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Drug Levels (drug + level)
Kinds of Drug Levels Selected AbstractsThe Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Pharmacokinetics and tissue distribution of intravenous pefloxacin for antibiotic prophylaxis in biliary surgeryBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002A.R. Gascón Abstract The plasma levels and tissue penetration of pefloxacin were studied after prophylactic administration to patients undergoing elective biliary surgery. Pefloxacin was administered as a single dose of 800 mg given intravenously as an infusion 1 h before surgery. Over a period of two years, cultures of bile and stone were performed after cholecystectomy in order to find the main pathogens present in the geographical area of the hospital of Txagorritxu (Vitoria, Spain), as well as to test the antimicrobial susceptibility of these bacteria to pefloxacin. Thirty seven per cent of the bile and stone cultures were positive, and 75 different species were isolated. E. coli was the predominant microorganism (25%). Other frequent microorganisms were E. faecium (9.3%), S. epidermidis (6.6%) and Cl. perfringens (6.6%). Most species isolated were susceptible to pefloxacin, with MIC90 values of 0.125 ,g/ml for E. coli, 0.5 ,g/ml for S. epidermidis and 1 ,g/ml for Cl. perfringens. E. faecium was resistant, with a MIC90 value of 8 ,g/ml but a MIC50 of 4 ,g/ml (intermediate). After pefloxacin infusion, adequate drug plasma levels (>MIC90) for the most frequent pathogens were found throughout the procedure. Elimination half-life was estimated as 22.03±6.91 h; the area under the concentration,time curve from zero to infinite had a value of 275.07±130.02 mg h/l and the values for volume of distribution at steady-state and plasma clearance were 96.48±28.65 L and 3.60±1.83 l/h, respectively. Bile pefloxacin concentrations generally exceeded the minimum inhibitory concentrations for most relevant pathogens. Drug levels in gallbladder and subcutaneous tissues were also above the MIC90 for extended periods. Patients were observed daily throughout their hospital stay. This included examination of the surgical wound and recording of body temperature. No cases of anaerobic infection were noted in the study patients. Other constants such as hospitalization stay and time of recuperation were normal for this type of surgery. According to these results, pefloxacin presents many features that make it suitable for use as a therapeutic prophylactic agent, such as its broad spectrum of antimicrobial activity and favorable pharmacokinetic properties. Copyright © 2002 John Wiley & Sons, Ltd. [source] Intermittent watt-level ultrasonication facilitates vancomycin release from therapeutic acrylic bone cementJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2009Xun-Zi Cai Abstract Ultrasound holds promise for enhancing the vancomycin release from cement though the length of time when local drug level exceeded the minimum inhibitory concentration (T>MIC) was not prolonged by the previous protocol of milliwatt-level ultrasonication. Here vancomycin-loaded cements were subjected to continuous watt-level ultrasonication (CUG), intermittent watt-level ultrasonication (IUG) or no ultrasonication (NUG) for 14 d during immersion in 40-ml phosphate buffered saline (PBS) for 28 d. The T>MIC for IUG was more than three times that for NUG. In contrast, T>MIC for CUG was slightly shortened. The subtherapeutic release of vancomycin between 15 d and 28 d for IUG was one-ninth that for NUG. The fitting equations indicated a significant enhancement on the burst release and the slow release for IUG; however, the continuous ultrasonication hampered the slow release. SEM images exhibited denser craters and pores with larger diameters and less residual drug in specimens from IUG relative to those from both CUG and NUG. Intermittent watt-level ultrasonication improved the ultrasound-enhanced vancomycin release from cement in view of the prolonged T>MIC and the inhibited subtherapeutic release compared with continuous ultrasonication. The mechanisms may be associated with the distinctive effects of detaching forces and pushing forces by acoustic microstreams. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009 [source] Preliminary results of interstitial motexafin lutetium-mediated PDT for prostate cancerLASERS IN SURGERY AND MEDICINE, Issue 5 2006K.L. Du MD Abstract Background and Objectives Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed. Study Design/Materials and Methods We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed. Results We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate. Conclusions PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution. Lasers Surg. Med. 38:427,434, 2006. © 2006 Wiley-Liss, Inc. [source] Continuous venovenous hemodiafiltration to treat controlled-release carbamazepine overdose in a pediatric patientPEDIATRIC ANESTHESIA, Issue 11 2006TULAY SAHIN YILDIZ MD Summary Carbamazepine (CBZ) intoxication is an important issue in acute poisoning practice. Highly protein-bound, CBZ is not removed efficiently through conventional hemodialysis. We describe the use of continuous venovenous hemodiafiltration (CVVHDF) in a 2-year-old boy who developed general tonic clonic seizure and respiratory depression due to controlled-release formula of CBZ overdose (peak drug level of >20 ,g·ml,1, therapeutic range: 5,10 ,g·ml,1). Serum CBZ concentrations fell to 0.25 ,g·ml,1 at the end of hemodiafiltration. The patient recovered rapidly and was discharged from hospital 4 days from the time of ingestion with no complications or neurologic impairment. [source] What is the best approach to an apparently nonmetastatic adrenocortical carcinoma?CLINICAL ENDOCRINOLOGY, Issue 5 2010Martin Fassnacht Summary In suspected nonmetastatic adrenocortical carcinoma (ACC) a careful preoperative diagnostic work up is needed including comprehensive endocrine analysis as recommended by the European Network for the Study of Adrenal Tumors (http://www.ENSAT.org/ACC.htm). Staging prior surgery, in particular chest CT, is indispensable to exclude distant metastases. Open surgery is still the recommended approach in ACC. However, in localized non-invasive ACC with a diameter <10 cm laparoscopic adrenalectomy by an expert surgeon is probably similarly effective and safe. As many patients will suffer from tumor recurrence after seemingly complete removal of ACC, adjuvant treatment based on the individual risk status is recommended. Key factors for risk assessment are tumor stage, resection status and the proliferation marker Ki67. All patients considered at high risk for recurrence should receive adjuvant mitotane for a minimum of 2 years aiming at a drug level of 14,20 mg/l. In selected patients (e.g. R1 resection) we recommend additional radiotherapy of the tumor bed. Patients with a low/intermediate risk for recurrence should be included in the Adiuvo trial comparing adjuvant mitotane with observation only (http://www.adiuvo-trial.org). In low/intermediate risk patients who cannot be included in this trial observation only can be justified in cases with a tumor diameter of <8 cm and no microscopic evidence for invasion of blood vessels or tumor capsule. In all patients a structured follow-up for 10 years is strongly recommended. [source] Optimal prophylactic dosage and disposition of micafungin in living donor liver recipientsCLINICAL TRANSPLANTATION, Issue 6 2004Satoshi Kishino Abstract:, Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean Cmax and Cmin (trough) values of micafungin in plasma were 6.31 ± 1.08 and 1.65 ± 0.54 ,g/mL, respectively. The mean elimination half-life (t1/2) and mean area under the curve up to 12 h post-dosing (AUC 0,12 h) were 13.63 ± 2.77 h and 50.04 ± 6.48 ,g·h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (±SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 ± 0.04 and 0.054 ± 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40,50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH. [source] Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 6 2001A. Jönsson SUMMARY Objective To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses. Material and methods Fifty patients with type 2 diabetes on regular Gb therapy (1.75,14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z -test (correlation coefficients) and paired Student t -tests were used when comparing values within the entire group and unpaired non-parametric Mann,Whitney tests were used when comparing high and low dose levels. A p-value <,0.05 was considered significant. Results There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), ,-insulin (r = , 0.59) and ,-proinsulin (r = , 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = , 0.40) and proinsulin (r = , 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on , 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0,120) and 33 (0,120) ng/ml) than those of Gb itself (18(0,64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen. Conclusions Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired ,-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Analysis of genotypic and phenotypic clinical cut-off levels for ritonavir-boosted saquinavirHIV MEDICINE, Issue 2 2006A Hill There is a need for new, clinically relevant interpretation algorithms for genotypic and phenotypic resistance for ritonavir-boosted saquinavir (SQV/r) at the current approved dosage [1000/100 mg twice a day (bid)]. Clinical cut-off levels, which correlate baseline measures of resistance with HIV RNA responses in large cohorts or clinical trials, are the ideal reference for developing such algorithms. Cut-off levels previously developed for unboosted saquinavir may no longer apply, as the plasma drug levels with SQV/r are significantly higher and may be able partially to overcome protease inhibitor-resistant HIV. Clinical cut-off levels for SQV/r, assessed in several cohort studies and clinical trials, also suggest that multiple genotypic mutations are required for complete loss of virological response. For phenotypic analysis of resistance, saquinavir cut-off levels 10,11-fold higher than the wild-type IC50 have best distinguished responders from non-responders in cohort studies. Using Virtual Phenotype, a 12.3-fold upper cut-off level was determined from analysis of large cohort databases. These genotypic and phenotypic algorithms need to be validated in larger prospective studies. [source] Increased risk of early virological failure in non-European HIV-1-infected patients in a Dutch cohort on highly active antiretroviral therapyHIV MEDICINE, Issue 5 2005JB Van Den Berg Objective To compare early and late responses to highly active antiretroviral therapy (HAART) in European and non-European HIV-1 infected patients in a Dutch cohort. Methods We retrospectively analysed the response to HAART of 216 previously treatment-naive HIV-1-infected patients using the University Medical Centre Utrecht HIV database. African (n=51), Asian (n=7), and Central/South American (n=6) patients were classified as non-European, and others as European (n=152). Early failure was defined as a viral load that remained above 400 HIV-1 RNA copies/mL after 6 months of treatment with HAART. Late-phase failure was determined in patients who were successfully treated in the early phase and was defined as two consecutive viral load measurements above 400 copies/mL, a new AIDS-defining event or death. Results In the early phase, four of 152 (2.6%) European and eight of 64 (12.5%) non-European patients failed HAART. A significant increased risk of virological failure in the early phase of treatment was observed for non-Europeans as compared to Europeans (odds ratio 4.6; 95% confidence interval 1.1,20.2). Low serum drug levels in the absence of resistant virus were often seen at the time of early failure. No difference in late-phase failure was observed between the two groups (adjusted hazard ratio 0.6; 95% confidence interval 0.3,1.2). Conclusions Non-European patients had a 4.6 times higher risk of virological failure than their European counterparts in the first 6 months of treatment with HAART. This failure seemed to be associated with low serum drug levels at the time of failure. However, if HAART was successful in the early phase, response rates in the late phase were similar for Europeans and non-Europeans. [source] Clinical benefit of interventions driven by therapeutic drug monitoringHIV MEDICINE, Issue 5 2005AL Rendón Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source] Measurement of serum salicylate levels by solid-phase extraction and desorption/ionization on silicon mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 8 2005Shoji Okuno Abstract The applicability of the matrix-free laser desorption/ionization on silicon mass spectrometry (DIOS-MS) to measuring serum drug levels was examined by analyzing serum salicylic acid. The optimized and simple solid-phase extraction (SPE) allowed good recovery, 88.9 ± 5.8%, for 1.4 mM (200 mg/L) of salicylic acid in serum. The negative ion MS allowed measurements of deprotonated molecules without interference from other signals. Using a deuterium-labeled internal standard, good linearity was obtained in the 0.14 to 4.2 mM (20,600 mg/L) range, which was sufficient for monitoring the therapeutic anti-inflammatory dose. SPE followed by DIOS-MS is anticipated to be a method of measuring drug levels in blood and may allow high throughput analysis. Copyright © 2005 John Wiley & Sons, Ltd. [source] Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI PilotJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2004J. H. Alexander Summary.,Background:,Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI). Objectives:,To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI. Patients and methods:,Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I,III were designed to achieve concentrations of >,100 ng mL,1, >,75 ng mL,1, and >,150 ng mL,1. Stage IV used the stage III regimen but included patients recently given heparin. Results:,At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL,1 in stages I,IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL,1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose. Conclusions:,Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study. [source] Hydrogenated castor oil nanoparticles as carriers for the subcutaneous administration of tilmicosin: in vitro and in vivo studiesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2009C. HAN Tilmicosin-loaded solid lipid nanoparticles (SLN) were prepared with hydrogenated castor oil (HCO) by o/w emulsion,solvent evaporation technique. The nanoparticle diameters, surface charges, drug loadings and encapsulation efficiencies of different formulations were 90,230 nm, ,6.5,,12.5 mV, 40.3,59.2% and 5.7,11.7% (w/w), respectively. In vitro release studies of the tilmicosin-loaded nanoparticles showed a sustained release and the released tilmicosin had the same antibacterial activity as that of the free drug. Pharmacokinetics study after subcutaneous administration to Balb/c mice demonstrated that a single dose of tilmicosin-loaded nanoparticles resulted in sustained serum drug levels (>0.1 ,g/mL) for 8 days, as compared with only 5 h for the same amount of tilmicosin phosphate solution. The time to maximum concentration (Tmax), half-life of absorption (T˝ ab) and half-life of elimination (T˝ el) of tilmicosin-loaded nanoparticles were much longer than those of tilmicosin phosphate solution. Tissue section showed that drug-loaded nanoparticles caused no inflammation at the injection site. Cytotoxicity study in cell culture and acute toxicity test in mice demonstrated that the nanoparticles had little or no toxicity. The results of this exploratory study suggest that the HCO,SLN could be a useful system for the delivery of tilmicosin by subcutaneous administration. [source] Antimicrobial resistance in livestockJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2003B. Catry Antimicrobial resistance may become a major problem in veterinary medicine as a consequence of the intensive use and misuse of antimicrobial drugs. Related problems are now arising in human medicine, such as the appearance of multi-resistant food-borne pathogens. Product characteristics, dose, treatment interval and duration of treatment influence the selection pressure for antimicrobial drug resistance. There are theoretical, experimental and clinical indications that the emergence of de novo resistance in a pathogenic population can be prevented by minimizing the time that suboptimal drug levels are present in the infected tissue compartment. Until recently, attention has been focused on target pathogens. However, it should be kept in mind that when antimicrobial drugs are used in an individual, resistance selection mainly affects the normal body flora. In the long term, this is at least equally important as resistance selection in the target pathogens, as the horizontal transfer of resistance genes converts almost all pathogenic bacteria into potential recipients for antimicrobial resistance. Other factors contributing to the epidemiology of antimicrobial resistance are the localization and size of the microbial population, and the age, immunity and contact intensity of the host. In livestock, dynamic herd-related resistance patterns have been observed in different animal species. [source] Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinomaLIVER TRANSPLANTATION, Issue 5 2008Michael A. Zimmerman Experience with sirolimus (SRL)-based immunosuppression following orthotopic liver transplantation (OLT) is rapidly accumulating. In combination with calcineurin inhibitors (CNIs), SRL may reduce the incidence of acute rejection and lower overall required drug levels. This study sought to quantify long-term outcome following OLT in patients with cirrhosis and concomitant hepatocellular carcinoma (HCC) who were treated with an SRL-based regimen as a primary therapy. From January 2000 to June 2007, 97 patients underwent OLT for end-stage liver disease and HCC at the University of Colorado Health Sciences Center. Of those, 45 patients received SRL, in addition to CNIs, as a component of their primary immunosuppression regimen post-OLT. Conversely, 52 patients received the standard immunosuppression regimen including CNIs, mycophenolate mofetil, and corticosteroids. The 2 treatment groups were compared with respect to the following variables: age, gender, tumor stage by explant, grade, size, presence of vascular invasion, focality, Child's class, baseline creatinine, and warm and cold ischemic times. The 2 groups were comparable by all factors save for cold ischemic time, which was significantly longer in the CNI-treated group. Overall survival at 1 and 5 years post-OLT for patients treated with SRL was 95.5% and 78.8%, respectively. Conversely, survival in patients treated with CNIs exclusively at the same time intervals was 83% and 62%. Although there was no difference in the incidence of major complications, the SRL group experienced a modest improvement in renal function. Cumulatively, these data suggest a potential survival benefit with SRL-based therapy in patients undergoing OLT for end-stage liver disease and concomitant malignancy. Liver Transpl 2008. © 2008 AASLD. [source] Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patientsLIVER TRANSPLANTATION, Issue 7 2004Martin Vogel Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV-infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug-to-drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12-hour pharmacokinetic profiles in 3 HIV-positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir-boosted indinavir or lopinavir-based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1-mg increments. Under ritonavir-boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood-levels throughout the dosing interval and prolonged elimination half-lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5,20% of the individual standard doses given before initiation of ritonavir-boosted HAART. Because of the flat absorption/elimination profiles under ritonavir-boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough-levels. (Liver Transpl 2004;10:939,944.) [source] Bispectral index, predicted and measured drug levels of target-controlled infusions of remifentanil and propofol during laparoscopic cholecystectomy and emergenceACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2000S. C. Hřymork Background: Target-controlled infusions (TCI) have been launched as simple, accurate and reliable delivery systems of intravenous drugs. Bispectral index of EEG (BIS) seems promising in measuring hypnotic effect of anaesthetic drugs. The aims of this study were to evaluate the accuracy of TCI systems in patients undergoing laparoscopic cholecystectomy and to correlate measured drug levels to BIS values. Data were analysed for possible gender differences during emergence. Methods: After written informed consent, 20 patients were enrolled in an open study. Remifentanil was set at 7.5 ng/ml as target throughout the whole procedure, and propofol at 5 ,g/ml at induction and 3 ,g/ml after intubation. Values in blood samples of remifentanil and propofol were correlated to the estimated values and to systolic blood pressure and BIS. BIS values and measured drug levels during emergence and emergence time were compared for the two sexes. Results: Measured drug values varied considerably from the set target with a prediction error of ,22% for remifentanil and 49% for propofol. The anaesthesia level was regarded as quite deep with a mean BIS during stable surgery of 42±7, and at this level we found no correlation between measured values of either of the two drugs and BIS. The emergence time was significantly shorter for women (12.6±2.5 min) than for men (19.0±4.2 min) (P=0.001), with no significant differences in measured levels of propofol or remifentanil or BIS during the emergence period. Conclusion: Present systems for TCI of remifentanil and propofol result in large intra- and interindividual variations in measured drug levels, and measured levels differ from target. There may be possible interaction between the two anaesthetics at a pharmacokinetic level. Within the level of anaesthesia studied here, BIS was not an indicator of the actual drug levels. Women woke up significantly faster than men. [source] Pediatric cardiac transplant: Results using a steroid-free maintenance regimenPEDIATRIC TRANSPLANTATION, Issue 1 2003H. Leonard Abstract: We report on survival, rejection, lymphoma and renal function following cardiac transplant using a steroid-free maintenance immunosuppressive regimen. We have performed 73 cardiac transplants in 71 children under 16 yr of age in the last 12 yr. There were eight perioperative and four late deaths giving actuarial survival of 88, 88, 85 and 70% at 1, 2, 5 and 10 yr, respectively. A total of 11 (15.3%) children had one episode of rejection (grade 3) in the first 6 months; one died and one was re-transplanted because of rejection. There was only one episode of late rejection (8 yr post-transplant) because of low drug levels in a patient with lymphoma and sepsis. This patient did not survive. Three other children (5.6%) also developed lymphoma and recovered but one died subsequently of graft failure. Four children have developed severe renal failure (glomerular filtration rate GFR <30 mL/min/m2). Two have not survived and one is expected to commence dialysis soon. The remainder have mild to moderate renal impairment. We report excellent survival and low rejection rates without use of long-term steroids. However the doses of cyclosporin used have had a significant effect on renal function in many cases. [source] Influence of dose on the distribution kinetics of ciprofloxacin and ofloxacin in the isolated hindlimb of the ratBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2000A.C. Casquero-Dorado Abstract The aim of this study was to determine whether the dose influences the distribution kinetics of ciprofloxacin and ofloxacin in muscle- bone- and skin-tissues included in the isolated hindlimb of the rat. Experiments were carried out in the isolated perfused hindlimb of the rat, administering a single dose of 45, 450 or 900 µg of each quinolone as a bolus injection. Outflow perfusate samples were collected for 20 min and drug levels were determined by an HPLC technique. The mean transit time (MTT) and the distribution volume of ciprofloxacin significantly increased with the dose injected (MTT=1.47±0.69, 8.74±0.27 and 9.52±2.95 min for 45, 450 and 900 µg, respectively). A similar situation was observed with ofloxacin, although the increase in these parameters was less pronounced (MTT=3.65±0.86, 7.92±2.03 and 8.32±1.70 min for 45, 450 and 900 µg, respectively). The distribution of ciprofloxacin and ofloxacin in the rat hindlimb appears to be a dose-dependent process, at least for the dose range considered in this study. This might explain the high variability in the distribution coefficients reported for these drugs in literature. Copyright © 2000 John Wiley & Sons, Ltd. [source] Paclitaxel and cisplatin as intravesical agents against non-muscle-invasive bladder cancerBJU INTERNATIONAL, Issue 11 2008Boris A. Hadaschik OBJECTIVES To investigate the effects of cisplatin and paclitaxel against human bladder cancer cells in vitro, and to obtain both pharmacokinetic and pharmacodynamic data after intravesical administration in mice. MATERIALS AND METHODS Six bladder cancer cell lines (J82, KU7, RT4, SW780, T24, UMUC3) were treated with various combined doses of both drugs and cell proliferation was evaluated 3 days later. In vivo, solutions of cisplatin and micellar paclitaxel were instilled transurethrally in female mice and pharmacokinetic data were acquired using high-performance liquid chromatography-mass spectrometry and atomic absorption methods. To obtain efficacy data, mice with orthotopic KU7-luc tumours were administered cisplatin and/or micellar paclitaxel intravesically, and the tumour burden quantified using bioluminescence imaging. RESULTS In vitro, both cisplatin and paclitaxel potently decreased the proliferation of all cell lines tested, and in combination had an additive but not a synergistic effect. After intravesical instillation, mouse serum concentrations of cisplatin and paclitaxel were in the low microgram/millilitre range and bladder tissue concentrations achieved were 82 and 241 µg/g, respectively. Similar drug levels were reached using combined therapy. In vivo, all chemotherapeutic agents significantly inhibited bladder tumour growth, with the best results for combined therapy and micellar paclitaxel alone. However, there was toxicity in the combined treatment arm. CONCLUSIONS Both cisplatin and paclitaxel were absorbed at effective amounts into bladder tissues. As intravesical agents, paclitaxel had slightly stronger anticancer potency than cisplatin. Due to increased adverse events, caution should be exercised when combining both cisplatin and paclitaxel intravesically. [source] The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamicsACTA NEUROLOGICA SCANDINAVICA, Issue 2000N. H. Greig Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long-lasting inhibition of AChE was achieved (half-life >8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. [source] Effect of Intravenous Albumin Infusion on Brain Salicylate ConcentrationACADEMIC EMERGENCY MEDICINE, Issue 6 2007Steven C. Curry MD Background:Salicylate poisoning appears to result in death, despite supportive care, once a critical brain salicylate concentration is reached. The binding of salicylate to albumin is saturable; free plasma salicylate concentrations rise disproportionately to total drug levels. Because unbound salicylate distributes into the brain, the authors questioned whether an intravenous (IV) infusion of albumin would cause a redistribution of salicylate from the brain back into the plasma, which might allow enough time for hemodialysis to be instituted. Objectives:To determine if IV albumin infusion would lower brain salicylate concentrations through redistribution in a porcine model of acute salicylate poisoning. Methods:In a randomized controlled trial, 17 swine under anesthesia and controlled ventilation received 400 mg/kg of sodium salicylate IV over 15 minutes. At 60 minutes, nine animals received 1.25 g/kg albumin (25% solution) IV over 15 minutes, while eight control animals received an equal volume of normal saline (5 mL/kg). Arterial pH was maintained between 7.45 and 7.55. Serial measurements of serum albumin as well as free and total salicylate concentrations were obtained, and urine was collected for measurement of total salicylate excretion. At 180 minutes, animals were killed and brains harvested for measurement of brain salicylate concentrations. Results:Average peak serum total salicylate concentrations of 105.5 and 109 mg/dL were achieved in control and albumin-treated animals, respectively. Albumin infusion was accompanied by statistically significant increases in serum total salicylate concentrations (median from 79.5 to 86.9 mg/dL at 75 minutes), while levels decreased slightly in control animals. Serum free salicylate concentrations decreased slightly in albumin-treated animals, but the difference was not statistically significant. Median brain salicylate concentrations were about 14% lower in the albumin treatment group (17.8 mg/100 g brain) compared with controls (20.5 mg/100 g brain); this approached statistical significance (p = 0.075). Median urinary salicylate excretion was higher in the albumin-treated group (0.83 vs. 0.48 g; p = 0.072), with similar urinary pH and volumes in both groups. Conclusions:In this animal model of salicylate poisoning, IV infusion of 1.25 g/kg albumin was accompanied by a 14% decline in median brain salicylate concentrations, which approached statistical significance. [source] Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New ConceptCHEMISTRY & BIODIVERSITY, Issue 11 2009Andreas Reichel Abstract Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood,brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic. [source] | ||||||||||||||||||||||||||||