Rainer Preiss

Serum interleukin-6 levels in colorectal cancer patients--a summary of published results.

IntroductionIt is now clear that inflammation and cancer initiation and progression are linked. Interleukin-6 (IL-6) is a pleiotropic inflammatory cytokine with described cancer stimulatory and also cancer inhibitory properties. The study’s aim was to assess the potential of circulating IL-6 as a prognostic indicator in colorectal cancer.Materials and methodsA literature search was conducted using PubMed, restricted to articles published in English language. We compared published results in regard to differences in IL-6 levels between healthy controls and colon cancer patients (seven published results), between patients with increasing tumor stages (eight published results), between patients with differences in tumor size (four published results), and between patients with and without liver (three published results) or lung metastasis (one published result). Furthermore, we reviewed the literature in regard to the possible correlation of IL-6 levels with survival time (five published results) and correlation of IL-6 levels and lymph node involvement (three published results).ResultsConcerning colon tumors, results are consistent. Colon cancer patients reveal higher serum IL-6 levels than healthy controls. Furthermore, higher IL-6 levels are associated with increasing tumor stages and tumor size, with metastasis and decreased survival.ConclusionTherefore, circulating IL-6 might be prognostic indicator in colorectal cancer.

Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers.

R(+)‐alpha‐lipoic acid is a natural occurring compound that acts as an essential cofactor for certain dehydrogenase complexes. The redox couple alpha‐lipoic acid/dihydrolipoic acid possesses potent antioxidant activity. Exogenous racemic alpha‐lipoic acid orally administered for the symptomatic treatment of diabetic polyneuropathy is readily and nearly completely absorbed, with a limited absolute bioavailability of about 30% caused by high hepatic extraction. Although the pharmacokinetics of the parent drug have been well characterized in humans, relatively little is known regarding the excretion of alpha‐lipoic acid and the pharmacokinetics of any metabolites in humans. In the present study, plasma concentration‐time courses, urinary excreted amounts, and pharmacokinetic parameters of alpha‐lipoic acid metabolites were evaluated in 9 healthy volunteers after multiple once‐daily oral administration of 600 mg racemic alpha‐lipoic acid. The primary metabolic pathways of alpha‐lipoic acid in man, S‐methylation and β‐oxidation, were quantitatively confirmed by an HPLC‐electrochemical assay newly established prior to the beginning of this study. Major circulating metabolites were the S‐methylated β‐oxidation products 4,6‐bismethylthio‐hexanoic acid and 2,4‐bismethylthio‐butanoic acid, whereas its conjugated forms accounted for the major portion excreted in urine. There was no statistically significant difference in the pharmacokinetic parameters Cmax, AUC, and tmax between day 1 and day 4. Despite the prolonged half‐lives of the major metabolites compared to the parent drug, no evidence of accumulation was found. Mean values of 12.4% of the administered dose were recovered in the urine after 24 hours as the sum of alpha‐lipoic acid and its metabolites. The results of the present study revealed that urinary excretion of alpha‐lipoic acid and five of its main metabolites does not play a significant role in the elimination of alpha‐lipoic acid. Therefore, biliary excretion, further electrochemically inactive degradation products, and complete utilization of alpha‐lipoic acid as a primary substrate in the endogenous metabolism should be considered.

Cyclophosphamide and related anticancer drugs

This article presents an overview of the methods of bioanalysis of oxazaphosphorines, in particular, cyclophosphamide, ifosfamide, and trofosfamide as well as their metabolites. The metabolism of oxazaphosphorines is complex and leads to a large variety of metabolites and therefore the spectrum of methods used is relatively broad. The various methods used are shown in a table and the particularly important assays are described.

Gender difference in ifosfamide metabolism by human liver microsomes

SummaryPharmacokinetic gender-dependent differences in cytochrome P450-mediated drug metabolism, especially CYP3A4, and their clinical implications are increasingly apparent. CYP3A4 seems to be the most important CYP isoform in both bioactivation and N-dechloroethylation of the alkylating prodrug ifosfamide, but informations about possible gender-related differences are lacking. Therefore we compared in 10 male and 10 female liver microsomal preparations the contents and activities of specific isoenzymes, involved in both metabolic pathways, especially CYP3A4, further CYP2A6, CYP2C9 and CYP2B6 and measured the in vitro activities of these microsomes in the ifosfamide 4-hydroxylation and N-dechloroethylation using high-sensitive HPLC/MS and--UV detection methods.Statistically significant differences between male and female livers were found in the mean CYP3A4 contents and activities. These differences had no consequences on the ifosfamide 4-hydroxylation activities of liver microsomes in vitro. In contrast, in the ifosfamide N-dechloroethylation reaction we found a statistically significant difference between the liver microsomes of male and female patients (0.13 ± 0.05 nmol/min · nmolP450 vs. 0.28 ± 0.13 nmol/min · nmolP450, respectively).In conclusion, we firstly demonstrated such gender-related difference in the ifosfamide N-dechloroethylation, which could result in a higher risk of partly severe neurotoxic side effects in female patients.

sIL-6R: more than an agonist?

On target cells, interleukin‐6 (IL‐6) interacts with its receptor complex consisting of the membrane‐bound IL‐6 receptor (IL‐6R) and the signal transducing protein gp130. IL‐6R can exist as a soluble protein (sIL‐6R), which binds the ligand IL‐6. This soluble complex can bind to gp130 on cells that lack the membrane‐bound IL‐6R and initiate signaling. This process is named transsignaling. The significance of transsignaling via sIL‐6R is underlined by different publications and exceeds very probably the significance of the membrane‐bound IL‐6R. It is the general assumption that sIL‐6R acts as an agonist in combination with IL‐6 resulting in an enhancement of the IL‐6 effects. In this article, we suppose ‘non‐agonistic’ properties. There are several publications that give reasons to speculate that sIL‐6R (a) has IL‐6‐antagonistic effects, (b) has orphan properties and (c) interacts with yet unknown binding partners different from IL‐6. Knowledge about additional properties of sIL‐6R will enlarge the biologic understanding of this molecule and might give an explanation for the sometimes contrasting effects of the cytokine IL‐6.

Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients

ABSTRACT The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher Cmax values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

Pharmacokinetics of Alpha-Lipoic Acid in Subjects With Severe Kidney Damage and End-Stage Renal Disease

In an open‐label, parallel‐group study involving 16 patients (8 with severely reduced renal function, 8 with end‐stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha‐lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha‐lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.2 and 0.05 in healthy subjects and subjects with severely reduced renal function, respectively. Assuming a bioavailability of 30%, this represents 0.67% and 0.17% of the bioavailable amount of alpha‐lipoic acid, respectively. The percentage of total urinary recovered amounts of alpha‐lipoic acid and 5 of its metabolites was 12.0 on both days. The respective values for patients with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total percentage of the administered dose removed by hemodialysis was 4.0 in patients with end‐stage renal disease. Renal clearance of alpha‐lipoic acid and its major metabolites, 6,8‐bismethylthio‐octanoic acid, 4,6‐bismethylthio‐hexanoic acid and 2,4‐bismethylthio‐butanoic acid, were significantly decreased in subjects with kidney damage compared to the reference group. Apparent total clearance of alpha‐lipoic acid was poorly correlated with creatinine clearance. There is strong evidence that alpha‐lipoic acid is mainly excreted by nonrenal mechanism or further degraded to smaller units in the catabolic process. The significantly increased area under the curve values of 4,6‐bismethylthio‐hexanoic acid and half‐lives of 2,4‐bismethylthio‐butanoic acid on both days in patients with severely reduced function and end‐stage renal disease were not considered to be clinically relevant. Although trough levels of both metabolites tend to increase slightly in these subjects, no accumulation effects were detected. We conclude that the pharmacokinetics of alphalipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end‐stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha‐lipoic acid. Hence, dose adjustment of alpha‐lipoic acid is not necessary in patients with renal dysfunction.

Determination of cyclophosphamide and its metabolites in human plasma by high-performance liquid chromatography: mass spectrometry

A sensitive HPLC-MS method was developed for the simultaneous determination of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide (aldocyclophosphamide), 4-ketocyclophosphamide, caboxyphosphamide and 3-dechloroethylifosfamide in human plasma. 4-Hydroxycyclophosphamide was converted with methylhydroxylamine to the stable methyloxime form. We used a solid-phase extraction with C18 cartridges followed by HPLC-MS with the single mass spectrometer SSQ 7000 of Finnigan. The limits of detection were 15 ng/ml for cyclophosphamide, 3-dechloroethylifosfamide and ketocyclophosphamide in each case and 30 ng/ml for carboxyphosphamide and 4-hydroxycyclophosphamide, respectively. First results of pharmacokinetics are shown.

Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

OBJECTIVE Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration. DESIGN Open-label crossover study with single boluses of rhGH. METHODS Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection. RESULTS Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 microg/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P < 0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14-18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study. CONCLUSIONS After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

Determination of voriconazole in human plasma and saliva using high-performance liquid chromatography with fluorescence detection.

Voriconazole is a widely used triazole antifungal agent with a broad spectrum including Aspergillus species. A simple, sensitive and selective high-performance liquid chromatography method for the determination of voriconazole in human plasma and saliva was developed. Drug and internal standard (UK-115 794) were extracted from alkaline plasma and saliva with n-hexane-ethyl acetate (3:1, v/v) and analyzed on a Luna C 18 column with fluorimetric detection set at excitation and emission wavelengths of 254 and 372 nm, respectively. The calibration curve was linear through the range of 0.1-10 microg/ml using a 0.3 ml sample volume. The intra- and inter-day precisions were all below 6.1% for plasma and below 9.1% for saliva. Accuracies ranged from 94 to 109% for both matrices. Mean recovery was 86+/-4% for voriconazole. The method showed acceptable values for precision, recovery and sensitivity and is well suited for routine analysis work and for pharmacokinetic studies.