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Therapeutic Range (therapeutic + range)
Kinds of Therapeutic Range Selected AbstractsTherapeutic range for unfractionated heparin therapy: age-related differences in response in childrenJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2006V. IGNJATOVIC [source] Augmentation of all- trans -retinoic acid concentration in plasma by preventing inflammation responses induced by atRA-loaded microspheres with concurrent treatment of dexamethasoneDRUG DEVELOPMENT RESEARCH, Issue 4 2004Kyeongsoon Park Abstract All- trans retinoic acid (atRA)-loaded microspheres severely induce inflammatory responses after microsphere implantation. Fibroblasts and a thick band of fibrous capsule resulting from the inflammatory responses could hamper drug permeation to the bloodstream because fibroblasts actively metabolize atRA into polar metabolites and the thick fibrous capsule acts as a diffusion barrier. In the present study, we investigated whether the fibroblast proliferation and collagen deposition induced by atRA released from microspheres might affect the atRA concentration in plasma and atRA metabolism with or without treatment of dexamethasone as an anti-inflammatory drug. After subcutaneous injection of atRA-loaded microspheres in rats, it was observed that atRA-loaded microspheres induced severe inflammatory responses and stimulated fibroblast proliferation and collagen deposition in fibrous capsules. On the other hand, the orally treated dexamethasone effectively prevented inflammatory responses in a dose-dependent manner and suppressed about 49% of the number of fibroblasts and collagen deposition in fibrous capsules at 14 days. In addition, after the treatment of dexamethasone, the atRA concentration in plasma was increased, and its metabolism was decreased approximately by 40% at 7 days, compared to the group treated alone with atRA-loaded microspheres. In conclusion, the concurrent treatment of dexmethasone with atRA-loaded microspheres could prevent inflammatory responses and metabolism of atRA, thereby maintaining the atRA concentration in plasma for longer periods in the therapeutic range. Drug Dev. Res. 61:197,206, 2004. © 2004 Wiley-Liss, Inc. [source] Absence Seizures Aggravated by Valproic AcidEPILEPSIA, Issue 7 2001Tally Lerman-Sagie Summary: ,Purpose: To report on pediatric patients with absence epilepsy who experienced absence seizure aggravation while receiving valproic acid (VPA). Methods: The charts of all children from four pediatric epilepsy clinics receiving VPA for absence epilepsy were reviewed. Patients were evaluated and followed up between 1994 and 2000. Results: Eight cases (six boys) of absence seizure aggravation were detected. Mean age at seizure onset was 5.8 years (range, 3,12 years). Six patients had simple absence seizures, one had myoclonic absences, and one had absences with automatisms. The electroencephalogram in all cases depicted generalized 3-Hz spike-and-wave activities. All eight patients experienced an increase in the frequency of absence seizures within days of VPA introduction. Dose increments resulted in further seizure aggravation. Serum levels of VPA were within therapeutic range in all patients. No case was attributed to VPA-induced encephalopathy. All patients improved on VPA discontinuation. In five children, VPA was reintroduced, resulting in further seizure aggravation. Conclusions: VPA can occasionally provoke absence seizure aggravation in patients with absence epilepsy. [source] BSc2118 is a novel proteasome inhibitor with activity against multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2010Jan Sterz Abstract Objectives:, The ubiquitin,proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC). Methods:, Human MM cell lines OPM-2, RPMI-8226, and U266 and primary MM cells from bone marrow aspirates were exposed to BSc2118. Cytotoxicity levels were evaluated using the MTT-test. BSc2118-induced apoptosis was analyzed by annexin-V assay. Further methods used included proteasomal activity determination, cell cycle analysis, western blot, and transcription factor assays. Results:, In OPM-2, RPMI-8226, U266 cell lines and primary MM cells, BSc2118 caused dose-dependent growth inhibitory effects. After 48 h, dose-dependent apoptosis occurred both in cell lines and primary myeloma cells irrespective of t(4;14). A significant G2-M cell cycle arrest occurred after 24 h. Furthermore, we observed a marked inhibition of intracellular proteasome activity, an increase in intracellular p21 levels, and an inhibition of NF-,B activation. The toxicity against PBMNC remained low, suggesting a broad therapeutic range of this agent. Conclusion:, Taken together, BSc2118 shows significant antimyeloma activity and may be considered as a promising agent in cancer drug development. [source] Matters of the heart: the physiology of cardiac function and failureEXPERIMENTAL PHYSIOLOGY, Issue 6 2007Godfrey Smith Heart failure as a result of a myocardial infarction (MI) is a common condition with a poor prognosis. The adaptive changes in the surviving myocardium appear to be insufficient in terms of both mechanical/contractile performance and electrical stability. The modification of the underlying myocardial physiology is complex, varying across the different layers within the wall of the ventricle and within one layer. Two therapeutic strategies are briefly discussed, as outlined here. (i) Enhancing contractility by alteration of the expression of a single protein (e.g. sarco-endoplasmic reticulum Ca2+ ATPase, SERCA) could potentially reverse both mechanical and electrical abnormalities. However, experimental data involving the upregulation of SERCA suggest that the therapeutic range of this approach is narrow. (ii) The use of regular exercise training to improve cardiac performance in heart failure. This appears to act by normalizing a number of aspects of myocardial physiology. [source] Population pharmacokinetics of ketanserin in pre-eclamptic patients and its association with antihypertensive responseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2005Lidwien M. Hanff Abstract Ketanserin is an antihypertensive drug that is increasingly being used parenterally in the treatment of pre-eclampsia. Because of lack of efficacy in a substantial part of our pre-eclamptic patients, we determined the plasma concentrations of ketanserin in 51 pre-eclamptic patients. Population pharmacokinetic parameters were assessed using the iterative two-stage Bayesian population procedure. The influence of individual pharmacokinetic parameters on antihypertensive response, expressed as the attainment of a diastolic blood pressure ,90 mmHg using ketanserin treatment, was analysed. Almost all plasma concentrations of ketanserin were in or above the therapeutic range. The individual pharmacokinetics of ketanserin in pre-eclamptic patients showed an accurate fit using a three-compartment model. The pharmacokinetic parameters in our pre-eclamptic population were a metabolic clearance (Clm) of 37.9 ± 10.86 L/h and volume of distribution (V1) of 0.544 ± 0.188 L/kg, which is comparable with data from healthy volunteers. Despite a considerable inter-individual variation, no correlation was found between differences in pharmacokinetic parameters and antihypertensive response. We conclude that therapeutic plasma levels can be obtained in pre-eclamptic patients with a fixed dosage schedule of ketanserin and differences in antihypertensive responses within a pre-eclamptic population cannot be attributed to pharmacokinetic differences. [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] Audit of community-based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?INTERNAL MEDICINE JOURNAL, Issue 11 2004L. Young Abstract Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long-term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing. (Intern Med J 2004; 34: 639,641) [source] Rheumatological presentations of anticoagulation related hemorrhagesINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2003S. R. Cox Abstract Background: Joint, back and muscle pain are common in patients referred to a rheumatology unit. Acute pain due to hemorrhage may be difficult to distinguish from more common causes of pain in these patients. This article describes a small case-series of patients who presented acutely with hemarthroses, spinal hemorrhage or muscle hematomas while receiving anticoagulant treatment. Methods: Case notes of nine patients were reviewed retrospectively. The demographic characteristics, indication for anticoagulation, international normalized ratio, and management were evaluated. Results: The majority of hemorrhages occurred when the INR was within the therapeutic range. Anticoagulation was held in all cases. Joint aspiration was performed in all cases of hemarthrosis. Surgical intervention was required in management of the spinal epidural bleed and also in one case of muscle hematoma. Conclusion: Cases described represent major hemorrhages in anticoagulated patients. There is little literature on specific treatment and prognosis, particularly with respect to hemarthrosis, and further studies are needed. [source] An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin timeACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2010M. ENGSTRÖM Background: Rotational thrombelastometry/thrombelastography with ROTEM® and TEG® is becoming available bedside in an increasing number of intensive care units, where many patients with heparin-induced thrombocytopenia (HIT) are treated. The study has been performed in an effort to find out whether ROTEM® could be an alternative to activated partial thromboplastin time (aPTT) when argatroban is used for anticoagulation. Methods: Argatroban was added in vitro to a series of citrated whole-blood samples from 10 healthy volunteers to obtain whole-blood concentrations of 0, 0.125, 0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 mg/l. ROTEM® and whole-blood aPTT analyses were performed at each argatroban concentration. Correlation analyses were performed using the Spearman correlation analysis. Results: There was a significant and strong correlation between argatroban concentrations and clotting time (CT in ROTEM® analysis with INTEM) (P<0.0001 and r=0.98). Also, the ROTEM® time to maximum clot formation velocity (MAXV-t) appeared to have a very strong and highly significant correlation to argatroban concentrations (P<0.0001 and r=0.95). When we studied the correlation between aPTT and CT, we found a highly significant and strong correlation between these two analyses (P<0.0001 and r=0.97), especially so in the clinically relevant therapeutic range up to 100 s aPTT prolongation for HIT patients. Conclusion: A significant and strong correlation was found between argatroban concentrations and several ROTEM® parameters. Rotational thrombelastometry/thrombelastography has a potential role in increasing the safety of argatroban anticoagulation in critically ill patients. [source] Review: nurses can improve patient nutrition in intensive careJOURNAL OF CLINICAL NURSING, Issue 17 2009Caroline Ros Aims and objectives., To review the literature and identify opportunities for nutritional practice improvement in the critically ill and opportunities to improve nurses' knowledge relating to enteral feeding. Background., The literature reports varying nutritional practices in intensive care. Design., Systematic review. Methods., A systematic search, selection, analysis and review of nursing, medical and dietetic primary research articles was undertaken. Fifteen studies met the selection criteria. Results., Delivery of nutrition to the critically ill varied widely. Patients were frequently underfed and less frequently, overfed. Both under- and overfeeding have been linked with unacceptable consequences including infections, extended weaning from mechanical ventilation, increased length of stay and increased mortality. Underfeeding was related to slow initiation and advancement of nutrition support and avoidable feed interruptions. The most common reasons for interrupting feeds were gastrointestinal intolerance and fasting for procedures. Certain nursing practices contributed to underfeeding such as the management of gastric residual volumes. Conclusions., Consistent and reliable nutrition support in intensive care units is hampered by a lack of evidence leading to varying nutrition practices. Factors impeding delivery of enteral nutrition were considered avoidable. A new concept of a therapeutic range of energy delivery in the critically ill has emerged implying the need for re-evaluation of energy recommendations and improved delivery of enteral nutrition. Relevance to clinical practice., This review supports the multi-disciplinary development and implementation of an evidence-based enteral feeding protocol in intensive care units as a strategy to improve adequacy of nutritional intake. Critical care nurses are well placed to improve this process. [source] Assessing the accuracy of a computerized decision support system for digoxin dosing in primary care: an observational studyJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005W. L. G. Kroese Drs Summary Background:, This study was carried out as part of a European Union funded project (PharmDIS-e+), to develop and evaluate software aimed at assisting physicians with drug dosing. A drug that causes particular problems with drug dosing in primary care is digoxin because of its narrow therapeutic range and low therapeutic index. Objectives:, To determine (i) accuracy of the PharmDIS-e+ software for predicting serum digoxin levels in patients who are taking this drug regularly; (ii) whether there are statistically significant differences between predicted digoxin levels and those measured by a laboratory and (iii) whether there are differences between doses prescribed by general practitioners and those suggested by the program. Methods:, We needed 45 patients to have 95% Power to reject the null hypothesis that the mean serum digoxin concentration was within 10% of the mean predicted digoxin concentration. Patients were recruited from two general practices and had been taking digoxin for at least 4 months. Exclusion criteria were dementia, low adherence to digoxin and use of other medications known to interact to a clinically important extent with digoxin. Results:, Forty-five patients were recruited. There was a correlation of 0·65 between measured and predicted digoxin concentrations (P < 0·001). The mean difference was 0·12 ,g/L (SD 0·26; 95% CI 0·04, 0·19, P = 0·005). Forty-seven per cent of the patients were prescribed the same dose as recommended by the software, 44% were prescribed a higher dose and 9% a lower dose than recommended. Conclusion:, PharmDIS-e+ software was able to predict serum digoxin levels with acceptable accuracy in most patients. [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] Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin usersJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2010D. M. WITT Summary., Background:, For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible. Objective:, To identify patients with stable INRs (INR values exclusively within the INR range) and comparator patients (at least one INR outside the INR range), compare occurrences of thromboembolism, bleeding and death between groups, and identify independent predictors of stable INR control. Methods:, The study was a retrospective, longitudinal cohort study using data extracted from electronic databases. Patient characteristics and risk factors were entered into multivariate logistic regression models to identify variables that independently predict stable INR status. Results:, There were 533 stable and 2555 comparator patients. Bleeding and thromboembolic complications were significantly lower in stable vs. comparator patients (2.1% vs. 4.1% and 0.2% vs. 1.3%, respectively; P < 0.05). Independent predictors of stable INR control were age >70 years, male gender and the absence of heart failure. Stable patients were significantly less likely to have target INR ,3.0 or chronic diseases. Conclusion:, A group of patients with exclusively therapeutic INR values over 12 months is identifiable. In general, these patients are older, have a target INR <3.0, and do not have heart failure and/or other chronic diseases. Our findings suggest that many patients whose INR values remain within the therapeutic range over time could be safely treated with INR recall intervals >4 weeks. [source] Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2010A. STEIB See also Douketis JD, Spyropoulos AC. Vitamin K to reverse the anticoagulant effect of vitamin K antagonists: can you teach an old dog new tricks? This issue, pp 496,8. Summary.,Background: After a vitamin K antagonist (VKA) overdose, 1,2 mg of oral vitamin K can lower the International Normalized Ratio (INR) to the therapeutic range. Objective: To establish whether oral vitamin K can substitute for heparin bridging and decrease the INR to , 1.5 before elective surgery. Methods: Patients on long-term VKAs were randomized either to heparin bridging after the last VKA dose on day , 5 before surgery (group H) or to VKA treatment until day , 2, followed by 1 mg of oral vitamin K on the day before surgery (group K). Blood clotting variables were assessed on days ,5/,2, 1 and 0, and postoperatively. If the target INR was not achieved 2 h before incision, surgery was deferred or performed after injection of prothrombin complex concentrate (PCC). Results: In 30 of 94 included patients, baseline INR was outside the chosen range (18, INR < 2; 12, INR > 3.5), leaving 34 eligible patients in group H and 30 in group K. The groups were balanced in terms of body mass index, VKA treatment duration and indication, scheduled surgery, preoperative and postoperative hemoglobin, and blood loss. The INR was significantly higher in group K on days , 1 and 0 than in group H. An INR , 1.5 was not achieved in 20 group K patients (66%). Surgery was postponed or performed after PCC injection in 12 of these 20 patients. Conclusions: Oral vitamin K (1 mg) cannot substitute for heparin bridging before surgery. In addition, one-third of patients on VKAs were exposed to a risk of bleeding (overdose) or thrombosis (underdose), thus highlighting the need for new oral anticoagulants. [source] Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patientsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2008P. A. LENZINI Summary.,Background:,Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. Methods:,In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. Results:,The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7,11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30,0.97). Conclusions:,Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org. [source] Pharmacodynamics of warfarin in catsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000S. A. SMITH The overall purpose of this study was to evaluate the pharmacodynamic response to warfarin in cats. The specific aim was to determine if a log-linear indirect response model (Nagashima et al., 1969) used to describe the in vivo effect of warfarin in humans could be applied to cats. The pharmacokinetics of racemic warfarin were described using a non-compartmental approach. The relationship between prothrombin complex activity (PCA) and normalized prothrombin time (PTR) was defined for feline plasma under our experimental conditions, and determined to be: %PCA=12.38+648 e,PTR/0.492. These data were then integrated and used to predict the warfarin dose associated with therapeutic anti-coagulation defined as an International Normalized Ratio (INR) of 2.0,3.0. The maximum prothrombinopenic response to warfarin in cats after a single intravenous dose of 0.5 mg/kg occurred at 24,48 h. Pharmacodynamic modeling suggested that each cat had a narrow therapeutic range of the steady-state concentration of total warfarin required to appropriately block prothrombin complex synthesis (median: 265.2,358.7 ng/mL). The median daily dose range predicted to yield therapeutic concentrations of warfarin was 0.061,0.088 mg/kg per day. Wide inter-individual variations in both pharmacokinetics and pharmacodynamic response suggest that a more optimal dosing of warfarin may be possible with the development of individual pharmacokinetic/pharmacodynamic algorithms, analogous to those currently employed in human patients. [source] Enfuvirtide: A safe and effective antiretroviral agent for human immunodeficiency virus,infected patients shortly after liver transplantationLIVER TRANSPLANTATION, Issue 10 2009Elina Teicher The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV),coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir,exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence. Liver Transpl 15:1330,1335, 2009. © 2009 AASLD. [source] Electric Parameters Optimization in Spinal Cord Stimulation.NEUROMODULATION, Issue 4 2010Study in Conventional Nonrechargeable Systems Background:, Spinal cord stimulation devices provide a means of creating an electric field. The parameters used to produce this electric field are: pulse amplitude, pulse width (Pw), and pulse frequency (F). Aims:, The purpose is to document the effects that the various stimulus parameters have on patient perception of paresthesia and the relationship that this perception has on pain relief. Methods:, Stimulus parameters were varied independently keeping the electrode polarity constant while recording stimulation thresholds. The Pw was varied from 195 to 300 µsec while maintaining the frequency at 50 Hz. The F was varied from 10 to 100 Hz while maintaining the Pw at 300 µsec. We also measured the paresthesia coverage percentage and the subjective perception of quality reported by the patients with each one of the parameter changes. Results:, There was a statistically significant correlation between Pw and all the stimulation thresholds. As for the therapeutic range, the differences observed also were statistically significant. Pw variation did not produce significant differences in coverage and subjective quality of the paresthesia. The perception threshold did not vary significantly with F changes. However, F significantly affected both coverage of the painful area and paresthesia perception quality. Conclusions:, In the usual Pw ranges, it seems that its usefulness is limited to obtaining finer adjustments in the stimulation amplitude. Frequency management may be significantly useful to get a wider coverage of the stimulated area. [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] A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia,ANNALS OF NEUROLOGY, Issue 6 2009Tanya Z. Fischer MD Objective Human and animal studies have shown that Nav1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Nav1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ). Methods We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Nav1.7 complementary DNA. Wild-type Nav1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents. Results Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Nav1.7 but does not affect these parameters in wild-type Nav1.7. Interpretation Our results demonstrate a normalizing effect of CBZ on mutant Nav1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Nav1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders. Ann Neurol 2009;65:733,741 [source] Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy,ARTHRITIS & RHEUMATISM, Issue 2 2010Lisa K. Stamp Objective There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlun concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment. Methods A cross-sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C-reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed. Results The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu4, MTXGlu5, MTXGlu3,5, and MTXGlu1,5 concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu5. RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlun concentration and adverse effects. Conclusion In contrast to other studies, the results of the present study did not show a relationship between the MTXGlun concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlun concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlun concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlun concentrations in patients receiving long-term treatment with MTX. [source] Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis,ARTHRITIS & RHEUMATISM, Issue 11 2008Judith M. Dalrymple Objective There is evidence supporting a therapeutic range for methotrexate polyglutamate (MTXGlu) concentrations in the treatment of rheumatoid arthritis (RA). Knowledge of the pharmacokinetics of MTXGlu1,5 is required for optimal timing of blood sampling. The aim of this study was to determine the time to steady state and the half-life of accumulation of red blood cell (RBC) MTXGlu1,5 in patients with RA commencing oral MTX, and the time for RBC MTXGlu1,5 to become undetectable and the half-life of elimination of RBC MTXGlu1,5 in patients ceasing treatment with oral MTX. Methods Ten patients beginning treatment and 10 patients stopping treatment with low-dose oral MTX were recruited. Blood samples were initially collected weekly, with gradual extension to monthly collection over the study period. RBC MTXGlu1,5 concentrations were assayed by high-performance liquid chromatography. Results were analyzed using a first-order exponential method. Results The median times to reach steady state in RBCs (defined as 90% of the maximum concentration) were 6.2, 10.6, 41.2, 149, and 139.8 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of accumulation for RBC MTXGlu1,5 ranged from 1.9 weeks to 45.2 weeks. The median times for MTXGlus to become undetectable in RBCs were 4.5, 5.5, 10, 6, and 4 weeks, respectively, for MTXGlu1, MTXGlu2, MTXGlu3, MTXGlu4, and MTXGlu5. The median half-life of elimination for RBC MTXGlu1,5 ranged from 1.2 weeks to 4.3 weeks. Conclusion There is wide interpatient variability of RBC MTXGlu1,5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu1,5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered. [source] Mathematical modeling of reactive transport of anti-tumor drugs through electro-active membranesASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 3 2009Parag Saurabh Abstract We present a mathematical modeling and design of an implantable polymer membrane-based drug-release device that uses alternate voltage scans across the electro-active membrane for delivery and reactive uptake of anionic anti-tumor drugs. Our mathematical model comprises Poisson,Boltzmann, Nernst,Planck and Diffusion,Reaction equations written for three compartments, namely, the drug reservoir, the polymer membrane and the diseased tissue, with the governing equations for the compartments being linked to each other through the boundary conditions. An analytical solution for the three-compartment model has been obtained using Laplace transforms and residue integration. We use this solution to quantify the various parameters controlling the spatiotemporal dynamics of drug delivery and analyze the efficacy of the reactive transport process for an anionic chemotherapeutic drug, Irinotecan-HCl, commercially also known as CPT-11. We show that a ,smart pill' with optimal drug efficacy may be designed by altering the thickness and the diffusivity of the electro-active membrane, and by tuning the applied voltage and the duration of the positive and the negative voltage scans such that the drug concentration in the tumor tissue is maintained within its therapeutic range. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd. [source] Human cytochromes mediating gepirone biotransformation at low substrate concentrationsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2003David J. Greenblatt Abstract Biotransformation of gepirone to 1-(2-pyrimidinyl)-piperazine (1-PP) and 3'-OH-gepirone, as well as two other hydroxylated metabolites, was studied in vitro using a human liver microsomal preparation and heterologously expressed human CYP3A4 and CYP2D6. The focus was on a low range of gepirone concentrations (1000 nM and below). Liver microsomes formed 1-PP and 3'-OH-gepirone with similar reaction velocities. Two other hydroxylated metabolites (2-OH- and 5-OH-gepirone) were also formed, but pure reference standards were not available for purposes of quantitative analysis. The CYP3A inhibitor ketoconazole completely eliminated 1-PP formation, reduced 3'-OH-gepirone formation to less than 20% of control, and reduced 2-OH-gepirone formation to 7% of control. All metabolites were formed by expressed CYP3A4; however, CYP2D6 formed 3'-OH- and 5-OH-gepirone, but not 1-PP or 2-OH-gepirone. Based on estimated relative abundances of the two isoforms in human liver, CYP3A4 was predicted to account for more than 95% of net clearance of gepirone in vivo at low concentrations approaching the therapeutic range. CYP2D6 would account for less than 5% of net clearance. The findings are consistent with previous in vitro studies of gepirone using higher substrate concentrations. Copyright © 2003 John Wiley & Sons, Ltd. [source] Effect of zolpidem on human Cytochrome P450 activity, and on transport mediated by P-glycoproteinBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2002Lisa L. von Moltke Abstract The influence of high concentrations of zolpidem (100 ,M, corresponding to approximately 200 times maximum therapeutic concentrations) on the activity of six human Cytochrome P450 (CYP) enzymes was evaluated in a model system using human liver microsomes. Zolpidem produced negligible or weak inhibition of human CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. Transport of rhodamine 123, presumed to be mediated mainly by the energy-dependent efflux transport protein P-glycoprotein, was studied in a cell culture system using a human intestinal cell line. High concentrations of zolpidem (100 ,M), exceeding the usual therapeutic range by more than 100-fold, produced only modest impairment of rhodamine 123 transport. The findings indicate that zolpidem is very unlikely to cause clinical drug interactions attributable to impairment of CYP activity or P-gp mediated transport. Copyright © 2002 John Wiley & Sons, Ltd. [source] Combined oral oestradiol valerate-norethisterone treatment over three years in postmenopausal women: correlation between oestrogen levels and bone mineral density sitesBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 11 2000W. Perry Consultant Endocrinologist Objective To compare trabecular and compact bone response and relationship to oestrogen status using continuous oestradiol valerate 2 mg and norethisterone 0.7 mg daily as hormone replacement and to determine the therapeutic range of 17 beta-oestradiol. Design Open label trial. Setting Independent endocrine clinic Sample One hundred and thirty-one patients were compared at point of entry and at 36 months. Methods Postmenopausal women were assessed using a Lunar dual photon and single photon bone scanner, and bone mineral density of the lumbar spine, right hip and left forearm were annually correlated with 17 beta-oestradiol and oestrone levels over three years. Total alkaline phosphatase was compared between improvers and decliners of bone mineral density. Results Significant improvement in bone mineral density (P < 0.0001) occurred at all sites except the left forearm, where bone loss was prevented. There was no correlation between oestrogen levels and bone mineral density improvements at hip sites. However, in the lumbar spine larger improvements in bone mineral density occurred in women with 17 beta-oestradiol levels > 185 pmol/L compared with those below, which were statistically significant for those with 17 beta-oestradiol levels > 248 pmol/L. Bone turnover, as quanitifed by total alkaline phosphatase measurements, was suppressed in most patients, but there were no differences in the mean alkaline phosphatase levels between the best improvers and worst decliners for lumbar spine bone mineral density. Improvers had an age mean of 5.21 years greater than decliners (P= 0.01) and a mean duration difference since the menopause of 5.1 years compared with decliners (P= 0.007). Conclusion This combined continuous preparation of hormone replacement therapy improves not only trabecular bone but prevents compact bone loss, and the data suggest that the therapeutic range of 17 beta-oestradiol is between 200 pmol/L and 350 pmol/L. [source] Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2006José Moltó What is already known about this subject ,,The concentration of protease and non-nucleoside reverse transcriptase inhibtors in plasma has been related to both efficacy and toxicity. ,,Most antiretroviral concentration data come from selected populations of patients undergoing therapeutic drug monitoring programmes, which may overestimate interindividual variability. What this study adds ,,Our study has demonstrated the large interindividual variability in antiretroviral drug concentrations in an unselected population of patients during routine clinical practice. ,,These results may provide interesting information to clinicians for the management of antiretroviral therapy in HIV-infected patients. Aims The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. Methods One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were >,4.0 mg l,1, >,6.0 mg l,1 and >,0.85 mg l,1, respectively. Results Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. Conclusion Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice. [source] Once daily dose gentamicin in neonates , is our dosing correct?ACTA PAEDIATRICA, Issue 7 2009Tiroumourougane V Serane Abstract Aim:, The aim of this paper is to study the safety and efficacy (measured by therapeutic level) of once daily gentamicin in neonates ,32 weeks of gestation and ,7 days of age. Setting:, Level II neonatal intensive care unit. Subjects:, Neonates ,32 weeks of gestation and ,7 days of age treated with gentamicin for presumed sepsis. Methods:, Gentamicin was administered by intravenous injection at 4 mg/kg/day once daily. Peak and trough gentamicin levels were measured at the third dose. Results:, In neonates with gestational age between 32 and 36 weeks, 14 out of 65 (22%) had trough serum concentration >2 mg/L. Only 39 (60%) had peak and trough levels within the therapeutic range. All babies who had audiometric evaluation (62 out of 65) had normal hearing. Out of the 65 babies, 60 had paired serum creatinine levels estimated and none had evidence of renal dysfunction. Among term neonates, only 2 out of 50 had the trough serum concentration of >2 mg/L. In 38 (76%) of the 50 neonates, the trough serum gentamicin concentration was <2.0 mg/L and the peak level was <10 mg/L. Forty-eight babies had audiometric evaluation which was normal. Conclusion:, A dose of 4 mg/kg/day produces serum gentamicin levels outside the therapeutic range in two-fifths of neonates between 32 and 36 ± 6 weeks. A single dose of 4 mg/kg/day of gentamicin is appropriate for term babies and probably excessive for 32,36 weeks' neonates. [source] Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantationCLINICAL TRANSPLANTATION, Issue 5 2005Xin Zhang Abstract:, Objective:, Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. Methods:, CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. Results:, The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 ± 17.7 and 41.6 ± 15.8 vs. 102.3 ± 51.2 at 1 wk; 33.1 ± 7.5 and 46.4 ± 12.9 vs. 103 ± 47.5 at 1 month; 35.3 ± 20.9 and 59.0 ± 20.6 vs. 150 ± 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. Conclusion:, CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy. 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