Pharmacokinetics of cyclophosphamide (CP) and 4-OH-CP/aldophosphamide in systemic vasculitis

Cyclophosphamide given in association with corticosteroids has markedly improved the prognosis of systemic vasculitis. Little information has been reported on cyclophosphamide pharmacokinetics in these diseases and data evaluating its metabolite, 4-hydroxycyclophosphamide/aldophosphamide, pharmacokinetics and concentrations are lacking. Cyclophosphamide was administered as a 1-h intravenous infusion every 3 weeks for six cycles to ten vasculitis patients. Serum cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were assayed on the first cycle of the treatment by reversed-phase high-pressure liquid chromatography with ultraviolet detection. The mean (+/- SD) 4-hydroxycyclophosphamide/aldophosphamide and cyclophosphamide areas under the serum concentration-time curves were, respectively, 1.86 +/- 1.12 and 154.1 +/- 62.7 mg/L x h with a ratio of 1.30 +/- 0.76%. The mean maximum serum 4-hydroxycyclophosphamide/aldophosphamide was reached 2.3 h after cyclophosphamide administration. The mean (+/- SD) cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide half-lives were, respectively, 5.5 +/- 3.1 and 7.6 +/- 2.3 h. The results are consistent with those obtained for cancer patients, in spite of a wide interpatient variability of concentrations and pharmacokinetic parameters.     

A Comparison of Phenytoin-loading Techniques in the Emergency Department

Objectives: To compare the effectivenesses of three phenytoin-loading techniques. Methods: Patients with subtherapeutic phenytoin concentrations who presented within 48 hours of a seizure were randomized to receive either 20 mg/kg of oral phenytoin (PO), divided in maximum doses of 400 mg every two hours, 18 mg/kg of intravenous phenytoin (IVP) at an initial infusion rate of 50 mg/min, or 18 mg/kg (phenytoin equivalents) of intravenous fosphenytoin (IVF) at an initial infusion rate of 150 mg/min. Results: A total of 45 patients were enrolled: 16 in the PO group, 14 in the IVP group, and 15 in the IVF group. The times required to reach therapeutic drug concentrations were (mean ± standard deviation [SD]) 5.62 ± 0.28 hours, 0.24 ± 0.3 hours, and 0.21 ± 0.28 hours, respectively. A total of 17, 27, and 32 adverse drug events were observed in the PO, IVP, and IVF groups, respectively, with significantly fewer events in the PO group (p = 0.02, p = 0.01). No significant difference was found between the numbers of necessary adjustments to the infusions in the two IV groups. The average time to safe emergency department discharge was significantly shorter for the IV groups compared with the PO group (p < 0.001). Conclusions: Oral loading has fewer adverse drug events than either IV loading method, but its use may be limited when therapeutic concentrations are required quickly. Although IVF loading is faster, from an adverse-drug event perspective, no advantage of IVF over IVP was apparent.     

Pharmacokinetics of conivaptan hydrochloride,a vasopressin V1A/V2-receptor antagonist,in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study

Background: Conivaptan is a nonpeptide vasopressin V_1A/V₂-receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hyper-volemic hyponatremia.Objective: This study evaluated the pharmacokinetics of conivaptan in patients with euvolemic or hypervolemic hyponatremia and with or without underlying congestive heart failure who were participating in an efficacy and tolerability clinical trial.Methods: Data from an open-label, multicenter study were used to evaluate the pharmacokinetics of conivaptan in hyponatremic patients. Patients received a 20-mg loading dose intravenously over 30 minutes, followed by a continuous 4-day infusion of 20 or 40 mg/d. In the entire cohort, plasma conivaptan concentrations were determined at baseline, at the end of the loading dose (0.5 hour), at 24 hours, on days 3 and 4, and at the follow-up visit on day 11. A subset of patients at 2 study sites (the “pharmacokineticrich” subset) provided additional samples for pharmacokinetic analysis on day 1 at 1, 4, and 24 hours; on day 2 at 24 hours; and on day 5 at 1, 2, 7, 12, and 24 hours.Results: Plasma conivaptan concentrations were evaluated in 31 patients who received conivaptan 20 mg/d (mean [SD] age, 73.1 [14.3] years; weight, 68.1 [17.2] kg; 71.0% female; 87.1% white, 9.7% black, 3.2% other) and 172 patients who received co-nivaptan 40 mg/d (mean [SD] age, 71.5 [14.4] years; weight, 65.6 [15.9] kg; 64.0% female; 90.1% white, 6.4% black, 3.5% other). The pharmacokinetic-rich subset included 8 patients who received conivap-tan 20 mg/d (mean [SD] age, 76.3 [12.4] years; weight, 71.5 [14.7] kg; 87.5% female; 100% white) and 8 who received conivaptan 40 mg/d (mean [SD] age, 78.3 [7.9] years; weight, 71.3 [15.6] kg; 37.5% female; 100% white). In the overall patient group, plasma conivaptan concentrations were the highest after the 30-minute (C_0.5h) loading dose (mean [SD] C_0.5h = 733 [323] and 701 [343] ng/mL with conivap-tan 20 and 40 mg/d, respectively) and then declined during day 1 to concentrations (C_24h) (mean [SD] C_24h = 84 [78] and 215 [129] ng/mL with conivaptan 20 and 40 mg/d, respectively) that were maintained by the continuous infusion of 20 or 40 mg/d. At the end of infusion (96 hours), the mean (SD) plasma conivaptan concentrations were 176 (196) and 308 (321) ng/mL for conivaptan 20 and 40 mg/d, respectively. A ratio of 1.75 indicated near dose proportionality; however, interpatient variability was evident. No apparent differences in plasma conivaptan concentrations measured at 0.5 or 96 hours were observed between patients with euvolemic or hypervolemic hypona-tremia or between patients with or without congestive heart failure. In the pharmacokinetic-rich subset, for conivaptan 20 and 40 mg/d, respectively, conivaptan clearance was 18.7 and 9.5 L/h, the elimination t1/2 was 5.3 and 10.2 hours, and exposure to conivaptan in terms of AUC_∞ was 6996 and 30,771 ng · h/mL.Conclusion: The results of this study suggest that the pharmacokinetics of conivaptan 20 and 40 mg/d do not differ by volume status or the presence or absence of congestive heart failure.     

镇静镇痛治疗辅助危重症患者无创机械通气的临床应用

目的比较单独应用右美托咪定及咪达唑仑或丙泊酚复合芬太尼用于无创机械通气患者镇静、镇痛的效果和安全性。 方法回顾性分析皖南医学院弋矶山医院ICU行无创机械通气患者64例,并根据接受镇静镇痛治疗方案分为右美托咪定组（Dex组,41例）和非右美托咪定组（non-Dex组,23例）。右美托咪定负荷量1 μg/kg,续以维持剂量0.2~0.5 μg/（kg?h）;咪达唑仑负荷量0.05 mg/kg,续以维持剂量0.02~0.10 mg/（kg?h）;丙泊酚负荷量3 mg/kg,续以维持剂量0.5~3.0 mg/（kg?h）;咪达唑仑和丙泊酚复合应用芬太尼,负荷剂量为1 μg/kg,续以维持剂量1~2 μg/（kg?h）。监测并记录注射药物前、注射药物后第1、3、6、12、24小时患者的Ramsay评分,记录注射药物前、注射药物后第1、12、24小时患者的心率、血压、呼吸频率及血气分析结果。观察记录谵妄、过度镇静、低血压、高血压、心动过缓等不良事件的发生率。 结果2组药物均能使患者达到镇静目标评分,注射药物1 h Dex组与non-Dex组患者的Ramsay评分分别为（2.3±0.5）、（2.3±0.4）分,差异无统计学意义（t=0.00,P=1.000）;12 h分别为（2.3±0.5）、（3.3±0.8）分;24 h分别为（2.4±0.5）、（3.2±0.6）分,差异具有统计学意义（t=6.16、5.71,均P<0.001）。Dex组患者ICU停留时间较non-Dex组短［（4.9±2.0）d vs （6.8±3.2）d,P=0.026］。2组患者在静脉输注药物后各时间点的氧合指数（PaO₂/FiO₂）、呼吸频率、平均动脉压,及气管插管、过度镇静、高血压、低血压、心动过缓等不良事件发生率差异无统计学意义（P>0.05）。输注药物1 h后Dex组与non-Dex患者的心率分别为（78.4±17.6）、（93.3±25.0）次;12 h分别为（77.1±10.7）、（86.5±13.4）次;24 h分别为（71.4±6.9）、（80.9±14.3）次,差异具有统计学意义（t=2.79、3.08、3.59,均P<0.01）。Dex组患者谵妄的发生率明显低于non-Dex组（7.3% vs 39.1%,P=0.023）。疾病亚组分析显示,急性心力衰竭患者应用镇静药物后低血压发生率均显著高于其他非急性心力衰竭疾病类型（Dex组：71.4% vs 8.8%,P=0.001;non-Dex组：66.7% vs 11.8%,P=0.008）。 结论单独应用右美托咪定与咪达唑仑或丙泊酚复合芬太尼等镇静方案均能安全应用于辅助无创机械通气,但急性心力衰竭患者应用时需注意低血压。     

Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers.

The pharmacokinetics of ceftazidime were investigated during intermittent (II) and continuous (CI) infusion in eight healthy male volunteers in a crossover fashion. The total daily dose was 75 mg/kg of body weight per 24 h in both regimens, given in three doses of 25 mg/kg/8 h (II) or 60 mg/kg/24 h with 15 mg/kg as a loading dose (CI). After the third dose (II) and during CI, serum and blister fluid samples were taken. Seven new blisters were raised for each timed sample by a suction blister technique. Blisters took 90 min to form. Samples were then taken from four blisters (A samples) and 1 h later were taken from the remaining three (B samples). The concentration of ceftazidime was determined using a high-performance liquid chromatography method. After II, the concentrations in serum immediately after infusion (t = 30 min) and 8 h after the start of the infusion were 137.9 (standard deviation [SD], 27.5) and 4.0 (SD, 0.7) micrograms/ml, respectively. The half-life at alpha phase (t1/2 alpha) was 9.6 min (SD, 4.6), t1/2 beta was 94.8 min (SD, 5.4), area under the concentration-time curve (AUC) was 285.4 micrograms.h/ml (SD, 22.7), total body clearance was 0.115 liter/h.kg (SD, 0.022), and volume of distribution at steady state was 0.178 liter/kg (SD, 0.023). The blister fluid (A) samples showed a decline in concentration parallel to that of the concentrations in serum during the elimination phase with a ratio of 1:1. The t1/2 of the A samples was 96.4 min (SD, 3.2). The concentration of ceftazidime in the B blister fluid samples was significantly higher (27%) than in the A samples over time. This shows that blisters may behave as a separate compartment and establishes the need to raise new blisters for each timed sample. The mean AUC/h during continuous infusion was 21.3 micrograms . h/ml (SD, 3.0). The total body clearance was 0.113 liter/h . kg (SD, 0.018), the urinary clearance was 0.105 liter/h . kg (SD, 0.012), and the ceftazidime/creatinine clearance ratio was 0.885. The mean AUC of blister fluid per hour was 84.5% (18.0 micrograms . h/liter; SD, 3.6) compared with that of serum. The A samples did not differ significantly from the B samples. The implications of continuous infusion of beta-lactams for treatment of serious infections are discussed.     

Intravenous Propafenone Versus Intravenous Amiodarone in the Management of Atrial Fibrillation of Recent Onset: A Placebo-Controlled Study

The efficacy and safety of intravenous propafenone, amiodarone, or placebo were compared in the treatment of atrial fibrillation (AF) of recent onset (duration ≤ 48 hours). Methods: 143 patients (77 men, mean age 63 ± 12 years) were studied, of whom 46 received propafenone (2 mg/kg over 15 minutes followed by 10 mg/kg over the next 24 hours), 48 received amiodarone (300 mg intravenously over 1 hour, followed by 20 mg/kg over the next 24 hours, plus 1,800 mg/day orally, in 3 divided doses), and 49 received placebo (the equivalent amount of saline IV over 24 hours). Digoxin was administered to all patients who had not previously received it. Results: Conversion to normal sinus rhythm occurred in 36 of 46 patients (78.2%) receiving propafenone, in 40 of 48 patients (83.3%) receiving amiodarone, and in 27 of the 49 (55.10%) controls (P < 0.02, drug vs placebo, between drugs NS). The mean time to conversion was 2 ± 3 hours for propafenone, 7 ± 5 hours for amiodarone, and 13 ± 9 for placebo (P < 0.05). Patients who converted had smaller atria than those who did not (diameter: 42.7 ± 5 vs 47.2 ± 7 mm, P < 0.001 for all). Treatment was discontinued in one patient in the amiodarone group because of an allergic reaction and in two patients in the propafenone group because of excessive QRS widening. No side effects were observed in the placebo group. Conclusions: Both drugs tested intravenously were equally effective and safe for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. However, propafenone offered the advantage of more rapid conversion than amiodarone.     

Pharmacokinetics of cefuroxime in infants and children with bacterial meningitis.

A total of 38 patients with bacterial meningitis received either 50 or 75 mg of cefuroxime per kg of body weight given as a 15-min intravenous infusion during the first to third days of therapy. The mean peak plasma concentrations of cefuroxime after doses of 50 and 75 mg/kg were 105 and 152 micrograms/ml, respectively. In five patients, pharmacokinetic values were determined after multiple doses of 50 mg of cefuroxime per kg every 6 h. The mean peak plasma concentrations were 120 micrograms/ml after the first dose and 130 micrograms/ml after the last dose. The concentrations at 6 h were 3.25 and 11.0 micrograms/ml after the first and last doses, respectively. The elimination half-life was approximately 1.5 h, and the apparent volume of distribution was 650 ml/kg. The plasma clearance rate was 195 to 198 ml/min per 1.73 m2. Penetration into the cerebrospinal fluid, expressed as the ratio of the cerebrospinal fluid to serum areas under the curve times 100, was 6.4% in patients given 50 mg of cefuroxime per kg and 10% in those who received 75 mg/kg. The cerebrospinal bactericidal activity in 27 patients was less than or equal to 1:8; only 2 patients had bactericidal activity of less than or equal to 1:2.     

Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study

Background: The emergence of multidrug-resistant nosocomial pathogens, such as Pseudomonas aeruginosa and Acinetobacter baumannii, has led to the revival of the systemic use of antimicrobial agent colistin in critically ill patients, but only limited data are available to define its pharmacokinetic profile in these patients. Objective: The aim of this study was to assess steady-state serum concentrations of colistin after IV administration of colistin methanesulfonate (CMS) in critically ill patients with stable kidney function. Methods: This prospective, open-label, uncontrolled study was conducted at 2 intensive care units in the Athens Trauma Hospital, KAT, Athens, Greece. Adult patients were nonconsecutively enrolled if they were critically ill and had stable kidney function (<0.5 mg/dL change in serum creatinine prior to and until the day of sample collection) and had been receiving CMS as part of a treatment regimen for sepsis irrespective of site of infection with multidrug-resistant, gram-negative bacilli. After IV administration of 225-mg CMS (with the exception of 1 patient who received 150 mg) every 8 or 12 hours for at least 2 days, blood samples were collected just before and at 10 minutes and 1, 2, 4, 6, and 8 hours after IV infusion (duration, 30 minutes) of the colistin dose on the sampling day. Results: Fourteen nonconsecutive patients were enrolled in the study (13 male, 1 female; mean [SD] age, 62.0 [19.2] years; mean [SD] estimated weight, 72.5 [8.5] kg; mean [SD] Acute Physiology And Chronic Health Evaluation II score on admission, 17.1 [6.0]). At steady state, mean (SD) colistin maximum and minimum concentrations were 2.93 (1.24) and 1.03 (0.44) mg/L, respectively, while mean (SD) apparent total body clearance, apparent volume of distribution, and t1/2 were 13.6 (5.8) L/h, 139.9 (60.3) L, and 7.4 (1.7) hours, respectively. Colistin-related nephrotoxicity was not observed in the study patients. Conclusion: CMS dosage regimens administered to these critically ill adult patients were associated with suboptimal Cmax/MIC ratios for many strains of gram-negative bacilli currently reported as sensitive (MIC, 相似文献   

Methylprednisolone reverses vasopressin hyporesponsiveness in ovine endotoxemia

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U x min(-1)) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 +/- 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U x min(-1)) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg x kg(-1)) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 +/- 15 pg x mL(-1)) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg x kg(-1)) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.     

Magnesium sulfate administered via continuous intravenous infusion in pediatric patients with refractory wheezing

PURPOSE: To evaluate the dosing and safety of intravenous magnesium sulfate administered via continuous infusion for refractory wheezing. MATERIALS AND METHODS: All patients admitted to the pediatric intensive care unit (PICU) between January 1998 and March 2001 who were prescribed magnesium sulfate via continuous infusion were identified via retrospective chart review. The patient's medical history, demographic data, vital signs, magnesium dosing history, and concurrent medications were recorded. RESULTS: Forty PICU patients represent our study population. The mean age was 82.6 +/- 64.6 mo; 18 patients were boys.The mean magnesium loading dose (mg/kg) was 29.6 +/- 13.2 with a mean infusion dose (mg/kg/h) of 18.4 +/- 6.5 with a significant difference in dosing noted between patients weighing less than 30 kg and those with a higher weight. The mean magnesium loading dose (mg/kg) in the less than 30 kg group was 35.3 +/- 12.7 compared with 21.9 +/- 9.9 in the higher weight group (P <.05). Mean infusion doses (mg/kg/h) were 21.6 +/- 6 and 14.6 +/- 4.2, respectively (P <.05). There was no significant difference between the mean concentrations (mg/dL) reported between the 2 groups (less than 30 kg group = 3.9 +/- 0.6; higher weight group = 3.6 +/- 0.5). All patients received nebulized albuterol, ipratropium, and intravenous methylprednisolone before magnesium therapy. Aminophylline and ketamine were prescribed to 28 and 4 patients, respectively. No cardiovascular adverse effects were noted during magnesium therapy. CONCLUSIONS: For the treatment of refractory wheezing, intravenous magnesium sulfate administered via continuous infusion represents a safe mode of drug delivery.     

Metabolism-based cyclophosphamide dosing for hematopoietic cell transplant

When cyclophosphamide (120 mg/kg) is used for hematopoietic cell transplant, the increased area under the curve of carboxyethylphosphoramide mustard (AUC(CEPM)) is related to liver toxicity and death. We determined the feasibility of dose-adjusting cyclophosphamide to a preset metabolic endpoint (AUC(CEPM), 325 +/- 25 micromol/L.h). In 20 patients blood sampling was done over a 16-hour period after administration of 45 mg/kg cyclophosphamide; AUC(CEPM) from 0 to 16 hours was calculated by noncompartmental analysis. The expected AUC(CEPM) for 0 to 48 hours was estimated, and the second cyclophosphamide dose was determined. The mean second cyclophosphamide dose was 42 mg/kg, and the mean total cyclophosphamide dose was 86 mg/kg (range, 54-120 mg/kg). The mean AUC(CEPM) for the time from 0 to 48 hours was 296 micromol/L.h (95% confidence interval, 275-317 micromol/L.h). A retrospective analysis indicated that AUC(CEPM) could be more accurately predicted by use of a population pharmacokinetic model. We conclude that metabolism-based dosing of cyclophosphamide is feasible and that a lower cyclophosphamide dose does not affect engraftment.     

Pharmacokinetics of vidarabine in the treatment of polyarteritis nodosa

The pharmacokinetics of vidarabine were studied in 8 patients with polyarteritis nodosa related to hepatitis B virus infection. The drug was administered by continuous infusion for three weeks at doses of 15 (1 week) and 7.5 (2 weeks) mg/kg per day, during which time 15 plasma exchanges were performed. Plasma was assayed for vidarabine and its principal metabolite, hypoxanthine arabinoside by high pressure liquid chromatography. Vidarabine was not detected in the plasma of any patients. Hypoxanthine arabinoside levels were used to evaluate vidarabine kinetics. The serum levels of hypoxanthine arabinoside ranged from 3.6 to 21.5 mg/l. The mean elimination half-life (+/- SD) was 3.0 +/- 1.7 h. The plasma clearance (mean +/- SD) was 195 +/- 270 ml/min when the dose was 7.5 mg/kg per day and 66.3 +/- 47 ml/min for a 15 mg/kg per day/dose (NS). Except for the elimination half-life, these results were not fully consistent with those observed in other studies. The influence of multiple plasma exchanges on vidarabine kinetics is limited and dosage adjustment is not required based on the continuous infusion of vidarabine.     

'Balanced analgesia' in the perioperative period: is there a place for ketamine?

We investigated whether intraoperative 'subanesthetic doses' of ketamine have a postoperative anti-hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. They were randomly assigned to receive no ketamine (group 1), i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5). All i.v. and epidural analgesics were stopped at the end of surgery and patients were connected to an i.v. morphine patient-controlled analgesia (PCA) device. Short-term postoperative analgesia (72 h) was assessed by pain visual analog scale scores at rest, cough, and movements as well as by PCA requirements. Wound mechanical hyperalgesia was evaluated and residual pain was assessed by asking the patients at 2 weeks, and 1, 6, and 12 months. The area of hyperalgesia and morphine PCA requirements were significantly reduced in group 3. These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route.     

Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: A randomized, open-label study

OBJECTIVE: The aim of this study was to assess the pharmacokinetic (PK) properties and tolerability of esomeprazole 20 and 40 mg after single and repeated oral doses in adolescents with symptoms of gastroesophageal reflux disease (GERD). RESULTS: The study included 15 boys and 13 girls (mean age, 14.3 years). Geometric mean AUC(0-infinity) values (overall drug exposure) were 1.58 and 5.57 micromol . h/L (0.027 and 0.083 pmol x h x L(-1)/kg) after single-dose administration of esomeprazole 20 and 40 mg, respectively, on day 1. Corresponding values with repeated doses (day 8) were 3.65 and 13.86 micromol x h/L (0.064 and 0.207 micromol x h x L(-1)/kg). Geometric mean Cmax values were 0.67 and 2.78 micromol/L (0.012 and 0.041 micromol/L x kg(-1)) with single-dose administration of esomeprazole 20 and 40 mg, respectively, and 1.45 and 5.13 micromol/L (0.026 and 0.075 micromol/L x kg(-1)), respectively, with repeated doses (day 8). These mean AUC(0-infinity) and CmaX values were >2-fold with the 40 mg dose compared with the 20-mg dose with single- and repeated-dose administration. The most common adverse event was headache (2 [7.1%] patients). CONCLUSIONS: The results of this study suggest that the PK parameters of esomeprazole were both dose- and time-dependent in these adolescents with GERD. Both doses of esomeprazole were well tolerated in this study population.     

Pharmacokinetic and Pharmacodynamic Characteristics of Single-dose Canakinumab in Patients With Type 2 Diabetes Mellitus

PurposeInterleukin (IL)-1β, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet β-cell function. Canakinumab, a human monoclonal antibody, targets IL-1β–dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion.MethodsThis multicenter, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in patients with T2DM (diagnosed ≥6 months before screening) on a stable daily dose of metformin. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The study was initially designed with 1 small cohort (15 patients, 0.3 mg/kg) on a stable dose of metformin ≥500 mg/d for an initial tolerability evaluation; all other patients were on a stable dose of ≥850 mg/d of metformin. The PK profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and hemoglobin (Hb) A_1c levels were assessed at weeks 4, 8, 12, and 24.FindingsOf the 231 enrolled patients, 222 completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Exposure to canakinumab was dose proportional. The mean half-life ranged from 17 to 26 days, and mean systemic clearance ranged from 0.094 to 0.128 mL/h/kg. Dose-related reductions in hsCRP were significantly greater with canakinumab compared with those with placebo at week 4 (−0.2 mg/L, −0.5 mg/L, −1.5 mg/L, and −1.7 mg/L with the 0.1-, 0.3-, 1.5-, and 10-mg/kg doses, respectively; all, P < 0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (−0.8 mg/L with 1.5 mg/kg and −1.3 mg/L with 10 mg/kg; both, P < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (P = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (P = 0.011).ImplicationsThe findings from this study suggest that IL-1β blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in patients with T2DM. ClinicalTrials.gov identifier: NCT00900146.     

Clinical Pharmacology of Sisomicin

Studies were conducted in 30 patients with neoplastic diseases. Twelve patients received sisomicin intramuscularly at doses of 20 mg/m(2) and 40 mg/m(2). The mean peak serum concentration occurred at 1 h and was 2.5 mug/ml and 4.0 mug/ml, respectively. Ten patients received intravenous sisomicin at doses of 30 mg/m(2) during 30-min infusion. Mean peak serum level determined at 30 min was 5.1 mug/ml. The levels gradually decreased and at 6 h was 0.6 mug/ml. The serum half-life was 160 min. Serum levels determined in eight patients who received sisomicin by continuous infusion at doses of 30 mg/m(2) every 6 h were greater than 1.4 mug/ml during the 6-h period. The urinary excretion of sisomicin during the 6-h period after intramuscular administration of 20 mg/m(2) and 40 mg/m(2) was 49 and 61%, respectively. The pharmacology of sisomicin is similar to gentamicin.     

Intracoronary magnesium is not protective against acute reperfusion injury in the regional ischaemic-reperfused dog heart

Abstract. Intravenous magnesium lowers mortality in patients with suspected myocardial infarction. We tested the hypothesis that the protective effect may be due to a direct, local influence of magnesium on myocardial reperfusion injury in a dog model of ischaemia/reperfusion. Ten anaesthetized open chest dogs underwent 1 h of left anterior descending artery (LAD) occlusion and 6 h of reperfusion. The animals received intracoronary (i.c.) magnesium aspartate (Mg, n = 5) or vehicle infusion ( n = 5) for the first hour of reperfusion. Mg infusion was adapted to actual LAD flow (ultrasonic flow probe) to increase regional plasma concentration by 4 mmol L^-1. Regional myocardial function was measured as percent systolic wall thickening (sWTh, sonomicrometry). Intracoronary Mg increased LAD flow during application (at 15min reperfusion; Mg, 194±44 (mean±SD); control, 116±41 mLmin^-1 100g^-1, P < 0.01). sWTh decreased during coronary occlusion from 14.3 ± 7.1 % to - 4.7 ± 2.7% in the control group and from 14.8±2.5% to -4.1 ±3.1% in the Mg group. Throughout the reperfusion period wall function remained depressed in both groups to a similar degree (control, - 3.5 ± 1.8%; Mg, - 3.0 ± 1.9% at 6 h reperfusion). Global haemodynamics were not different. Infarct size after 6h reperfusion (TTC staining) was similar in both groups (Mg, 20.6±5.0; control, 24.4±8.7% of area at risk). Regional magnesium application (i.e.) to post-ischaemic reperfused myocardium had no influence on infarct size or post-ischaemic regional wall function in this model. The beneficial action of systemic Mg in patients with myocardial infarction is probably not due to an early direct protective effect on ischaemic-reperfused myocardium.     

Anticoagulant-induced intramural intestinal hemorrhage

Background

Long-term use of warfarin can provide benefits in the treatment of many diseases, but adverse bleeding events are unpreventable because of a narrow therapeutic range.

Objective

The aim of this retrospective chart review with data abstraction was to investigate the clinical presentations of intestinal intramural hemorrhage in emergency department (ED) patients.

Methods

We reviewed the cases of 17 patients with acute abdominal pain in our ED. Medical records including demographic data and results of abdominal computed tomography were retrospectively reviewed and analyzed.

Results

The mean ± SD age of the reviewed patients was 77.7 ± 8.5 years (range, 60-93 years). The mean ± SD duration from onset of symptoms to ED visit was 2.5 ± 1.3 days (range, 1-5 days). All patients had abdominal pain, and 64.7% had nausea/vomiting. A total of 64.7% of patients had peritoneal signs. The jejunum was most commonly involved (88.2% of all cases). The maximal mean ± SD wall thickening of the bowel was 14.1 ± 4.4 mm (range, 7.4-26.7 mm), and the estimated mean ± SD length was 35.6 ± 24.4 cm (range, 9-105 cm). The mean ± SD prothrombin time and activated partial thromboplastin time were prolonged to 86.5 ± 26.9 and 116.2 ± 43.1 seconds, respectively. All patients received medical treatment and survived. At the last follow-up (mean, 27.4 months), none of the patients had recurrence of intestinal intramural hemorrhage or intestinal obstruction.

Conclusion

Prolonged prothrombin time and drug history can indicate the possibility of intramural intestinal hemorrhage, and abdominal computed tomography may help to exclude surgical diseases and prevent unnecessary surgery.     

Comparison of the pharmacokinetics of lansoprazole 15- and 30-mg sachets for suspension versus intact capsules

OBJECTIVE: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules. METHODS: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase 1, open-label, single-dose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-mg sachet mixed with water and 1 lansoprazole 15-mg oral capsule; in the second study, each subject received 1 lansoprazole 30-mg sachet mixed with water and 1 lansoprazole 30-mg oral capsule. Administration of the 2 formulations was separated by a washout period of > or =7 days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. RESULTS: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 mg. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 mg. The pharmacokinetic parameters of the 15- and 30-mg lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for C(max) and AUC from time 0 to infinity (AUC(0-infinity) for the lansoprazole 15-mg sachet (591.9 [242.3] ng/mL and 1614 [2065] ng.h/mL, respectively) did not differ significantly from those for the lansoprazole 15-mg capsules (578.6 [275.2] ng/mL and 1620 [2290] ng.h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-mg sachet and 30-mg capsule: mean (SD) C(max), 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUC(0-infinity), 2655 (1338) and 2669 (1311) ng.h/mL, respectively. The 90% Cls for C(max) and AUC(0-infinity) ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. CONCLUSIONS: These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations.     

Pharmacokinetics and safety of prochlorperazine in paediatric patients receiving cancer chemotherapy.

Nausea and vomiting are common clinical problems in patients receiving cancer chemotherapy. Metoclopramide is often used but frequently causes extrapyramidal reactions. As an alternative, prochlorperazine is prescribed but no data on its pharmacokinetics in paediatric patients are available to guide the choice of suitable dosages. The primary objective of this study was to evaluate the pharmacokinetics and safety of intravenous prochlorperazine in paediatric patients receiving cancer chemotherapy. Eleven patients (ages 1-9 years) who received high doses of cisplatin or cyclophosphamide were given three to four intermittent doses of 0.2 mg/kg prochlorperazine i.v. over a period of 6-9 h. Multiple blood samples were collected and prochlorperazine was quantified by a specific gas-liquid chromatographic method. The peak serum concentrations ranged from 402 to 5,608 ng/ml. The total clearance and elimination half-life ranged from 0.03 to 0.28 (mean: 0.12) litre/kg/h, and from 1.2 to 15.5 (mean: 5.6) h, respectively. No adverse effects were observed in our patients. Three patients had uncontrolled episodes of vomiting during prochlorperazine therapy. These data suggest: (i) that there was a substantial interpatient variability in prochlorperazine pharmacokinetics thus the dose requirement differed among patients; and (ii) that prochlorperazine appeared safe at the doses used but higher doses may be required to control nausea and vomiting in some paediatric patients receiving high-dose cisplatin or cyclophosphamide therapy.