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Dose Range (dose + range)
Selected AbstractsTime-action profile of insulin detemir and NPH insulin in patients with type 2 diabetes from different ethnic groups,DIABETES OBESITY & METABOLISM, Issue 5 2006M. Hompesch Aim:, To evaluate the time-action profiles and the dose,response relationship of the long-acting insulin analogues insulin detemir (IDet) and NPH insulin (NPH) in type 2 diabetic patients belonging to different ethnic groups. Methods:, Forty-eight type 2 diabetic patients belonging to different ethnic groups (three groups of 16 African Americans (AA), 16 Hispanics/Latinos (HL) and 16 Caucasians) participated in this double-blind crossover trial. Each patient took part in six 16-h isoglycaemic glucose clamps (clamp target 7.2 mmol/l) and was randomly allocated to three doses (0.3, 0.6 and 1.2 (I)U/kg) of IDet and NPH, respectively. Results:, IDet and NPH showed comparable pharmacodynamic effects [the area under the glucose infusion rate curve (AUCGIR 0-16 h) (mg/kg)] in the investigated dose range: IDet, 0.3 U/kg, 207 AA, 535 HL, 285 Caucasians; 0.6 U/kg, 1203 AA, 824 HL and 1126 Caucasians; 1.2 U/kg, 1502 AA, 1977 HL and 2269 Caucasians; NPH, 0.3 IU/kg, 733 AA, 1148 HL and 1148 Caucasians; 0.6 IU/kg, 1395 AA, 1976 HL and 1077 Caucasians; 1.2 IU/kg, 2452 AA, 3296 HL and 2455 Caucasians. Both IDet and NPH showed a linear dose,response relationship in all three groups (p = 0.31), without any significant differences in slope (p = 0.71) or intercept (p = 0.51). Comparable results were obtained for pharmacokinetics. Conclusions:, These results confirm a linear dose,response relationship of IDet, without any relevant differences between ethnic groups. This suggests that similar dosing recommendation can be used for IDet in type 2 diabetic patients belonging to different ethnic group. [source] Evaluation of the rodent micronucleus assay by a 28-day treatment protocol: Summary of the 13th Collaborative Study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Environmental Mutagen Society of Japan (JEMS),Mammalian Mutagenicity Study Group (MMS)ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2001Shuichi Hamada Abstract To examine whether micronucleus tests can be incorporated into general toxicology assays, we performed micronucleus tests applying the treatment protocols typically used in such assays. In this 13th Collaborative Study of the CSGMT, both rats and mice were tested, although rats were used in the majority of the studies. Fifteen mutagens were tested in rats, mainly by oral (p.o.) administration. Micronucleus induction was evaluated 2, 3, and 4 days, and 1, 2, 3, and 28 days after the beginning of the treatment in the peripheral blood, and at 28 days in the bone marrow. Of the 15 chemicals that induced micronuclei in rats in short-term assays, two chemicals (1,2-dimethylhydrazine·2HCl and mitomycin C) were negative in all our experiments, possibly because of insufficient dose levels. The remaining 13 were positive within the estimated dose range of a general toxicology assay, suggesting the possibility of integrating the micronucleus assay into general toxicology assays. Three patterns were observed in micronucleus induction during the period of repeated treatment: (1) gradual increases in micronucleus frequency with sequential doses, (2) a peak at 3,5 days followed by gradual decreases in micronucleus frequency with sequential doses, and (3) a rapid increase in micronucleus frequency followed by a plateau. We evaluated factors that might have been involved in those patterns, such as the spleen function, target organ exposure, extramedullary hematopoiesis, hypothermia, and hypoxia. Another factor we considered was dosage. Because the dosages employed in a general toxicity assay are usually lower than those used in short-term micronucleus assays, this discrepancy was considered the greatest potential problem for integrating the micronucleus assay into general toxicology assays. Our results indicate that the integration of the micronucleus assay into a 28-day toxicological assay is feasible. To serve this purpose, blood samples collected 4 days after the beginning of treatment and blood and bone marrow samples collected at autopsy should be examined. Furthermore, although it is recognized that mice may be suitable for performing independent micronucleus assays, we propose that rats can provide biologically important and relevant information regarding potential chemical mutagens that can be evaluated under conditions used in the conduct of general toxicology studies. Environ. Mol. Mutagen. 37:93,110, 2001 © 2001 Wiley-Liss, Inc. [source] Does prescribing for opiate addiction change after national guidelines?ADDICTION, Issue 5 2007Methadone, buprenorphine prescribing to opiate addicts by general practitioners, hospital doctors in England ABSTRACT Aim To assess changes in opiate prescribing (1995,2005) following a decade of national guidelines to address substandard opiate substitution prescribing for heroin addiction. Design A repeat national survey (1995 and 2005) using random one-in-four samples of all community pharmacies in England, achieving response rates of 75% (1847/2475) in 1995 and 95% (2349/2473) in 2005. Data were obtained on 3732 (1995 data) and 9620 (2005 data) prescriptions dispensed in the preceding month from the 936 and 1463 pharmacies who were currently dispensing. Measurements We have measured impact on practice for seven specific recommended changes. Findings Between 1995 and 2005 the number of substitute opiate prescriptions doubled (×2.03). By 2005, methadone still dominated (down from 97% to 83%), buprenorphine increased (from 1% to 16%) and other opiate medications virtually disappeared. Changes in the direction of national guidelines included: increased daily dose of methadone (from 47.3 mg to 56.3 mg), more frequent dispensing (from 38% to 60% as daily instalments), more supervised consumption (from 0% to 36%) and fewer methadone tablets (from 10.9% to 1.8%). Nevertheless, despite the increased mean daily dose, only 41.0% of prescriptions for methadone were for daily doses in the recommended 60,120 mg dose range. Only one change was not in the direction of the national guidelines,the proportion of prescriptions from GPs fell from 41% to 30%, although this still represented an approximate 50% increase in the extent of GP prescribing. Conclusion Doubling in provision of opiate substitute treatment has occurred, alongside significant improvements in the nature of this treatment. These positive changes have occurred in the direction of six out of seven of the UK national guidelines. [source] Dose-dependent stimulation of hepatic retinoic acid hydroxylation/oxidation and glucuronidation in brook trout, Salvelinus fontinalis, after exposure to 3,3,,4,4,-tetrachlorobiphenylENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2000Patrick M. Boyer Abstract Extremely low stores of vitamin A have been reported in fish and birds inhabiting regions contaminated by coplanar polychlorinated biphenyls (PCBs) and other organochlorines, suggesting many possible effects on retinoid biochemical pathways. Metabolic imbalances associated with biologically active retinoids (e.g., retinoic acid) could be associated with teratogenesis, edema, growth inhibition, reproductive impairment, immunosuppression, and susceptibility to cancer. Sexually mature brook trout were injected intraperitoneally with the coplanar PCB 3,3,,4,4,-tetrachlorobiphenyl (TCBP) and again 4 weeks later. At 8 weeks, retinoic acid metabolism was measured in liver microsomes. To our knowledge, retinoic acid conjugation by UDP-glucuronyltransferase is described here for the first time in fish. A substantial rate of glucuronidation was detected in the microsomes from control brook trout, which tended to increase over the dose range of TCBP. Glucuronidation was significantly greater in fish receiving the 10 ,g/g body weight dose level. Metabolism through the cytochrome P450 system was also dose-dependent, resulting in significantly greater production of 4-hydroxyretinoic acid at the 10 ,g/g dose level. In contrast, subsequent oxidation to 4- oxo -retinoic acid was greatest at the 1 ,g/g dose level and did not increase further at higher doses. Liver stores of dehydroretinyl palmitate/oleate were significantly decreased at the 5 and 10 ,g/g dose levels. [source] Rufinamide: Clinical pharmacokinetics and concentration,response relationships in patients with epilepsyEPILEPSIA, Issue 7 2008Emilio Perucca Summary Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6,10 h. The apparent volume of distribution (Vd/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of ,13.7% in female children comedicated with vigabatrin to a maximum of ,46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related. [source] Dose Range-Finding Studies With Frovatriptan in the Acute Treatment of MigraineHEADACHE, Issue 2002Alan Rapoport MD Objective.,To determine the optimum dose of frovatriptan for the acute treatment of migraine. Background.,Frovatriptan is a new triptan developed for the acute treatment of migraine. The dose-response characteristics and safety of frovatriptan have been investigated across a broad range of doses from 0.5 to 40 mg. Design.,Two randomized, placebo-controlled, double-blind, parallel-group trials, with a total of 1453 patients, were performed to determine the optimal dose of the 5-HT1B/1D agonist, frovatriptan, for the acute treatment of migraine. The dose ranges studied were 2.5 to 40 mg in the high-dose study and 0.5 to 5 mg in the low-dose study. Results.,At 2 hours postdosing for initial moderate or severe headache (International Headache Society grades 2 or 3), there was an approximate two-fold difference in the proportion of patients taking frovatriptan doses of 2.5 to 40 mg with mild or no headache compared to placebo. Frovatriptan doses of 0.5 mg and 1 mg were not more effective than placebo at 2 hours postdose, and 2.5 mg was identified as the lowest effective dose for the relief of migraine and accompanying symptoms. Above 2.5 mg, no dose-response relationship was observed for any efficacy parameters. There was an increase in the incidence of adverse events from 10 mg and above, but the vast majority were rated as mild in severity and did not impact upon tolerability in a significant manner. Conclusions.,Frovatriptan was well tolerated throughout the dose range of 0.5 to 40 mg. The 2.5-mg dose confers the optimal balance of efficacy and tolerability for the acute treatment of migraine. [source] Effect of gamma irradiation and sulphitation treatments on keeping quality of white button mushroom Agaricus bisporus (J. Lge)INTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 5 2009Ali M. Wani Summary Gamma irradiation, alone and in combination with sulphitation, was tested for preventing the browning and maintaining the quality attributes of the white button mushrooms. Mushrooms were subjected to treatment of gamma irradiation in the dose range of 0.5,2.0 kGy and to combination treatments of sulphitation at a concentration of 0.1% potassium metabisulphite (KMS) and gamma irradiation (dose range 0.5,2.0 kGy) followed by storage at 10 ± 2 °C (RH 85%). A dose of 2.0 kGy significantly reduced the weight loss, prevented browning and mould growth. Cap and veil opening of mushrooms was delayed by 9 days and shelf life was extended by 12 days at a dose level of 2.0 kGy. Sulphitation alone at a concentration of 0.1% KMS was effective in controlling browning only upto 3 days, beyond which both browning and cap opening increased significantly (P , 0.05) and the samples were unacceptable after 6 days of storage. No synergistic effect of sulphitation and irradiation was observed with respect to the shelf-life extension of mushroom. [source] ESR detection of irradiated broad bean (Vicia faba L.) and kinetics of the radiation induced free radical and Mn2+ signalsINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 6 2003Mustafa Polat Summary An ESR (Electron Spin Resonance) investigation on irradiated dry broad bean gave a spectrum which was composed of an equally spaced sextet and a single resonance line. These lines appeared at g = 2.0045 (±0.0005) and originated from Mn2+ ions and radiation induced radicals, respectively. Ground broad bean was used throughout the work to avoid any artefacts arising from a microwave cavity filling factor. Free radical signal intensity was observed to increase exponentially in relation to the increase in absorbed dose over the dose range 1.25,15 kGy. Although the Mn2+ signal increases below room temperature, the signal due to the natural and radiation induced radicals decreases. Above room temperature, they both decreased and these decreases were irreversible. The kinetics of these decreases were studied in detail over a temperature range of 308,373 K by annealing samples at different temperatures for various times. [source] Use of electron spin resonance measurements on irradiated sperma lentil seeds to indicate accidental irradiationINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 1 2003Mustafa Korkmaz Summary The results of electron spin resonance studies on ,-irradiated micro- and macrosperma lentil seeds are reported. Spectra of non-irradiated intact sperma were composed of an equally spaced sextet originating from the presence of Mn2+ ions and a single weak resonance line. Irradiation produced a linear increase in the radical signal intensity in the radiation dose range (0.5,5 kGy) studied, without affecting the Mn2+ signal. Signal intensities of both sperma followed compound exponential decay curves originating from the presence of three different radical species. Heating the sperma cause irreversible decreases in both radical and Mn2+ signal intensities. Two radical species, described in the present work, and a radical of unknown origin were used to explain the experimental results. [source] Alendronate Interacts With the Inhibitory Effect of 1,25(OH)2D3 on Parathyroid Hormone-Related Protein Expression In Human Osteoblastic Cells,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2003L Gómez-García Abstract The bisphosphonate alendronate is a potent inhibitor of bone resorption by its direct action on osteoclasts. In addition, there is some data suggesting that alendronate could also inhibit bone resorption indirectly by interacting with osteoblasts. Parathyroid hormone-related protein (PTHrP) produced by osteoblasts and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are regulators of bone remodeling, which have interrelated actions in these cells. In this study, we assessed whether alendronate can affect PTHrP expression in the presence or absence of 1,25(OH)2D3 in human primary osteoblastic (hOB) cells from trabecular bone. Cell total RNA was isolated, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out using human PTHrP-specific primers. PTHrP in the hOB cell-conditioned medium was analyzed by a specific immunoradiometric assay. We found that PTHrP mRNA and secreted PTHrP were maximally inhibited by 10,8 -10,6 M of 1,25(OH)2D3 treatment within 8,72 h in hOB cells. Alendronate (10,14 -10,8 M) modified neither PTHrP mRNA nor PTHrP secretion, although it consistently abrogated the decrease in PTHrP production induced by 1,25(OH)2D3 in these cells. On the other hand, alendronate within the same dose range did not affect either the vitamin D receptor (VDR) mRNA or osteocalcin secretion, with or without 1,25(OH)2D3, in hOB cells. The inhibitory effect of alendronate on the 1,25(OH)2D3 -induced decrease in PTHrP in these cells was mimicked by the calcium ionophore A23187 (5 × 10,6 M), while it was eliminated by 5 × 10,5 M of nifedipine. Furthermore, although alendronate alone failed to affect [Ca2+]i in these cells, it stimulated [Ca2+]i after pretreatment of hOB cells with 10,8 M of 1,25(OH)2D3, an effect that was abolished by 5 × 10,5 M of nifedipine. These results show that alendronate disrupts the modulatory effect of 1,25(OH)2D3 on PTHrP production in hOB cells. Our findings indicate that an increase in calcium influx appears to be involved in the mechanism mediating this effect of alendronate. [source] Venous air embolism induces both platelet dysfunction and thrombocytopeniaACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2009S. T. SCHÄFER Background: In vitro, air bubbles can induce platelet activation and platelet to air bubble binding. We therefore tested in vivo the hypothesis that venous air embolism (VAE) induces (1) platelet dysfunction and (2) thrombocytopenia. Methods: Adult swine (60.8±3.9 kg; n=8) were anaesthetized, mechanically ventilated, and placed in a semi-upright position. Air boli (0.5,80 ml) were injected randomly via an ear vein, and arterial blood was sampled after cumulative air dosages of 0, 80, 160, and 240 ml. Coagulation was assessed by impedance aggregometry, rotational thrombelastometry, whole blood count, plasmatic coagulation variables, and fibrinogen, d -dimer, protein C, and antithrombin plasma concentrations, respectively. Results: VAE induced a 47% decrease in platelet count (303 vs. 160 nl,1; P<0.001) over the dose range assessed, with haematocrit being unaltered. Furthermore, VAE-impaired platelet aggregation induced by adenosine diphosphate, arachidonic acid, collagen, and the thromboxan analogue U46619 over the dose range assessed independent of thrombocytopenia. (P<0.05 vs. baseline). In contrast, rotational thrombelastometry alone was quite insensitive in detecting VAE-induced coagulation changes, showing only at near lethal air dosages a prolonged clot formation time following activation with tissue factor, contact activator, and during spontaneous coagulation (P<0.05 vs. baseline). Conclusions: VAE induces both a dose-dependent decrease in platelet count and a marked decrease in platelet aggregation, independent of thrombocytopenia (P<0.05 vs. baseline). [source] Cultured Granule Cells and Astrocytes from Cerebellum Differ in Metabolizing SphingosineJOURNAL OF NEUROCHEMISTRY, Issue 2 2000Laura Riboni Sphingosine metabolism was studied in primary cultures of differentiated cerebellar granule cells and astrocytes. After a 2-h pulse with [C3 - 3H]sphingosine at different doses (0.1-200 nmol/mg of cell protein), both cell types efficiently incorporated the long chain base ; the percentage of cellular [3H]sphingosine over total label incorporation was extremely low at sphingosine doses of <10 nmol/mg of cell protein and increased at higher doses. Most of the [3H]sphingosine taken up underwent metabolic processing by N -acylation, 1-phosphorylation, and degradation (assessed as 3H2O released in the medium). The metabolic processing of exogenous sphingosine was extremely efficient in both cells, granule cells and astrocytes being able to metabolize, respectively, an amount of sphingosine up to 80- and 300-fold the cellular content of this long chain base in 2 h. At the different doses, the prevailing metabolic route of sphingosine was different. At lower doses and in a wide dose range, the major metabolic fate of sphingosine was N -acylation. With increasing doses, there was first increased sphingosine degradation and then increased levels of sphingosine-1-phosphate. The data demonstrate that, in neurons and astrocytes, the metabolic machinery devoted to sphingosine processing is different, astrocytes possessing an overall higher capacity to synthesize the bioactive compounds ceramide and sphingosine-1-phosphate. [source] Genetically engineered normal flora for oral polypeptide delivery: Dose,absorption responseJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2009Gagan Kaushal Abstract Genetically modified Lactococcus lactis (L. lactis), a probiotic bacterium, able to secrete ,-lactamase (29 kDa), was used as a vector for the oral delivery of ,-lactamase to the rats. Three different doses of L. lactis were administered to the rats, and the resulted ,-lactamase oral bioavailability was studied, and compared to the solution form. The oral administration of 1.2,×,107, 3,×,107, and 8,×,107 colony-forming units of L. lactis led to 145, 209, and 364 mU of ,-lactamase absorbed, and the corresponding bioavailability was 8.7%, 15.5%, and 20.8% based on the in vitro production of ,-lactamase by L. lactis. The oral administration of 504 mU and 1008 mU ,-lactamase free solution resulted in 30 and 47 mU absorbed, a bioavailability of 5.9% and 4.7%, respectively. L. lactis significantly (p,<,0.01) increased the oral bioavailability compared to the free solution form. A significant (p,<,0.01) increase in the MAT value as compared to the solution, demonstrated that L. lactis can be used as a sustained delivery system. In conclusion, there is a linear relationship between L. lactis dose and these absorption PK parameters within L. lactis dose range of the current study. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2573,2580, 2009 [source] The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] Alcohol, Cocaine, and Brain Stimulation-Reward in C57Bl6/J and DBA2/J MiceALCOHOLISM, Issue 1 2010Eric W. Fish Background:, Pleasure and reward are critical features of alcohol drinking that are difficult to measure in animal studies. Intracranial self-stimulation (ICSS) is a behavioral method for studying the effects of drugs directly on the neural circuitry that underlies brain reward. These experiments had 2 objectives: first, to establish the effects of alcohol on ICSS responding in the C57Bl6/J (C57) and DBA2/J (DBA) mouse strains; and second, to compare these effects to those of the psychostimulant cocaine. Methods:, Male C57 and DBA mice were implanted with unipolar stimulating electrodes in the lateral hypothalamus and conditioned to spin a wheel for reinforcement by the delivery of rewarding electrical stimulation (i.e., brain stimulation-reward or BSR). Using the curve-shift method, the BSR threshold (,0) was determined immediately before and after oral gavage with alcohol (0.3, 0.6, 1.0, 1.7 g/kg) or water. Blood alcohol concentration (BAC) was measured to determine the influence of alcohol metabolism on BSR threshold. Separately, mice were administered cocaine (1.0, 3.0, 10.0, 30.0 mg/kg) or saline intraperitoneally. Results:, In C57 mice, the 0.6 g/kg dose of alcohol lowered BSR thresholds by about 20%, during the rising (up to 40 mg/dl), but not falling, phase of BAC. When given to the DBA mice, alcohol lowered BSR thresholds over the entire dose range; the largest reduction was by about 50%. Cocaine lowered BSR thresholds in both strains. However, cocaine was more potent in DBA mice than in C57 mice as revealed by a leftward shift in the cocaine dose,response curve. For both alcohol and cocaine, effects on BSR threshold were dissociable from effects on operant response rates. Conclusions:, In C57 and DBA mice, reductions in BSR threshold reflect the ability of alcohol to potentiate the neural mechanisms of brain reward. The DBA mice are more sensitive to the reward-potentiating effects of both alcohol and cocaine, suggesting that there are mouse strain differences in the neural mechanisms of brain reward that can be measured with the ICSS technique. [source] Estimates of the efficiency of transfer of L -histidine from blood to milk when it is the first-limiting amino acid for secretion of milk protein in the dairy cowJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 12 2001Chang-Hyun Kim Abstract The efficiency of transfer of L -histidine into milk protein was measured in two experiments in which L -histidine was infused intravenously into dairy cows eating a basal diet of grass silage and a cereal-based supplement containing feather meal. Both experiments used Latin square designs, and infusion periods lasted 10 days. In Experiment 1, histidine was infused alone at doses of 3, 6 and 9,g,day,1. The output of milk protein increased up to the 6,g,day,1 dose but fell back to the basal level when 9,g,day,1 was infused. The efficiency of transfer was highest for the 6,g,day,1 dose, for which the value was 0.38. In Experiment 2 the same three histidine doses as in Experiment 1 were used, but this time the histidine was accompanied by 8,g L -methionine, 28,g L -lysine and 2.5,g L -tryptophan, to ensure that histidine remained first-limiting over the whole dose range. The output of histidine in milk protein (Y) increased linearly with histidine dose (X) such that Y,,=,0.431 X,+,0.070 r,,=,0.998; n,,=,4, indicating an efficiency of transfer of 0.43. © 2001 Society of Chemical Industry [source] Dose determination and confirmation of a long-acting formulation of ceftiofur (ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory diseaseJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2002B. HIBBARD Hibbard, B., Robb, E. J., Chester Jr., S. T., Dame, K. J., Boucher, J. F., Alaniz, G. R. Dose determination and confirmation of a long-acting formulation of Ceftiofur (Ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease. J. vet. Pharmacol. Therap.25, 175,180. The objective of this work was to determine and confirm an effective dose of ceftiofur crystalline free acid sterile oil suspension (CCFA-SS, 100 mg ceftiofur equivalents (CE)/mL], a long-acting single-administration ceftiofur formulation, for the treatment of the bacterial component of bovine respiratory disease (BRD). Study 1 was a dose determination study that used an intratracheal Mannheimia haemolytica (Pasteurella haemolytica) challenge model to evaluate single-administration doses of CCFA-SS at 0.0, 1.1, 2.2, 3.3, 4.4 or 5.5 mg CE/kg body weight (BW) for the treatment of BRD. Data from this study were used to select doses for field testing in three multi-location clinical studies. In Study 2, the efficacy of a single administration dose of CCFA-SS at 4.4 mg CE/kg BW was compared with a negative control for the treatment of naturally occurring BRD in feedlot cattle. Treatments were administered when uniform clinical signs of BRD were present. Study 3 used a design similar to Study 2, and compared single-administration doses of CCFA-SS at 3.0 or 4.4 mg CE/kg BW with the positive-control tilmicosin (Micotil® 300 Injection, Elanco Animal Health) at 10 mg/kg BW. Study 4 compared the efficacy of single doses of CCFA-SS of 1.1,8.8 mg CE/kg BW with tilmicosin at 10 mg/kg BW. A total of 1176 cattle were included in these clinical studies. In Study 1, a dose of 4.55 mg CE/kg BW was determined to be effective. This was rounded to 4.4 mg CE/kg for field testing. In Study 2, a single dose of CCFA-SS at 4.4 mg CE/kg BW had a higher treatment success rate on day 14 (61%) than negative controls (26%, P < 0.01). However, in Study 3 this dose was judged to be at the beginning of an efficacious dose range for the treatment of BRD when compared with tilmicosin. In Study 4, day 28 treatment success rates were higher for CCFA-SS at 4.4,8.8 CE/kg BW than for tilmicosin (P=0.002) or the noneffective CCFA-SS dose of 1.1 mg CE/kg BW (P < 0.001). Based on decision criteria for Study 4, the effective dose was determined to be 4.4,5.5 mg CE/kg BW. These clinical studies demonstrated that a single dose of CCFA-SS (100 mg CE/mL) administered subcutaneously (s.c.) in the neck at 4.4,5.5 mg CE/kg BW is an effective treatment for BRD in feedlot cattle. However, this route of administration is no longer being considered for this formulation because of the ceftiofur residues that are present at the injection site for extended periods of time. [source] Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2002M. COULET The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (tmax) 1.5 h], reaching a mean maximum concentration (Cmax) of 6 ,g/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (Vss) and Varea of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both Cmax and area under the concentration,time curve (AUC) showed dose proportionality over the dose range tested (7.5,30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing Cmax and AUC, but did not change tmax. High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9,99.9% of the dose within 48 h. [source] Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposureMOVEMENT DISORDERS, Issue 5 2003Lance A. Smith MSc Abstract Levodopa (L -dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L -dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L -dopa with the peripheral catechol- O -methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0,7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L -dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L -dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L -dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L -dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L -dopa alone, but with no obvious change in duration of L -dopa's effect. However, combining entacapone with L -dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L -dopa alone. Importantly, increasing pulsatile exposure of brain to L -dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society [source] Delivery characteristics of a combined nitric oxide nasal continuous positive airway pressure systemPEDIATRIC ANESTHESIA, Issue 6 2002DEAA, R. Lindwall MD Summary Background: Nitric oxide (NO), when inhaled, has a synergistic effect with airway recruitment strategies such as positive endexpiratory pressure (PEEP) or continuous positive airway pressure (CPAP) in improving oxygenation in lung injury. Methods: We modified a commercially available nasal CPAP (nCPAP) system to enable the concomitant delivery of inhaled NO (iNO) and nCPAP to neonates and term babies. Oxygen, NO and nitrogen dioxide (NO2) concentrations were measured, comparing the effects of using 50 or 1000 parts per million (p.p.m.) NO stock gas cylinders. Results: Stable and accurate delivery of iNO was found for both stock gas concentrations. Using a 50 p.p.m. NO stock gas resulted in limited NO2 formation, with a maximum inspired NO2 concentration of , 0.3 p.p.m. (dose range up to 37 p.p.m. iNO), which was interpreted as the result of progressive dilution with nitrogen. In contrast, using a 1000 p.p.m. NO stock gas cylinder, inspired NO2 levels increased nonlinearly as expected with an increasing inspired concentration of NO. Conclusions: Inhaled NO can be safely and reliably delivered by the system we describe. The NO2 levels generated by the system are low, at least up to a dose of 37 p.p.m. NO, regardless of a stock gas concentration of 50 or 1000 p.p.m. NO. Using a 50 p.p.m. NO stock gas concentration, up to 80% oxygen can be given at 10 p.p.m. iNO. [source] Echocardiographic evaluation of patients cured of childhood cancer: A single center study of 117 subjects who received anthracyclinesPEDIATRIC BLOOD & CANCER, Issue 6 2001Grazia Bossi MD Abstract Background The risk of cardiomyopathy following exposure to anthracycline in asymptomatic long-term survivors of childhood cancer is still hard to predict and precisely quantify. To identify the impact of different cumulative doses, even within a non-high dose range, and the echocardiographic parameters suitable for evaluating cardiac function, we studied diastolic and systolic echocardiographic parameters in a cohort of patients followed in a single center. Procedure A total of 117 subjects were studied at a median time of 7 years after treatment completion. A complete M-mode, two-dimensional and Doppler echocardiographic study was obtained at rest in all patients according to the standard recommendations of the American Society of Echocardiography. Results Ninety-nine patients (85%) had completely normal cardiac function, while 18 had abnormal echocardiographic findings: 12 had one abnormal value, 5 had two, and 1 had three abnormal values. All the changes were in left ventricular dimensions, wall thickness or indices of systolic function; no alterations in left ventricular diastolic function parameters were found. None of the echocardiographic parameters correlated significantly with the cumulative dose of anthracyclines administered either at univariate analysis or after adjusting for sex, body surface area or considered risk factors. Conclusions Subjects exposed to a median cumulative dose of 214,mg/m2 had no echographic abnormalities a median of 7 years later. We did not find any correlation between cumulative anthracycline dose and the echocardiographic parameters tested. We now offer echocardiographic follow-up to patients with mildly reduced fractional shortening and/or ejection fraction to rule out late onset dysfunction. Med. Pediatr. Oncol. 36:593,600, 2001. © 2001 Wiley-Liss, Inc. [source] Imaging of uranium on rat brain sections using laser ablation inductively coupled plasma mass spectrometry: a new tool for the study of critical substructures affined to heavy metals in tissuesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 18 2008J. Sabine Becker The specific toxicity of trace metals and compounds largely depends on their bioavailability in different organs or compartments of the organism considered. Imaging mass spectrometry (IMS) using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) with a spatial resolution in the 100,µm range was developed and employed to study heavy metal distribution in brain tissues for toxicological screening. Rat brain post-mortem tissues were stained in an aqueous solution of either uranium or neodymium (metal concentration 100,µg,g,1) for 3,h. The incubation of heavy metal in thin slices of brain tissue is followed by an imaging mass spectrometric LA-ICP-MS technique. Stained rat brain tissue (thickness 30,µm) were scanned with a focused laser beam (wavelength 266,nm, diameter of laser crater 100,µm and laser power density 3,×,109,W,cm,2). The ion intensities of 235U+, 238U+, 145Nd+ and 146Nd+ were measured by LA-ICP-MS within the ablated area. For quantification purposes, matrix-matched laboratory standards were prepared by dosing each analyte to the pieces of homogenized brain tissue. Imaging LA-ICP-MS allows structures of interest to be identified and the relevant dose range to be estimated. Copyright © 2008 John Wiley & Sons, Ltd. [source] Antimalarial activities of gedunin and 7-methoxygedunin and synergistic activity with dillapiolANNALS OF APPLIED BIOLOGY, Issue 2 2003S OMAR Summary Gedunin from Cedrela odorata (Meliaceae), a potent in vitro antimalarial agent, was investigated for its in vivo efficacy in CD-1 mice infected with Plasmodium berghei. When orally administered at 50 mg kg-1 day-1 for 4 days, gedunin was able to suppress the parasitaemia level by 44%. However, no clear dose-response effects were observed in the 0,100 mg kg-1 day-1 dose range. Preliminary pharmacokinetics in Sprague-Dawley rats showed poor absorption. However, a binary treatment of 50 mg kg-1 day-1 gedunin with 25 mg kg-1 day-1 dillapiol, a cytochrome P450 inhibitor, increased parasitaemia clearance in mice to 75%. A clear dose-response was observed in the 0,50 mg kg-1 day-1 gedunin dose range when administration was combined with 25 mg kg-1 day-1 dillapiol. In addition, 7-methoxygedunin, a semi-synthetic derivative which is more stable to degradation than gedunin, suppressed the level in mice by 67% at 50 mg kg-1 day-1. When administered at this dose in combination with 25 mg kg-1 day-1 dillapiol, clearance increased to 80%. These results demonstrate the potentialefficacy of antimalarial drugs and phytomedicines based on gedunin and the value of the combination therapy. [source] CANCER INPATIENTS MORPHINE USAGE: A NEW ENGLAND AREA SURVEYAUSTRALIAN JOURNAL OF RURAL HEALTH, Issue 4 2003John Trollor ABSTRACT:,This is a one year study of the use of morphine in cancer patients in 10 inpatient facilities in the New England Area Health Service in the north-west of New South Wales. The study explored 170 admissions relating to 122 patients, most of whom were cared for by their general practitioners. The use of morphine in these cancer patients was compared with the recommendations made by the expert working group of the European Association of Palliative Care.1 Those items which matched the recommendations included the initial doses for new users of morphine and the subcutaneous route being the preferred parenteral route. The data in this study differed from the recommendations in that only half of the patients received the immediate release morphine when first given oral morphine, only 43% had orders for immediate release oral morphine for breakthrough pain (with a variable frequency) and a significant number of orders for parenteral and immediate release oral morphine for breakthrough pain were outside the recommended doses (100% and 86.2%, respectively). Written orders for immediate release oral and parenteral morphine involved a dose range in significant numbers while only 30% of patients had orders for parenteral morphine for breakthrough pain. There was a low use of fixed interval variable dose (FIVD) morphine charts despite these being available in most facilities. (See summary Appendix A.) [source] Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urotheliumAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2006M. M. Khattab Summary 1 Both ATP and diadenosine tetraphosphate (AP4A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP4A dose,response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. 2 Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP4A by 42% (at highest AP4A concentration) to 68% at lower concentration. 3 Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP4A-induced contractions were significantly decreased by 27% at low AP4A level to 38% at higher concentrations. 4 Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP4A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36,40%, and those to AP4A by 44,49%. 5 In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP4A-induced contractility. [source] Closure Procedures for Monotone Bi-Factorial Dose,Response DesignsBIOMETRICS, Issue 1 2005M. Hellmich Summary Two goals of multiple-dose factorial trials are (i) demonstrating improved effectiveness of a fixed combination over each of its components as well as (ii) identifying a safe and effective dose range. The authors address both goals though with focus on the second by closure procedures that guarantee strong control of the familywise error rate. Two different families of null hypotheses are investigated for bi-factorial dose,response designs that are monotone with respect to the matrix partial order. One is suitable to find the minimum effective dose(s) and the other one is large enough to identify the highest effective dose step(s). Likelihood ratio tests and appropriate multiple contrast tests are applied to an unbalanced clinical trial example taken from Hung (2000, Statistics in Medicine19, 2079,2087). Full computer code written in the R language is available from the Internet. [source] Pharmacokinetic modelling of blood,brain barrier transport of escitalopram in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2007Christoffer Bundgaard Abstract This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood,brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 µl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents. Copyright © 2007 John Wiley & Sons, Ltd. [source] Liquid chromatographic,mass spectrometry analysis and pharmacokinetic studies of a novel rabeprazole formulation, sterile powder for injection, in dogs and ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2007Feng Shao Abstract Rabeprazole is among the most potent proton pump inhibitors (PPI) identified to date and it has been demonstrated that it is effective in such diseases as gastroesophageal reflux disease (GERD), duodenal ulcer and gastric ulcer. There is currently interest in developing a new formulation: rabeprazole sterile powder for injection (RSPI). This investigation was conducted to evaluate the preclinical pharmacokinetics of RSPI in rats and at the same time a comparative study was carried out in dogs between RSPI and Pariet® tablets using liquid chromatographic,mass spectrometry analysis. The liquid chromatographic,mass spectrometry method was first conducted and validated as being specific, and having accuracy, precision, sensitivity and a satisfactory recovery. After intravenous administration of RSPI (i.v.: 2, 6 and 18 mg/kg) to rats, no significant dose-dependency was found in the CL (4.20,5.72 l/h/kg), Varead (0.94,1.32 l/kg), dose-normalized AUC (197.20,245.82 µg/l*h based on 1 mg/kg) and t1/2 (p>0.05). In the dog, a randomized, open-label, crossover experiment was carried out to show that the mean area under the plasma concentration-time curve (AUC0,,) after i.v. administration of RSPI was at least four times larger than that following oral administration of Pariet® tablet at an equivalent dose but the elimination half-life of these two formulation was similar (p>0.05). The results showed that the pharmacokinetics of RSPI was linear (r2 = 0.98) in the dose range 2,18 mg/kg and the RSPI had a much higher AUC0,, and similar t1/2 values compared with the enteric-coated tablet. Copyright © 2007 John Wiley & Sons, Ltd. [source] Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2006Beom Soo Shin Abstract This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8,1.1 h, 59.6,68.0 ml/min/kg and 2.4,2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%,0.020% and 0.049%±0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9,1.1 h, 520.3,621.2 ml/min/kg and 67.6,84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats. Copyright © 2005 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||||||||