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Selected AbstractsDisposition and pharmacokinetics of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide, a selective iNOS inhibitor, in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Ji Y. Zhang Abstract The metabolism, pharmacokinetics, tissue distribution, and excretion of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide (L-NIL-TA), a selective inducible NO synthase (iNOS) inhibitor, were investigated in rats. [14C]L-NIL-TA is extensively metabolized after either oral or IV administration with a minor amount (<1%) excreted as the prodrug. L-NIL-TA is metabolized via a single hydrolysis pathway to form the active drug, L-N6-(1-iminoethyl)lysine (L-NIL). The oxidative deamination of 2-amino group of L-NIL forms a 2-keto metabolite (M5), which further loses carbon dioxide to yield a carboxylic acid metabolite (M6). Acetylation of L-NIL and M5 resulted in the formations of metabolites M7 and M4, respectively. Complete recovery of the radioactive dose was achieved after either oral (91.2% in urine and 4.66% in feces) and IV (99.3% in urine and 5.11% in feces) administration. L-NIL-TA-related material was extensively distributed to the tissues, with the highest concentration of radioactivity being found in muscle. Maximal concentration of radioactivity was reached between 0.5 and 1 h post-dose in the majority of tissues, with the exception of muscle and skin where the maximal concentrations were achieved at 8 h post-dose. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1229,1240, 2004 [source] Pharmacokinetic profile of immediate-release omeprazole in patients with gastro-oesophageal reflux associated with gastroparesisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2010J. M. WO Aliment Pharmacol Ther,31, 516,522 Summary Background, Immediate-release omeprazole has a more rapid absorption compared with delayed-release omeprazole in asymptomatic volunteers. However, effects of delayed gastric emptying on omeprazole absorption remain unknown. Aim, To compare pharmacokinetics between immediate and delayed-release omeprazole in patients with GERD associated with gastroparesis. Methods, Open-label, randomized, cross-over study was performed. Antireflux and prokinetic medications were discontinued. Subjects were randomized into: (i) Immediate-release omeprazole 40 mg suspension o.m. for 7 days, wash-out for 10,14 days, followed by delayed-release omeprazole 40 mg capsule o.m. for 7 days, or (ii) the same schedule in reverse order. On day 7, omeprazole concentrations were obtained before and up to 5 h after taking the study drug. Patient Assessment of GI Disorders,Symptom Severity Index was obtained. Results, A total of 12 women (mean age 51 years) completed the protocol. Time to maximal omeprazole concentration was significantly shorter for omeprazole. Maximal concentration was significantly greater for omeprazole, but total area under concentration,time curves was similar. Pharmacokinetic profile was less variable for immediate compared with delayed-release omeprazole. Conclusions, Immediate-release omeprazole was associated with a more rapid absorption and less variable pharmacokinetic profile compared with delayed-release omeprazole in reflux patients associated with gastroparesis. [source] Indigo production by Pseudomonas sp.JOURNAL OF BASIC MICROBIOLOGY, Issue 3 2010a marine naphthalene-degrading strain Abstract A technique developed to determine naphthalene dioxygenase (NDO) activity was optimized and used to study the biotransformation of indole to indigo by Pseudomonas sp. J26 whole cells. The maximum production of indigo was achieved at 25 °C using 2.5 mM indole when J26 was grown in the complex medium JPP, while indole concentrations higher than 4 mM proved toxic for cells. The maximum rate of indigo production was 0.56 nmol min,1 mg dry biomass,1, obtaining 75.5 ,M of indigo after 8 h of incubation, while a maximal concentration (138.1 ,M) of indigo was obtained after 20 h. (© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Reduced oral itraconazole bioavailability by antacid suspensionJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005M. Lohitnavy Summary Aims:, To investigate the effects of antacid suspension on oral absorption of itraconazole. Methods:, A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. Results:, Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0--,) were markedly decreased in antacid-treated group. Tmax for treatment A was 3·0 ± 0·4 and 5·1 ± 2·7 h for treatment B. Cmax and AUC0--, of treatments A and B were 146·3 ± 70·5 vs. 43·6 ± 16·9 (ng/mL) and 1928·5 ± 1114·6 vs. 654·8 ± 452·2 (ng·h/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--, were 24·1,42·1 and 16·2,65·9 respectively. Conclusions:, Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided. [source] Improvement of Subcutaneous Bioavailability of Insulin by Sulphobutyl Ether ,-Cyclodextrin in RatsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KEIICHI TOKIHIRO The objective of this study was to examine and compare how hydrophilic ,-cyclodextrin derivatives (,-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of ,-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-,-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-,-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-,-cyclodextrin with a degree of substitution of the sulphobutyl group of 3,9 (SBE4-,-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8h. The bioavailability of the insulin/SBE4-,-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-,-CyD may be in part due to the inhibitory effects of SBE4-,-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-,-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin. [source] Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantationPEDIATRIC TRANSPLANTATION, Issue 2003Bruce Bostrom Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4,12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis. [source] Pharmacokinetic parameters estimation using adaptive Bayesian P-splines modelsPHARMACEUTICAL STATISTICS: THE JOURNAL OF APPLIED STATISTICS IN THE PHARMACEUTICAL INDUSTRY, Issue 2 2009Astrid Jullion Abstract In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated in order to summarize the complete drug's kinetic profile: area under the curve (AUC), maximal concentration (Cmax), time at which the maximal concentration occurs (tmax) and half-life time (t1/2). Several methods have been proposed to estimate these PK parameters. A first method relies on interpolating between observed concentrations. The interpolation method is often chosen linear. This method is simple and fast. Another method relies on compartmental modelling. In this case, nonlinear methods are used to estimate parameters of a chosen compartmental model. This method provides generally good results. However, if the data are sparse and noisy, two difficulties can arise with this method. The first one is related to the choice of the suitable compartmental model given the small number of data available in preclinical experiment for instance. Second, nonlinear methods can fail to converge. Much work has been done recently to circumvent these problems (J. Pharmacokinet. Pharmacodyn. 2007; 34:229,249, Stat. Comput., to appear, Biometrical J., to appear, ESAIM P&S 2004; 8:115,131). In this paper, we propose a Bayesian nonparametric model based on P-splines. This method provides good PK parameters estimation, whatever be the number of available observations and the level of noise in the data. Simulations show that the proposed method provides better PK parameters estimations than the interpolation method, both in terms of bias and precision. The Bayesian nonparametric method provides also better AUC and t1/2 estimations than a correctly specified compartmental model, whereas this last method performs better in tmax and Cmax estimations. We extend the basic model to a hierarchical one that treats the case where we have concentrations from different subjects. We are then able to get individual PK parameter estimations. Finally, with Bayesian methods, we can get easily some uncertainty measures by obtaining credibility sets for each PK parameter. Copyright © 2008 John Wiley & Sons, Ltd. [source] Ultraviolet B Light-induced Nitric Oxide/Peroxynitrite Imbalance in Keratinocytes,Implications for Apoptosis and NecrosisPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2010Shiyong Wu Elevation of nitric oxide (NO,) can either promote or inhibit ultraviolet B light (UVB)-induced apoptosis. In this study, we determined real-time concentration of NO, and peroxynitrite (ONOO,) and their role in regulation of membrane integrity and apoptosis. Nanosensors (diameter 300,500 nm) were used for direct in situ simultaneous measurements of NO, and ONOO, generated by UVB in cultured keratinocytes and mice epidermis. An exposure of keratinocytes to UVB immediately generated ONOO, at maximal concentration of 190 nm followed by NO, release with a maximal concentration of 91 nm. The kinetics of UVB-induced NO,/ONOO, was in contrast to cNOS agonist stimulated NO,/ONOO, from keratinocytes. After stimulating cNOS by calcium ionophore (CaI), NO, release from keratinocytes was followed by ONOO, production. The [NO,] to [ONOO,] ratio generated by UVB decreased below 0.5 indicating a serious imbalance between cytoprotective NO, and cytotoxic ONOO,,a main component of nitroxidative stress. The NO,/ONOO, imbalance increased membrane damage and cell apoptosis was partially reversed in the presence of free radical scavenger. The results suggest that UVB-induced and cNOS-produced NO, is rapidly scavenged by photolytically and enzymatically generated superoxide (O2,,) to produce high levels of ONOO,, which enhances oxidative injury and apoptosis of the irradiated cells. [source] Disposition and pharmacokinetics of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide, a selective iNOS inhibitor, in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Ji Y. Zhang Abstract The metabolism, pharmacokinetics, tissue distribution, and excretion of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide (L-NIL-TA), a selective inducible NO synthase (iNOS) inhibitor, were investigated in rats. [14C]L-NIL-TA is extensively metabolized after either oral or IV administration with a minor amount (<1%) excreted as the prodrug. L-NIL-TA is metabolized via a single hydrolysis pathway to form the active drug, L-N6-(1-iminoethyl)lysine (L-NIL). The oxidative deamination of 2-amino group of L-NIL forms a 2-keto metabolite (M5), which further loses carbon dioxide to yield a carboxylic acid metabolite (M6). Acetylation of L-NIL and M5 resulted in the formations of metabolites M7 and M4, respectively. Complete recovery of the radioactive dose was achieved after either oral (91.2% in urine and 4.66% in feces) and IV (99.3% in urine and 5.11% in feces) administration. L-NIL-TA-related material was extensively distributed to the tissues, with the highest concentration of radioactivity being found in muscle. Maximal concentration of radioactivity was reached between 0.5 and 1 h post-dose in the majority of tissues, with the exception of muscle and skin where the maximal concentrations were achieved at 8 h post-dose. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1229,1240, 2004 [source] Seasonal changes in melatonin concentrations in female Iberian red deer (Cervus elaphus hispanicus)JOURNAL OF PINEAL RESEARCH, Issue 3 2003Andrés García Abstract: In deer, most of the earlier investigations on pineal function examined the effects of artificial photoperiods or the administration of melatonin to manipulate reproduction. However, endogenous melatonin rhythms have not been studied in red deer. Thus, we monitored seasonal changes in plasma melatonin concentrations in 16 adult female Iberian red deer living in outdoor enclosures. Blood was sampled on the day of each seasonal change every 3,4 hr overnight and 1 hr before and after sunset and sunrise. In addition, in six of the previous hinds, blood sampling during the hour prior and after sunset and sunrise was collected every 20 min. Significant differences were found both in amplitude and duration of the nocturnal plasma melatonin profiles in the four seasonal changes (P<0.01). The nocturnal mean level of melatonin, the duration of nocturnal secretion levels and maximal concentrations were significantly higher at the winter solstice than in summer solstice or equinoxes (P<0.05). Moreover, the mean overnight concentrations were significantly higher at the spring equinox and winter solstice than during the summer solstice and autumn equinox (P<0.05). A pronounced elevation from low levels was recorded 1 hr after sunset, remained elevated during the hours of darkness and declined to low levels 1 hr after dawn. Concentrations close to sunrise were higher than those near sunset at all changes of season (P<0.05). These results show for the first time in red deer that the pineal gland of the adult female is highly responsive to both daily and seasonal changes in natural environmental illumination, although overnight levels lasted longer than the photoperiodic night is all cases, particularly at the winter solstice. [source] Detection and pharmacokinetics of tetrahydrogestrinone in horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2009M. MACHNIK The anti-doping rules of national and international sport federations ban any use of tetrahydrogestrinone (THG) in human as well as in horse sports. Initiated by the THG doping scandals in human sports a method for the detection of 3-keto-4,9,11-triene steroids in horse blood and urine was developed. The method comprises the isolation of the analytes by a combination of solid phase and liquid,liquid extraction after hydrolysis and solvolysis of the steroid conjugates. The concentrations of THG in blood and urine samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A THG excretion study on horses was conducted to verify the method capability for the analysis of postadministration urine samples. In addition, blood samples were collected to allow for determination of the pharmacokinetics of THG in horses. Following the administration of a single oral dose of 25 ,g THG per kg bodyweight to 10 horses, samples were collected at appropriate intervals. The plasma levels of THG reached maximal concentrations of 1.5,4.8 ng/mL. Twenty-four hours after the administration plasma levels returned to baseline. In urine, THG was detectable for 36 h. Urinary peak concentrations of total THG ranged from 16 to 206 ng/mL. For the 10 horses tested, the mean plasma clearance of THG was 2250 mL/h/kg and the plasma elimination half-life was 1.9 h. [source] Pharmacokinetics of altrenogest in horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007M. MACHNIK The Federation Equestre Internationale has permitted the use of altrenogest in mares for the control of oestrus. However, altrenogest is also suspicious to misuse in competition horses for its potential anabolic effects and suppression of typical male behaviour, and thus is a controlled drug. To investigate the pharmacokinetics of altrenogest in horses we conducted an elimination study. Five oral doses of 44 ,g/kg altrenogest were administered to 10 horses at a dose interval of 24 h. Following administration blood and urine samples were collected at appropriate intervals. Altrenogest concentrations were measured by liquid chromatography-tandem mass spectrometry. The plasma levels of altrenogest reached maximal concentrations of 23,75 ng/mL. Baseline values were achieved within 3 days after the final administration. Urine peak concentrations of total altrenogest ranged from 823 to 3895 ng/mL. Twelve days after the final administration concentrations were below the limit of detection (ca 2 ng/mL). [source] Using a GnRH agonist to obtain an index of testosterone secretory capacity in the cockatiel (Nymphicus hollandicus) and sulphur-crested cockatoo (Cacatua galerita)AUSTRALIAN VETERINARY JOURNAL, Issue 1-2 2010EM Lovas Objective Validation of a stimulation test for determining the steroidogenic capacity of the parrot testis. The major aim was to characterise testosterone secretion after injection of a gonadotropin-releasing hormone agonist (GnRHa), then use the test to investigate seasonal reproduction in the male cockatiel. Procedure A synthetic GnRHa (buserelin; 8.0 µg of peptide/kg bodyweight) was injected IM into male cockatiels (n = 7) and sulphur-crested cockatoos (n = 3) and serial blood samples collected at 0, 30, 60, 90 and 120 min after administration. Once validated, the technique was subsequently used to examine seasonal changes (23 months) in the testosterone profile of a captive cockatiel population. Results Injection of buserelin resulted in a significant increase in the testosterone concentration of cockatiel plasma, with maximal concentrations occurring at approximately 60 (1.33 ± 0.08 ng/mL) to 90 min (1.22 ± 0.08 ng/mL) after injection. Although no clear pattern of seasonal variation in testosterone secretion was detected in cockatiel plasma, samples taken 60 and 90 min after administration showed a significant increase in all seasons. Injection of buserelin in the sulphur-crested cockatoo also resulted in increased testosterone secretion, with maximal concentrations obtained after 90 min. Conclusion Buserelin can be used to obtain a reliable index of the prevailing testosterone capacity of the cockatiel and cockatoo testis. With further studies, this test may be incorporated into clinical assessment of reproductive status. [source] Heterologous desensitization of the sphingosine-1-phosphate receptors by purinoceptor activation in renal mesangial cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2004Cuiyan Xin Sphingosine-1-phosphate (S1P) is considered a potent mitogen for mesangial cells and activates the classical mitogen-activated protein kinase (MAPK) cascade via S1P receptors. In this study, we show that S1P signalling is rapidly desensitized upon S1P receptor activation. A complete loss of S1P sensitivity occurs after 10 min of S1P pretreatment and remains for at least 8 h. A similar desensitization is also seen with the S1P mimetic FTY720-phosphate, but not with the nonphosphorylated FTY720, nor with sphingosine or ceramide. Prestimulating the cells with extracellular ATP or UTP, which bind to and activate P2Y receptors on mesangial cells, a similar rapid desensitization of the S1P receptor occurs, suggesting a heterologous desensitization of S1P receptors by P2Y receptor activation. Furthermore, adenosine binding to P1 receptors triggers a similar desensitization. In contrast, two other growth factors, PDGF-BB and TGF,2, have no significant effect on S1P-induced MAPK activation. S1P also triggers increased inositol trisphosphate (IP3) formation, which is completely abolished by S1P pretreatment but only partially by ATP pretreatment, suggesting that IP3 formation and MAPK activation stimulated by S1P involve different receptor subtypes. Increasing intracellular cAMP levels by forskolin pretreatment has a similar effect on desensitization as adenosine. Moreover, a selective A3 adenosine receptor agonist, which couples to phospholipase C and increases IP3 formation, exerted a similar effect. Pretreatment of cells with various protein kinase C (PKC) inhibitors prior to ATP prestimulation and subsequent S1P stimulation leads to a differential reversal of the ATP effect. Whereas the broad-spectrum protein kinase inhibitor staurosporine potently reverses the effect, the PKC- , inhibitor CGP41251, the PKC- , inhibitor rottlerin and calphostin C show only a partial reversal at maximal concentrations. Suramin, which is reported as a selective S1P3 receptor antagonist compared to the other S1P receptor subtypes, has no effect on the S1P-induced MAPK activation, thus excluding the involvement of S1P3 in this response. In summary, these data document a rapid homologous and also heterologous desensitization of S1P signalling in mesangial cells, which is mechanistically triggered by PKC activation and eventually another staurosporine-sensitive protein kinase, as well as by increased cAMP formation. British Journal of Pharmacology (2004) 143, 581,589. doi:10.1038/sj.bjp.0705980 [source] | |||||||||||||||||||||||||