Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers

To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.     

Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients.

The steady-state pharmacokinetics of ciprofloxacin were evaluated in nine elderly patients with lower respiratory tract infections after an intravenous dosage regimen of 200 mg every 12 h (n = 9) and an oral dosage regimen of 750 mg every 12 h (n = 6). Ciprofloxacin concentrations in serum and urine were measured by high-performance liquid chromatography. The peak concentration in serum, total body clearance (CLs), steady-state volume of distribution (Vss), and terminal elimination half-life after intravenous dosing were 3.5 +/- 0.8 micrograms/ml, 4.38 +/- 1.80 ml/min per kg, 1.6 +/- 0.6 liters/kg, and 5.8 +/- 2.4 h, respectively. The peak concentration in serum, time to peak concentration in serum, absorption lag time, and absolute bioavailability (F) after oral dosing were 7.6 +/- 2.2 micrograms/ml, 1.9 +/- 1.0 h, 0.4 +/- 0.5 h, and 7.7 +/- 24.2%, respectively. The elevated drug concentrations in serum samples from the elderly after oral dosing, compared with data obtained from younger subjects, appear to be a function of reduced CLs, renal clearance, and Vss. The increased F observed in some patients may be due to the effect of concomitant or proximate administration of tube feedings, medications which may alter gastric motility or acidity, or decreased first-pass metabolism. The results demonstrate that factors related to age and declining renal function, rather than infectious disease state, may be primary in determining alterations in pharmacokinetic parameters in the elderly. In elderly patients with normal renal function for their age, no dosage adjustment for intravenous or oral ciprofloxacin is necessary.     

Use of population modeling to define rational monitoring of amiodarone hepatic effects

BACKGROUND: Amiodarone causes hepatotoxicity in experimental models, but in humans, the relationships between drug administration, serum concentrations, markers of liver function, and how to monitor for hepatotoxicity have not been well characterized. METHODS: An open-dose, prospective study collected serum amiodarone, desethylamiodarone, ALT, AST, lactate dehydrogenase (LDH), alkaline phosphatase, total bilirubin, and albumin concentrations over a 5-year period from 125 patients. Nonlinear mixed-effects modeling (NONMEM) was used to explore the relationship between markers of hepatotoxicity and concentrations of amiodarone and desethylamiodarone. RESULTS: No patients had clinical symptoms of hepatotoxicity during follow-up. The natural history of changes in hepatic makers showed ALT to have the strongest independent relationship to changes in serum amiodarone (r = 0.32, P <.001). An ALT greater than 3 times the upper limit of normal developed in only 8 patients (7%), with the earliest occurrence at 55 days of therapy. A mixed-effects model relating ALT elevation to serum amiodarone was improved by the addition of an effect compartment having an equilibration half-time of 87 days (r = 0.81, P <.001). The model predicts that 6% of patients will have an ALT greater than 3 times the upper limit of normal if amiodarone concentrations are maintained at less than 2.5 mg/L, and virtually no patients will have such ALT elevations if amiodarone concentrations are maintained at less than 1.5 mg/L. CONCLUSIONS: Concentrations of amiodarone below a threshold of 1.5 mg/L are associated with a minimal risk of hepatotoxicity, whereas concentrations greater than 2.5 mg/L are associated with a greater than 6% risk of hepatotoxicity. There is significant hysteresis between changes in amiodarone concentration and the resulting change in ALT. The model suggests that monitoring ALT at baseline, 1, 3, and 6 months, and then semiannually would be an efficient strategy to detect amiodarone-induced hepatotoxicity.     

Pharmacokinetics of intermittent intraperitoneal cefazolin in continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: To investigate the pharmacokinetic parameters of intermittent intraperitoneal (IP) cefazolin, and recommend a cefazolin dosing regimen in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Prospective nonrandomized open study. SETTING: CAPD outpatient clinic in Albany, New York. PATIENTS: Seven volunteer CAPD patients without peritonitis.Three of the patients were nonanuric while 4 were anuric. INTERVENTIONS: Cefazolin (15 mg/kg total body weight) was given to each patient during the first peritoneal exchange. Blood and dialysate samples were collected at times 0, 0.5, 1,2,3,6 (end of the first antibiotic-containing dwell), 24, and 48 hours after the administration of IP cefazolin. Urine samples were collected in nonanuric patients over the study period. RESULTS: The mean+/-SD amount of cefazolin dose absorbed from the dialysate after the 6-hour dwell was 69.7%+/-8.0% of the administered dose. The cefazolin absorption rate constant from dialysate to serum was 0.21+/-0.1/hr (absorption half-life 3.5+/-0.8 hr). The mean serum concentrations reached at 24 and 48 hours were 52.4+/-3.7 mg/L and 30.3+/-5.9 mg/L, respectively. The mean dialysate cefazolin concentrations reached at 24 and 48 hours were 15.1+/-3.4 mg/L and 7.9+/-1.4 mg/L, respectively.The cefazolin serum elimination rate constant was 0.02+/-0.01/hr (elimination half-life 31.5+/-8.8 hr). The total cefazolin body clearance was 3.4+/-0.6 ml/min. In the 3 nonanuric patients the mean renal clearance of cefazolin was 0.6+/-0.4 ml/min. The peritoneal clearance of cefazolin was 1.0+/-0.3 mL/min. The systemic volume of distribution of cefazolin was 0.2+/-0.05 L/kg. No statistical difference was detected in pharmacokinetic parameters between anuric and nonanuric patients, although this may be due to the small number of patients in each group. CONCLUSION: A single daily dose of cefazolin dosed at 15 mg/kg actual body weight in CAPD patients is effective in achieving serum concentration levels greater than the minimum inhibitory concentration for sensitive organisms over 48 hours, and dialysate concentration levels over 24 hours. Caution is warranted in extrapolation of dosing recommendations to patients who maintain a significant degree of residual renal function.     

Pharmacokinetics of chlormezanone in healthy volunteers

The kinetics of chlormezanone were determined after oral administration of single (400 mg) and multiple doses (400 mg/day during 8 days) in eight young healthy male subjects. Plasma levels determination had been carried out by HPLC. After single dose administration, Cmax concentrations 4.62 +/- 0.75 mg/l were obtained (Tmax) 2.18 +/- 1.49 h after drug intake. Area under plasma concentrations time curve was 224.93 +/- 27.79 mg.h/l and terminal half-life 40.50 +/- 4.19 h. On chronic regimen, chlormezanone accumulates in the body: trough plasma concentrations are significantly increased from Day 7 (2.97 +/- 0.45 mg/l) to Day 9 (5.41 +/- 0.90 mg/l) and reach the steady state faster than it can be expected from half-life (40 hours) and dosing interval (24 hours). Elimination is faster (T1/2 beta = 37.14 +/- 3.18 h) after chronic regimen. Area under curve during dosing interval at steady state (164.19 +/- 21.70 mg.h/l) is significantly lower than the area under curve between zero and infinity in the single dose sequence (224.93 +/- 27.79 mg.h/l). These results agree with probable induction effect of chlormezanone on its own metabolism.     

抗胸腺细胞球蛋白在HLA配型部分相合的造血干细胞移植患者的药代动力学

为了研究抗胸腺细胞球蛋白(antithymocyte globulin,ATG)在HLA配型部分相合造血干细胞移植患者体内的药代动力学,将2003年10月至2004年10月北京大学血液病研究所骨髓移植部15例患者纳入本研究方案并应用ATG,其中AML5例、CML6例、ALL3例、AA1例。给15例接受HLA部分配型相合造血干细胞移植术患者静脉滴注ATG,剂量为10mg/kg,分4天给药,用ELISA Fc法检测ATG血药浓度,用3P97程序根据房室模型进行数据处理。结果表明:ATG为超长半衰期药物,剂量2.5mg/d连续应用4天,血药浓度随之升高,移植前5天血药浓度上升到44.8%。根据AIC(Akaike's information criterion),该值符合一级消除动力学的二室模型;主要药代动力学参数:AUC0-t3415.9±216.2mg/(L·d);Cmax136.0±10.31mg/L,ATG的达峰时间(Tmax)为4.8±0.7天;t1/2为29.7±2.60天;ATG表观分布容积的平均值为0.12±0.02L/kg;CL(s)为0.002927L/d,ATG体内有效的血药浓度至少维持90天。在给药期间患者未出现严重药物不良反应,耐受性好。结论:含总剂量10mg ATG预处理方案,临床有效,患者安全耐受,适宜用于HLA部分相合的造血干细胞移植患者,ATG在机体的药代动力学无种族差异性。     

Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones.

2-n-Butyl-3-(4'-diethylaminoethoxy-3',5'-diiodobenzoyl)-benzofurane (amiodarone), a drug used in arrythmias and angina pectoris, contains 75 mg of organic iodine/200 mg active substance. Four studies were performed to test its effect on thyroid hormone metabolism: (a) nine male subjects were treated with 400 mg of amiodarone for 28 days; (b) five male subjects received, for the same period of time, 150 mg of iodine in the form of Lugol's solution; (c) five subjects received 300 mug L-thyroxine (T4) for 16 days; from the 10th to the 16th day, 400 mg of amiodarone was added; and (d) five euthyroid subjects received 300 mug L-T4 for 16 days. The changes in serum thyroid-stimulating hormone (TSH), serum total T4, 3,5,3'-triiodothyronine (T3), free T3, and 3,5',3'-triiodothyronine (reverse T3, rT3) were measured, and the pituitary reserve in TSH was evaluated by a thyrotropin-releasing hormone (TRH) test. The results show that amiodarone induced a decrease in serum T3 (28+/-5.1 ng/100 ml, mean+/-SEM, P less than 0.0S and 82.7+/-9.3 ng rT3/100 ml, P less than 0.01). The control study with an equal amount of inorganic iodine did not induce these opposite changes but slightly lowered serum rT3, T3, and T4. In the third study, serum rT3 increased as under amiodarone treatment, thereby proving that these changes were peripheral. It is suggested that amiodarone changes thyroid hormone metabolism, possibly by reducing deiodination of T4 to T3 and inducing a preferential production of rT3. Amiodarone also increased the response of TSH to TRH. The maximal increment of serum TSH above base line was 32+/-4.5 muU/ml under treatment and 20+/-3 muU/ml before treatment (P less than 0.01). During this test, the serum T3 increase was more pronounced than during the control period (83+/-13 and 47+/-7.4 ng/100 ml, P less than 0.05).     

Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration

OBJECTIVES: Voriconazole is a new triazole antifungal agent that is frequently used in intensive care patients with severe fungal infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporal renal replacement therapy in critically ill patients suffering from severe infections and multiple organ failure. This study investigates the pharmacokinetics of voriconazole in anuric patients undergoing CVVHDF. PATIENTS AND METHODS: Pharmacokinetic analysis was performed in nine intensive care patients-one of them with liver cirrhosis-with suspected or proven fungal infection and acute renal failure undergoing CVVHDF who received voriconazole intravenously. The concentration of voriconazole in serum and ultradiafiltrate was determined by HPLC. RESULTS: Mean peak pre-filter voriconazole concentration in eight patients without cirrhosis was 5.9 +/- 2.9 mg/L and mean pre-filter trough level was 1.1 +/- 0.3 mg/L. Mean elimination half-life, mean volume of distribution, mean AUC(0-12) and mean sieving coefficient were 14.7 +/- 6.5 h, 228 +/- 42 L, 22.4 +/- 3.7 mg.h/L and 0.56 +/- 0.16, respectively. The total clearance was 12.9 +/- 6.7 L/h and the clearance via CVVHDF was 1.1 +/- 0.3 L/h. In the patient with liver cirrhosis, elimination half-life, volume of distribution, AUC(0-12) and sieving coefficient were 52 h, 301 L, 19.8 mg.h/L and 0.31, respectively. CONCLUSIONS: Voriconazole should be given without a dosage adaptation in critically ill patients without liver cirrhosis undergoing CVVHDF. However, according to results in one patient, reduction of the maintenance dosing regimen of voriconazole seems to be meaningful in patients with liver cirrhosis.     

Effect of the induction of amiodarone biotransformation on ventricular refractory periods in rats

Amiodarone is a potent class III antiarrhythmic agent that has a slow onset of action in patients (ca. 20 days). To determine if myocardial accumulation of desethylamiodarone (DEA), its main metabolite, influences its antiarrhythmic activity, three groups of six Wistar rats were given amiodarone, 50 mg/kg/day i.p. (A groups), and three groups received the same dose of amiodarone in combination with 80 mg/kg/day of phenobarbital to induce hepatic biotransformation (AP groups). After 3, 7 or 21 days, the rats were sacrificed and the ventricular effective refractory period (VERP) was determined by the extrastimulus technique in endocardial preparations superfused in the tissue bath. Control measurements of VERP were done in untreated rats. Myocardial concentrations of DEA measured by high-performance liquid chromatography were significantly higher in the AP groups than in the A groups (7.5 +/- 0.83 vs. 2.27 +/- 0.11 micrograms/g at 3 days, 6.09 +/- 0.70 vs. 2.82 +/- 0.30 micrograms/g at 7 days and 11.93 +/- 1.22 vs. 4.79 +/- 1.84 micrograms/g at 21 days: mean +/- S.E.). Control VERP value was 33.4 +/- 1.2 msec and was increased by 9, 35 and 42% after 3, 7 and 21 days in the A groups, and by 9, 38 and 39% in the AP groups. After 7 days of DEA administration yielding myocardial concentrations similar to those obtained after amiodarone treatment, there was a slight but nonsignificant prolongation of the VERP (12%). Thus, the prolongation of VERP after amiodarone administration did not appear to depend on myocardial DEA accumulation, suggesting that the slow onset of amiodarone class III action may not be related to DEA disposition.     

围术期应用胺碘酮预防心脏不停跳冠状动脉搭桥术后房颤的研究

目的探讨围手术期应用胺碘酮在预防非体外循环下心脏不停跳冠状动脉搭桥术后房颤中的作用。方法采用随机对照的研究方法,将2009年1月至2011年1月在我科进行非体外循环下心脏不停跳冠状动脉搭桥术的患者随机分为试验组和对照组,每组各100例。A组为试验组,术前口服胺碘酮,600mg/d(200mgtid),连续7d,之后改为200mg/d至术前,术后当天开始静脉滴注胺碘酮,负荷量为5mg/kg,之后给予维持量0.5mg.kg-1.h-1,能进食后改为200mg/d口服。B组为对照组,不给予胺碘酮治疗而仅用常规药物。观察两组患者术后房颤发生率及心率变化,同时检测试验组患者术前及术后第2天的胺碘酮血药浓度。结果两组患者的术前一般特征及手术情况相近。试验组100例患者中术后有10例(10.0%)发生房颤,对照组100例患者中有36例(36.0%)发生房颤(P=0.015)。试验组房颤时最大心室率为(126.0±20.8)次/min,房颤持续时间为1.0d,对照组房颤时最大心室率为(150.0±25.6)次/min,房颤持续时间为(3.0±1.5)d(P<0.05)。试验组术后心率慢于对照组,两组Q-T间期、术后并发症的发生及死亡率无统计学差异。试验组的住院时间为(10.6±2.8)d,对照组住院时间为(15.4±3.2)d(P<0.05)。胺碘酮血药浓度平均值术前为(797±136)ng/ml,术后第2天为(763±94)ng/ml(P>0.05)。结论胺碘酮在预防非体外循环下心脏不停跳冠状动脉搭桥术后房颤中的作用显著,能安全有效地降低术后房颤的发生率,缩短房颤持续时间,且无明显不良反应。     

Pharmacokinetic studies of linezolid and teicoplanin in the critically ill

OBJECTIVES: To determine the pharmacokinetic characteristics of linezolid and teicoplanin in critically ill patients. PATIENTS AND METHODS: Serum was collected frequently during day 0 and then pre- and 1 h post-dose on days 1, 2, 3, 5, 7 and every third day thereafter during treatment. Serum linezolid concentrations were analysed using HPLC. Serum teicoplanin levels were analysed by fluorescence polarization immunoassay. RESULTS: A two-compartment model was required to characterize linezolid pharmacokinetics (n=28) and account for the accumulation seen after multiple dosing. The estimated clearance was 0.049 +/-0.016 L/h/kg (+/-s.e.m. of estimate). At steady state (dosing interval 12 h), linezolid serum concentrations exceeded the breakpoint of 4 mg/L for 10.88 h (95% CI 10.09-11.66) after a 600 mg dose with an AUC/MIC of 92.4 (95% CI 57.2-127.7). Teicoplanin was best described by a two-compartment model (n=26). The clearance was 4.97+/-1.58 L/h. Serum levels exceeded the breakpoint of 4 mg/L for the entire dosing interval in all subjects (400 mg dose every 12 h) with an AUC/MIC of 399.3 (95% CI 329.6-469.0). However, only four of 14 exceeded trough serum concentrations of 10 mg/L. For both agents, trough levels were similar in those who survived and those who died. CONCLUSIONS: Linezolid dosage at 600 mg every 12 h was adequate in the critically ill without need for adjustment for renal function. For teicoplanin, further study is needed to confirm if a trough of 10 mg/L is associated with a higher rate of cure than 5 mg/L. If so, serum drug assays would be needed to ensure a therapeutic level.     

Amiodarone (cordarone) efficiency in atrial extrasystole

AIM: To assess antiarrhythmic amiodarone efficacy of suppressing atrial extrasystoles resistant to other antiarrhythmic modalities. MATERIAL AND METHODS: The antiarrhythmic effect of amiodarone was studied in 70 patients (38 males, 32 females, mean age 49.6 +/- 1.7 years, mean duration of arrhythmia 4.9 +/- 1.5 years). The loading oral dose of amiodarone was 600-1200 mg/day for 10 days, mean maintenance dose--1656.25 mg a week, mean duration of treatment--27.5 +/- 3.2 months. The response to amiodarone was estimated by repeated 24-h Holter monitoring. RESULTS: A complete response was observed in 78.5% patients in loading and in 65.7% patients in maintenance therapy. A partial antiarrhythmic response was seen in 8.57 and 16.41% patients, respectively. CONCLUSION: Amiodarone is a basic drug against ventricular arrhythmia. Its effectiveness in suppression of atrial extrasystole is weaker but also appropriate.     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses.

Teicoplanin is an investigational glycopeptide antibiotic that is structurally and microbiologically similar to vancomycin. Since teicoplanin possesses a very long elimination half-life, the manufacturer suggests that the drug be administered every 12 h for the first day of therapy and once daily thereafter. We studied the multiple-dose (6 mg/kg per dose) pharmacokinetics of teicoplanin in volunteers following intravenous administration every 12 h for 5 days and then every 24 h for 9 days in an attempt to identify the optimal duration of the every-12-h loading-dose regimen. Multiple serum samples were obtained throughout the study, including intensive sampling after the first and last doses; urine was collected during the entire study. A three-exponential equation was fitted to the serum concentration data. The mean terminal-phase half-life was 157 +/- 93 h. Concentrations of teicoplanin in serum similar to those observed after the administration of the last dose (day 14) were observed following the fourth or fifth dose given every 12 h. Therefore, it is suggested that for clinical dosing regimens for teicoplanin, dosing every 12 h for approximately 48 h should be used, followed by once-daily dosing thereafter.     

Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil

BACKGROUND: Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinemia. To evaluate the effect of pivalate prodrug treatment on carnitine homeostasis, we administered a pivalate prodrug, cefditoren pivoxil, to healthy subjects and performed carnitine balance studies. METHODS: Cefditoren pivoxil was administered in one of two dosing regimens (200 mg cefditoren twice daily for 10 days or 400 mg cefditoren twice daily for 14 days) to gender-balanced groups of 15 subjects. Plasma and urine concentrations of carnitine, acetylcarnitine, pivaloylcarnitine, and total carnitine were quantified before, during, and after treatment. RESULTS: Plasma carnitine concentrations fell during cefditoren pivoxil dosing. The nadir in carnitine concentration was dependent on the dose of cefditoren and subject gender (decrease from 44.8 +/- 10.9 micromol/L to 9.2 +/- 1.9 micromol/L in male patients and from 32.5 +/- 5.4 micromol/L to 6.3 +/- 1.7 micromol/L in female patients after 14 days of 400 mg cefditoren twice daily). Urinary elimination of pivaloylcarnitine resulted in a marked increase in total carnitine excretion, as well as net losses of total carnitine of approximately 4.6 mmol with the 200-mg, 10-day regimen and up to 14.9 mmol with the 400-mg, 14-day regimen. Pivaloylcarnitine was the dominant form of excreted pivalate. DISCUSSION: Short-term administration of cefditoren pivoxil results in hypocarnitinemia and increased net losses of total carnitine. It is estimated that net carnitine losses were only 10% of body stores, even with the highest dose regimen tested. Losses of this magnitude would not be anticipated to result in adverse clinical effects.     

Pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion

OBJECTIVE: This study assessed the pharmacokinetics and pharmacodynamics of cefepime administered by intermittent and continuous infusion against clinical isolates of Pseudomonas aeruginosa, Enterobacter cloacae, and Staphylococcus aureus. BACKGROUND: Because beta-lactam antibiotics exhibit time-dependent bactericidal activity and lack prolonged postantibiotic effects against many bacteria, the goal of therapy is to maintain serum drug concentrations above the minimum inhibitory concentration (MIC) for the relevant pathogen over most of the dosing interval. Continuous infusion is a mode of drug administration that can provide serum drug concentrations continuously above the MIC for most bacterial pathogens. METHODS: Twelve healthy volunteers were enrolled. Each received cefepime 2 g by intermittent bolus q12h and, on another day, was randomly assigned to receive 4 or 3 g administered by continuous infusion over 24 hours. RESULTS: For the intermittent regimen, the mean (+/- SD) pharmacokinetic findings were: maximum serum concentration, 112.9 +/- 21.1 microg/mL; minimum serum concentration, 1.3 +/- 0.5 microg/mL; and half-life, 2.6 +/- 0.4 hours. For the 3- and 4-g continuous infusion regimens, steady-state serum concentrations (C(SS)) were 13.9 +/- 3.8 and 20.3 +/- 3.3 microg/mL, respectively. MICs ranged from 2 to 4, 0.125 to 8, and 2 to 8 microg/mL against P. aeruginosa, E. cloacae, and S. aureus, respectively. For the intermittent regimen, serum inhibitory titers (SITs) at 24 hours were > or = 1:2 in 46% of subjects against P. aeruginosa, 48% against E. cloacae, and 2% against S. aureus. For both continuous infusion regimens, SITs for each organism were > or = 1:2 in all subjects. CONCLUSIONS: The intermittent regimen maintained serum concentrations above the MIC for P. aeruginosa and E. cloacae in > or = 92% (11/12) of subjects for > or = 70% of the dosing interval, provided the MIC was < or = 4 microg/mL. Both continuous infusion regimens provided a C(SS) above the MIC for all organisms. However, the C(SS) was > or = 4 times the MIC only if the MIC was < or = 2 microg/mL. Only the 4-g regimen provided such concentrations against isolates with an MIC of 4 microg/mL, and neither regimen provided such concentrations when the MIC was 8 microg/mL. These findings should be applied in comparative clinical studies.     

Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity

OBJECTIVE: To describe the fifth reported instance, as of February 15, 2006, of a severe interaction between simvastatin and amiodarone and hypothesize inhibition of CYP3A4 as the major mechanism. CASE SUMMARY: A 72-year-old white man (178 cm, 77.2 kg) with diabetes mellitus, hyperlipidemia, hypertension, and mild azotemia was hospitalized on September 21, 2004, with thigh weakness, achiness, and dark urine for 7 days. Coronary artery bypass had been performed on July 7, 2004. Amiodarone 200 mg/day was started on July 10, and simvastatin 80 mg/day was initiated on August 13. Laboratory testing on the present admission included creatine kinase (CK) 19,620 U/L (reference range 60-224), blood urea nitrogen 50 mg/dL, creatinine 2.6 mg/dL, aspartate aminotransferase (AST) 912 U/L (30-60), alanine aminotransferase (ALT) 748 U/L (30-60), urine myoglobin 71,100 microg/L (<50), and serum myoglobin 13,877 microg/L (<110). Simvastatin and amiodarone were discontinued, and the patient was hydrated with forced alkaline diuresis. Thirteen days later, his CK was 323 U/L, creatinine 1.7 mg/dL, ALT 145 U/L, and AST 37 U/L. DISCUSSION: Simvastatin is metabolized primarily by CYP3A4, and amiodarone is a recognized inhibitor of this enzyme. This may, therefore, account for the presumed drug interaction. CONCLUSIONS: An objective causal assessment suggests that rhabdomyolysis, renal failure, and possibly hepatotoxicity were probably related to an amiodarone-simvastatin interaction.     

Pharmacokinetics of the bronchodilator tulobuterol in man after repeated oral doses

Plasma levels and elimination half-life of tulobuterol, a new beta-adrenergic agonist, were determined in ten healthy male volunteers after repeated dosing with 2 mg, twice daily, for seven days. Peak plasma levels attained (2.8 +/- 0.8 ng/ml), the time to peak plasma concentration (1.0 +/- 0.3 hr) and the elimination half-life (2.4 +/- 0.4 hr) were generally unchanged from the first to the final study dose. This suggests that tulobuterol does not accumulate in plasma after repeated administration of a dose regimen known to be clinically effective.     

Acute cardiodepressant effects induced by bolus intravenous administration of amiodarone in rabbits

Amiodarone is a potent anti-arrhythmic with a large pharmacological spectrum that shares the mechanisms of action of all classes of anti-arrhythmic drugs. Originally used in the treatment of supraventricular arrhythmias, it has also been used to treat ventricular tachyarrhythmias. The recent inclusion of amiodarone in the Advanced Cardiac Life Support protocols warrants the characterization of the hemodynamic profile resulting from the rapid venous administration of the drug. Thus, the main purpose of the present study was to investigate the acute hemodynamic profile resulting from the bolus i.v. injection of amiodarone, compared with bolus i.v. administration of lidocaine. We investigated the acute hemodynamic effects of amiodarone and lidocaine, in an experimental model of open-chest pentobarbital-anesthetized rabbits (n = 24). Amiodarone (5 mg/kg) induced immediate reductions in mean arterial pressure (MAP) of 32 +/- 5% (P < 0.001), accompanied by reductions in cardiac contractility and relaxation, as assessed by left ventricular (LV) +dP/dt(max) and -dP/dt(max) (40 +/- 4 and 36 +/- 4% respectively) (P < 0.001), heart rate (HR) 10 +/- 1% (P < 0.05), cardiac output (CO) 24 +/- 5% (P < 0.001) and systemic vascular resistance (SVR) 19 +/- 3.5% (P < 0.05). Lidocaine (3 mg/kg) induced reductions in: MAP of 18 +/- 7% (P < 0.001), LV +dP/dt(max) and -dP/dt(max) (40 +/- 5 and 22 +/- 7% respectively) (P < 0.001), HR 7 +/- 1% (P < 0.01) and CO of 23 +/- 6% (P < 0.001). SVR increased by 9 +/- 1.5% (P > 0.05). It is concluded that rapid i.v. administration of both amiodarone and lidocaine induces significant cardiovascular depression mainly characterized by immediate reductions in cardiac contractility.