PubMed Health⌕ Search

Biomedical subjects

M Radtke

Publications and source records attributed to M Radtke.

14 recordsLinked to original sources
PubMed2006

Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib.

PURPOSE: This single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafenib, a multi-kinase inhibitor, combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. PATIENTS AND METHODS: In an initial dose-escalation phase, patients received irinotecan 125 mg/m(2) and sorafenib 100, 200 and 400 mg twice daily (bid) (cohorts 1-3). In an extended phase, colorectal cancer (CRC) patients received fixed-dose irinotecan 140 mg and sorafenib 400 mg bid (cohort 4). RESULTS: Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Frequent drug-related adverse events were gastrointestinal symptoms, dermatological reactions and constitutional symptoms. The maximum tolerated dose was not reached. Generally, concomitant administration of irinotecan had no impact on the PK of sorafenib. Sorafenib 100 or 200 mg bid had no impact on the PK of irinotecan or its metabolite SN38. In contrast, sorafenib 400 mg bid significantly increased irinotecan and SN38 exposures; however, this was not associated with increased toxicities. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1-3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a K(i) value of 2.7 micromol/l. CONCLUSION: Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m(2) or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.

Adult↗
PubMed2002

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations.

Solid lipid nanoparticles (SLN) were developed at the beginning of the 1990 s as an alternative carrier system to emulsions, liposomes and polymeric nanoparticles. The paper reviews advantages-also potential limitations-of SLN for the use in topical cosmetic and pharmaceutical formulations. Features discussed include stabilisation of incorporated compounds, controlled release, occlusivity, film formation on skin including in vivo effects on the skin. As a novel type of lipid nanoparticles with solid matrix, the nanostructured lipid carriers (NLC) are presented, the structural specialties described and improvements discussed, for example, increase in loading capacity, physical and chemical long-term stability, triggered release and potentially supersaturated topical formulations. For both SLN and NLC, the technologies to produce the final topical formulation are described, especially the production of highly concentrated lipid nanoparticle dispersions >30-80% lipid content. Production issues also include clinical batch production, large scale production and regulatory aspects (e. g. status of excipients or proof of physical stability).

Administration, Topical↗
PubMed2002

Electron probe microanalysis (EPMA) measurement of thin-film thickness in the nanometre range.

The thickness of thin films of platinum and nickel on fused silica and silicon substrates has been determined by EPMA using the commercial software STRATAGEM for calculation of film thickness. Film thickness ranged in the order 10 nm. An attempt was made to estimate the confidence range of the method by comparison with results from other methods of analysis. The data show that in addition to the uncertainty of the spectral intensity measurement and the complicated fitting routine, systematic deviation caused by the underlying model should be added. The scattering in the results from other methods does not enable specification of a range of uncertainty, but deviations from the real thickness are estimated to be less than 20%.

Journal Article↗
PubMed2002

Nanostructured lipid matrices for improved microencapsulation of drugs.

At the beginning of the nineties solid lipid nanoparticles (SLN) have been introduced as a novel nanoparticulate delivery system produced from solid lipids. Potential problems associated with SLN such as limited drug loading capacity, adjustment of drug release profile and potential drug expulsion during storage are avoided or minimised by the new generation, the nanostructured lipid carriers (NLC). NLC are produced by mixing solid lipids with spatially incompatible lipids leading to special structures of the lipid matrix, i.e. three types of NLC: (I) the imperfect structured type, (II) the structureless type and (III) the multiple type. A special preparation process-applicable to NLC but also SLN-allows the production of highly concentrated particle dispersions (>30-95%). Potential applications as drug delivery system are described.

Crystallization↗
PubMed1998

Biotransformation of cerivastatin in mice, rats, and dogs in vivo.

Biotransformation of cerivastatin was investigated in mice, rats, and dogs in vivo using the 14C-labeled drug. Marked species differences exist, both in pathways and extent of cerivastatin metabolism. Unchanged drug, together with its lactone, predominates in dog plasma and represents 40% of the dose in the excreta, whereas in rat bile they account for approximately 10% of the dose. In mice, the drug is metabolized rapidly and almost completely. Biotransformation of cerivastatin occurs by three distinct phase I routes and by phase II conjugation with sugar-type moieties and taurine. Phase I routes are demethylation of the pyridinyl methyl ether, beta-oxidation of the 3,5-dihydroxy acid side chain, and reductive removal of the side chain 3-hydroxy group. In dogs, demethylation is the dominating phase I biotransformation. Phase II conjugation is equally important. In dog bile, different regioisomeric drug glucuronides and the benzylic glucuronide and glucoside conjugate of the demethylated drug were found. In rats, besides demethylation, beta-oxidation of the dihydroxy acid side chain-followed by reductive removal of the 5-hydroxy group-is the major reaction. The resulting pentenoic acid derivatives are observed in plasma and liver homogenate. These metabolites are subsequently conjugated with taurine and excreted in the bile. This metabolic sequence is also important in mice. Furthermore, only in mice, cerivastatin is subject to reductive removal of the 3-hydroxy group, together with demethylation. The 5-hydroxyheptenoic acids formed predominate in plasma and liver homogenate, whereas the corresponding taurine conjugates are excreted in the bile.

Animals↗
PubMed1997

Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved.

Biotransformation of cerivastatin, a new cholesterol-lowering drug, by human liver microsomes was investigated using the 14C-labeled drug. Metabolite profiles were established by HPLC and structures of metabolites were elucidated. Two metabolic pathways were equally important, demethylation of the benzylic methyl other and hydroxylation at one methyl group of the 6-isopropyl substituent. The product of combined hydroxylation and demethylation was observed as a minor metabolite. During sample preparation the lactone forms of both primary metabolites were isolated in small amounts. Detailed structural analysis by NMR and LC-ESI-MS showed that hydroxylation occurred with high regio- and stereoselectivity. The proposed structures were confirmed by chemical synthesis of enantiomerically pure reference compounds. Microsomes from a human lymphoblastoid AHH-1 cell line, stably expressing CYP 3A4, catalyzed the demethylation reaction. Upon incubation of cerivastatin with human liver microsomes in the presence of the specific CYP 3A inhibitor TAO, both hydroxylation and demethylation were considerably reduced. This indicates that CYP 3A enzymes play a major role in cerivastatin metabolism.

Anticholesteremic Agents↗
PubMed1996

Pharmacokinetics of atropine in dogs after i.m. injection with newly developed dry/wet combination autoinjectors containing HI 6 or HLö 7.

To cope with the rapid onset of the life-threatening cholinergic crisis after poisoning with organophosphorus compounds, atropine-oxime preparations should be available in autoinjectors allowing i.m. administration also in the absence of a physician. Such a scenario is conceivable in the battlefield, when nerve agents are disseminated, and can no longer be excluded in civilian areas, as demonstrated most recently in Tokyo. In addition, autoinjectors may be of value in agriculture when medical care is remote. The use of second generation oximes with broad antidotal spectrum, e.g., HI 6 (1-(((4-(aminocarbonyl)pyridinio)methoxy)methyl)-2-((hydr oxyimino)methyl) pyridinium dichloride monohydrate; CAS 34433-31-3) and HLö 7 (1-(((4-(aminocarbonyl)pyridinio)methoxy)methyl) 2,4-bis((hydroxyimino)methyl) pyridinium dimethanesulfonate; CAS 145613-73-6) is only possible in dry/wet autoinjectors because their stability is limited in concentrated solution. To detect a possible delay in atropine absorption by the two oximes, the pharmacokinetics of atropine after "autoinjection" in beagle dogs were determined. Commercially available autoinjectors from two manufacturers [STI International Ltd (BJ) and Astra Tech (AT)] were filled with atropine sulfate, either alone (2 mg) or in combination with HI 6 (500 mg) and HLö 7 (200 mg), respectively, and injected according to a complete cross-over design. Atropine concentration was determined as l-hyoscyamine equivalents in a radioreceptor assay (RRA). In the range of 0.1-6.9 ng/ml, atropine sulfate displaced [N-methyl-3H]-scopolamine methyl chloride ([3H]NMS) competitively from rat cerebral cortex membranes. At 200 pmol/l [3H]NMS, IC50 was 1.4 +/- 0.1 x 10(-9) M atropine (CV = 8.1%). The intra-assay deviation was about 6%; day-to-day deviation in determination of 1 nM (0.695 ng/ml) atropine was 2.6% (CV = 5.2%). AT autoinjectors containing HI 6 delivered only 1.81 mg atropine sulfate while 2.14 mg was released by the other injectors. According to the manufacturer, the reduced delivery was caused by a defective Teflon-coated O-ring as detected later on in the batch used. To allow comparison of the bioavailability of atropine from various autoinjectors, the AUCs were normalized to a constant dose. The atropine absorption half-time (7 min) was not affected either by the autoinjector type or by the combination with oximes. The other pharmacokinetic data likewise did not reveal any differences between the groups. Maximal plasma concentration was 33 ng ml-1, elimination half-life 52 min, Vapp 3.2 l kg-1 and Clpl 44 ml min-1 kg-1. The relatively high clearance of l-hyoscyamine is discussed.

Animals↗
PubMed1992

Biotransformation of nifedipine in rat and dog.

Following oral and/or intraduodenal administration, the biotransformation of 14C-labelled nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3, 5-dicarboxylate, Bay a 1040, Adalat, CAS 21829-25-4) has been reinvestigated in rats and dogs (dose: 5 mg/kg body weight in both species) to complete the metabolic data. Thirteen metabolites were isolated from the perfusate and bile of the isolated perfused rat liver model. Their structures were elucidated by spectroscopic methods (FAB-MS, combined GC/MS, NMR). The analyzed samples were used for the chromatographic (HPLC) comparison with urine and bile from the in vivo studies. The metabolites identified in rat urine (oral dose) account for 47.4% of the dose administered. 82.8% (rat) and 62.8% (dog) of the dose, resp., could be attributed to known structures in urine and bile following intraduodenal administration. Based on the structures identified the following biotransformation steps occurred: dehydrogenation of the 1,4-dihydropyridine system, hydroxylation of the methyl groups at 2- or 6-position followed by glucuronidation or by subsequent oxidation to the carboxylic acid, and oxidative ester cleavage.

Administration, Oral↗
PubMed1989

[Differentiation of the dormouse Eliomys quercinus (Linnaeus 1766) fro the murid Mus caroli (Bonhote 1902) based on the masticatory muscles].

Investigated were the masticatory musculature of the murid, Mus caroli, and the glirid, Eliomys quercinus. Differences between both species could be found, which includes different mastication. Mus caroli eats mixed food. The masticatory musculature admits mainly antero-posterior mandibular movements with a minimal transverse component. The food of Eliomys quercinus exists of mainly insects. The masticatory muscles, in particular the M. pterygoideus internus and the well developed M. zygomaticomandibularis, pars posterior, include high frequency of lateral movements between mastication.

Animals↗
PubMed1988

Assessment of the efficacy of medical countermeasures in space flight.

Changes in body fluids, electrolytes, and muscle mass are manifestations of adaptation to space flight and readaptation to the 1-g environment. The purposes of this paper are to review the current knowledge of biomedical responses to short- and long-duration space missions and to assess the efficacy of countermeasures to 1-g conditioning. Exercise protocols, fluid hydration, dietary and potential pharmacologic measures are evaluated, and directions for future research activities are recommended.

Adaptation, Physiological↗
PubMed1977

[Interpretation and misinterpretation of sperm findings as fertility criterion].

In any case of sterility the andrological examination is absolutely necessary; firstly because 50 per cent of the examined men don't show normospermic ejaculate and secondly because nearly 14 per cent of the examined men are infertil. Fertility of man is normal in hypospermia (20 to 40 mill. spermatozoa per ml); it is decreased in oligospermia (less than 20 mill per ml), but real possible. Even kryptospermia (less than one million spermatozoa per ml) can not be identified absolutely with infertility. Hypokinesis and increase of pathomorphic spermatozoa apparently prevent the opportunity of conceptions. It is doubtful that fructose of spermaplasma is a certain criterion of fertility. Extra-matrimonial conceptions probably often occur, for that reason any statement about fertility of man is inaccurately.

Adult↗