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Drug Monitoring (drug + monitoring)
Kinds of Drug Monitoring Selected AbstractsIntroducing triage logic as a new strategy for the detection of signals in the WHO Drug Monitoring Database,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2004M. Stĺhl Abstract Purpose An important role for the WHO Programme for International Drug Monitoring is to identify signals of international drug safety problems as early as possible. The signal detection strategy, operated at the Uppsala Monitoring Centre (UMC), gave too many drug,adverse drug reaction (ADR) combinations for individual review. Therefore additional selection strategies were needed to improve the likely signal-to-noise ratio and for the UMC to complement the efforts of national centres in an efficient way. Methods The combinations database of the first quarter of 2001 was analysed using algorithms representing different strategies for finding relevant signals using triage logic. Results The strategies that together gave a manageable number of combinations, i.e. around 600, for further consideration in a single quarter were the algorithms for ,Rapid reporting increase', ,Serious reaction and new drug' and ,Special interests'. These filters began to be used routinely on the combinations database in late 2001. Conclusions While stressing that human review is essential, triage strategies are useful when attempting analysis of large amounts of data. By definition, the use of triage strategies may exclude some potential signals from consideration, although the intention is to improve the chances of detection by focussing on areas of greatest importance. Copyright © 2004 John Wiley & Sons, Ltd. [source] Endogenous Fluorescence Spectroscopy of Cell Suspensions for Chemopreventive Drug Monitoring,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2005Nathaniel D. Kirkpatrick ABSTRACT Cancer chemopreventive agents such as N -4-(hydroxyphenyl)-retinamide (4HPR) are thought to prevent cancers by suppressing growth or inducing apoptosis in precancerous cells. Mechanisms by which these drugs affect cells are often not known, and the means to monitor their effects is not available. In this study endogenous fluorescence spectroscopy was used to measure metabolic changes in response to treatment with 4HPR in ovarian and bladder cancer cell lines. Fluorescence signals consistent with nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD) and tryptophan were measured to monitor cellular activity through redox status and protein content. Cells were treated with varying concentrations of 4HPR and measured in a stable environment with a sensitive fluorescence spectrometer. Results suggest that redox signal of all cells changed in a similar dose-dependant manner but started at different baseline levels. Redox signal changes depended primarily on changes consistent with NADH fluorescence, whereas the FAD fluorescence remained relatively constant. Similarly, tryptophan fluorescence decreased with increased drug treatment, suggesting a decrease in protein production. Given that each cell line has been shown to have a different apoptotic response to 4HPR, fluorescence redox values along with changes in tryptophan fluorescence may be a response as well as an endpoint marker for chemopreventive drugs. [source] Therapeutic drug monitoring in a developing country: an overviewBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2001N. J. Gogtay Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic diff;erences, nutritional defi;ciencies, quality of medicines and availability of generic products; its utility as a research tool and its future. [source] A simple and rapid high-performance liquid chromatographic (HPLC) method for 5-fluorouracil (5-FU) assay in plasma and possible detection of patients with impaired dihydropyrimidine dehydrogenase (DPD) activityJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2004J. Ciccolini PharmD PhD Summary Background:, Dihydropyrimidine dehydrogenase (DPD) gene polymorphism may lead to severe toxicity with 5-fluorouracil (5-FU), a major anticancer drug extensively used in clinical oncology. Drug monitoring combined with early detection of patients at risk would enable timely dose adaptation so as to maintain drug concentrations within a therapeutic window. However, the best method to identify such patients remains to be determined. Objective:, The aim of this study was to develop a rapid and simple high-performance liquid chromatographic (HPLC) method for estimating uracil/dihydrouracil (U/UH2) ratio in plasma, as an index of DPD status, and for assaying 5-FU as part of drug level monitoring. Method:, Assay of 5-FU, and U/UH2 detection were performed on a HPLC system equipped with UV detector. Analytes were separated at room temperature using a 5 ,m particles, 25 cm RP-18 X-Terra column. The mobile-phase consisted of a KH2PO4 salt solution (0·05 m) + 0·1% triethylamine (TEA) pumped at 0·4 mL/min. Detection of 5-FU and 5-bromouracil were performed at 254 nm; U and UH2 elution was monitored at 210 nm. Results:, The method was sensitive and specific for assaying 5-FU within the 5,500 ng/mL concentration range, which covers exposure levels currently met in clinical practice. The method was simple, and relatively cheap, and rapid, with an analytical run time of about 30 min. Data from a patient with 5-FU toxicity suggest that the method was capable of identifying DPD metabolic phenotype in cancer patients, based on measurement of plasma U/UH2 ratio. Conclusion:, The method described should be suitable both for detecting patients at high risk of 5-FU toxicity, and for drug level monitoring during chemotherapy. [source] Rheumatology nurse practitioners' perceptions of their roleMUSCULOSKELETAL CARE, Issue 2 2006Leslie Goh MRCP(UK) Abstract Objectives:,To identify the current practices of rheumatology nurse practitioners and ascertain their perceptions of how their role could be enhanced. Method:,A cross-sectional questionnaire study of currently employed nurse practitioners in rheumatology in the United Kingdom (UK) was undertaken. Results:,200 questionnaires were distributed and 118 nurses responded. Ninety-five respondents met the inclusion criteria for undertaking an advanced nursing role. Typical conditions dealt with included: rheumatoid arthritis (96.8%); psoriatic arthritis (95.8%); osteoarthritis (63.2%); ankylosing spondylitis (62.8%); systemic lupus erythematosus (51.6%); and scleroderma (34.7%). Drug monitoring, education, counselling of patients and arranging basic investigations were routinely performed by more than 80% of respondents. A smaller proportion performed an extended role that included dealing with referrals, research and audit, the administration of intra-articular injections, and admission of patients. Specific attributes identified as being necessary for competence were: knowledge and understanding of rheumatic diseases (48.4%); drug therapy (33.7%); good communication skills (35.8%); understanding of the roles of the team (27.4%); working effectively (23.2%) as part of a multidisciplinary team; assessment of patients by physical examination (28.4%); teaching (26.3%), research (17.9%); organizational skills (14.7%); and the interpretation of investigations (9.5%). Factors that could enhance their role included: attendance at postgraduate courses (30.5%); obtaining further qualifications (13.7%); active participation in the delivery of medical education (41.1%); training in practical procedures (31.6%); protected time and resources for audit and research (11.6%); formal training in counselling (11.6%); and implementation of nurse prescribing (10.5%). Conclusion:,Nurse practitioners already have a wide remit and play an invaluable part in the delivery of modern rheumatology services. An extended role could improve patient care and enhance nursing career pathways in rheumatology. Copyright © 2006 John Wiley & Sons, Ltd. [source] Amisulpride , dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoringACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2009A. Sparshatt Objective:, To evaluate the relationships between dose, plasma concentration, pharmacological activity and clinical outcome to evaluate the appropriateness of therapeutic drug monitoring (TDM) in patients receiving amisulpride. Method:, Literature search of Embase, Medline and PubMed databases. Results:, Amisulpride plasma concentration is closely correlated with dose (r2 = 0.96, P < 0.0001), dopamine occupancy, response and with extra-pyramidal symptoms (EPS). Dose is correlated with response, dopamine occupancy and EPS. Optimal clinical response was found at doses of 400,800 mg/day, corresponding to plasma levels of approximately 200,500 ng/ml. EPS appears to be more reliably predicted by a plasma level above 320 ng/ml than by a particular dose. Conclusion:, The effects and safety of amisulpride in the treatment of schizophrenia and schizoaffective disorder are predicted by daily dose. The plasma concentration threshold for response appears to be approximately 200 ng/ml. EPS are more reliably predicted by plasma level than by dose. TDM for patients prescribed amisulpride is thus of some clinical value. [source] A simple and rapid CZE method for the analysis of mycophenolic acid and its phenol glucuronide metabolite in human serum,ELECTROPHORESIS, Issue 17 2008Kaname Ohyama Abstract A simple and rapid capillary electrophoretic method was developed for simultaneous determination of mycophenolic acid and its metabolite, phenol glucuronide, in human serum. The sample preparation in the proposed method required only the precipitation by acetonitrile. Separation was performed by capillary zone electrophoresis using 75,mM phosphate buffer (pH 7.5) as running buffer, an applied voltage of 10,kV, and UV detection at 217,nm. Each serum sample analysis was completed within 15,min. The optimized method demonstrated good performance concerning specificity, linearity (r>0.9955), accuracy (95.9,113%), precision (<6.4%) and enough sensitivity for therapeutic drug monitoring. This method was successfully applied to measurements of mycophenolic acid and mycophenolic acid glucuronide in renal transplant patient samples and was a useful alternative to high-performance liquid chromatography-based methods. [source] Advances in the enantioseparation of second-generation antidepressant drugs by electrodriven methodsELECTROPHORESIS, Issue 1 2006Roberto Mandrioli Abstract Stereochemistry is steadily increasing in importance in the development of new drugs, and the availability of pure enantiomer drugs can make therapy safer and more efficacious. In particular, almost all second-generation antidepressant drugs possess one or more chiral centres; however, only some of them are administered as single enantiomers. A fundamental part of the quality control of pharmaceutical formulations is the determination of enantiomeric excess and enantiomeric purity; this is also important for the therapeutic drug monitoring of depressed patients. For this purpose, efficient and reliable analytical methods are needed and electrodriven techniques (most of all CE, CEC and MEKC) are very efficient and inexpensive candidates for the role. In this review, the enantioselective electrodriven methods available for the analysis of second-generation antidepressant are presented and discussed. In particular, the following pharmacological classes of antidepressants will be considered: selective serotonin reuptake inhibitors (fluoxetine, citalopram, paroxetine, sertraline); norepinephrine reuptake inhibitors (reboxetine); serotonin and norepinephrine reuptake inhibitors (venlafaxine, milnacipran, duloxetine); and noradrenergic and specific serotonergic antidepressants (mirtazapine). [source] Determination of ribavirin in human serum and plasma by capillary electrophoresisELECTROPHORESIS, Issue 10-11 2004Michael C. Breadmore Abstract The electrophoretic separation of ribavirin and 5-methylcytidine (internal standard) by capillary electrophoresis was examined. Separation was achieved using reverse polarity in a 100 mM borate electrolyte, pH 9.1, with 5 mM spermine added to reduce the electroosmotic flow. Sample preparation based on acetonitrile protein precipitation was found to be unsuitable for ribavirin analysis in patient samples due to insufficient sensitivity and interferences. Solid-phase extraction employing phenyl boronic acid cartridges provided cleaner separations. Using this approach with 500 ,L sample and reconstitution of the dried extract into 100 ,L of 33% v/v 100 mM phosphate buffer, pH 6.4 / 67% v/v acetonitrile, the detection and quantitation limits were determined to be 0.05 and 0.10 ,g/mL, respectively, a sensitivity that is suitable for therapeutic drug monitoring of ribavirin in human plasma and serum samples. The method was validated and compared to a high-performance liquid chromatography (HPLC) method, showing excellent agreement between the two for a set of samples that stemmed from patients being treated with ribavirin and interferon-,-2b for a hepatitis C virus infection. [source] Controversies in Blood-level Monitoring: Reexamining Its Role in the Treatment of EpilepsyEPILEPSIA, Issue 2000Tracy A. Glauser Summary: This article reexamines the role of blood-level monitoring (therapeutic drug monitoring, TDM) of antiepileptic drugs (AEDs) in the current treatment of epilepsy and identifies situations in which TDM can be useful. Basic pharmaco-kinetic and pharmacodynamic principles are reviewed, with specific emphasis on kinetics of absorption/distribution/metabolism, elimination half-life, time to steady state, and plasma drug concentrations. The relationship between AED intensity of effect (pharmacodynamics) and plasma concentration (pharmacokinetics) is expressed mathematically, examined in the context of the major old and new AEDs, and integrated with a historical look at the role of TDM. Situations in which TDM can be useful in the modern treatment of epilepsy are presented and discussed. For both older and newer AEDs, TDM is useful in six clinical situations: establishing "baseline" effective concentrations, evaluating potential causes for lack of efficacy, evaluating potential causes for toxicity, evaluating potential causes for loss of efficacy, judging "room to move' or when to change AEDs, and minimizing predictable problems. TDM remains a valuable tool in the modern treatment of epilepsy. It can be selectively and appropriately utilized to help maximize seizure control and minimize side effects if levels are obtained in response to a patient-specific pharmacokinetic or pharmacodynamic issue or problem. [source] Population pharmacokinetics of imipenem in burn patientsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2003Eric Dailly Abstract The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47, 118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear,inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 ± 0.204 L/h) and of the distribution volume of the central compartment (0.376 ± 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance. [source] Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2002Annick Rousseau Abstract Over the last 10 years, proofs of the clinical interest of therapeutic drug monitoring (TDM) of certain anticancer drugs have been established. Numerous studies have shown that TDM is an efficient tool for controlling the toxicity of therapeutic drugs, and a few trials have even demonstrated that it can improve their efficacy. This article critically reviews TDM tools based on pharmacokinetic modelling of anticancer drugs. The administered dose of anticancer drugs is sometimes adjusted individually using either a priori or a posteriori methods. The most frequent clinical application of a priori formulae concerns carboplatin and allows the computation of the first dose based on biometrical and biological data such as weight, age, gender, creatinine clearance and glomerular filtration rate. A posteriori methods use drug plasma concentrations to adjust the subsequent dose(s). Thus, nomograms allowing dose adjustment on the basis of blood concentration are routinely used for 5-fluorouracil given as long continuous infusions. Multilinear regression models have been developed, for example for etoposide, doxorubicin, carboplatin, cyclophosphamide and irinotecan, to predict a single exposure variable [such as area under concentration,time curve (AUC)] from a small number of plasma concentrations obtained at predetermined times after a standard dose. These models can only be applied by using the same dose and schedule as the original study. Bayesian estimation offers more flexibility in blood sampling times and, owing to its precision and to the amount of information provided, is the method of choice for ensuring that a given patient benefits from the desired systemic exposure. Unlike the other a posteriori methods, Bayesian estimation is based on population pharmacokinetic studies and can take into account the effects of different individual factors on the pharmacokinetics of the drug. Bayesian estimators have been used to determine maximum tolerated systemic exposure thresholds (e.g. for topotecan or teniposide) as well as for the routine monitoring of drugs characterized by a very high interindividual pharmacokinetic variability such as methotrexate or carboplatin. The development of these methods has contributed to improving cancer chemotherapy in terms of patient outcome and survival and should be pursued. [source] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infectionHIV MEDICINE, Issue 10 2009PENTA Steering Committee PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: ,When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. ,What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained. [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] The therapeutic promise of single enantiomers: introductionHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001Irving W. Wainer Abstract This review uses several examples drawn from the literature to show how using active enantiomers as therapeutic agents may yield several benefits, including more predictable pharmacokinetics, more accurate drug monitoring and enhanced tolerability. As a result of these benefits, the therapeutic use of single enantiomers will become increasingly important not only in psychopharmacology, but in medicine generally. Indeed, over the early years of the new millennium, the therapeutic use of single active enantiomers is set to redefine the benefit,risk ratio in the management of many common conditions. Copyright © 2001 John Wiley & Sons, Ltd. [source] Enantiomeric antidepressant drugs should be considered on individual meritHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue S2 2001Pierre Baumann Abstract Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug,drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression. Copyright © 2001 John Wiley & Sons, Ltd. [source] Frequently discordant results from therapeutic drug monitoring for digoxin: clinical confusion for the prescriberINTERNAL MEDICINE JOURNAL, Issue 1 2010N. M. Rogers Abstract Background: Digoxin remains a commonly prescribed medication for the treatment of congestive cardiac failure or atrial tachyarrhythmias. Its utility is offset by its narrow therapeutic index requiring regular blood concentration monitoring. Recent evidence suggests that a lower therapeutic range (0.5,0.8 µg/L, or 0.6,1.0 nmol/L) is associated with reduced mortality in patients with congestive cardiac failure. Therapeutic drug monitoring for digoxin is carried out by immunoassays that are well established in routine clinical practice. Laboratories using different immunoassays may be involved in monitoring individual patients throughout the protracted course of therapy. These results should be concordant to ensure consistent dose individualization and optimum clinical management. We have investigated the discordance in digoxin measurements involving five different laboratories across the Adelaide metropolitan area. Methods: Aliquots from routine digoxin samples (n= 261) were analysed by accredited laboratories using commercially available immunoassays. Results: The results showed that 119 (46%) of 261 samples were so varied that a different clinical outcome was indicated when reviewed by the treating physician. The differences between the highest and lowest readings from any one sample were also substantial, with 45% of the measurements exceeding 0.3 µg/L. Conclusions: Our study shows the considerable variation in the routine monitoring of digoxin. This makes therapeutic drug monitoring difficult to interpret and complicates clinical management when treating physicians are endeavouring to avoid toxicity and optimize dosing. These results raise a significant concern for the quality of therapeutic drug monitoring of digoxin and have direct repercussions on patient care. [source] Simultaneous determination of maraviroc and raltegravir in human plasma by HPLC-UVIUBMB LIFE, Issue 4 2009Stefania Notari Abstract Therapeutic drug monitoring is pivotal to improve the management of HIV infection. Here, a new HPLC,UV method to quantify simultaneously maraviroc and raltegravir levels in human plasma is reported. Remarkably, this is the first method for maraviroc determination in human plasma. The volume of the plasma sample was 600 ,L. This method involved automated solid-phase extraction with Oasis HLB Cartridge 1 cc (30 mg divinylbenzene and N -vinylpyrrolidone) and evaporation in a water bath under nitrogen stream. The extracted samples were reconstituted with 200 ,L 50/50 of mobile-phase solution (0.01 M KH2PO4 and acetonitrile). Twenty microliters of these samples were injected into a HPLC,UV system, the analytes were eluted on an analytical dC18 Atlantis column (150 mm × 4.6 mm I.D.) with a particle size of 5 ,m. The mobile phase (0.01 M KH2PO4 and acetonitrile) was delivered at 1.0 mL/min with isocratic elution. The total run time for a single analysis was 10 min; maraviroc and raltegravir were detected by UV at 197 and 300 nm. The calibration curves were linear up to 2,500 ng/mL. The absolute recovery ranged between 93 and 100%. The HPLC,UV method reported here has been validated and is currently applied to monitor plasma levels of maraviroc and raltegravir in HIV-infected patients. © 2009 IUBMB IUBMB Life, 61(4):470,475, 2009 [source] Determination of terephthalic acid isopropylamide in urine with a liquid chromatography/mass spectrometry (LC/MS) methodJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 1 2008F. Baumann Abstract A sensitive and simple liquid chromatography/mass spectrometry (LC/MS) method was developed for the determination of terephthalic acid isopropylamide, the final metabolite of procarbazine in human urine. A solid-phase extraction with C18 cartridges was used followed by LC/MS with a single mass spectrometer (SSQ 7000 from Finnigan). Terephthalic acid isobutylamide was the internal standard. The quantification limit was 30,ng/mL in urine (6,×,noise). This assay was applied for drug monitoring of terephthalic acid isopropylamide in urine after oral administration of procarbazine in children and adolescents with Hodgkin lymphomas. J. Clin. Lab. Anal. 22:21,28, 2008. © 2008 Wiley-Liss, Inc. [source] ORIGINAL ARTICLE: Investigation of the prediction accuracy of vancomycin concentrations determined by patient-specific parameters as estimated by Bayesian analysisJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2010Y. Hiraki BSc Summary Background/Objective:, There have been many studies of therapeutic drug monitoring (TDM) of vancomycin (VCM) based on Bayesian analysis, but there have been no reports of the accuracy of prediction based on Bayesian-estimated patient-specific parameters. This study was conducted to compare the accuracy of prediction based on the population pharmacokinetic (PPK) method and Bayesian-estimated parameters. Method:, The subjects were 22 patients who were treated with VCM for MRSA infection and whose blood was sampled twice or more during the administration period. The concentrations between the blood samples were predicted based on the concentrations in the first blood samples based on the PPK method using mean parameters for the Japanese population and Bayesian-estimated patient-specific pharmacokinetic parameters. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were compared to examine the accuracy of prediction based on Bayesian-estimated patient-specific parameters. Results and discussion:, The mean measured VCM concentration was 10·43 ± 5·19 ,g/mL, whereas the mean concentration predicted based on the PPK method was 8·52 ± 4·34 ,g/mL, with an ME of ,1·91, MAE of 2·93 and RMSE of 3·21. The mean concentration predicted based on patient-specific parameters was 9·62 ± 4·95 ,g/mL with ME of ,0·81, MAE of 1·38 and RMSE of 1·74. The ME and MAE for the concentrations predicted using patient-specific parameters were smaller compared with those predicted using the PPK method (P = 0·0471 and 0·0003, respectively), indicating superior prediction with a significant difference between approaches. Conclusion:, Prediction using Bayesian estimates of patient-specific parameters was better than by the PPK method. However, when using patient-specific parameters it is still necessary to fully understand the clinical status of the patient and frequently determine VCM concentrations. [source] Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosageJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2006I. B. Bondareva PhD Summary Background:, Proper use of antiepileptic drugs in the elderly involves knowledge of their pharmacokinetics to ensure a patient-specific balance between efficacy and toxicity. However, populations of epileptic patients on chronic carbamazepine (CBZ) therapy which have been studied have included data of relatively few elderly patients. Aims:, The aim of the present study was to evaluate the population pharmacokinetics of CBZ in elderly patients on chronic monotherapy. Methods:, We have used the non-parametric expectation maximization (NPEM) program in the USC*PACK collection of PC programs to estimate individual and population post-induction pharmacokinetics of CBZ in epileptic elderly patients who received chronic CBZ monotherapy. Age-related changes of CBZ population pharmacokinetics were evaluated from routine therapeutic drug monitoring (TDM) data of 37 elderly and 35 younger patients with epilepsy. As a ,historical control' we used previously published population modelling results from 99 young epileptic patients on chronic CBZ monotherapy. In that control group, TDM was performed in the same pharmacokinetic (PK) laboratory, using the same sampling strategy as in the present study, and the same PK population modelling software was used for data analysis. Results and conclusions:, A poor correlation was found between daily CBZ dose and serum concentrations in the elderly patients (r = 0·2, P = 0·25). Probably statistically significant difference in the median values of the CBZ metabolic rate constant (P < 0·001) between elderly and relatively young epileptic patients was found. Our results showed that age-related influences in CBZ pharmacokinetics in elderly patients should be considered in the optimal planning of CBZ dosage regimens. Most elderly patients with epilepsy will usually need CBZ dosages lower than those based on the median population PK parameter values obtained from younger patients. The present population model is also uniquely well suited for the new ,multiple model' design of dosage regimens to hit target therapeutic goals with maximum precision. [source] Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring,JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2005M. Takada PhD Summary Objective:, In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. Methods:, Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. Results:, A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. Conclusions:, It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM. [source] Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implications for dosageJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2004I. B. Bondareva Summary Therapeutic drug monitoring (TDM) of valproate (VAL) is important in the optimization of its therapy. The aim of the present work was to evaluate the ability of TDM using model-based, goal-oriented Bayesian adaptive control for help in planning, monitoring, and adjusting individualized VAL dosing regimens. USC*PACK software and routine TDM data were used to estimate population and individual pharmacokinetics of two commercially available VAL formulations in epileptic adult and pediatric patients on chronic VAL monotherapy. The population parameter values found were in agreement with values reported earlier. A statistically significant (P < 0.001) difference in median values of the absorption rate constant was found between enteric-coated and sustained-release VAL formulations. In our patients (aged 0·25,53 years), VAL clearance declined with age until adult values were reached at about age 10. Because of the large interindividual variability in PK behavior, the median population parameter values gave poor predictions of the observed VAL serum concentrations. In contrast, the Bayesian individualized models gave good predictions for all subjects in all populations. The Bayesian posterior individualized PK models were based on the population models described here and where most patients had two (a peak and a trough) measured serum concentrations. Repeated consultations and adjusted dosage regimens with some patients allowed us to evaluate any possible influence of dose-dependent VAL clearance on the precision of total VAL concentration predictions based on TDM data and the proposed population models. These nonparametric expectation maximization (NPEM) population models thus provide a useful tool for planning an initial dosage regimen of VAL to achieve desired target peak and trough serum concentration goals, coupled with TDM soon thereafter, as a peak,trough pair of serum concentrations, and Bayesian fitting to individualize the PK model for each patient. The nonparametric PK parameter distributions in these NPEM population models also permit their use by the new method of ,multiple model' dosage design, which allows the target goals to be achieved specifically with maximum precision. Software for both types of Bayesian adaptive control is now available to employ these population models in clinical practice. [source] Mass spectrometry in newborn and metabolic screening: historical perspective and future directionsJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 2 2009Donald H. Chace Abstract The growth of mass spectrometry (MS) in clinical chemistry has primarily occurred in two areas: the traditional clinical chemistry areas of toxicology and therapeutic drug monitoring and more recent, human genetics and metabolism, specifically inherited disorders of intermediary metabolism and newborn screening. Capillary gas chromatography and electrospray tandem MS are the two most common applications used to detect metabolic disease in screening, diagnostics and disease monitoring of treated patients. A few drops of blood from several million newborn infants are screened annually throughout the world making this the largest application of MS in medicine. Understanding the technique, how it grew from a few dozen samples per week in the early 1990s to increasing daily volume today will provide important information for new tests that either expand newborn screening or screening in other areas of metabolism and endocrinology. There are numerous challenges to the further expansion of MS in clinical chemistry but also many new opportunities in closely related applications. The model of newborn screening and MS in medicine may be useful in developing other applications that go beyond newborns and inherited metabolic disease. As MS continues to expand in clinical chemistry, it is clear that two features will drive its success. These features are excellent selectivity and multiple analyte or profile analysis; features recognized in the 1950s and remain true today. Copyright © 2008 John Wiley & Sons, Ltd. [source] Development and validation of a liquid chromatographic/tandem mass spectrometric assay for the quantitation of nucleoside HIV reverse transcriptase inhibitors in biological matricesJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 1 2005Séverine Compain Abstract Besides liquid chromatographic (LC)/UV methods adapted to therapeutic drug monitoring, there is still a need for more powerful techniques that can be used for pharmacological research and clinical purposes. We developed an LC method coupled with tandem mass spectrometry (MS/MS) to separate, detect and quantify with high sensitivity the nucleoside analogues used in multitherapies (zidovudine, stavudine, zalcitabine, didanosine, lamivudine and abacavir) in plasma and in the intracellular medium. We worked on two essential issues: (i) the need to use two ionization modes in order to achieve the best sensitivity, which leads to the optimization of the chromatographic separation of drugs detected in the positive ionization mode and drugs detected in the negative ionization mode, and (ii) the need to optimize the extraction step in order to enhance sample recovery. The peripheral blood mononuclear cells were lysed in Tris buffer,MeOH. A clean-up procedure was performed by solid-phase extraction only for plasma samples. The LC separation was carried out on a Zorbax Stable Bond C18 column followed by MS/MS analysis after electrospray ionization in either the negative or positive mode. The positive ionization mode was applied at the beginning of the run to detect zalcitabine and lamivudine, then the ionization mode was changed to negative for the detection of didanosine, stavudine, internal standard and zidovudine. The calibration range for all the analytes was 0.5,200 ng ml,1. The recoveries were between 64 and 90%, with coefficients of variation (CVs) lower than 15%. The inaccuracy (bias) was ±15% with CVs always lower than 12%. The analytes were stable at room temperature and in the extraction solvent for at least 24 h, after storage at ,80 °C for 3 months, after three freeze,thaw cycles and in the injection solvent after 48 h at 4 °C. Together with the measurement of intracellular triphosphorylated metabolites thanks to the powerful plasma and intracellular assay method for intact drugs, it is possible to describe the behaviour of nucleoside analogues against HIV through plasma pharmacokinetics, cell membrane diffusion including drug transport involvement, and also the intracellular metabolism. Copyright © 2005 John Wiley & Sons, Ltd. [source] Simultaneous quantification of cyclophosphamide, 4-hydroxycyclophosphamide, N,N,,N, -triethylenethiophosphoramide (thiotepa) and N,N,,N, -triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 3 2004Milly E. de Jonge Abstract The alkylating agents cyclophosphamide (CP) and N, N,, N, -triethylenethiophosphoramide (thiotepa) are often co-administered in high-dose chemotherapy regimens. Since these regimens can be complicated by the occurrence of severe and sometimes life-threatening toxicities, pharmacokinetically guided administration of these compounds, to reduce variability in exposure, may lead to improved tolerability. For rapid dose adaptations during a chemotherapy course, we have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of CP, thiotepa and their respective active metabolites 4-hydroxycyclophosphamide (4OHCP) and N, N,, N, -triethylenephosphoramide (tepa) in plasma. Because of the instability of 4OHCP in plasma, the compound is derivatized with semicarbazide (SCZ) immediately after sample collection and quantified as 4OHCP-SCZ. Sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using 100 µl of plasma. Chromatographic separation was performed on an Zorbax Extend C18 column (150 × 2.1 mm i.d., particle size 5 µm), with a quick gradient using 1 mM ammonia solution and acetonitrile, at a flow-rate of 0.4 ml min,1. The analytical run time was 10 min. The triple quadrupole mass spectrometer was operating in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 200,40 000 ng ml,1 for CP, 50,5000 ng ml,1 for 4OHCP-SCZ and 5,2500 ng ml,1 for thiotepa and tepa, using 100 µl of human plasma. These dynamic concentration ranges proved to be relevant in daily practice. Hexamethylphosphoramide was used as an internal standard. The coefficients of variation were <12% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (±15%). This robust and rapid LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring of CP, thiotepa and their metabolites in our hospital. Copyright © 2004 John Wiley & Sons, Ltd. [source] Liquid chromatography,tandem mass spectrometry method for simultaneous determination of cyclosporine A and its three metabolites AM1, AM9 and AM4N in whole blood and isolated lymphocytes in renal transplant patientsJOURNAL OF SEPARATION SCIENCE, JSS, Issue 15 2010Hana Brozmanová Abstract A LC-MS/MS method was developed and validated for the determination of cyclosporine A (CsA) and its three phase 1 metabolites AM1, AM9, and AM4N in whole blood and lymphocytes isolated on the Histopaque gradient. 200,,L of whole blood was precipitated with 10,mol/L zinc sulfate in acetonitrile/methanol (40:60, v/v) and lymphocytes isolated from 1.5,mL blood were extracted with acetonitrile/methanol (40:60, v/v). The analytes and internal standard cyclosporine D were separated on RP column BEH C18, 2.1×50,mm, 1.7,,m using gradient LC-MS/MS analysis in positive electrospray mode. Time of analysis was 5,min. Linearity in blood was 5,2000,,g/L for CsA, AM1, and AM9; 2,500,,g/L for AM4N; and 2,500,,g/L for all substances in lymphocytes. Coefficient of variations was 1.8,9.8% and recovery was 92.0,110.0%. The method was used in early and chronic renal transplant patients for therapeutic drug monitoring of CsA to compare either its share in lymphocytes as target organ or binding to one lymphocyte. The same parameters were calculated for all metabolites tested. [source] Pharmacodynamics of Carvedilol in Conscious, Healthy DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Sonya G. Gordon The purpose of the study reported here was to determine the magnitude and duration of beta-blocking efficacy, determine an effective dose and dosing interval, and document safety and tolerability of carvedilol given orally in clinically normal dogs. Pharmacodynamic data were evaluated in conscious, unrestrained, healthy hound dogs at baseline and after long-term oral administration of carvedilol (1.5 mg/kg of body weight PO q12h for >5 days). At baseline, heart rate (HR) and blood pressure (BP) data were collected continuously for 24 hours, and complete echocardiography was performed. This protocol was repeated after long-term oral carvedilol administration. Additionally, isoproterenol was administered to evaluate the magnitude and duration of the nonselective beta-blocking efficacy of carvedilol. An isoproterenol challenge was performed 0.75, 1.5, 2.25, 4, 6, 12, and 24 hours after carvedilol administration, with echocardiography being performed once at 2 hours. Plasma samples were obtained prior to each challenge time point for determination of plasma carvedilol concentration. Time series regression analysis indicated no difference between baseline and carvedilol-induced HR or BP trend lines in 6 of 8 dogs. In 2 of 8 dogs, HR, after long-term carvedilol administration, was reduced. Carvedilol attenuated isoproterenol-induced changes in HR by 54,76% through 12 hours and by 30% at 24 hours. The BP changes were attenuated by 80,100% through 12 hours. These data suggest that carvedilol (1.5 mg/kg PO q12h) in healthy, conscious dogs confers nonselective beta blockade for 12 hours, with minimal effects on resting HR, BP, and echocardiographic variables. Additionally, the magnitude of beta blockade correlated strongly to peak plasma carvedilol concentration, suggesting that therapeutic drug monitoring may be clinically useful. [source] Population pharmacokinetics of pyrazinamide in elephantsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005M. ZHU This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20,30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0,24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with Tmax at or before 2 h regardless of the method of drug administration. Cmax at a mean dose of 25.6 (±4.6) mg/kg was 19.6 (±9.5 ,g/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 ± 4.2 mg/kg, Cmax was 25% (4.87 ± 4.89 ,g/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 ± 15.2 mg/kg yielded Cmax of 12.3 ± 6.3 ,g/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher Cmax and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved Cmax values are below the recommended 20,50 ,g/mL range. [source] A randomized, prospective, pharmacoeconomic trial of neoral 2-hour postdose concentration monitoring versus tacrolimus trough concentration monitoring in de novo liver transplant recipientsLIVER TRANSPLANTATION, Issue 2 2008Surendra Shenoy Two-hour postdose cyclosporine (C2) monitoring is becoming an accepted method of therapeutic drug monitoring, although it is not known whether C2 monitoring is superior to tacrolimus (FK)-based immunosuppression. The purpose of this trial was to compare the safety, efficacy, and pharmacoeconomics of cyclosporine A (CsA) monitored by C2 levels versus FK monitored by trough levels in de novo liver transplant recipients. After informed consent, 60 de novo liver transplant recipients were randomized in a 1:1 fashion to receive either FK (trough, 6-10 ng/mL) or CsA (C2, 600-1200 ng/mL) and corticosteroids. The 2 groups were similar for gender, race, indication for liver disease, and age. At 1 year, patient survival was similar (93% for FK versus 90% for C2). One patient in the FK arm was retransplanted because of recurrent hepatitis C virus (HCV). Early acute rejection occurred in 27% of FK-treated patients and 23% of CsA-treated recipients [P = not significant (NS)]. Recurrent HCV occurred in 21% of FK-treated patients and 61% of CsA-treated patient (P = 0.04). The incidence of other infections, new onset diabetes mellitus, requirement for antihypertensives, and requirement for cholesterol medications were similar between the groups. Annual calcineurin inhibitor costs were lower in the C2 arm ($5432 ± 2091 for C2 versus $8291 ± 3948 for FK, P = 0.001). Annual pretransplant drug costs ($2292 ± 2331 for C2 versus $2831 ± 2358 for FK, P = NS) and 1-year posttransplant drug costs ($17,214 ± 16,600 for C2 versus $15,151 ± 11,699 for FK, P = NS) were similar. In conclusion, immunosuppression with CsA, monitored by C2 levels, is safe, effective, and economical in liver transplant recipients and provides immunosuppression at least equivalent to that of FK. Liver Transpl 14:173,180, 2008. © 2008 AASLD. [source] | |||||||||||||||||||||||||||||||||||||