Development of a high-performance liquid chromatography method for the determination of caspofungin with amperometric detection and its application to in vitro microdialysis experiments.

Microdialysis is an increasingly employed technique for the determination of tissue pharmacokinetics. A high-performance liquid chromatography method for the quantitative determination of caspofungin in human microdialysates with amperometric detection is described. Since microdialysis of caspofungin is performed with a 100,000 molecular mass cut-off membrane, microdialysates contain protein that was precipitated at pH 4 with acetonitrile.

A bioequivalence study of two oral desmopressin tablet formulations.

The present study was carried out to test bioequivalence between two different oral desmopressin formulations. Sixty healthy volunteers were enrolled in the study and were randomly assigned to receive the test (T) and reference (R) drug in a two-period two-sequence, crossover, analyst-blinded study design. Subjects received an oral dose of 400 mug of desmopressin acetate separated by a wash-out period of at least 7 days.

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.

Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation.

Aims: The aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability.

Methods: Two phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of (153)Sm-labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco-scintigraphy.

The effect of food on plasma and tissue concentrations of linezolid after multiple doses.

In the present pilot study we investigated the effect of food ingestion on target site pharmacokinetics of linezolid, the first clinically approved oxazolidinone. For this purpose we determined free concentrations of linezolid at steady state in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue under fasting and non-fasting conditions in healthy volunteers (n = 9) by means of in vivo microdialysis. Ingestion of food led to a marked delay in the time to reach the peak concentration (T(max)), whereas the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h)) remained unchanged.

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.

Lung microdialysis--a powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review).

In vivo measurement of concentrations of drugs and endogenous substances at the site of action has become a primary focus of research. In this context the minimal invasive microdialysis (MD) technique has been increasingly employed for the determination of pharmacokinetics in lung. Although lung MD is frequently employed to investigate various drugs and endogenous substances, the majority of lung MD studies were performed to determine the pharmacokinetic profile of antimicrobials that can be related to the importance of respiratory tract infections.

Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans.

Unlabelled: Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e.

Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles.

The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined.

Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation.

Aims: The study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN 50 mg enteric coated tablets.

Methods: Diclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14-day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days.

Safety and potential of drug interactions of caspofungin and voriconazole in multimorbid patients.

Due to their broad antimycotic spectrum and the relatively low rate of side effects, the two antifungals caspofungin and voriconazole are considered as attractive therapeutic alternatives to amphotericin B. However, treatment of severe mycotic infections in patients taking co-medication is associated with the risk of severe adverse drug interactions. The risk of such interactions is increased if voriconazole and, much less pronounced caspofungin, are co-administered with drugs which have an inducing or inhibiting effect on the CYP 450 system, primarily on the isoenzymes CYP2C19, CYP2C9 and CYP3A4.

Increase of microcirculatory blood flow enhances penetration of ciprofloxacin into soft tissue.

The present study addressed the effect of microcirculatory blood flow on the ability of ciprofloxacin to penetrate soft tissues. Twelve healthy male volunteers were enrolled in an analyst-blinded, clinical pharmacokinetic study. A single intravenous dose of 200 mg of ciprofloxacin was administered over a period of approximately 20 min.

Wine ingestion has no effect on lipid peroxidation products.

Objective: Moderate alcohol consumption has been associated with beneficial effects on coronary heart disease. This positive effect has been partly attributed to the flavonol contents which promote vasodilatory, anti-aggregatory and antioxidative effects and protect low-density lipoprotein (LDL) cholesterol from oxidation. Thus, the present study was carried out to determine the acute effects of different wines on LDL oxidization in healthy volunteers.

Colonic spread and serum pharmacokinetics of budesonide foam in patients with mildly to moderately active ulcerative colitis.

Background: Local treatment with foams in patients suffering from ulcerative proctitis or proctosigmoiditis is considered a rational treatment option.

Aims: To investigate colonic spread, safety, tolerability and acceptance of a newly developed budesonide foam formulation.

Methods: Twelve patients (four females, eight males) with acute proctosigmoiditis or left-sided ulcerative colitis were rectally administered a single dose of [99Tcm]-labelled budesonide foam (Budenofalk; Dr Falk Pharma GmbH, Freiburg, Germany) containing 2 mg budesonide in 20 mL foam after diagnostic colonoscopy.

Microdialysis: current applications in clinical pharmacokinetic studies and its potential role in the future.

Microdialysis is a probe-based sampling method, which, if linked to analytical devices, allows for the measurement of drug concentration profiles in selected tissues. During the last two decades, microdialysis has become increasingly popular for preclinical and clinical pharmacokinetic studies. The advantage of in vivo microdialysis over traditional methods relates to its ability to continuously sample the unbound drug fraction in the interstitial space fluid (ISF).

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.

Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans.

Background And Objective: Single nucleotide polymorphisms in the human multidrug-resistance gene ABCB1 have been reported to be associated with altered expression and function of P-glycoprotein, an efflux transporter, expressed at the blood-brain barrier. To test whether certain ABCB1 haplotypes contribute to interindividual differences in central nervous system drug distribution, brain distribution of a model P-glycoprotein substrate, the calcium channel inhibitor verapamil, was measured by positron emission tomography (PET) in 2 groups of healthy volunteers.

Methods: Ten homozygous carriers (cases) of the TTT haplotype (3435T, 1236T, and 2677T) and 10 controls homozygous for the wild-type CGC haplotype (3435C, 2677G, and 1236C) were administered a mean intravenous bolus of 412 +/- 114 MBq carbon 11-labeled verapamil containing less than 15 nmol of unlabeled verapamil.

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs.

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution.

Determination of telithromycin in human plasma and microdialysates by high-performance liquid chromatography.

A high-performance liquid chromatography method for the quantitative determination of telithromycin in biological fluids is described. The method is suitable for plasma and microdialysates from the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue. Plasma samples were deproteinised with trichloroacetic acid and neutralised with sodium hydroxide.

Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses.

The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously.

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).

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.

In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET.

Purpose: The suitability of the 18F-labelled fluoroquinolone antibiotic ciprofloxacin ([18F]ciprofloxacin) for imaging of bacterial infections with positron emission tomography (PET) was assessed in vitro and in vivo.

Methods: For the in vitro experiments, suspensions of various E. coli strains were incubated with different concentrations of [18F]ciprofloxacin (0.

Pharmacokinetics and pharmacodynamics of cefpirome in subcutaneous adipose tissue of septic patients.

The objective of the present study was to evaluate whether cefpirome, a member of the latest class of broad-spectrum cephalosporins, sufficiently penetrates subcutaneous adipose tissue in septic patients. After the administration of the drug at 2 g, tissue cefpirome concentrations in septic patients (n = 11) and healthy controls (n = 7) were determined over a period of 4 h by means of microdialysis. To assess the antibacterial effect of cefpirome at the target site, the measured pharmacokinetic profiles were simulated in vitro with select strains of Staphylococcus aureus and Pseudomonas aeruginosa.

Interstitial glucose in skeletal muscle of diabetic patients during an oral glucose tolerance test.

Aim: The presence of a transcapillary arterial-interstitial gradient for glucose (AIG(glu)) in skeletal muscle may be interpreted as a consequence of intact cellular glucose uptake. We hypothesized that the AIG(glu) decreases in Type 2 diabetes mellitus as a consequence of insulin resistance, whereas it remains intact in Type 1 diabetes.

Methods: Glucose concentrations were measured in serum and interstitial space fluid of skeletal muscle during an oral glucose tolerance test (OGTT) in patients with Type 1 and Type 2 diabetes and in young and middle-aged healthy volunteers, using microdialysis.