Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 8 Articles
Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp)\r\nexpression. Confirmation of P-gp expression during ontogeny is needed for understanding the differences in\r\ntherapeutic efficacy of any drug in juvenile and adult animals. In this study, Abcb1 mRNA levels in the liver and\r\nintestine of broilers during ontogeny were analysed by RT qPCR. Cellular distribution of P-gp was detected by\r\nimmunohistochemstry. Age-related differences of enrofloxacin pharmacokinetics were also studied. It was found that\r\nbroilers aged 4 week-old expressed significantly (P<0.01) higher levels of P-gp mRNA in the liver, jejunum and ileum,\r\nthan at other ages. However, there was no significant (P>0.05) age-related difference in the duodenum. Furthermore,\r\nthe highest and lowest levels of Abcb1 mRNA expression were observed in the jejunum, and duodenum,\r\nrespectively. P-gp immunoreactivity was detected on the apical surface of the enterocytes and in the bile canalicular\r\nmembranes of the hepatocytes. Pharmacokinetic analysis revealed that the 8 week-old broilers, when orally\r\nadministrated enrofloxacin, exhibited significantly higher Cmax (1.97 vs. 0.98 �µgâ�¢ml-1, P=0.009), AUC(14.54 vs. 9.35\r\n�µgâ�¢ml-1â�¢h, P=0.005) and Ka (1.38 vs. 0.43 h-1, P=0.032), as well as lower Tpeak (1.78 vs. 3.28 h, P=0.048) and T1/2ka\r\n(0.6 vs. 1.64 h, P=0.012) than the 4 week-old broilers. The bioavailability of enrofloxacin in 8 week-old broilers was\r\nincreased by 15.9%, compared with that in 4 week-old birds. Interestingly, combining verapamil, a P-gp modulator,\r\nsignificantly improved pharmacokinetic behaviour of enrofloxacin in all birds. The results indicate juvenile broilers had\r\na higher expression of P-gp in the intestine, affecting the pharmacokinetics and reducing the bioavailability of oral\r\nenrofloxacin in broilers. On the basis of our results, it is recommended that alternative dose regimes are necessary\r\nfor different ages of broilers for effective therapy....
The aim of the present work was to prepare and evaluate osmotic controlled drug delivery system of Cyproheptadine hydrochloride that can provide continuous drug release for period of 24 hours. Different formulations were made using different osmotic agent like Kcl, mannitol, Fructose and mannose. SLS used as wicking agent and OPADRY CA was used as a semi permeable coating membrane which is co process excipient of cellulose acetate and PEG 6000(9:1). The tablets were subjected to thickness, hardness, friability, weight variations, and drug content by assay and in vitro dissolution studies. Drug release was observed in different pH media and different agitation study and was observed that batch containing Kcl shows sustain delivery of the drug for 24 hr with zero order release. And also drug release was independent from pH media and agitation intensity....
Purpose.Heme oxygenase-1 (HO-1) has been proposed to exert pharmacological benefits by its antioxidative and anti-inflammatory\r\neffects. HO-1 expression may be affected by the GT length polymorphism in the promoter region of the HO-1 gene.We investigated\r\nthe inducibility of HO-1 by orally administered curcumin in healthy male subjects and its correlation with the GT length\r\npolymorphism. Methods. In an open label uncontrolled phase-1 pilot study, ten male subjects received 12 g of oral curcumin. To\r\ninvestigate the effects of theGT length polymorphism on the inducibility ofHO-1, five subjectswith homozygous short and five with\r\nhomozygous long GT genotypes were studied. Plasma concentrations of curcumin, bilirubin, HO-1 mRNA, and protein expression\r\nin peripheral blood mononuclear cells (PBMCs) were analyzed over 48 hours. Results. At a detection limit of 1 ug/mL curcumin\r\ncould not be detected in plasma of any subject.Compared to baseline,HO-1mRNAand protein levelswere not induced inPBMCs at\r\nany time point up to 48 hours.There was no correlation between any of the parameters and GT length polymorphism. Conclusions.\r\nOral curcumin administration has low bioavailability and does not induce HO-1 on mRNA or protein level in PBMCs....
Background. There is no FDA-approved medication for cocaine dependence or consensus on the statistical approach for analyzing\r\ndata from cocaine dependence pharmacotherapy trials. The goal of this paper is to illustrate the importance of understanding\r\nmedication�s pharmacodynamics when specifying the statistical model to test its efficacy. Method. Data from a double-blind\r\nplacebo controlled trial of reserpine for cocaine dependence are analyzed. Since the antihypertensive properties of reserpine\r\nare well established, blood pressure data are utilized to evaluate the ability of two statistical models, one that does not take the\r\npharmacodynamics of reserpine into account and one that does, to detect reserpine�s antihypertensive effect. Results. The statistical\r\nmodel specified without regard to reserpine�s pharmacodynamics failed to find a significant medication effect for either systolic\r\nP = 0.49) or diastolic (P = 0.59) blood pressure. Contrariwise, the model based on the pharmacodynamics of reserpine found a\r\nsignificant effect for both systolic (P = 0.002) and diastolic (P = 0.004) blood pressure. Conclusions. If the pharmacodynamics of a\r\nstudy medication are not considered when specifying statistical models, then erroneous conclusions may be reached. This trial is\r\nregistered with NCT00033033....
Purpose. TRPV1 is a multimodal channel mainly expressed in sensory neurons. We aimed to explore the pharmacodynamics of\r\nthe TRPV1 agonists, capsaicin, natural capsaicinoids, and piperine in an in vitro bioassay using human PC-3 cells and to examine\r\ndesensitization and the effect of the specific antagonist SB366791. Methods. PC-3 cells expressing TRPV1were incubated with Fluo-4.\r\nFluorescence emission changes following exposition to agonists with and without preincubation with antagonists were assessed\r\nand referred to maximal fluorescence following the addition of ionomycin. Concentration-response curves were fitted to the Hill\r\nequation. Results. Capsaicin and piperine had similar pharmacodynamics (Emax 204.8 �± 184.3% piperine versus 176.6 �± 35.83%\r\ncapsaicin, P = 0.8814, Hill coefficient 0.70 �± 0.50 piperine versus 1.59 �± 0.86 capsaicin, P = 0.3752). In contrast, capsaicinoids had\r\nlower Emax (40.99 �± 6.14% capsaicinoids versus 176.6 �± 35.83% capsaicin, P < 0.001). All the TRPV1 agonists showed significant\r\ndesensitization after the second exposition and their effects were strongly inhibited by SB366791. Conclusion. TRPV1 receptor is\r\nsuccessfully stimulated by capsaicin, piperine, and natural capsaicinoids. These agonists present desensitization and their effect\r\nis significantly reduced by a TRPV1-specific antagonist. In addition, PC-3 cell bioassays proved useful in the study of TRPV1\r\npharmacodynamics....
Aim. To compare the pharmacokinetics and pharmacodynamics of herbal ointment Liu-He-Dan (LHD) and micron LHD (MLHD)\r\nin rats with acute pancreatitis (AP). Methods. Twenty rats were allocated into normal, AP, LHD, andMLHDgroups. LHD orMLHD\r\nwas applied on ratsââ?¬â?¢ abdomens. Plasma levels of emodin, rhein, aloe emodin, physcion, and chrysophanol were determined by high\r\nperformance liquid chromatographyââ?¬â?mass spectrometryââ?¬â?mass spectrometry (HPLC-MS-MS) at different time points, and the\r\npharmacokinetic parameters were calculated. Serumamylase, TNF-a, IL-6, and IL-10 levels, and the pancreatic pathological scores\r\nwere determined at 48 h after LHD or MLHD treatment. Results. T1/2a and area under the curve (AUC) of emodin in the MLHD\r\ngroup were lower than those in the LHD group, while T1/2a and AUC of aloe emodin in the MLHD group were higher than\r\nthose in the LHD group (P < 0.05). T1/2a and Tmax of physcion in the MLHD group were significantly shorter than those in the\r\nLHD group (P < 0.05). Compared with the AP group, the amylase, malondialdehyde (MDA), TNF-a, and IL-6 levels decreased\r\nsignificantly after three days of treatment in LHD and MLHD groups, while the levels of superoxide dismutase (SOD), TNF-a,\r\nand the pancreatic pathological score, were similar. The pharmacodynamic parameters between the LHD and MLHD groups were\r\nsimilar. Conclusion.MLHD had better pharmacokinetics than, and similar pharmacodynamics to, LHD in the management of rats\r\nwith AP, which indicated thatMLHDmight be substituted for LHD in the treatment ofAP and thus reduce the amount ofmedicinal\r\nherbs used....
Background: Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration\r\nof fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies:\r\n1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in\r\nthe United States.\r\nMethods: Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in\r\nCohort 1 (age 5ââ?¬â??12 years) and Cohort 2 (age 6ââ?¬â??59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and\r\n10 mg/kg CQ once daily for 3 days (for =20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ\r\n150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg\r\nper tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations\r\nfrom both studies were pooled. Population PK models were constructed using standard approaches to evaluate the\r\nconcentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour.\r\nResults: A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a\r\ntwo-compartment model with linear clearance and absorption and an absorption lag adequately described CQ\r\ndata. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive\r\nchecks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were\r\nsignificantly lower AZ (0.488 vs 0.745 [mgââ?¬Â¢h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mgââ?¬Â¢h/L]/[mg/kg],\r\np < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults.\r\nConclusions: The PK of AZ and CQ following administration of AZCQ was well described using a three- and twocompartment\r\nmodel, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included\r\nan absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ\r\nand CQ exposure in children would be expected to be lower than that in adults, suggesting that children may\r\nrequire a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure....
Aim.The aim of this study was to establish population pharmacokinetic models of tacrolimus in Chinese adult liver transplantation\r\npatients. Methods. Tacrolimus dose and concentration data (n = 435) were obtained from 47 Chinese adult liver transplant\r\nrecipients, and the data were analyzed using a nonlinear mixed-effectmodeling (NONMEM) method. Results.The structuralmodel\r\nwas a two-compartment model with first-order absorption. The typical population values of tacrolimus for the pharmacokinetic\r\nparameters of apparent clearance (CL/F), apparent distribution volume of the central compartment (V2/F), intercompartmental\r\nclearance (Q/F), apparent distribution volume of the peripheral compartment (k3/F), and absorption rate (ka) were 11.2 L/h, 406 L,\r\n57.3 L/h, 503 L, and 0.723 h-1, respectively.The interindividual variabilities of these parameters were 16.2%, 163%, 19.7%, 199%, and\r\n74.3%, respectively, and the intraindividual variability of observed concentration was 26.54%. The covariates retained in the final\r\nmodels were postoperative days (POD) and dosage per day (DOSE) on CL/??. Conclusion. Population pharmacokinetic models of\r\ntacrolimus were developed in Chinese adult liver transplant patients. These results could provide the interpretation of the outcome\r\nof pharmacokinetics modeling and the impact of covariate tested on individualized tacrolimus therapy....
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