis measurement, a significant reduction in apoptosis levels was observed in both series as compared to untreated knees. NO production was lower in knees treated with HA, with significant differences after cartilage digestion. CONCLUSION: The administration of HA has been effective ameliorating the damage associated with the process of osteoarthritis induced by experimental surgery as evidenced by decreased apoptosis (TUNEL method), the results more promising in the earlier phases of the disease.

Animals↗

PubMed2003

Intestinal elimination of albendazole sulfoxide: pharmacokinetic effects of inhibitors.

Albendazole (ABZ) is an anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic ABZ metabolism leads to albendazole sulfoxide (ABZSO), the active metabolite. This work examines the mechanism involved in intestinal elimination of ABZSO and their pharmacokinetic consequences in rat and sheep. To assess the drug intestinal elimination, an upper small intestine segment was isolated and perfused in situ with saline, after ABZSO administration (10 mg/kg i.v.). The intestinal clearance of ABZSO was 0.106+/-0.010 ml/min, exhibiting a stereoselective intestinal elimination to (-)ABZSO form. Oxfendazole, ampicillin and cyclosporine significantly reduced the intestinal elimination of ABZSO to 0.079+/-0.008, 0.069+/-0.009 and 0.065+/-0.012 ml/min, respectively. Glucose significantly induced ABZSO intestinal elimination. Pharmacokinetic results showed a clear and statistically significant interaction between ABZ metabolites and drug efflux inhibitors. In rat, an increased area under the curve (AUC) for ABZSO in the groups co-administered with ABZ plus verapamil (43%) and plus ketoconazole (29%) was obtained. In sheep, the AUC for ABZSO in the groups co-administered with the inhibitors were significantly higher 53.68% with verapamil, 78.62% with quinidine, and 50.55% with ivermectin.

Albendazole↗

PubMed2003

Mitochondrial, sarcoplasmic membrane integrity and protein degradation in heart and skeletal muscle in exercised rats.

Several different exercise regimens varied in the severity of tissue damage induced. Therefore, this study investigated the effects of a single bout of exercise versus endurance training in heart and skeletal muscles with different predominant fiber types on indices of mitochondrial, endoplasmic reticulum (ER) integrity and protein degradation. Male Wistar rats performed different treadmill exercise protocols: exhaustive, maximal exhaustive, eccentric, training and exhaustive exercise after training. The maximal and eccentric exercises resulted in a significant loss of integrity of the sarcoplasmic and ER muscle, while no changes were observed in cardiac muscle. Mitochondrial membrane fluidity measured by the fluorescence polarization method was significantly increased post-acute exercises in heart and oxidative muscles. Regular exercise can stabilize and preserve the viscoelastic nature of mitochondrial membranes in both tissues. The highest increase in carbonyl content was obtained in heart after exhaustive exercise protocol, from 1+/-0.1 to 3.6+/-0.14 nmol mg protein(-1), such increase were not found after regular exercise with values significantly decreased. Nitrate heart levels showed attenuated generation of nitric oxide after training. Muscle protein oxidation was produced in all exhaustive exercises including eccentric exercise.

Alkaline Phosphatase↗

PubMed2003

Ginseng increases intestinal elimination of albendazole sulfoxide in the rat.

Herbal products show potential drug interactions, some of them with adverse effects. The main aim of this work was to study the effect of Panax ginseng on the intestinal elimination of the benzimidazole derivative albendazole sulfoxide (ABZSO). An upper small intestine segment was isolated and perfused in situ with saline, while ABZSO solution (10 mg/kg i.v.) was administered intravenously. Blood samples and intestinal secretion were collected over 60 min and analysed by HPLC. The intestinal clearance of ABZSO was 0.106+/-0.010 ml/min. Systemic co-administration of ginseng (10 mg/kg i.v.) increased significantly (P<0.05) the clearance of ABZSO (0.132+/-0.005 ml/min). The increase in ABZSO elimination could be the result of the effect of ginseng on metabolic pathways. These results highlight the interactions between herbal products (sometimes dietary constituents) and drugs such as benzimidazoles, since ginseng modifies the luminal clearance of this anthelminthic drug and could potentially interfere with drugs that undergo the same intestinal processes.

Albendazole↗

PubMed2002

Quantitative assessment of nitric oxide in rat skeletal muscle and plasma after exercise.

Nitric oxide (NO), a short-lived vasoactive substance that has multiple physiological functions, is also involved in skeletal muscle physiology. This work examines the levels of nitrate (the metabolic end-product of NO) in muscle and plasma after different exercise protocols: namely acute, eccentric, cardiac stress and training. Plasma nitrate levels were augmented after strenuous exercise and did not change after training. The vastus intermedius and the gastrocnemius, both oxidative muscles, showed the highest concentrations of cytosolic nitrate after strenuous exercise. NO levels varied, depending on the fibre type, and this may correlate well with the specific contractile function performed.

Animals↗

PubMed2002

The anthelminthic agent albendazole does not interact with p-glycoprotein.

Albendazole is a clinically important anthelminthic agent known to have variable and low oral bioavailability. The aim of this work was to determine whether albendazole, a CYP3A4 substrate, is also a substrate for the multidrug efflux transporter P-glycoprotein. Both in vitro and in vivo methods were used to assess the role of P-glycoprotein-mediated albendazole transport. In cultured LLC-PK1, L-MDR1, and Caco-2 cells, albendazole was found not to be a P-glycoprotein substrate; the transport across LLC-PK1 and L-MDR1 cells revealed basal to apical versus apical to basal transport to a similar extent. In addition, there was no inhibitory effect of albendazole on digoxin transport in Caco-2 cells, and P-glycoprotein inhibitors (verapamil and quinidine) did not affect transport across Caco-2 cells. The in vivo relevance of P-glycoprotein to albendazole disposition was assessed using mdr1a/1b(-/-) mice after intravenous administration of albendazole (15 mg/kg). A similar pattern of tissue distribution in both P-glycoprotein-deficient and wild-type mice was observed. In conclusion, albendazole is neither a substrate nor an inhibitor of P-glycoprotein. Therefore, interactions between albendazole and P-glycoprotein substrates or inhibitors are unlikely to be clinically important.

ATP Binding Cassette Transporter, Subfamily B↗