Target Plasma Levels Research Articles

The effect of alpha(2) agonist-induced sedation and its reversal with an alpha(2) antagonist on organ blood flow in sheep.

We investigated changes in cardiac output and organ blood flow induced by medetomidine in sheep and determined changes in cardiac output and organ blood flow after reversal of medetomidine-induced sedation by atipamezole. Eight sheep were chronically instrumented. Medetomidine was infused IV to target plasma levels of 0, 0.8, 1.6, 3.2, 6.4, and 12.8 ng/mL for 25 min each, followed by a 5-min infusion of atipamezole. Hemodynamic values and organ blood flow (using colored microspheres) were measured just before medetomidine infusion (baseline), at the end of each medetomidine infusion step, and 30 min after the administration of atipamezole. Medetomidine (12. 8 ng/mL) decreased cardiac output from 6.3 +/- 1.0 to 3.2 +/- 0.7 L/min (P < 0.0001) and increased systemic vascular resistance from 1310 +/- 207 to 3467 +/- 1299 dynes. s(-1). cm(-5) (P < 0.0001). Blood flow decreased in the cerebral cortex from 1.29 +/- 0.40 to 0. 66 +/- 0.12 mL. g(-1). min(-1) (P < 0.0001), left ventricle from 2. 11 +/- 0.61 to 1.40 +/- 0.40 mL. g(-1). min(-1) (P < 0.0001), kidney from 8.28 +/- 3.17 to 6.07 +/- 2.65 mL. g(-1). min(-1) (P < 0.0001), skin from 0.09 +/- 0.04 to 0.05 +/- 0.02 mL. g(-1). min(-1) (P < 0. 0001), intestine from 0.56 +/- 0.13 to 0.27 +/- 0.07 mL. g(-1). min(-1) (P < 0.0001), and skeletal muscle from 0.28 +/- 0.15 to 0.04 +/- 0.01 mL. g(-1). min(-1) (P < 0.0001). Blood flow in the liver (hepatic artery) increased from 0.05 +/- 0.03 to 0.24 +/- 0.16 mL. g(-1). min(-1) (P < 0.0001). After atipamezole infusion, cardiac output and systemic vascular resistance returned to baseline, but the cerebral cortex, left ventricle, and renal blood flows remained below baseline at 0.89 +/- 0.22, 1.37 +/- 0.50, and 6.25 +/- 2.76 mL. g(-1). min(-1), respectively; skeletal muscle blood flow increased above baseline to 0.44 +/- 0.27 mL. g(-1). min(-1), spleen blood flow decreased below baseline to 1.65 +/- 0.61 mL. g(-1). min(-1) (P < 0.0001), and liver, intestine, and lung blood flows returned to baseline values. In conclusion, medetomidine decreased and redistributed organ blood flow in sheep. Atipamezole reversed the medetomidine-induced hemodynamic changes, but redistributed blood flow from the brain, heart, and kidney to the skeletal muscle.

Hemopoietic stem cell transplantation for myelodysplastic syndrome.

The term myelodysplastic syndrome (MDS) describes a spectrum of disorders that are characterized by dysplastic marrow cell morphology, the development of peripheral blood cytopenias, and a tendency to evolve into acute myeloid leukemia. MDS has been recognized as a stem-cell disease, and hemopoietic stem-cell transplantation is currently the only potentially curative therapy. In patients with less advanced MDS (<5% blasts in the marrow), 3-year survival rates of 70% and 65% can be achieved with HLA-identical related and HLA-matched unrelated donors, respectively. The overall probability of disease recurrence in these patients is less than 5%. Of patients with advanced disease (5% marrow blasts or more), about 40% to 45% and 25% to 30% are surviving in remission after transplantation from a related or an unrelated donor, respectively. This inferior outcome is largely due to a higher incidence of post-transplantation relapse (20% to 30%). Inclusion of the International Prognostic Scoring System criteria into outcome analyses shows an inverse correlation between overall risk category and relapse-free survival after transplantation. Future trials should explore the usefulness of different transplantation regimens for different risk categories. Among patients with less advanced disease, use of a conditioning regimen that combines cyclophosphamide and busulfan, dose adjusted to reach target plasma levels, has been associated with improved survival in recipients of transplants from related and unrelated donors. It has also permitted successful hemopoietic stem-cell transplantation in patients as old as 66 years of age. Improved survival with transplants from unrelated volunteer donors has been achieved with selection of donors based on high-resolution HLA typing. Autologous stem-cell transplantation may provide excellent consolidation for selected patients who have obtained complete remission with conventional chemotherapy. High treatment-related morbidity and mortality rates, particularly after allogeneic transplantation, remain challenges that must be addressed with innovative approaches.

Conscious Sedation Using Target-Controlled Infusion with Propofol in Regional Anesthesia Patients

Background : The technique using target-controlled infusion (TCI) with propofol produces safe intra- operative sedation during regional anesthesia with rapid recovery and high patient satisfaction. The objective of this study was to define the blood propofol concentration necessary for conscious sedation in regional allesthesia patients according to age. Methods : Sixty patients scheduled to undergo regional anesthesia were allocated into one of three groups according to age, .such as group 1 (n = 20): 16-24 yr, group 2 (n=20): 30-39 yr, group 3 (n = 20): 40-55 yr. Thirty minutes after performing regional anesthesia, TCI of propofol started at a target plasma level of 1 ug/ml adjusted in steps of 0.2 ug/ml to maintain a sedation level 3 on a 5-point sedation scale. Results : The mean target concentration was 0.9ug/ml (group 1), 0.8 ug/ml (group 2), 0.7 ug/ml (group 3). The nlean propofol consumption was 38.5 ug/kg/min (group 1), 34.3 ug/kg/min (group 2), and 30.8 ug/kg/min (group 3). The recuvery time was significantly delayed in group 3 (2.8 min) compared to group 1 (1.5 min) and group 2 (1.8 min). Conclusions : TCI of propofol within at 0.7-0.9ug/ml blood concentration range poduces safe intraoperative sedation during regional anesthesia with rapid induction, rapid recovery and high patient satisfaction without severe complications in 16-55 yr old patients. (Korean J Anesthesiel 2000; 38 : 20∼24)

Target-Controlled Infusion of Propofol for Conscious Sedation Using BIS Monitor

Background : Propofol has been found to be an ideal anesthetic for sedation during regional anesthesia with the advantage of rapid onset of action and recovery. Inusion of propofol by target-controlled infusion (TCI) has been shown to be effective in achieving conscious sedation. The purpose of this study was to define the optimal target concentration of profofol evaluated by bispectral index (BIS) which is necessary for conscious sedation in patients to achieve a local or regional blockade. Methods : Sixty patients scheduled to undergo local or regional anesthesia were divided into 3 groups. 10-20 min after performing local anesthesia with 2% lidocaine 10 ml (group 1), spinal anesthesia with 0.5% hyperbaric bupivacaine 12-18 mg (group 2) or brachial plexus block with 1% lidocaine 40 ml (group 3), TCI of propofol was started at a target plasma level of 1 ug/ml and the target concentration was adjusted in step of 0.2 ug/ml to maintain a sedation level comparable to an Observer''s Assessment of Alertness/Sedarion (OAA/S) score of 3. BIS, EKG, heart rate, noninvasive arterial blood pressure, respiratory rate and SpO2 were recorded during the operation. Results: Grour I had a significantly higher mean (range) target concentration [1.8 (0.9-2.8) ug/ml] than group 2 [0.9 (0.2-2.4) ug/ml] and group 3 [1.0 (0.2-2.6) ug/ml]. A target concentration of 0.9-1.5 ug/ml of popofol produced BIS 78.2 (group 1), 73.4 (group 2) and 75.4 (group 3). Conclusions: TCI of propofol with a 0.9-1.8 ug/m1 blood concentration produces safe sedation durirg locoregional anesthesia without severe complications. (Korean J Anesthesiol 2000; 38: 8∼ 13)

Optimal dosing of intravenous tacrolimus following pediatric heart transplantation

Background: Early experience with intravenous tacrolimus at high doses (0.1–0.15 mg/kg/day) was associated with frequent clinical toxicity. The optimal dosing regimen after pediatric heart transplantation is unknown. Methods We retrospectively reviewed data on the last 45 pediatric heart transplant recipients to document the time required to achieve therapeutic blood levels and the safety of 2 differing intravenous dosing regimens (tacrolimus 0.03 & 0.05 mg/kg/day as continuous IV infusion). Target plasma levels were (1.2–1.7 ng/ml) with levels >2.0 ng/ml considered toxic, and target whole blood levels were 15–20 ng/ml with levels >25 ng/ml considered toxic. Results Mean age at transplantation was 7.5 ± 5.6 years (0.1–18), and 14 were infants. Intravenous tacrolimus was commenced at a mean of 7 ± 3 hours (range 2–16) after arrival in the ICU. Eight patients were excluded from analysis because of protocol modifications. Of the remaining 37 pts, 9 received initial infusion at 0.03 mg/kg/day; 3 (33%) achieved ‘therapeutic’ levels within 48 hours and 1 patient had a toxic level (27 ng/ml) at 36 hours. Twenty-eight patients received 0.05 mg/kg/day; 18 (64%) achieved therapeutic levels within 48 hours and 9 (32%) developed toxic levels. Patients with toxic whole blood levels had higher tacrolimus levels on first blood assay compared to those who did not develop toxicity (16.4 ± 3.4 vs 9.3 ± 3.9, p < .0001; level >10 ng/ml on first assay in 7/7 toxic patients vs 7/19 without toxicity, p = .004). Patients receiving the higher dose regimen had fewer episodes of moderate or severe rejection (≥Grade 3A) at first biopsy than those receiving the lower dose infusion (32% vs 75%; p = .046). No patient required renal dialysis. Conclusions Dosing below 0.05 mg/kg/day may result in clinically important delay in achieving therapeutic levels. Toxicity may be reduced by frequent monitoring of levels for the first 48 hours after transplantation especially when the initial level is >10 ng/ml.

The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.

We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect. Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device. Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli). An EEG was recorded to quantitate the hypnotic effect, relating the median frequency of the power spectrum to the plasma level by a sigmoid Emax model, including an effect compartment. Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model. The total doses needed to reach the defined end points were 71+/-9 mg and 35+/-6 mg for the younger and elderly subjects, respectively (P < .001). Pharmacokinetic parameters were similar in both groups (clearance, 399+/-91 and 388+/-97 mL/min; steady-state volume of distribution, 85+/-22 and 104 +/-11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522+/-236 ng/mL; elderly subjects, 223+/-56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis. We found much interindividual variability in the plasma concentrations necessary to achieve the clinical end points, regardless of age. These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.

13. Application of the elucigene™ CF20 test for neonatal screening of cystic fibrosis using blood spot samples

Background: Initial clinical experience with recombinant factor VIIa (rVIIa) for treatment of haemophilia patients with inhibitors against factor VIII or IX has been obtained by administration of rVIIa by repeated intravenous bolus injections. However, continuous infusion of rVIIa may be a more appropriate administration method if prolonged treatment is indicated.Methods: We have surveyed and analysed the initial experience with continuous infusion of rVIIa in the Netherlands and Belgium.Results: Five hospitals treated 7 haemophilia patients with inhibitors on 9 different occasions (4 bleedings, 5 surgical interventions) by continuous infusion of rVIIa over a total of 59 days. Haemostatic coverage was considered effective in 8 out of 9 cases and partially effective in 1 case. Continuous infusion of rVIIa was aimed at rVIIa target plasma levels of 10 U/ml and a decrease in prothrombin time (PT) of 3 s compared to control levels. This was obtained by an initial bolus injection of 90 μg/kg prior to continuous infusion of rVIIa at doses between 30–6 μg/kg/h (mean 17.5 μg/kg/h). A conventional one-stage factor VII coagulation assay, often used in combination with a PT, was satisfactory in monitoring rVIIa treatment. The additional clinical value of anti-fibrinolytic and anti-thrombophlebitic treatment was unclear.Conclusion: In our experience, rVIIa appeared to be efficacious and safe when administered by continuous infusion. Continuous infusion of rVIIa is more convenient than bolus injections of rVIIa, easy to monitor and provides a cost reduction of >50%. These advantages make continuous infusion an attractive administration method for prolonged treatment with rVIIa.

S1.1. Actin-binding compounds as potential therapeutic agents in cystic fibrosis

Background: Initial clinical experience with recombinant factor VIIa (rVIIa) for treatment of haemophilia patients with inhibitors against factor VIII or IX has been obtained by administration of rVIIa by repeated intravenous bolus injections. However, continuous infusion of rVIIa may be a more appropriate administration method if prolonged treatment is indicated.Methods: We have surveyed and analysed the initial experience with continuous infusion of rVIIa in the Netherlands and Belgium.Results: Five hospitals treated 7 haemophilia patients with inhibitors on 9 different occasions (4 bleedings, 5 surgical interventions) by continuous infusion of rVIIa over a total of 59 days. Haemostatic coverage was considered effective in 8 out of 9 cases and partially effective in 1 case. Continuous infusion of rVIIa was aimed at rVIIa target plasma levels of 10 U/ml and a decrease in prothrombin time (PT) of 3 s compared to control levels. This was obtained by an initial bolus injection of 90 μg/kg prior to continuous infusion of rVIIa at doses between 30–6 μg/kg/h (mean 17.5 μg/kg/h). A conventional one-stage factor VII coagulation assay, often used in combination with a PT, was satisfactory in monitoring rVIIa treatment. The additional clinical value of anti-fibrinolytic and anti-thrombophlebitic treatment was unclear.Conclusion: In our experience, rVIIa appeared to be efficacious and safe when administered by continuous infusion. Continuous infusion of rVIIa is more convenient than bolus injections of rVIIa, easy to monitor and provides a cost reduction of >50%. These advantages make continuous infusion an attractive administration method for prolonged treatment with rVIIa.

Continuous infusion of recombinant factor VIIa in patients with haemophilia and inhibitors: Experience in the Netherlands and Belgium.

Background: Initial clinical experience with recombinant factor VIIa (rVIIa) for treatment of haemophilia patients with inhibitors against factor VIII or IX has been obtained by administration of rVIIa by repeated intravenous bolus injections. However, continuous infusion of rVIIa may be a more appropriate administration method if prolonged treatment is indicated.Methods: We have surveyed and analysed the initial experience with continuous infusion of rVIIa in the Netherlands and Belgium.Results: Five hospitals treated 7 haemophilia patients with inhibitors on 9 different occasions (4 bleedings, 5 surgical interventions) by continuous infusion of rVIIa over a total of 59 days. Haemostatic coverage was considered effective in 8 out of 9 cases and partially effective in 1 case. Continuous infusion of rVIIa was aimed at rVIIa target plasma levels of 10 U/ml and a decrease in prothrombin time (PT) of 3 s compared to control levels. This was obtained by an initial bolus injection of 90 μg/kg prior to continuous infusion of rVIIa at doses between 30–6 μg/kg/h (mean 17.5 μg/kg/h). A conventional one-stage factor VII coagulation assay, often used in combination with a PT, was satisfactory in monitoring rVIIa treatment. The additional clinical value of anti-fibrinolytic and anti-thrombophlebitic treatment was unclear.Conclusion: In our experience, rVIIa appeared to be efficacious and safe when administered by continuous infusion. Continuous infusion of rVIIa is more convenient than bolus injections of rVIIa, easy to monitor and provides a cost reduction of >50%. These advantages make continuous infusion an attractive administration method for prolonged treatment with rVIIa.

Individualization of Amikacin (AMK) Therapy in Neonates (NN) less than 2-day old 1421

Introduction: Considering a very large inter-individual pharmacokinetic (PK) variability in neonates, a standard amikacin dosage regimen does not allow to obtain efficacy or safety in all cases of suspected spesis especially in just-born ones. This study was aimed to elaborate and validate an once-a-day amikacin dosing nomogram for the first days of life, using population PK models. Patients/material and methods: We used three population PK models built using NPEM2 algorithm from 63 NNdivided into 3 groups according to gestational age (G1: 34 SA, n = 31) were prospectively included for the nomogram validation. AMK doses given by the nomogram, depending on gestational age and body weight, were determined by simulation of target plasma levels on USCPACK software. Target AMK peak levels were between 28 and 34 μg/ml for G1 and G2, between 33 and 37 μg/ml for G3, and target trough levels < 7 μg/ml for G1,< 5 μg/ml for G2 and G3. The nomogram was used in the 55 NN and validated by comparing estimated and observed AMK peak and trough levels. Percentage of accurately predicted plasma levels were evaluated in each NN group after the first D1 and second D2 doses. Results: 62% of satisfying AMK peak levels after D1 and 100% after D2 were obtained in S1, 80% after D1 and 80% after D2 in S2, 63% after D1 and 90% after D2 in S3. Non toxic AMK plasma levels were obtained in 100% of NN. Conclusion: The nomogram allows the use of once-a-day AMK dosage regimens adapted to each NN in the first two days of life. These regimens guarantee a better efficiency and a better safety than conventional regimens, despite a persistent intra-individual variability.

FK 506 and Successful Pregnancy in a Patient After Renal Transplantation

Our patient developed end-stage renal failure in the settingof focal sclerosing glomerulonephritis (FSGN) and was puton a hemodialysis regimen for 6 months. In September1993, at the age of 31 years, she underwent kidney trans-plantation. She was informed about the potential risks ofpregnancy during immunosuppressive therapy. Her immu-nosuppressive regimen was azathioprine, prednisolone, andFK 506. In the first week after transplantation, she threetimes required hemodialysis. No episode of graft rejectionwas observed. Azathioprine was gradually reduced anddiscontinued after 4 months. Prednisolone (5 mg/d) and FK506—with a target plasma level between 10 and 20 mg/mL(microparticle enzyme immunoassay, IMX, Abbott Diag-nostics, Chicago)—were maintained. The further courseremained uneventful. Mean serum creatinine level was 1.5mg/dL, mean creatinine clearance was 77 mL/min/1.73 m

Citalopram‐lithium combination treatment of elderly depressed patients: A pilot study

AbstractFourteen elderly depressive patients (age 67‐88 yr), phenotyped with dextromethorphan and mephenytoin before and during the trial, were treated for 4 weeks with citalopram (final dose 20‐30 mg/day, except one patient 60 mg/day). The clinical state of the patients was recorded weekly using the Hamilton Depression Rating Scale, the CGI (psychopathology) scale, the VAS and the UKU scale for side‐effects. As assessed by the Hamilton Depression Rating Scale, nine patients improved by more than 50% and continued with their citalopram treatment. The treatment of the five non‐responders was then continued for another 2 weeks by addition of lithium (target plasma levels 0.4‐0.8 mmol/l) to the ongoing citalopram medication. After 1 week, one patient had to be withdrawn for non‐response, three were responders, while the fifth patient was a responder only after 2 weeks of lithium addition. Due to side‐effects, the lithium dose had to be decreased in one patient who had responded to the combination therapy. Plasma levels of citalopram were within 145‐459 nmol/l after 4 weeks of citalopram treatment. All patients were extensive metabolizers of dextromethorphan, and all but possibly one also of mephenytoin. After 4 weeks of citalopram, there was a highly significant correlation between the ratios of S/R‐mephenytoin in urine and citalopram/desmethylcitalopram in plasma, which suggests a common mechanism in the metabolism of these drugs. The preliminary finding that a citalopram‐Li combination therapy may be useful in elderly depressive patients resistant to citalopram alone needs to be replicated by a controlled double‐blind study.

Effect of temafloxacin on the pharmacokinetics of theophylline

A number of fluoroquinolones have been shown to interact adversely with theophylline. We studied the influence of coadministration of temafloxacin, a new fluoroquinolone antimicrobial agent, on steady-state theophylline pharmacokinetics. Twelve healthy subjects (8 males, 4 females; average age and weight 34 years and 62 kg, respectively) were given oral controlled-release theophylline in an individualized dosage to achieve a target plasma level of 10 mg/L. Once steady state was achieved, temafloxacin 600 mg given orally twice daily was concomitantly administered for 4–5 days. Serial blood samples were collected before and during simultaneous temafloxacin administration and plasma assayed for theophylline using a high-performance liquid chromatography technique. Theophylline pharmacokinetic parameters were determined noncompartmentally, and results of single and combined administration were compared. Theophylline plasma concentrations did not differ significantly with temafloxacin coadministration, and similar area-under-the-curve (AUC) values were observed. Theophylline oral clearance increased from 2.67 ± 1.01 L/hour to 2.69 ± 0.93 L/hour, when given alone and with temafloxacin, respectively (p = 0.92). Only 2 of 12 subjects showed an appreciable decrease in clearance when theophylline and temafloxacin were administered together, while 2 subjects demonstrated increases >15% and 8 showed no change. We conclude that temafloxacin does not interact significantly with theophylline and that these agents can be safely administered together.

Phase I Clinical Investigation of Fludarabine Phosphate by a Loading-Dose and Continuous-Infusion Schedule

Fludarabine phosphate was studied in a phase I trial of a loading-dose/continuous-infusion schedule. The schedule was chosen to rapidly achieve and maintain concentrations that have been shown in vitro to achieve maximal inhibition of cell growth. The initial level was a loading dose of 20 mg/m2 followed by a 48-hour continuous iv (CIV) infusion of 30 mg/m2 every 24 hours. For the single-dose escalation, the loading dose was held constant while the CIV dose was increased to 45 mg/m2/24 hours for 48 hours. The dose-limiting toxicity was myelosuppression, especially leukopenia. No other significant toxicity was encountered. The maximum tolerated dose was 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours for 48 hours. The recommended starting dose for phase II trials is 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours. This dose level achieved the target plasma levels in the 2 patients studied.