Topical use of amitriptyline and linoleic acid to restore ceramide rheostat in atopic dermatitis lesions - a case report.

Rebuilding, stabilizing and maintaining the dermal lipid barrier is an encouraging disease management concept (relief and care) in the treatment and prevention of atopic dermatitis. Prevention and topical treatment, however, lack a simple, safe, effective and modular approach. For decades, the mainstay of topical therapy of atopic dermatitis has been corticosteroids, with innovations being rare. Our case report demonstrates the struggle of a patient with little relief of itchy dermal lesions and the recurrence of skin lesions following current therapeutic guidelines which proved to be ineffective. Therefore we decided to try an advanced C16-ceramide pathomechanism derived topical therapeutic measure since it offers hope of re-establishing skin and alleviating suffering. Amitriptyline in combination with linoleic acid offers a chance to release from dry and itchy skin, mild to moderate atopic dermatitis lesions without known serious adverse effects of topical corticosteroids, while preventing recurrence.

Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) provides controlled operative conditions but induces a whole-body inflammatory response capable of initiating devastating morbidity and mortality. Although technically more demanding, deliberate avoidance of CPB in off-pump surgery attenuates the physiological insult associated with CABG. METHODS AND RESULTS: To systematically assess the molecular mechanisms underlying the better-preserved remote organ function, we studied gene expression patterns in leukocytes and plasma proteomic response to on-pump and off-pump CABG. Proteomic analysis confirmed (tumor necrosis factor-alpha, interleukin [IL]-6, IL-10) and expanded (eg, interferon [IFN]-gamma, granulocyte colony-stimulating factor [G-CSF], monocyte chemotactic protein-1, macrophage inflammatory protein-1beta) the mediators released on CPB, whereas blood leukocyte transcriptomics suggested that circulating leukocytes are not primarily responsible for this response. Interestingly, release of some cytokines (eg, IL-6, IFN-gamma, G-CSF) was observed on off-pump surgery to a similar extent but with delayed kinetics. A total of 45 of 4868 transcripts were identified to be significantly altered as a result of initiation of CPB. Systematic analysis of transcriptional activation by CPB revealed primarily genes involved in inflammation-related cell-cell communication (such as L-selectin or intercellular adhesion molecule-2) and signaling (such as IL-1, IL-8, or IL-18 receptors and toll-like receptors 4, 5, and 6), thus confirming a "primed" phenotype of circulating peripheral blood mononuclear cells. CONCLUSIONS: Gene array and multiplex protein analysis, only in concert, can illuminate the molecular mechanisms responsible for systemic sequelae of CPB and indicate that circulating leukocytes overexpress adhesion and signaling factors after contact with CPB, which potentially facilitates their trapping, eg, in the lungs and may promote a subsequent tissue-associated inflammatory response.

Effect of alterations of blood cholesterol levels on macrophages in the myocardium of New Zealand White rabbits.

We investigated the effect of alterations of blood cholesterol levels on macrophages (mphi) in the myocardium of New Zealand White (NZW) rabbits. Three groups of NZW rabbits were used: controls, rabbits fed a 0.5% cholesterol-enriched diet (CH-D) for 96 days, and rabbits fed a 0.5% CH-D for 96 days followed by normal chow for 4 months. Immunohistochemical analysis by mAbs directed against mphi (RAM-11) and Mn superoxide dismutase (MnSOD) were quantified by computer-assisted morphometry. Using cultured human and rabbit mphi, a cross-reaction of the human MnSOD mAbs was found as well as the predominant localization of MnSOD-immunoreactivity (IR) in mitochondria. In group 1, only a very few RAM-11-immunoreactive (ir) mphi occurred in the interstitial space of the myocardium. In group II blood cholesterol levels significantly increased in parallel with the numbers of mphi, which often contained lipid droplets (foam cells). Although blood cholesterol concentrations regressed about 10-fold in group III, mphi in the myocardium were found to be reduced only about 20%. Most mphi were also MnSOD-ir. In atherosclerotic coronary arteries RAM-11-IR was located in mphi and also extracellularly, whereas MnSOD-IR was found only in mphi. Drastically induced MnSOD in the mitochondria of mphi is suggested as an indicator of increased oxidative stress caused by in vitro conditions or by phagocytosis of low-density lipoprotein in vivo. Elevation of the cholesterol level leads to a long-term increase and its regression results in a delayed reduction of such mphi, which seem to play a key role in the atherogenesis of the coronary arteries as well.

Stereospecific induction of apoptosis in tumor cells via endogenous C16-ceramide and distinct transcripts.

Concentration and distribution of individual endogenous ceramide species is crucial for apoptosis induction in response to various stimuli. Exogenous ceramide analogs induce apoptosis and can in turn modify the composition/concentrations of endogenous ceramide species and associated signaling. In this study, we show here that the elevation of endogenous C16-ceramide levels is a common feature of several known apoptosis-inducing triggers like mmLDL, TNF-alpha, H2O2 and exogenous C6-ceramide. Vice versa apoptosis requires elevation of endogenous C16-ceramide levels in cells. Enantiomers of a synthetic ceramide analog HPL-1RS36N have been developed as probes and vary in their capacity to inducing apoptosis in macrophages and HT-29 cells. Apoptosis induction by the two synthetic ceramide analogs HPL-39N and HPL-1R36N correlates with generation of cellular C16-ceramide concentration. In contrast to the S-enantiomer HPL-1S36N, the R-enantiomer HPL-1R36N shows significant effects on the expression of distinct genes known to be involved in cell cycle, cell growth and cell death (CXCL10, CCL5 and TNF-alpha), similarly on apoptosis induction. Enantioselective effects on transcription induced by metabolically stable synthetic probes provide clues on molecular mechanisms of ceramide-induced signaling, as well as leads for future anti-cancer agents.

Effect of platelet activating factor on the kinetics of LDL oxidation in vitro.

Oxidatively modified low-density-lipoprotein (LDL) might contribute to the atherosclerotic process. This study was performed to examine an effect of platelet-activating factor (PAF) and of synthetic PAF analogs on Cu(II) induced oxidation of LDL in vitro: The D- and L-isomers of PAF and analogs with short-chain sn-2-substituents, 1-O-alkyl-2-butyryl-sn-glycero-3-phosphocholine and 1-O-alkyl-2-heptanoyl-sn-glycero-3-phosphocholine, were found to be the most effective inhibitors of LDL oxidation. Oxidation was inhibited completely at PAF concentrations above 100 microM. Lyso-PAF and analogs carrying longer chains at the sn-2 position were less effective. These results thus provide evidence for the involvement of other parameters in LDL oxidation beyond the content of natural antioxidants like vitamin E and beta-carotene.

Stimulation of mitogen activated protein kinase by LDL and oxLDL in human U-937 macrophage-like cells.

Mitogen activated protein kinase in extracts of U-937 macrophage-like cells was stimulated by LDL and oxLDL. A maximum value (161% of the basal phosphotransferase activity) was obtained after 6 min exposure to oxidized LDL (27 microgram/ml) using APRTPGGRR peptide substrate. The activatory effect was more pronounced (LDL 181%, oxLDL 201%) when MAPK of stimulated cells was immunoprecipitated with anti-p42MAPK antibodies and phosphotransferase activity was assayed in immune complexes. Stimulation produced by oxLDL was inhibited by poly I, fucoidan, dextran sulfate and by the MAPKK inhibitor PD 098059 but not by PMA-mediated depletion of PKC or by pre-treatment with chloroquine or with pertussis toxin. These results suggest a direct mitogenic effect of LDL which, in the case of oxLDL, is dependent on scavenger receptor ligation but not on G-protein mediated or PKC-dependent signal transduction.

Susceptibility of phospholipids of oxidizing LDL to enzymatic hydrolysis modulates uptake by P388D1 macrophage-like cells.

Addition of the phospholipids 1-O-hexadecyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PLE) and 1-O-hexa-decyl-2-desoxy-2-amino-arachidonyl-sn-glycero-3- phosphocholine (PLA) to [125I]LDL and subsequent Cu(2+)-induced oxidation result in significant differences in protein modification and uptake by P388D1 macrophage-like cells. PLE-treated LDL is ingested at a 1.27-fold rate compared to PLE-treated LDL and displays enhanced electrophilic mobility. Similar results (1.43-fold enhanced uptake of LDL preloaded with PLE) are obtained when the uptake of phospholipid-enriched oxLDL particles are examined. The preference for ingestion as well as protein modification of both preparations is, however, reversed under experimental conditions allowing diffusion and inactivation of a fraction of the peroxidation products. These findings suggest that LDL-associated PAF-acetylhydrolase can exert a dual role and, to be protective to LDL, require an appropriate microenvironment, capable of binding certain species of oxidatively fragmented lipids.

Modified low density lipoprotein delivers substrate for ceramide formation and stimulates the sphingomyelin-ceramide pathway in human macrophages.

Exposure of human blood monocytes derived macrophages to modified (oxidized or acetylated) LDL induced a approximately 40% elevation (60 pmol/10(6) cells) of the endogenous level of the sphingolipid ceramide. A rise of both neutral and acidic SMase activity was found after treatment with oxidized LDL (250 and 80%), while addition of acLDL stimulated only the neutral enzyme (280%). Sphingo(phospho)lipids from LDL were transferred to the cell membrane and distributed into intracellular compartments as observed with acLDL containing BODIPY-FL-C5-SM. Quantitation of ceramide after the addition of [3H-N-acetyl]- or BODIPY-FL-C5-SM-labeled modified LDL (27 microg/ml) to the cell culture medium indicated that approximately 210 pmol CA/10(6) cells was generated from exogenous (ox/acLDL) SM. These results demonstrate a stimulation of the sphingomyelin-ceramide pathway by modified LDL utilizing primarily exogenous (LDL-derived) substrate and suggest that the effects of modified LDL are at least partially due to an increased level of the messenger ceramide.

Modulating apoptosis: current applications and prospects for future drug development.

Agents modulating apoptosis are of extraordinary promise for the treatment of several states of disease including cancer, AIDS, neurodegenerative and ischemic diseases. In this review a brief summary of cellular pathways relevant to programmed cell death first is given and potential therapeutic targets therein are emphasized. Current efforts in drug development are discussed from a mechanistic, biochemical point of view and pro- and anti-apoptotic strategies are related to the respective diseases. Therapeutic approaches addressed in this paper include the design and activity of novel low molecular weight agents (e.g. caspase inhibitors) as well as gene therapy (e.g. p53, adenovirus as vector in cancer treatment). In final sections, the latest findings in the field of apoptosis are highlighted and future applications are outlined.

Novel reversible, irreversible and fluorescent inhibitors of platelet-activating factor acetylhydrolase as mechanistic probes.

Phosphatidylcholines (1-O-alcoxy-2-amino-2-desoxy-phosphocholines and 1-pyrene-labeled analogs) were synthesized and used to examine interactions with recombinant human PAF-acetylhydrolase (PAF-AH), an enzyme purified from plasma, and with macrophage-like U937 cells. Novel phosphatidylcholines containing a sn-2-carbamoylester group such as 1-O-hexadecyl-2-desoxy-2-amino-methylcarbamoyl-2-methyl-rac-glycer o-3-phosphocholine 11 were found to act as site-specific irreversible enzyme inhibitors with Ki-values up to 83 (K(irev)) and 177 (Ki(inact)) microm. The compounds exhibit only marginal inhibition of Ca2+-dependent phospholipases. Kinetic data show that phosphocholines carrying a terminal sn-1-pyrene moiety inhibit PAF-AH activity with an effectivity similar to analogs with an aliphatic chain. 1-O-Decyloxy-[10-(4-pyrenyl)-butoxy]-2-desoxy-2-amino-carbamoyl-me thyl-rac(-glycero-3-phosphocholine 13 could be used for enzyme labeling and to demonstrate an inhibitor-enzyme stoichiometry of 0.7:1. At 8 degrees C, the compound accumulated in the membranes of U937 cells, at 37 degrees C it was internalized into intracellular compartments. Structure activity studies in a mixed micelle assay indicated that the inhibition power of reversible and irreversible inhibitors increases along with the (sn)-1-chain length similar to the structure-dependent binding of ether phospholipids to the PAF-receptor. Unlike the situation at the (sn)-1-position, increasing chain length at the sn-2-position, or an alkyl branching of the glycerol backbone significantly reduced the inhibitory potency.

Characterization of apoptotic macrophages in atheromatous tissue of humans and heritable hyperlipidemic rabbits.

Apoptotic macrophages are regularly found in atherosclerotic plaques indicating programmed cell death as one of their regulatory controls. The objective of this study was to characterize in more detail apoptotic macrophages in atherosclerotic lesions of humans and heritable hyperlipidemic (HHL) rabbits. Macrophages were immunohistochemically analyzed using antibodies directed against alphaMbeta2-integrins (CD11b/CD18), CD44, major histocompatibility complex (MHC) class I and II, inducible nitric oxide synthase (iNOS), manganese superoxide dismutase (MnSOD), tumor necrosis factor alpha (TNFalpha), p53, c-jun/AP-1 and rabbit macrophages (RAM-11) and the TUNEL (TdT-mediated dUTP nick end labeling) technique. Colocalization studies of human atherosclerotic carotid and aortic tissue showed apoptotic plaque macrophages also being MnSOD-, alphaMbeta2-integrin-, CD44-, MHC class I- and II-, iNOS-, TNFalpha- and p53-immunoreactive. Similar results occurred in atherosclerotic aortas of HHL rabbits. Computer-assisted morphometric analyses revealed a positive correlation of the area density of MnSOD-immunoreactive macrophages with those of alphaMbeta2-integrin- and CD44-immunoreactive ones, but not with those of MHC class I- and II- as well as of RAM-11-immunoreactive macrophages. We conclude that apoptotic macrophages located in atherosclerotic vessel wall are activated, antigen-presenting, integrin-expressing and oxidatively stressed cells. Since all these processes have been demonstrated to cause apoptosis of macrophages in vitro, we propose their potency accelerates the susceptibility of the macrophages to programmed cell death in atherosclerotic lesions.

Modulation of the ceramide level, a novel therapeutic concept?

The sphingomyelin (SM) pathway is an ubiquitous and evolutionarily conserved signaling system in which ceramide (CA), generated from SM by the action of various isoforms of sphingomyelinases (SMases) functions as an important second messenger. Recent evidence suggests that branching pathways of sphingolipid metabolism mediate either apoptotic or mitogenic responses depending on cell type and the nature of the stimulus. Events involving SM metabolites and CA in particular include proliferation, differentiation and growth arrest as well as the induction of apoptosis. An improved understanding of SMase-dependent signaling may afford relevant insights into the pathogenesis of diseases and provide novel strategies and selective targets for a therapeutic intervention e.g. in cancer, cardiovascular and neurodegenerative diseases, HIV and septic shock. This article briefly summarizes the role of SMases in signaling pathways, its potential contribution in the development and maintenance of various pathobiological states and analyzes the perspective of a potentially isotype-specifc inhibition of SMases as a novel therapeutic concept.

Apoptosis modulators in the therapy of neurodegenerative diseases.

Apoptosis is a prerequisite to model the developing nervous system. However, an increased rate of cell death in the adult nervous system underlies neurodegenerative disease and is a hallmark of multiple sclerosis (MS) Alzheimer's- (AD), Parkinson- (PD), or Huntington's disease (HD). Cell surface receptors (e.g., CD95/APO-1/Fas; TNF receptor) and their ligands (CD95-L; TNF) as well as evolutionarily conserved mechanisms involving proteases, mitochondrial factors (e.g. , Bcl-2-related proteins, reactive oxygen species, mitochondrial membrane potential, opening of the permeability transition pore) or p53 participate in the modulation and execution of cell death. Effectors comprise oxidative stress, inflammatory processes, calcium toxicity and survival factor deficiency. Therapeutic agents are being developed to interfere with these events, thus conferring the potential to be neuroprotective. In this context, drugs with anti-oxidative properties, e.g., flupirtine, N-acetylcysteine, idebenone, melatonin, but also novel dopamine agonists (ropinirole and pramipexole) have been shown to protect neuronal cells from apoptosis and thus have been suggested for treating neurodegenerative disorders like AD or PD. Other agents like non-steroidal anti-inflammatory drugs (NSAIDs) partly inhibit cyclooxygenase (COX) expression, as well as having a positive influence on the clinical expression of AD. Distinct cytokines, growth factors and related drug candidates, e.g., nerve growth factor (NGF), or members of the transforming growth factor-beta (TGF-beta ) superfamily, like growth and differentiation factor 5 (GDF-5), are shown to protect tyrosine hydroxylase or dopaminergic neurones from apoptosis. Furthermore, peptidergic cerebrolysin has been found to support the survival of neurones in vitro and in vivo. Treatment with protease inhibitors are suggested as potential targets to prevent DNA fragmentation in dopaminergic neurones of PD patients. Finally, CRIB (cellular replacement by immunoisolatory biocapsule) is an auspicious gene therapeutical approach for human NGF secretion, which has been shown to protect cholinergic neurones from cell death when implanted in the brain. This review summarises and evaluates novel aspects of anti-apoptotic concepts and pharmacological intervention including gene therapeutical approaches currently being proposed or utilised to treat neurodegenerative diseases.

Procalcitonin and CGRP-1 mrna expression in various human tissues.

Procalcitonin (PCT) is a highly sensitive and specific marker of systemic bacterial infection and sepsis. In contrast to its diagnostic significance, the cellular sources of plasma procalcitonin remain to be clarified. Two forms of PCT mRNAs originate from calcitonin/calcitonin gene-related peptide gene (CALC-I gene) along with mRNA for calcitonin gene-related peptide-I (CGRP-I). Reverse transcription polymerase chain reaction with newly designed primers detecting different PCT mRNAs and CGRP-I mRNA was used to identify tissues that might contribute to PCT production. Our study indicates that a variety of human tissues (13 of the 16 analyzed overall) express PCT-I, PCT-II, and/or CGRP-I mRNAs, with the highest levels detected for liver, testis, lung, prostate, kidney, and small intestine. Various tissues differ in the proportions of PCT-I, PCT-II, and CGRP-I mRNA expression levels. Thus we demonstrate the complexity of tissue-specific regulation of CALC-I gene expression and suppose a variety of tissues as a potential source of CALC-I-encoded peptides.

Rapid synthesis of 2-desoxy-2-amino-3-phosphocholine-glycerinic-acid- alkylester, 1-alkyl-1-desoxy- and 1-O-alkyl-2-desoxy-2-amino-sn-glycero-3- phosphocholines, -3-phospho-N,N'-dimethylethanolamine and -3-phospho-Fmoc- serine-methylester.

A convenient sequence for the rapid synthesis of 2-desoxy-2-amino-3-phosphocholine-glycerinic-acid-alkylester , 1-alkyl-1-desoxy- and 1-O-alkyl-2-amino-2-desoxy-3-phospho-derivatives is described. Key steps are the reaction of 1-carbonyloxyalkyl-, 1-alkyl- or 1-O-alkyl-amino-alcohols with phosphorus oxychloride to 1-carbonyloxyalkyl-, 1-alkyl- or 4-substituted 2-chloro-2-oxo-1,3,2-oxazaphospholane followed by nucleophilic displacement with choline tosylate, 1-bromoethane-2-ol or Fmoc-L-serine-methylester and subsequent hydrolysis to 2-amino-lysophospholipids giving the desired compounds in yields ranging between 68% and 81%. Several 2-amino-lysophospholipid analogs can then be prepared by this synthetic scheme utilizing the same oxazaphospholane intermediate. A brief method for the preparation of 2-amino-3-hydroxy-propionic-acid-pentyl- and -octylester from L-serine is described, opening a facile access to chiral precursors of phospholipid analogs.

Oxidized low density lipoprotein stimulates protein kinase C (PKC) activity and expression of PKC-isotypes via prostaglandin-H-synthase in P388D1 cells.

Treatment of P388D1 macrophage-like cells with oxLDL enhanced protein kinase C (PKC) activity in cell extracts. Similar effects were induced by acetylated LDL (acLDL) and maleylated albumin (malBSA). Treatment with oxLDL, acLDL and malBSA was also accompanied by increased production of prostaglandins as well as by an enhanced level of prostaglandin H synthase 2 (cyclooxygenase 2, COX 2). Modified (lipo)proteins differentially affected the levels of individual cytosolic PKC-isoenzymes. Effects of oxLDL on PKC activity/expression were abrogated by indometacin, by pre-exposure to the dual lipoxygenase/cyclooxygenase inhibitor ML 3000 and by treatment with N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide (NS-398). These results suggest a predominantly COX 2-dependent and isotype-specific effect of modified (lipo)proteins on PKC.

Challenges in mass spectrometry based targeted metabolomics.

The gap of the post-genomic era is increasingly being filled by the metabolomics approach, comprising a technology for analyzing small molecule endogenous metabolites (<1500 Dalton) in complex biological samples. This new analytical science has progressed within the last years particularly with regard to improvements in mass spectrometry based detection, now allowing highly robust, reproducible, selective and sensitive qualitative or quantitative analysis of endogenous metabolites. The precise and accurate quantitation of these metabolites via targeted metabolomics, now critically contributes to the quantitative analysis of endogenous compounds in biomarker discovery and validation thus to future personalized therapy. The analytical methods of choice in (MS-based) targeted metabolomics primarily are HPLC-API-MS/MS, FIA-APIMS/MS and GC-MS. In the parent paper, we provide an introduction and brief survey on the technological basis of targeted metabolomics in biomarker research, discuss various relevant analytical aspects in mass spectrometry including comparison to non-targeted approaches, effects of sample preparation, impact of sample stability, carryover- and matrix effects, need for standardization and for proficiency tests, standardization of analytical methods as well as the requirement for method validation.

Approaching clinical reality: markers for monitoring systemic inflammation and sepsis.

The 'systemic inflammatory response syndrome (SIRS)' reflects a non-specific inflammatory reaction to various insults. In sepsis, defined as SIRS triggered by infection, a complex and overwhelming network of mediators contributes to the clinical syndrome. The host response in sepsis is characterized by unspecific physiologic criteria, which are unable to identify patients adequately who might benefit from either conventional anti-infective therapies or from novel therapies targeting specific mediators of sepsis. The early diagnosis of sepsis, the identification of the origin, adequate therapeutical management and the monitoring of the disease may help to overcome sepsis-associated mortality, which is unacceptably high and the third leading cause of death in Western Countries. Molecular techniques for identification of pathogens, their associated molecular patterns (PAMPs) and the ensuing host response may help to stratify patients with the urgent need for antibiotic therapy and those where it is safe to withhold or to de-escalate therapy. Beyond analysis of danger associated molecular patterns (DAMPs) at a single molecular level, the advent of genome-wide screening allows for an assessment of a wide variety of effectors and mediators in response to PAMPs. Also their purposeful targeting in animal models of sepsis revolutionized our understanding of pathophysiology in the critically ill. Molecular tools are about to challenge "state-of-the-art" diagnostic tests such as blood culture as they not only increase sensitivity but also dramatically reduce time requirements to identify pathogens and their resistance patterns. Mounting evidence suggests that our pathophysiological understanding might in the near future help to identify "patients at risk", i.e. those with a high likelihood to develop organ dysfunction and/or to guide therapeutic interventions in particular regarding resource-consuming and expensive therapies ("theragnostics"). The clinical utility for most of the discussed markers for monitoring systemic inflammation and sepsis has still to be evaluated in prospective trails. In conclusion, there is an unmet medical need for identification and validation of reliable biomarkers of sepsis; the clinical information obtained from the use of novel biomarkers might contribute to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders, to improve diagnosis and therapeutic decision making for high-risk patients, to monitor the response to therapy and to ensure the enrollment of seriously characterized patients in clinical studies.

UV-resonance Raman spectroscopic study of human plasma of healthy donors and patients with thrombotic microangiopathy.

Various diseases shift the composition of human plasma; hence, the relative quantification of plasma constituents offers the opportunity to use the dynamic and complex composition of plasma to gain information on novel diagnostic and prognostic factors. Since plasma contains, besides water, mostly proteins, UV-resonance Raman spectroscopy (UVRR) seems to be a suitable method for investigating plasma. With this method the signals of aromatic amino acids and proteins are selectively enhanced. In this study an UV-resonance Raman approach was used for the investigation of human plasma of healthy volunteers and patients with thrombotic microangiopathy. For comparison, selected plasma components were analyzed for a more detailed characterization of cryoprecipitates from human plasma.

[Pharmacokinetics of 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6-endo] dec-8-en-3-one in the rat]. / Pharmakokinetik von 4-Oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3on an der Ratte.

Pharmacokinetics of 4-Oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3one in the Rat The pharmacokinetics of 4-oxa-5-exo-(N-methylcarbamoyloxy)-tricyclo- [5.2.1.0. 2,6endo]dec-8-en-3one (Lu 253) were investigated after oral application in male Wistar rats. The compound is extensively absorbed and mainly renally eliminated. Within 60 h, 63% of the activity is recovered in urine and faeces. After 12 h 27% of the activity is eliminated (application in polyethylene glycol). The highest total concentration of the activity in the plasma is found after 2 h, the highest of the unchanged drug is found after 1 h. The half-life is 2.9 h. The concentration in plasma is mathematically characterized by the parameters of a two-compartiment model and also independent of a model. Lu 253 is distributed in the whole organism, a maximum of activity is achieved 2 h after application. By whole-body autoradiography the entrance of the compound into liquor and an enduring accumulation in the frontal cavity is detected.