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Administered Dose (administered + dose)
Selected AbstractsRadioevaluation of PAMs, CMs, and PS-Lip as an oral carrier for vaccine delivery into intestinal Peyer's patchesDRUG DEVELOPMENT RESEARCH, Issue 12 2006Chang-Moon Lee Abstract The aim of the present study was to evaluate the utility of pullulan acetate microparticles (PAMs), chitosan micropaticles (CMs), and dipalmitoylphosphatidyl-serine-liposomes (PS-Lip) as oral carriers for delivery to the intestinal Peyer's patches (PPs). To monitor PP delivery after oral administration, PAMs, CMs, and PS-Lip were radiolabeled with 99mTc. Radiolabeling efficiencies of the particles were 95±2.5% (PAMs), 87±4.3% (CMs), and 77.2±5.8% (PS-Lip). In delivery studies to the PPs, the percentage of PS-Lip taken up to the PPs was 3.8 × 10,3±0.3% of the administered dose with PS-Lip group showed significantly high uptake compared to the PAM and CM groups. These results suggest that PS-Lip may be used as a potential system for developing an oral delivery carrier. Drug Dev. Res. 67:884,889, 2006. © 2007 Wiley-Liss, Inc. [source] Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literatureHAEMOPHILIA, Issue 2 2008A. OBERGFELL Summary., Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven®) is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 ,g kg,1 bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences. [source] Distribution of carbon-14 labeled C60 ([14C]C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urineJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2010Susan C. J. Sumner Abstract This study was conducted to determine the distribution of [14C]C60 in the pregnant rat and fetuses, and in the lactating rat and offspring. Pregnant rats were dosed on gestation day (gd) 15 and lactating rats were dosed on postnatal day (pnd) 8 via tail vein injection with a suspension of ,0.3,mg [14C]C60,kg,1 body weight prepared in polyvinylpyrrolidone (PVP), or with PVP alone. Tissues were collected at 24 and 48 h after dosing. The largest portion of the administered dose was detected in the liver (,43%, pregnant dam; ,35%, lactating dam) and lung (,25%, lactating dam). Radioactivity (,6%) was distributed to the reproductive tract, placenta and fetuses of the pregnant dam. Lactating rats had radioactivity distributed to the milk (3140,dpm,g,1 tissue, 24,h; 1620,dpm,g,1 tissue, 48,h), and to the pups' GI tract (2.8%, 24,h; 4.4% 48,h) and liver (<1%). Blood radioactivity was significant at 24,h (14,19%) and at 48,h (7%) after dosing; largely accounted for in the plasma fraction. Less that 4% of the dose was recovered in the maternal spleen, heart, brain, urine or feces. Metabolomics analysis of urine indicated that dams exposed to [14C]C60 had decreased metabolites derived from the Krebs cycle and increased metabolites derived from the urea cycle or glycolysis, as well as alterations in the levels of some sulfur-containing amino acids and purine/pyrimidine metabolites. This study demonstrated that [14C]C60 crosses the placenta and is transmitted to offspring via the dam's milk and subsequently systemically absorbed. Copyright © 2009 John Wiley & Sons, Ltd. [source] Interindividual variation of serum haloperidol concentrations in Japanese patients , clinical considerations on steady-state serum level,dose ratiosJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2003E. Yukawa Summary Objective:, Marked interpatient variability in haloperidol (HAL) level,dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. Objective:, To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Method:, Retrospective analysis of dose and HAL blood level data from 168 patients. Results:, The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 24·9% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 27·2% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. Conclusion:, There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication. [source] Tissue distribution of radioactivity following intranasal administration of radioactive microspheresJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2001J. E. Eyles The aim of this study was to increase understanding of the kinetics of microparticle distribution and elimination following intranasal application. To do this we investigated the in-vivo distribution of radioactivity following intranasal instillation of scandium-46 labelled styrene-divinyl benzene 7-,m-diameter microspheres. Groups of BALB/c mice received 0.250 mg (47.5 kBq) particles suspended in either 50-,l or 10-,l volumes of phosphate buffered saline. The in-vivo distribution of radioactivity was influenced by the volume of liquid that was used to instil the microsphere suspension. Comparatively large (50 ,l) administration vehicle volumes resulted in substantial bronchopulmonary deposition (, 50% of administered dose). Intranasal instillation of microspheres suspended in 10-,l volumes tended to restrict particle deposition initially to the nasal cavity. For both administration vehicle volumes tested, the radioactivity per unit mass of excised nasal-associated lymphoid tissue (NALT) was found to be consistently elevated relative to other tissues. This corroborates the findings of other workers who have previously identified NALT as an active site of microparticle accumulation following intranasal application. Elimination via the alimentary canal was the principal fate of intranasally applied radiolabeled material. No significant concentration of radioactivity within excised gut-associated lymphoid tissue (GALT) (Peyer's patches) was noted. At latter time points we observed, in mice that received the 50-,l volume particle suspension nasally, accumulation of potentially relevant quantities of radioactivity in the liver (0.3% after 576 h) and spleen (0.04% after 576 h). Thus, our data corroborate the notion that epithelial membranes in the lung are probably less exclusive to the entry of microparticulates into systemic compartments than are those mucosae in the gastrointestinal tract or nasopharynx. This effect may contribute to the effectiveness of pulmonary delivered antigen-loaded microparticles as humoral immunogens. [source] Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney functionPEDIATRIC BLOOD & CANCER, Issue 6 2003Lutz Hempel MD Abstract Background The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment. Patients and Methods Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2,34.1)] suffering from acute lymphoblastic leukemia (ALL, n,=,28), Non Hodgkins lymphoma (NHL, n,=,13), osteosarcoma (n,=,8), malignant brain tumor (n,=,6), or an ALL relapse (n,=,3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N -acetyl-,- D -glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m2 BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX. Results The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX. Conclusion MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance. Med Pediatr Oncol 2003;40:348,354. © 2003 Wiley-Liss, Inc. [source] Toxico-kinetics, recovery efficiency and microsomal changes following administration of deltamethrin to black Bengal goatsPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2001Sanis Juliet Abstract A study of the toxico-kinetics, recovery percentage from different substrates, cytotoxicity and role of cytochrome P450 and b5 of liver microsome in the metabolism of deltamethrin were carried out in female black Bengal goat. The ALD50 value of deltamethrin in goat by intravenous route lies between 0.2 and 0.6,mg,kg,1. Intravenous disposition kinetics using a dose of 0.2,mg,kg,1 showed that the maximum blood concentration of deltamethrin was recorded at 0.5,min, followed by rapid decline, and a minimum concentration was detected at 6,min after administration. The following values were obtained,:,Vdarea 0.148 (±,0.02) litre,kg,1; t1/2 (,) 0.22 (±,0.02),min; t1/2 (,) 2.17 (±,0.37),min; Kel 1.05 (±,0.24) min,1; AUC 4.30(±,0.45),µg min,ml,1; ClB 0.05 (±,0.006) litre,kg,1 min,1; T,B 1.93 (±,0.58); fc 0.40(±,0.05). After 10,min, liver retained the maximum residue, and heart, adrenal gland, kidney, spleen, fat and brain also held the insecticide; liver, fat, heart and spleen retained residue after 30,min, and bone, liver and fat retained residue after 60,min of intravenous administration. Oral absorption of deltamethrin was poor and inconsistent, and approximately 65% of administered dose was recovered from faeces and gastrointestinal contents. The excretion of deltamethrin through urine was meagre, and only 0.01 and 0.013% of the administered dose was recovered after 3 and 5 days of oral administration respectively. All the tissues retained the residue after 3 days; while fat, rumen, reticulum, omasum, abomasum, large and small intestine and bone retained the residue after 5 days of oral administration; and the percentage recoveries were 1.73 and 0.027 respectively. Deltamethrin reduced the level of cytochrome P450 content of liver microsomal pellet of goat after 5 days of oral administration. Histopathological examination of liver, kidney, heart, spleen brain and lung sections of treated goats did not reveal any pathological changes. © 2001 Society of Chemical Industry [source] The metabolism and excretion of 2-methylaminoethoxycarbonyl-4,4,-dimethoxy-5,6,5,,6,-dimethylenedioxybiphenyl-2,-carboxylic acid (DDB-S) in rats and humanRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 13 2006Hye Hyun Yoo The metabolism and excretion of 2-methylaminoethoxycarbonyl-4,4,-dimethoxy-5,6,5,,6,-dimethylenedioxybiphenyl-2,-carboxylic acid (DDB-S) were investigated in both rats and humans using liquid chromatography/electrospray ion trap mass spectrometry (LC/ESI-MS/MS). In rats, DDB-S was rapidly eliminated from the body after a single 50,mg/kg intravenous injection, with urine being a major excretion route. DDB-S was metabolically stable; approximately 96% of the administered dose was recovered in the form of the parent compound. Nevertheless, 12 metabolites were detected in the urine and feces collected from DDB-S-treated rats. The structural characterizations of the metabolites were elucidated from the MSn spectral analysis. Because DDB-S has a pseudo-symmetrical methylenedioxy biphenyl structure, regioselective deuterium-substituted DDB-S (d5 -DDB-S) was used to assign the metabolic modification. The major metabolic pathways of DDB-S were identified as demethylenation of the methylenedioxy moiety, O-demethylation of the methoxy moiety and glucuronidation. In addition, N-demethylation of the methylaminoethyl group was also detected as a minor reaction. Copyright © 2006 John Wiley & Sons, Ltd. [source] Ketamine for emergency anaesthesia at very high altitude (4243 m above sea-level),ANAESTHESIA, Issue 9 2007M. P. W. Grocott Summary A 22-year-old woman presenting with postpartum haemorrhagic shock at 4243 m altitude required anaesthesia to identify and treat the source of bleeding. Slow intravenous administration of ketamine (0.5 mg.kg,1) resulted in deep anaesthesia and apnoea requiring hand ventilation for 5 min. Haemodynamic stability was maintained throughout the procedure. Haemostasis was achieved following uterine packing and suture of a second-degree vaginal tear and small cervical tear. Confusion and visual hallucinations occurred upon awakening but recovery was otherwise uneventful. Ketamine can be used for emergency anaesthesia in a wilderness environment over 4000 m but it is probable that the benefits outweigh the risks only where life or limb are acutely threatened. Careful titration of the administered dose is strongly advised, particularly in patients where hypovolaemia and/or hypoxaemia are present. The availability of airway management equipment and the skills to use them may significantly reduce the risks associated with anaesthetic administration at very high altitude. [source] Bayesian Optimal Designs for Phase I Clinical TrialsBIOMETRICS, Issue 3 2003Linda M. Haines Summary. A broad approach to the design of Phase I clinical trials for the efficient estimation of the maximum tolerated dose is presented. The method is rooted in formal optimal design theory and involves the construction of constrained Bayesian c - and D -optimal designs. The imposed constraint incorporates the optimal design points and their weights and ensures that the probability that an administered dose exceeds the maximum acceptable dose is low. Results relating to these constrained designs for log doses on the real line are described and the associated equivalence theorem is given. The ideas are extended to more practical situations, specifically to those involving discrete doses. In particular, a Bayesian sequential optimal design scheme comprising a pilot study on a small number of patients followed by the allocation of patients to doses one at a time is developed and its properties explored by simulation. [source] Disposition of acamprosate in the rat: Influence of probenecidBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002Teodoro Zornoza Abstract The purpose of the present study was to investigate the disposition of acamprosate (calcium bis acetyl-homotaurine) in the rat. Initially, we studied the linearity of acamprosate disposition and the fraction of acamprosate excreted unchanged in the urine of the animals. Rats received 9.3, 36.6 or 73.3 mg/kg of the drug as an intravenous bolus. The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. On average, 95% of the administered dose was excreted unchanged in the urine of the animals in the 0,6 h post-administration period indicating that renal excretion is the main elimination route for this drug. Acamprosate was also administered by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530 ,g/min) in order to quantify total (Clt) and renal (Clr) plasma clearances at steady-state conditions. The mean Clr values were, respectively, 4.60±0.42, 4.28±0.52 and 4.08±0.67 ml/min, practically equivalent to the Clt values (4.78±0.38, 4.51±0.36 and 4.21±0.56 ml/min), confirming that the drug is mainly eliminated via renal excretion. Moreover, Clr values were clearly higher than the glomerular filtration rate (2.61±0.26 ml/min), suggesting the existence of a highly efficient tubular secretion mechanism in the renal excretion of the drug. To confirm this hypothesis, two groups of rats were intravenously treated with probenecid (33.3 or 66.6 mg/kg) prior to acamprosate administration (9.3 mg/kg). Probenecid provoked a statistically significant dose-dependent reduction in the total clearance of acamprosate (from 5.8±0.7 ml/min in the control group to 2.6±0.1 ml/min in the animals treated with 66 mg/kg of probenecid) demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat. Copyright © 2002 John Wiley & Sons, Ltd. [source] Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara®) in breast cancer patientsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2001Christian U. Pfister Abstract Letrozole (trademark Femara®) is a new orally active, potent and selective aromatase inhibitor for the hormonal treatment of advanced breast cancer in postmenopausal women. The pharmacokinetics of letrozole and the suppression of peripheral estrogens were studied in 28 breast cancer patients after a single dose and at steady state. The pharmacokinetics of two distinct age groups (,50, ,65, N=15 and ,70 years old, N=9) were compared. There were no significant differences in area under the curve (AUC) or terminal half-life between the two age groups neither after a single dose nor at steady state. However, when comparing steady state to single dose kinetics, half-life and AUC increased significantly by 42% (90% CI: 1.13, 1.78) and 28% (90% CI: 1.12, 1.47), respectively. This deviation from linearity was probably due to a partial saturation or auto-inhibition of the dominant metabolic clearance mechanism of letrozole. At steady state, approximately 70% of the administered dose was excreted in urine as unchanged letrozole (6.0±3.8%) or as the glucuronide of the major, pharmacologically inactive metabolite CGP44645 (64.2±22.7%). A single dose of letrozole caused suppression of serum estrogen levels close to the quantification limit of the assay. No difference between single dose suppression and suppression at steady state could be detected. Copyright © 2001 John Wiley & Sons, Ltd. [source] Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazoleBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2000Mark A. Bush Abstract Utilization of nitric oxide (NO) synthase (NOS) inhibitors to probe the role of NO in various central nervous system processes requires use of an inhibitor selective for neuronal NOS, and is facilitated by knowledge of the pharmacokinetics of the inhibitor. The present project was undertaken to elucidate the disposition of the selective neuronal NOS inhibitor 7-nitroindazole (7-NI). A simple, specific HPLC assay was developed with requisite sensitivity to quantitate 7-NI in serum after administration of pharmacologically relevant doses. Further experiments were performed to assess the effects of administered dose on 7-NI disposition. 7-NI displayed marked nonlinearity, consistent with saturable elimination, when administered by ip injection in peanut oil. The nonlinearity was related to total dose, but not to the concentration of 7-NI in the vehicle. Binding of 7-NI in rat serum was concentration-independent and does not contribute to the nonlinearity. Various formulations for iv administration of this water-insoluble compound were evaluated; the optimal vehicle, from the standpoint of 7-NI solubility, appeared to inhibit the clearance of 7-NI from the systemic circulation. Considering the nonlinear disposition of 7-NI, knowledge of the pharmacokinetics of this inhibitor is requisite to designing administration protocols to achieve the desired magnitude and duration of NOS inhibition. Copyright © 2000 John Wiley & Sons, Ltd. [source] Absence of large intragenic rearrangements in the DPYD gene in a large cohort of colorectal cancer patients treated with 5-FU-based chemotherapyBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Laia Paré WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the elimination of approximately 80% of the administered dose of 5-fluorouracil (5-FU). , Mutations in the DPD-coding gene have been shown to increase the risk of severe toxicity in 5-FU treated patients. , The IVS14+1G>A is the most common DPYD mutation. WHAT THIS STUDY ADDS , The intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification (MLPA) were studied for the first time in a large series of 234 colorectal cancer patients treated with 5-FU-containing chemotherapy. , No deletions or duplications of one or more DPYD exons were detected. The presence of the IVS14+1G>A mutation was also excluded. , These data show that neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation are responsible for the serious toxicity associated with a 5-FU containing regimen in this cohort of Spanish patients. AIMS To study the relationship between the toxicity associated with a 5-FU-based therapy and the presence of (i) the large intragenic rearrangements in the DPYD gene and (ii) the IVS14+1G>A mutation. METHODS We used the multiplex ligation-dependent probe amplification technique (MLPA) to study genomic DNA from 234 colorectal cancer patients treated with 5-FU-based chemotherapy. RESULTS We did not detect any deletion/duplication in the DPYD gene. The presence of the IVS14+1G>A mutation was also excluded. CONCLUSIONS Neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation play a significant role in the development of serious toxicity associated with a 5-FU containing regimen. [source] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] L-asparaginase as a marker of chemotherapy dose modification in children with acute lymphoblastic leukemiaCANCER, Issue 12 2005Jacques Baillargeon Ph.D. Abstract BACKGROUND The objective of the current study was to compare chemotherapy dose modifications in obese (a body mass index [BMI] > 95%) and nonobese (a BMI , 95%) pediatric patients with acute lymphoblastic leukemia (ALL). METHODS The study cohort was comprised of 199 pediatric patients diagnosed with ALL who were treated at 1 of 2 South Texas pediatric oncology centers between 1990,2000. The relative chemotherapy dose modification during the induction phase of chemotherapy was calculated as the ratio of 1) the actual administered dose of L-asparaginase and 2) the protocol-calculated dose of L-asparaginase. The extent to which the chemotherapy dose modification varied according to obesity status was assessed using stratified Student t tests and an ordinary least-squares regression analysis. RESULTS Obese ALL patients were found to exhibit a 7% decrease in the mean relative modification of L-asparaginase during induction chemotherapy compared with their nonobese counterparts. This finding was statistically significant (P = 0.009), even after adjustment for gender, age, ethnicity, and clinical institution. CONCLUSIONS To the authors' knowledge, the current study is the first published report of an obesity-associated chemotherapy dose modification in pediatric patients with ALL, the most common childhood malignancy. It will be important to examine whether these findings are consistent with those observed in future studies, and ultimately to assess the association between obesity-related dose modifications and long-term cancer outcomes. Cancer 2005. © 2005 American Cancer Society. [source] Disposition of isosteviol in the rat isolated perfused liverCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2010Hongping Jin Summary 1. The aim of the present study was to investigate the mechanisms involved in the clearance of isosteviol using the rat isolated perfused liver. 2. Six livers from male Sprague-Dawley rats were perfused with 15.7 ,mol isosteviol in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. All samples collected were incubated with ,-glucuronidase. Isosteviol,glucuronide was determined as equivalent isosteviol. Isosteviol concentrations were determined using a previously developed liquid chromatography,tandem mass spectrometry method. The final isosteviol liver/perfusate (L/P), bile/liver (B/L) and isosteviol-glucuronide in bile/liver (BG/LG) ratios were determined. 3. Isosteviol has a high clearance (21.4 ± 4.8 mL/min) from the perfusate, with a short half-life (13 ± 4 min). ,-Glucuronidase incubation revealed that isosteviol is conjugated in the liver and excreted into the bile. There was no isosteviol-glucuronide detected in perfusate samples. The total recovery of the rat isolated perfused liver system is 74 ± 14% and glucuronidated isosteviol accounted for 23 ± 4% of the administered dose. 4. In conclusion, we are the first to characterize the metabolism of isosteviol using rat isolated liver perfusion. Our results strongly suggest that the liver is the main organ of isosteviol elimination and that isosteviol is glucuronidated in the liver before it is excreted into the bile. [source] Bioavailability and pharmacokinetic model for ritonavir in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2007R. Lledó-García Abstract The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6,±,2.5 mg of diluted Norvir®. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a two-compartmental model with zero-order kinetic in the incorporation process of ritonavir into the body better fitted intravenous and oral data. The estimated oral bioavailability by means of noncompartmental and compartmental approaches resulted in 74% and 76.4%, respectively. These values confirm the ones obtained by other authors in the rat. In conclusion, a zero-order kinetic in the incorporation process at the administered doses suggests the saturation of the possible specialized transport mechanisms involved in the incorporation of ritonavir into the body. These results could justify the use of low doses of ritonavir when improving the bioavailability of other protease inhibitors (PIs) is required. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] Topical antiinflammatory activity of an innovative aqueous formulation of actichelated® propolis vs two commercial propolis formulationsPHYTOTHERAPY RESEARCH, Issue 9 2007Silvio Sosa Abstract A novel aqueous commercial formulation of a new hydrophilic propolis product (Actichelated® Propolis, contained in ,LeniGola PropolEffect Spray Senza Alcohol'; Pharbenia, Milan, Italy) was evaluated for its topical antiinflammatory activity in comparison with a hydroglyceric propolis spray solution (,Propoli LeniGola Spray Senza Alcool'; Pharbenia, Milan, Italy) and a hydroalcohol preparation (,Propoli LeniGola Spray Forte'; Pharbenia, Milan, Italy). Actichelated® propolis (Actimex, Trieste, Italy) is a multicomposite material obtained with a patented technology, mechano-chemical activation, which application led to a new hydrosoluble form of propolis. Each propolis preparation provoked a dose-dependent inhibition of the croton oil-induced ear oedema in mice. Considering the administered doses of flavonoids, ,LeniGola PropolEffect Spray Senza Alcool' (ID50 = 13.6 µL/cm2, corresponding to 13.6 µg flavonoids/cm2) is slightly more active than the hydroglyceric formulation ,Propoli LeniGola Spray' (ID50 = 13.7 µL/cm2, corresponding to 20.6 µg flavonoids/cm2) and six times more active than the hydroalcohol preparation ,Propoli LeniGola Spray Forte' (ID50 = 5.5 µL/cm2, corresponding to 82.5 µg flavonoids/cm2). As a reference, 15 µL/cm2 of the commercial sprays Tantum® Verde and Froben®, containing 37.5 or 45 µg of the non-steroidal antiinflammatory drugs benzidamine hydrochloride or flurbiprofen, induced 18% and 35% oedema inhibition, respectively. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||