Plasma pharmacokinetics of daptomycin in critically ill patients with renal failure and undergoing CVVHD.

BACKGROUND: Daptomycin is a novel antibiotic with primarily renal elimination. METHODS: In an open-label, prospective trial, the pharmacokinetics of daptomycin after single (8 mg/kg BW) and multiple intravenous doses (4 mg/kg BW) at steady state were determined in critically ill, dialysis-dependent patients treated with continuous veno-venous hemodialysis (CVVHD). Daptomycin levels were determined by HPLC. Subjects with normal renal function received one dose of 4 mg/kg BW of daptomycin. RESULTS: In the normal controls, daptomycin administration resulted in a mean maximum concentration (Cmax) of 60.7 ± 10.7 mg/l and an area under the time-versus-concentration curve from 0 to 24 h (AUC0-24) of 402 ± 56 mg × h/l. In the CVVHD-treated patients, a loading dose of 8 mg/kg lead to Cmax of 87.5 ± 15.0 mg/l, AUC0-24 of 537 ± 97 mg × h/l and AUC24-48 of 193 ± 69 mg × h/l, respectively. After multiple doses of 4 mg/kg every 48 h, Cmax was 41.8 ± 5.0 mg/l, AUC0-24 302 ± 43 mg × h/l and AUC 24-48 h 102 ± 24 mg × h/l, respectively. Approximately 40% of the daptomycin dose administered was removed by CVVHD. Mean plasma half-lives of daptomycin in patients were 2 - 3 times longer than in healthy controls. CONCLUSIONS: The dosing regimen of 4 mg/kg TBW of daptomycin administered to CVVHD patients every 48 h is inappropriate to achieve effective antimicrobial plasma concentrations of daptomycin in the second half of the dosing interval (24 - 48 h). Doses of ≥ 4 mg/kg TBW administered intravenously every 24 h are necessary in CVVHD patients to assure that plasma daptomycin levels are comparably high to subjects with normal renal function and to avoid underdosing.

Fosfomycin: an old, new friend?

Fosfomycin (FOM) is an antibiotic which has varying application indications across the globe. European, Japanese, South African and Brazilian usage practices are much broader, involving multiple formulations of FOM than the currently limited application of FOM in the United States, where uncomplicated urinary tract infection represents the only indication for FOM-tromethamine. Based on early difficulty in determining FOMs genuine in vitro activity, there was initial skepticism about its efficacy and application range. However, in the mid 1970s, correctly executed experiments coupled with an improved understanding of microbiological concepts opened the door for broader use of FOM. During the following 40 years FOM was evaluated in pre-clinical and clinical trials in a wide range of applications and in a multitude of settings. The gathering of pharmacokinetic and pharmacodynamic data was incorporated into large scale studies in which FOM efficacy was further explored and proven. Among European nations, intravenous FOM-disodium for patients presenting with soft tissue infections, sepsis or deep seated infectious processes has become well accepted over the last two decades. The recent emergence of bacterial strains, which impede and encumber pharmacotherapy, namely, MRSA, ESBL and MSSA, lends itself to the idea of reviving long-standing, sensibly used antimicrobial agents like FOM. This review provides a comprehensive conspectus on FOM's history, mode of action, tissue penetration characteristics, resistance, antibacterial activity, combination partners and clinical uses among other facets of interest.

Does linezolid inhibit its own metabolism? Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients.

Few studies investigating the population pharmacokinetics of linezolid in critically ill patients have been reported, yielding controversial results. Therefore, a population pharmacokinetic analysis using NONMEM was performed to thoroughly understand the pharmacokinetics of unbound linezolid in plasma. Data were obtained from 10 healthy volunteers and 24 septic patients. Intensive sampling was performed after single and multiple dosing. The pharmacokinetics of unbound linezolid was best described by a two-compartment model with an absorption rate constant (K(A), 1.81 h(-1)), clearance (CL, 11.1 l/h), volumes of distribution (V(2) and V(3), 20.0 and 28.9 liters, respectively), and intercompartmental clearance Q, 75.0 l/h). However, clearance was inhibited over time to 76.4% of its original value, dependent on the concentration in an empirical inhibition compartment. Overall, imprecision of parameter estimates was low to moderate. Comparison of goodness of fit graphics and of the predictive performance revealed that the presented model was superior to previously published models using linear elimination or parallel linear and Michaelis-Menten elimination and also to other of our own investigated model alternatives. The observed nonlinearity in linezolid pharmacokinetics might be a result of an inhibition of the formation of the major linezolid metabolite due to the inhibition of respiratory chain enzyme activity. To our knowledge, this study presents the first attempt to mechanistically explain the observed nonlinearity in linezolid pharmacokinetics. Finally, simulations demonstrated that the model might also serve as a tool to predict concentration-time profiles of linezolid, thus providing a rationale for a more targeted antimicrobial therapy.

CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model.

BACKGROUND: This study set out to investigate the antitumor effects of a treatment strategy combining the mTOR inhibitor CCI-779 with cisplatin in vitro and in a human melanoma SCID mouse model. METHODS: In vitro 518A2, Mel-JUSO or 607B cell lines were incubated with CCI-779, cisplatin and CCI-779 plus cisplatin. Based on these results, a 4-group, parallel, controlled experimental study design was initiated in vivo. SCID mice were injected with melanoma cells, and after the development of tumors the mice received daily injections of CCI-779 or solvent. On treatment days 2 and 6 cisplatin or mock solution were administered. RESULTS: In vitro a synergistic antitumor effect was observed for the treatment regimen of CCI-779 plus cisplatin. In SCID mice after 2 weeks of therapy with CCI-779 plus cisplatin 4 of 6 tumors of the 518A2 cell line were completely eradicated. In the two remaining 518A2 xenografts this treatment strategy reduced the tumor weight by 94 +/- 9% compared to solvent. CCI-779 plus cisplatin also exerted a significant antitumor effect in Mel-JUSO and 607B xenografts compared to mock-treated animals. CONCLUSION: We provide circumstantial evidence that the use of CCI-779 plus cisplatin might qualify as a promising strategy in the treatment of human melanoma.

Plasma pharmacokinetics of desmopressin following sublingual administration: an exploratory dose-escalation study in healthy male volunteers.

OBJECTIVE: Desmopressin is usually administered intranasally in the treatment of central diabetes insipidus or nocturnal enuresis. The sublingual administration of desmopressin is expected to be an alternative to the intranasal route with advantages to children and to patients with allergic rhinitis or chronic rhinosinusitis. Therefore, the present study was carried out to explore the time-versus-concentration profile of desmopressin in plasma after sublingual administration to healthy volunteers. SUBJECTS AND METHODS: A total of 16 healthy male volunteers were enrolled in this open, exploratory, 1-period, randomized, dose-escalation study. Volunteers received a single sublingual dose of either 20, 40, 80, 160, 240 or 320 microg of desmopressin acetate. Desmopressin plasma concentrations were measured over a 12-hour period using a validated radioimmunoassay method. Safety and tolerability were assessed simultaneously. RESULTS: Plasma concentrations of desmopressin were below the lower limit of quantification (LLOQ) of 5 pg/ml for doses lower than 80 microg. For the doses of 160 - 320 microg the time-versus-concentration profiles were higher than the LLOQ. The area under the curve from 0 - 12 h (AUC0-12h) was 54.66 +/- 25.92 pg x h/ml after the 160 microg dose, 104.38 +/- 79.10 pg x h/ml following the 240 microg dose and 133.18 +/- 181.84 pg x h/ml following the 320 microg dose. Given the data from previous experiments, the time-versus-concentration profile of desmopressin in plasma after a sublingual dose of 240 microg appeared to be in the range of previously published data on an intranasal dose of 20 microg. Sublingual administration of desmopressin proved to be safe and was well tolerated by all volunteers. CONCLUSION: A very high inter-individual variability in desmopressin plasma concentrations was detected after sublingual administration. A sublingual dose of 240 microg of desmopressin appeared to result in a pharmacokinetic profile comparable to 20 microg administered intranasally. These data, however, need to be verified in a separate well-designed prospective clinical study.

The ability of statins to protect low density lipoprotein from oxidation in hypercholesterolemic patients.

OBJECTIVE: It is unclear at the present time whether hydroxy-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors; statins) exert a protective effect on low-density lipoproteins (LDL) oxidation in vivo. In addition, it is speculated that pharmacological differences between statins may account for differences in their antioxidative capacities. This is of clinical relevance, because there is strong evidence that oxidized LDL initiates the atherosclerosis process. MATERIAL AND METHODS: In a controlled, randomized, double-blind study we compared the effects of three different statins (simvastatin, pravastatin and atorvastatin) on the ability to protect LDL from oxidation in 70 hypercholesterolemic but otherwise healthy subjects. Statins were administered in doses which were nearly equi-effective in lowering LDL-cholesterol. Changes in LDL oxidation were measured using diene conjugation (DIENES) and thiobarbituric acid reactive substances (TBARS) at entry and three months after beginning therapy with the statins. RESULTS: Levels of DIENES, usually generated during the early phases of lipid peroxidation, were significantly reduced by 10.2 +/- 5.5% (mean +/- SEM; p < 0.03), 6.0 +/- 2.0% (p < 0.005) versus baseline in the case of pravastatin and atorvastatin but simvastatin had no significant effect with a mean reduction of 5.5 +/- 6.4% (p > 0.23). Levels of TBARS, reflecting late phases of LDL oxidation, showed no significant changes against baseline (p > 0.34). Pooled data (n = 70) indicated that statins reduce DIENES levels by approximately 9% versus baseline (p < 0.005) but had no significant effect on TBARS levels (p > 0.29) after three months of therapy. CONCLUSION: This study showed that atorvastatin and pravastatin were capable of protecting LDL from oxidation in vivo in the early treatment phase. Pooled data levels of DIENES were significantly affected by statin therapy over a period of 3 months. No protective effect appeared to be present in the late phases of oxidation evaluated using measurement of TBARS but it should be noted that the clinical impact of such observations are currently discussed controversially in the literature.

Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis.

OBJECTIVES: Pharmacokinetic (PK)/pharmacodynamic (PD) models have become increasingly important in optimizing antimicrobial therapy. This approach is highly recommended by regulatory authorities intending to force the evaluation of antimicrobial action at the site of infection. METHODS: Clinical isolates of Pseudomonas aeruginosa and Staphylococcus aureus with MICs of 4, 8 and 16 mg/L for piperacillin were used in an in vivo PK/in vitro PD model. Bacteria were exposed in vitro to the concentration-versus-time profiles of piperacillin in plasma and subcutaneous adipose tissue measured in vivo in septic patients. Samples were withdrawn at defined intervals and the numbers of bacteria per mL were counted and plotted against time. RESULTS: Piperacillin levels determined in plasma were able to effectively inhibit bacterial growth of all bacterial strains used in the present study (MIC ranged from 4-16 mg/L). In contrast, concentration-versus-time profiles of subcutaneous adipose tissue were effective in killing isolates with MICs of 4 and 8 mg/L only, while bacterial growth of S. aureus and P. aeruginosa with MICs of 16 mg/L was not inhibited. CONCLUSIONS: Bacteria with MICs < 16 mg/L were effectively inhibited in subcutaneous adipose tissue in patients with sepsis. The prediction of microbiological outcome based on concentrations of piperacillin in plasma resulted in a marked overestimation of antimicrobial activity at the site of infection.

Effect of exercise on transdermal nicotine release in healthy habitual smokers.

OBJECTIVE: Transdermal nicotine patches have become a frequently prescribed tool in smoking cessation programs during the past years. However, there is circumstantial evidence that transdermal nicotine release substantially varies with physical activity producing toxic plasma concentrations that may account for severe adverse events. METHODS: We, therefore, compared nicotine release from two different transdermal nicotine systems (TDNS) at rest and during strenuous physical activity in a two-period crossover study in healthy smokers (n = 10). The subjects were randomly assigned to receive either 21 mg/day of formulation A or B on study Day 1 and 2. Patches were applied eight hours before starting standardized physical activity, and nicotine concentrations were measured in plasma and topically in the tissue layers underneath the application site by microdialysis. RESULTS: There was no difference between groups in the mean values for area under the time-concentration curve at rest from 0 - 8 hours AUC(0-8) (p < 0.799) and during exercise from 8 - 11 hours AUC(8-11) (p < 0.878). C(max) values between groups with C(max) values of 16.4 +/- 9.5 ng/ml and 16.0 +/- 10.7 ng/ml at rest (p < 0.919, NS) and 10.05 +/- 6.8 ng/ml and 10.2 +/- 6.9 ng/ml (p < 0.959, NS) during exercise did not differ significantly. Nicotine tissue concentrations increased two-fold during exercise versus baseline (p < 0.878). Skin blood flow increased significantly during exercise compared with baseline (p < 0.001). No adverse events were observed. CONCLUSION: The present study provides evidence that transdermal nicotine release from TDNS increases during exercise. However, this increase has no significant effect on overall plasma pharmacokinetics. Our pharmacokinetic data further indicate that the two TDNS formulations are equivalent during conditions of rest and exercise.

Pharmacokinetics of scopolamine in serum and subcutaneous adipose tissue in healthy volunteers.

OBJECTIVE: The objective was to develop a microdialysis set-up to measure the concentration-time course of scopolamine in the interstitium of subcutaneous adipose tissue. MATERIALS AND METHODS: Six healthy male volunteers were eligible for data analysis. Subjects received 0.5 mg scopolamine as a 15-minute intravenous infusion. Microdialysis samples from interstitial space fluid of subcutaneous adipose tissue and blood samples were taken at predefined intervals over a period of 360 minutes. Scopolamine concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). RESULTS: High inter-individual variability was observed in all pharmacokinetic parameters. The mean peak serum concentration (C(max)) of 6.5 +/- 3.9 ng/ml (data in mean +/- SD) was attained after 15 +/- 3 minutes (t(max)), whereas in dialysate, a mean peak concentration of 2.7 +/- 1.7 ng/ml was measured after 27 +/- 8 minutes. The ratio of the area under the concentration versus time curve from 0-360 min for interstitium (AUC(interstitium 0-360 min0) to the AUC for serum (AUC(serum 0-360 min)) was 0.96 +/- 0.7. The elimination half-life of scopolamine was 121 +/- 85 minutes in serum and 166 +/- 117 minutes in dialysate. Values for total clearance and volume of distribution in serum were 99.1 +/- 35.0 1/h and 188 +/- 76 1, respectively. CONCLUSIONS: In the present study, we were able to define a microdialysis set-up, which allows for the measurement of scopolamine concentrations in target tissues. In addition, we demonstrated that the concentrations of scopolamine in subcutaneous adipose tissue resemble closely the concentration-time course in serum of healthy volunteers.

Impact of plasma protein binding on antimicrobial activity using time-killing curves.

OBJECTIVES: Plasma protein binding (PPB) is known to impair the antimicrobial activity of beta-lactams, but its impact on the activity of other classes of antimicrobials such as fluoroquinolones is controversial. This study was undertaken to investigate the effect of PPB on bacterial killing by selected antibiotics and moxifloxacin, which served as a model compound for the class of fluoroquinolones. METHODS: Bacterial time-killing curves were employed in the absence and presence of physiological albumin concentrations (40 g/L). Moxifloxacin, ampicillin and oxacillin were investigated. Fosfomycin, a non-protein bound antibiotic was used for comparison. Simulations were carried out by employing concentrations of antibiotics of one-fourth of the minimal inhibitory concentration (MIC), equal to the MIC and four-fold the MIC of one select bacterial strain (Staphylococcus aureus ATCC 29213). To correlate bacterial killing to the extent of PPB, bacterial time-killing curves were plotted using the calculated free and the total drug concentration. RESULTS: Bacterial killing by fosfomycin was not affected by the addition of albumin. The antimicrobial activity of oxacillin and ampicillin was reduced in the presence of albumin as expected by the calculation of the free fraction of these antibiotics. Adding albumin to moxifloxacin resulted in a significant decrease in bacterial killing of more than 1 log10 cfu/mL after a period of 8 h when the moxifloxacin concentration was equal to the respective MIC. CONCLUSIONS: Our data confirm the view that albumin substantially impairs the antimicrobial activity of antibiotics including moxifloxacin, a member of the class of fluoroquinolones.

Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis.

Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC(0-8)) for muscle tissue (AUC(0-8 muscle)) to the AUC(0-8) for free drug in plasma (AUC(0-8 plasma free)) (AUC(0-8 muscle)/AUC(0-8 plasma free) ratio) of 0.85. The individual values of tissue penetration and maximum concentration (C(max)) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 microg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 microg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual C(max)/MIC and AUC(0-8 muscle)/AUC(0-8 plasma free) ratios (R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 microg/ml.

Target site bacterial killing of cefpirome and fosfomycin in critically ill patients.

We employed an in-vivo pharmacokinetic/in-vitro pharmacodynamic method to simulate bacterial killing in plasma and the interstitium of skeletal muscle tissue after intravenous administration of 2 g of cefpirome and 8 g of fosfomycin alone and in combination to patients with sepsis. Interstitial antimicrobial concentrations were determined by use of in-vivo microdialysis. CFU/ml of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (clinical isolate) decreased by approximately 2log(10) for plasma and muscle tissue 6 h after cefpirome and fosfomycin administration compared with the baseline, respectively. The simulation of plasma and tissue pharmacokinetics for the combined administration of these antibiotics resulted in complete eradication of S. aureus within 5 h after drug exposure. No bacterial re-growth occurred in any of the simulations within 6 h. The in-vitro simulation of in-vivo plasma and tissue pharmacokinetics of cefpirome and fosfomycin has shown that both antimicrobial agents kill S. aureus and P. aeruginosa strains effectively after single dose administration. This effect was most pronounced by the combined use of these antimicrobial agents. Therefore, this data corroborates antimicrobial strategies of simultaneous administration of cefpirome and fosfomycin in patients with severe soft tissue infection.

Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?

BACKGROUND: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established. OBJECTIVE: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin. DESIGN: Prospective, controlled, open-labeled study. SETTING: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital. PATIENTS: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7). CONCLUSION: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.

Transcapillary insulin transfer in human skeletal muscle.

BACKGROUND: Transcapillary insulin transfer is considered a rate-limiting step in insulin action at supraphysiological insulin concentrations. However, it remains unclear whether this concept also applies for physiological conditions. MATERIALS AND METHODS: In the present study we set out to characterize transcapillary insulin transfer by measuring insulin concentrations in plasma and interstitial space fluid of skeletal muscle during an oral glucose tolerance test and euglycaemic hyperinsulinaemic clamp conditions, respectively. For this purpose we employed in vivo microdialysis of skeletal muscle in conjunction with an ultrasensitive insulin assay in eight healthy lean male volunteers (aged 25 +/- 1 years). RESULTS: Insulin concentrations at baseline were 48 +/- 8 pmol x L(-1) in plasma and 19 +/- 4 pmol x L(-1) in the interstitium (P = 0.002). The mean interstitium to plasma ratio at baseline was 0.48 +/- 0.09 pmol x L(-1). During the oral glucose tolerance test the interstitium to plasma ratio remained unchanged (0.43 +/- 0.12, P = NS vs. baseline), but was significantly reduced during euglycaemic hyperinsulinaemic clamp conditions at steady-state hyperinsulinaemia (0.12 +/- 0.01, P = 0.01 vs. baseline). CONCLUSION: In summary there is a substantial transcapillary insulin gradient in healthy human skeletal muscle under baseline and glucose-stimulated conditions. Our findings support the hypothesis of a saturable transcapillary insulin transport representing a partly rate-limiting step for insulin action.

Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease.

OBJECTIVE: Patients with peripheral arterial occlusive disease are prone to soft tissue infections and frequently require antibiotics. To date, however, it is not known whether improvement of arterial blood flow by angioplasty of stenosis increases antibiotic concentrations in ischemic lesions. PATIENTS AND METHODS: All patients were scheduled to undergo elective percutaneous transluminal angioplasty (n = 10). Following a single, 400-mg dose of ciprofloxacin, drug concentrations in plasma, ischemic and healthy soft tissue; arterial peak systolic velocity; and ankle-brachial pressure index were assessed before and after angioplasty. Unbound ciprofloxacin concentrations were measured at the site of infection with use of in vivo microdialysis. RESULTS: Angioplasty increased peak systolic velocity and ankle-brachial pressure index compared with baseline (P <.002). Before angioplasty area under concentration-time curve (AUC(0-300)) values for ciprofloxacin were lower in ischemic tissue than in healthy tissue, with median values of 7.1 mg.h/L (range, 3.5-13.0) and 11.3 mg.h/L (range, 3.4-19.0), respectively (P =.03). After angioplasty AUC(0-300) values were identical in ischemic and healthy adipose tissue; median AUC(0-300) values were 8.0 mg.h/L (range, 4.0-20.7) and 8.5 mg.h/L (range, 4.4-22.9), respectively (P =.7). A combined in vivo pharmacokinetic/in vitro pharmacodynamic simulation based on tissue concentration data indicates that this difference in pharmacokinetics is also reflected in antimicrobial effect. CONCLUSION: Antibiotic concentrations are reduced significantly in ischemic lesions compared to those of healthy adipose tissue in patients with peripheral arterial occlusive disease. From the present data it might be speculated that improvement of arterial blood flow at the affected extremity is associated with increased cure rates of soft tissue infections in these patients.

Penetration of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide into cutaneous metastases of human malignant melanoma.

BACKGROUND: Dacarbazine has been on the market for approximately 3 decades but remains the most effective single agent available for the therapy of metastatic malignant melanoma (MMM). Most MMMs, however, respond poorly to dacarbazine therapy. Apart from tumor resistance at a molecular level, several studies support the notion that therapeutic failure in tumor therapy also might be attributed to an impaired transcapillary drug transfer. METHODS: On the basis of this hypothesis, the authors measured intratumor transcapillary transfer rates of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide (AIC) by in vivo microdialysis after intravenous administration of dacarbazine at doses of 200 mg/m(2) to 1000 mg/m(2) (n = 7) in patients suffering from MMM. RESULTS: For all doses, area under the concentration curve (AUC) values for dacarbazine and AIC were not significantly different between plasma and tumor interstitium with AUC(tumor)/AUC(plasma) ratios of 0.97 +/- 0.08 (mean +/- standard error of the mean) for dacarbazine and 0.76 +/- 0.22 for AIC. AUC(0-240) values for dacarbazine and AIC measured in plasma correlated closely with corresponding AUC(0-240)values measured in the interstitium of MMMs with values of r(s) = 0.82 (P = 0.042) and r(s) = 0.90 (P = 0.037), respectively. CONCLUSIONS: The results of this study indicate favorable tumor penetration characteristics of dacarbazine and its active metabolite AIC. The relative lack of response to antineoplastic therapy with dacarbazine, thus might be explained by resistance of melanoma cells at a molecular level rather than by an inability of dacarbazine and AIC to penetrate into the interstitium of MMM.

Microdialysis. A novel tool for clinical studies of anti-infective agents.

In vivo microdialysis (MD) is an innovative clinical technique that has been employed in preclinical research and metabolic studies in patients for more than a decade. Recently, MD has been adopted for human drug studies and has opened up the opportunity to quantify tissue drug distribution in vivo. The particular advantage of MD for the anti-infective field relates to the fact that MD allows for online measurement of the unbound, pharmacologically active drug fraction in the interstitial space fluid (ISF), the anatomically defined target site for most bacterial infections. The aim of this review is to provide an overview of the current literature about MD in anti-microbial drug studies. It will be shown that MD has become feasible in most human tissues including brain and lung. So far, several MD studies have demonstrated that anti-microbial concentrations at the effect site may be subinhibitory, although effective concentrations are attained in serum, a finding that has significant impact on clinical decision making. In addition to its property as a pharmacokinetic sampling technique, MD offers unique opportunities in pharmacokinetic-pharmacodynamic (PK-PD) research and has the potential to streamline the decision process on proper drug dosing in drug development.

Pharmacokinetics of emedastine difumarate, a new anti-histaminic agent in patients with renal impairment.

OBJECTIVE: Emedastine difumarate is a new H1 receptor antagonist with well defined pharmacokinetic and pharmacodynamic profiles in healthy volunteers. However, to date it is not known whether impaired renal function in patients with chronic renal insufficiency affects its pharmacokinetics and probably also its tolerability. Therefore, we here set out to compare the pharmacokinetics of emedastine difumarate in patients suffering from different degrees of renal failure with a control group of healthy volunteers. METHODS AND RESULTS: For this purpose we conducted an open, single-centre, comparative parallel group study in patients and healthy volunteers. Emedastine difumarate 2 mg was administered orally to the study population in single and seven repetitive doses twice daily (b.i.d.). Pharmacokinetics differed markedly between volunteers (n = 6) and patients (n = 17). The maximum serum concentration of emedastine (Cmax), area under the serum concentration-time curve, mean residence time and terminal disposition half-life were significantly higher in patients (P < 0.05), while time to reach Cmax and apparent volume of disposition were not statistically different after single and repeated (steady-state) oral administrations. Blood pressure and heart rate were also not affected by the study medication. CONCLUSION: The present study shows that impaired renal function alters the pharmacokinetics of emedastine in plasma. Thus, dose adjustment of emedastine difumarate is advisable in patients with impaired renal function.