Biomedical subjects

M Braun

Publications and source records attributed to M Braun.

At least 73 records · Page 4Linked to original sources

PubMed2001

Gravisensing in single-celled systems: characean rhizoids and protonemata.

Gravitropically tip-growing cell types are attractive unicellular model systems for investigating the mechanisms and the regulation of gravitropism. Especially useful for studying the mechanisms of positive and negative gravitropic tip-growth are characean rhizoids and protonemata. They originate from the same cell type, show the same overall cell shape, cytoplasmic zonation, arrangement of actin and microtubule cytoskeleton, use statoliths for gravisensing, but show opposite gravitropism. In both cell types, actin microfilaments are complexly organized in the apical dome,where a dense spherical actin array is colocalized with spectrin-like epitopes and a unique endoplasmic reticulum aggregate, the structural center of the Spitzenkörper. The opposite gravitropic responses seem to be based on differences in the actin-organized anchorage of the Spitzenkörper and the actin-mediated transport of statoliths. In negatively gravitropic (upward bending) protonemata, the statoliths-induced drastic upward shift of the cell tip is preceded by a relocalization of dihydropyridine-binding calcium channels and of the apical calcium gradient to the upper flank (bending by bulging). Such relocalizations have not been observed in positively gravitropically responding (downward growing) rhizoids in which statoliths sedimentation is followed by differential flank growth (bending by bowing). This paper reviews the current knowledge and hypotheses on the mechanisms of the opposite gravitropic responses in characean rhizoids and protonemata.

Calcium Channels↗

PubMed2001

A role for eosinophils in transplant rejection.

Eosinophils release inflammatory mediators and cationic proteins that are instrumental in the pathogenesis of allergic diseases such as bronchial asthma. Here, we review experimental observations indicating that eosinophils are also involved in the rejection of allografts. We propose that their role as effectors of transplant damage becomes crucial when classical pathways of rejection are inhibited and T helper 2 (Th2) cells dominate the alloimmune response.

Animals↗

PubMed2001

Evidence for functionally active protease-activated receptor-4 (PAR-4) in human vascular smooth muscle cells.

1. This study investigates, whether in addition to the protease-activated receptor-1 (PAR-1), PAR-4 is present in vascular smooth muscle cells (SMC) of the human saphenous vein and whether this receptor is functionally active. PAR-1 and PAR-4 are stimulated by thrombin and by the synthetic peptides SFLLRN and GYPGQV, respectively. 2. mRNAs for both, PAR-1 and PAR-4, were detected in the SMC by using reverse transcriptase polymerase chain reaction (RT - PCR). 3. Treatment of the SMC with GYPGQV (200 microM) resulted in a transient increase in free intracellular calcium. This calcium signal was completely abolished after a preceding challenge with thrombin (10 nM), indicating homologous receptor desensitization. 4. Stimulation of the SMC with 10 nM thrombin or 200 microM SFLLRN caused a time-dependent activation of the extracellular signal-regulated kinases-1/2 (ERK-1/2) with a maximum at 5 min. In contrast, 100 nM thrombin as well as 200 microM of GYPGQV induced a prolonged phosphorylation of ERK-1/2 with a maximum at 60 min. These data suggest that PAR-1 and PAR-4 are activated by thrombin at distinct concentrations and with distinct kinetics. 5. GYPGQV stimulated [(3)H]-thymidine incorporation in SMC. At 500 microM, the peptide increased DNA synthesis 2.5 fold above controls. A comparable mitogenic effect was obtained after stimulation of the SMC by 10 nM thrombin or 100 microM SFLLRN, respectively. 6. These data indicate that a functionally active PAR-4 is present in SMC and, in addition to PAR-1, might contribute to thrombin-induced mitogenesis.

Amino Acid Sequence↗

PubMed2001

Effects of beta-blockers on sexual performance in men with coronary heart disease. A prospective, randomized and double blinded study.

In a prospective trial assessing the effects of beta-blockers on sexual function men with coronary heart disease were randomized to a 4 month treatment with sustained release metoprolol 95 mg or placebo. A standardized and validated self-report questionnaire (KEED = Kölner Erhebungsbogen der Erektilen Dysfunktion) dealing with several aspects of sexual performance in men had to be answered at the beginning and at the end of the study. Based on 65 patients completing the study, sex life seemed unaffected by metoprolol treatment.

Adrenergic beta-Antagonists↗

PubMed2001

Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation.

OBJECTIVE: To develop and to characterize a human preadipocyte cell strain with high capacity for adipose differentiation serving as a model for studying human adipocyte development and metabolism in vitro. METHODS: Cells were derived from the stromal cells fraction of subcutaneous adipose tissue of an infant with Simpson-Golabi-Behmel syndrome (SGBS). Adipose differentiation was induced under serum-free culture conditions by exposure to 10 nM insulin, 200 pM triiodothyronine, 1 microM cortisol and 2 microM BRL 49653, a PPAR gamma agonist. RESULTS: During the differentiation process SGBS cells developed a gene expression pattern similar to that found in differentiating human preadipocytes with a characteristic increase in fat cell-specific mRNAs encoding lipoprotein lipase (LPL), glycero-3-phosphate dehydrogenase (GPDH), GLUT4, leptin and others. Differentiated SGBS cells exhibited an increase in glucose uptake upon insulin stimulation and in glycerol release upon catecholamine exposure. SGBS adipocytes were morphologically, biochemically and functionally identical to in vitro differentiated adipocytes from healthy subjects. However, while preadipocytes from healthy control infants rapidly lost their capacity to differentiate after a few cell divisions in culture, SGBS cells maintained their differentiation capacity over many generations: upon appropriate stimulation 95% of SGBS cells of generation 30 developed into adipocytes. A mutation in the glypican 3 gene was not detected in the patient. Thus, it remains unclear whether the molecular alteration in SGBS cells is also responsible for the high differentiation capacity and further investigations are required. CONCLUSION: The human cell strain described here provides an almost unlimited source of human preadipocytes with high capacity for adipose differentiation and may, therefore, represent a unique tool for studying human fat cell development and metabolism. International Journal of Obesity (2001) 25, 8-15

Adipocytes↗

PubMed2001

Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers.

AIMS: To study the recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. METHODS: Ten healthy volunteers were treated with clopidogrel (75 mg day(-1)) for 7 days. CD62P expression and PAC-1 binding were measured by flow cytometry. RESULTS: Adenosine diphosphate (ADP, 30 microM)-induced platelet responses were almost completely inhibited by clopidogrel. After discontinuation of the drug, platelet function gradually increased and complete recovery was seen 7 days after the last clopidogrel dose. The mean difference (95% CI) for ADP-induced PAC-1 binding (fluorescence intensity) between baseline and 7 days after the last dose was 0.01 (0.61, -0.59). Single cell analysis provides direct evidence for an irreversible mode of action of clopidogrel. CONCLUSIONS: This is the first report to directly demonstrate irreversibility of clopidogrel action in humans.

Adenosine Diphosphate↗

PubMed2001

The prevalence of Peyronie's disease: results of a large survey.

OBJECTIVES: To determine the prevalence of Peyronie's disease, a localized connective tissue disorder of the penile tunica albuginea, the symptoms of which include palpable plaque, painful erections and curvature of the penis, in a large sample of men in Germany. SUBJECTS AND METHODS: A standardized questionnaire was sent to 8000 male inhabitants (age range 30-80 years) of the greater Cologne area (approximately 1.5 million inhabitants). Three questions about the self-diagnosis of Peyronie's disease were previously assessed for validity on 158 healthy men and 24 patients with confirmed Peyronie's disease. To optimize the response rate, the questionnaire was mailed three times to all the men. RESULTS: The response rate after the third mailing was 55.4% (4432 men): 142 men (3.2%, mean age 57.4 years, SD 13.4) reported the new appearance of a palpable plaque which, from the previous validation, was the most sensitive question and the main symptom of the disease. In men aged 30-39 years only 1.5% reported localized penile induration, compared with 3.0% in those 40-49 and 50-59 years, 4.0% in those 60-69 years and 6.5% of those > 70 years old. Newly occurring angulation was reported by 119 of the 142 men (84%) and painful erection by 66 (46.5%). The combination of the three symptoms (plaque, deviation and painful erection) was reported by 46 of the 4432 respondents (1.04%), i.e. 32% of the 142 men with penile induration; 58 of the 142 men (41%) reported erectile dysfunction. CONCLUSIONS: This is the first large cross-sectional, community-based study to examine the prevalence of Peyronie's disease. Using previously validated questions the prevalence of Peyronie's disease in the sample was 3.2%; this is much higher than indicated in previous reports. A comparably high prevalence is reported for diabetes and urolithiasis, suggesting that this 'rare' disease is more widespread than previously thought.

Adult↗

PubMed2001

Platelet CD40 ligand (CD40L)--subcellular localization, regulation of expression, and inhibition by clopidogrel.

This study compares the subcellular localization and the regulation of expression of the platelet activation markers CD62P and CD63 with CD40 ligand (CD40L) on the surface of washed human platelets. CD40L was expressed upon stimulation with a wide range of platelet activators. However, quantitative flow cytometry demonstrated that, as compared with CD62P and CD63, CD40L expression was low. Upon stimulation with thrombin receptor-activating peptide (TRAP-6), all activation markers were expressed. In contrast, upon stimulation with low concentrations of collagen (1-3 microg/ml), CD40L, but not the granule proteins (CD62P, CD63), were expressed. Using immunofluorescence microscopy, a cytoplasmic staining was observed for CD40L, and cytoplasmic localization of CD40L was verified by Western blotting of subcellular platelet fractions. The staining of CD40L was different from that of filamentous actin and only little association of CD40L with platelet cytoskeleton was found. Surface expression of CD40L was dependent on internal Ca2+ stores and protein kinase C, while the mitogen-activated protein kinases (ERK, p38) or tyrosine kinases were not involved. ADP (30 microM)-induced CD40L expression was not inhibited by aspirin. In contrast, clopidogrel treatment completely abolished ADP-induced expression of CD40L. Finally, the expression level of CD40L was shown to be upregulated by phorbol myristate acetate (PMA) in the promegakaryocytic cell line MEG-01.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Non-rigid image registration using a median-filtered coarse-to-fine displacement field and a symmetric correlation ratio.

Conventional approaches to image registration are generally limited to image-wide rigid transformations. However, the body and its internal organs are non-rigid structures that change shape due to changes in the body's posture during image acquisition, and due to normal, pathological and treatment-related variations. Inter-subject matching also constitutes a non-rigid registration problem. In this paper, we present a fully automated non-rigid image registration method that maximizes a local voxel-based similarity metric. Overlapping image blocks are defined on a 3D grid. The transformation vector field representing image deformation is found by translating each block so as to maximize the local similarity measure. The resulting sparsely sampled vector field is median filtered and interpolated by a Gaussian function to ensure a locally smooth transformation. A hierarchical strategy is adopted to progressively establish local registration associated with image structures at diminishing scale. Simulation studies were carried out to evaluate the proposed algorithm and to determine the robustness of various voxel-based cost functions. Mutual information, normalized mutual information, correlation ratio (CR) and a new symmetric version of CR were evaluated and compared. A T1-weighted magnetic resonance (MR) image was used to test intra-modality registration. Proton density and T2-weighted MR images of the same subject were used to evaluate inter-modality registration. The proposed algorithm was tested on the 2D MR images distorted by known deformations and 3D images simulating inter-subject distortions. We studied the robustness of cost functions with respect to image sampling. Results indicate that the symmetric CR gives comparable registration to mutual information in intra- and inter-modality tasks at full sampling and is superior to mutual information in registering sparsely sampled images.

Algorithms↗

PubMed2001

Characterization of rat and human UDP-glucuronosyltransferases responsible for the in vitro glucuronidation of diclofenac.

In the current study, the identification of the rat and human UDP-glucuronosyltransferase (UGT) isoforms responsible for the glucuronidation of diclofenac was determined. Recombinant human UGT1A9 catalyzed the glucuronidation of diclofenac at a moderate rate of 166-pmol/min/mg protein, while UGT1A6 and 2B15 catalyzed the glucuronidation of diclofenac at low rates (<20-pmol/min/mg protein). Conversely, human UGT2B7 displayed a high rate of diclofenac glucuronide formation (>500 pmol/min/mg protein). Recombinant rat UGT2B1 catalyzed the glucuronidation of diclofenac at a rate of 250-pmol/min/mg protein. Rat UGT2B1 and human UGT2B7 displayed a similar, low apparent Km value of <15 microM for both UGT isoforms and high Vmax values 0.3 and 2.8 nmol/min/mg, respectively. Using diclofenac as a substrate, enzyme kinetics in rat and human liver microsomes showed that the enzyme(s) involved in diclofenac glucuronidation had a low apparent Km value of <20 microM and a high Vmax value of 0.9 and 4.3 nmol/min/mg protein, respectively. Morphine is a known substrate for rat UGT2B1 and human UGT2B7 and both total morphine glucuronidation (3-O- and 6-O-glucuronides) and diclofenac glucuronidation reactions showed a strong correlation with one another in human liver microsome samples. In addition, diclofenac inhibited the glucuronidation of morphine in human liver microsomes. These data suggested that rat UGT2B1 and human UGT2B7 were the major UGT isoforms involved in the glucuronidation of diclofenac.

Animals↗

PubMed2001

Association of spectrin-like proteins with the actin-organized aggregate of endoplasmic reticulum in the Spitzenkörper of gravitropically tip-growing plant cells.

Spectrin-like epitopes were immunochemically detected and immunofluorescently localized in gravitropically tip-growing rhizoids and protonemata of characean algae. Antiserum against spectrin from chicken erythrocytes showed cross-reactivity with rhizoid proteins at molecular masses of about 170 and 195 kD. Confocal microscopy revealed a distinct spherical labeling of spectrin-like proteins in the apices of both cell types tightly associated with an apical actin array and a specific subdomain of endoplasmic reticulum (ER), the ER aggregate. The presence of spectrin-like epitopes, the ER aggregate, and the actin cytoskeleton are strictly correlated with active tip growth. Application of cytochalasin D and A23187 has shown that interfering with actin or with the calcium gradient, which cause the disintegration of the ER aggregate and abolish tip growth, inhibits labeling of spectrin-like proteins. At the beginning of the graviresponse in rhizoids the labeling of spectrin-like proteins remained in its symmetrical position at the cell tip, but was clearly displaced to the upper flank in gravistimulated protonemata. These findings support the hypothesis that a displacement of the Spitzenkörper is required for the negative gravitropic response in protonemata, but not for the positive gravitropic response in rhizoids. It is evident that the actin/spectrin system plays a role in maintaining the organization of the ER aggregate and represents an essential part in the mechanism of gravitropic tip growth.

Actins↗

PubMed2001

Identical words are read differently in different languages.

It is hypothesized that written languages differ in the preferred grain size of units that emerge during reading acquisition. Smaller units (graphemes, phonemes) are thought to play a dominant role in relatively consistent orthographies (e.g., German), whereas larger units (bodies, rhymes) are thought to be more important in relatively inconsistent orthographies (e.g., English). This hypothesis was tested by having native English and German speakers read identical words and nonwords in their respective languages (zoo-Zoo, sand-Sand, etc.). Although the English participants exhibited stronger body-rhyme effects, the German participants exhibited a stronger length effect for words and nonwords. Thus, identical items were processed differently in different orthographies. These results suggest that orthographic consistency determines not only the relative contribution of orthographic versus phonological codes within a given orthography; but also the preferred grain size of units that are likely to be functional during reading.

Adolescent↗

PubMed2001

FhuA barrel-cork hybrids are active transporters and receptors.

The crystal structure of Escherichia coli FhuA reveals a beta-barrel domain that is closed by a globular cork domain. It has been assumed that the proton motive force of the cytoplasmic membrane through the interaction of the TonB protein with the TonB box of the cork opens the FhuA channel. Yet, deletion of the cork results in an FhuA derivative, FhuADelta5-160, that still displays TonB-dependent substrate transport and phage receptor activity. To investigate this unexpected finding further, we constructed FhuADelta5-160 derivatives of FhuA proteins from Salmonella paratyphi B, Salmonella enterica serovar Typhimurium, and Pantoea agglomerans. The FhuADelta5-160 proteins inserted correctly into the outer membrane, and with the exception of the P. agglomerans protein, transported ferrichrome and albomycin. FhuA hybrids consisting of the beta-barrel of one strain and the cork of another strain were active and showed higher TonB-dependent ferrichrome transport rates than the corkless derivatives. Exceptions were the E. coli beta-barrel/Salmonella serovar Typhimurium cork hybrid protein and the Salmonella serovar Typhimurium beta-barrel/P. agglomerans cork hybrid protein, both of which were less active than the beta-barrels alone. Each of the FhuA mutant proteins displayed activity for each of their ligands, except for phage T5, only when coupled to TonB. The hybrid FhuA proteins displayed a similar activity with the E. coli TonB protein as with their cognate TonB proteins. Sensitivity to phages T1, T5, and phi80, rifamycin CGP 4832, and colicin M was determined by the beta-barrel, whereas sensitivity to phage ES18 and microcin J25 required both the beta-barrel and cork domains. These results demonstrate that the beta-barrel domain of FhuA confers activity and specificity and responds to TonB and that the cork domains of various FhuA proteins can be interchanged and contribute to the activities of the FhuA hybrids.

Bacterial Outer Membrane Proteins↗

PubMed2001

Intracranial aneurysms: clinical value of 3D digital subtraction angiography in the therapeutic decision and endovascular treatment.

PURPOSE: To evaluate three-dimensional (3D) digital subtraction angiography (DSA) as a supplement to two-dimensional (2D) DSA in the endovascular treatment (EVT) of intracranial aneurysms. MATERIALS AND METHODS: In 22 ruptured aneurysms, neck visualization, aneurysm shape, and EVT feasibility were analyzed at 2D DSA (anteroposterior, lateral, and rotational views) and at maximum intensity projection (MIP) and surface shaded display (SSD) 3D DSA. The possibility of obtaining a working view for EVT at 3D DSA and the relevance of measurements in choosing the first coil also were assessed. RESULTS: Two-dimensional DSA images clearly depicted the aneurysm neck in four of 22 aneurysms; MIP images, in 10; and SSD images, in 21, but SSD led to overestimation of the neck size in one aneurysm. Aneurysm shape was precisely demonstrated in five of 22 aneurysms at 2D DSA, in eight at MIP, and in all cases at SSD. In two of 22 aneurysms, EVT seemed to be nonfeasible at 2D DSA; however, SSD demonstrated feasibility and EVT was successfully performed. In one aneurysm, only SSD demonstrated the extension of the neck to a parent vessel, which was proved at surgery. Working views for EVT were deduced from 3D DSA findings in 20 of 21 aneurysms. The choice of the first coil was correct in 19 of 21 aneurysms. CONCLUSION: Three-dimensional DSA is valuable for evaluating the potential for EVT, finding a working view, and performing accurate measurements.

Adult↗

PubMed2001

'Viagra effect' - influence of mass media on patient behavior.

INTRODUCTION: The effects of modern mass media and communication on the public health system are well known. So far however, these different influences of the media have not been objectively evaluated by physician-patient contacts. PATIENTS AND METHODS: In this study we asked urologists, primary care physicians and internists in private practices in Cologne and a rural area (Erftkreis, Germany) to quantify their weekly contacts with patients suffering from erectile dysfunction (ED). The poll was conducted by four separately mailed questionnaires whereas a double counting was avoided. Between the second and third mailing, an unbelievable public attention was seen following the FDA approval of Viagra in the United States. When Viagra was available in Germany, a fourth questionnaire was sent (4 months later) to all practitioners (n = 751). RESULTS: During this time span, there was a statistically (p <or= 0.01; t test) significant increase in weekly physician-patient contacts (WPC; 13.1-19.1 WPC for urologists, 4.4-5.5 WPC for general practitioners/internists) for ED in the region of Cologne-Erftkreis. In the fourth mailing, there was a slight decrease, but overall WPC was still higher compared to the first two mailings (17 WPC for urologists, 5.2 WPC for other specialists). CONCLUSIONS: Our investigation shows that urologists are accepted as the competent advisory partners for therapy with Viagra. This was seen by the higher increase (20.1%) in patient contacts with urologists in comparison to colleagues of other medical disciplines (45.8 vs. 25.7% between mailing 1+2 and 3). In this investigation we were able to demonstrate the effects of mass media on patient behavior.

Adult↗

PubMed2001

Vasospasm after subarachnoid hemorrhage: interest in diffusion-weighted MR imaging.

BACKGROUND AND PURPOSE: Vasospasm secondary to subarachnoid hemorrhage (SAH) is responsible for severe ischemic complications. Although effective, angioplasty must be performed at a very early stage to produce any clinical recovery. Diagnostic investigations to assess arterial narrowing (transcranial Doppler, angiography) or cerebral perfusion (xenon CT, single-photon emission CT) do not provide evidence of the extent of parenchymal ischemia. In stroke, diffusion-weighted MR imaging (DWI) appears to be the most sensitive procedure to detect cerebral ischemia. We studied asymptomatic vasospasm in patients with aneurysmal SAH to assess whether DWI provides predictive markers of silent ischemic lesions and/or progression toward symptomatic ischemia. METHODS: Seven asymptomatic vasospasm patients (average blood velocity rates >120 cm/s), 3 patients with symptomatic vasospasm, and 4 patients with SAH but without vasospasm were studied at regular intervals by DWI, and their apparent diffusion coefficients (ADCs) were calculated. RESULTS: All patients with vasospasm including those without symptoms presented abnormalities on DWI with a reduction of the ADC prevalently in the white matter. No such abnormalities were observed in patients without vasospasm. The abnormalities on DWI resolved completely in 4 of the 7 patients, with no parenchymal lesion. Resolution was partial in 3 patients whose white matter still presented residual round, focal ischemic lesions. CONCLUSIONS: Being able to correlate abnormalities on DWI with parenchymal involvement in asymptomatic patients would be of considerable clinical significance. It is hoped that larger studies will be undertaken to determine whether the ADC has a reversibility threshold, because this would facilitate patient management.

Adult↗

PubMed2001

[Morphological abnormalities of limbic lobe structures in partial temporal lobe epilepsy].

PURPOSE: To evaluate lesions of the different structures of the Papez circuit in association with hippocampal sclerosis. MATERIAL: and methods. 13 patients (32.1+/-8.2 y.o.) suffering from partial, temporal lobe, drug-resistant epilepsy and 20 normal volunteers (31.8+/-7.7 y.o.) were evaluated by MRI on a 1.5 T scanner (Philips): axial T1w 3D Gradient Echo acquisitions, thickness: 1.5mm. Hippocampus and cingulate gyrus volume were calculated after semi-automated segmentation of intrasulcal gray matter using the "Surgiscope Scopeplan" Elekta((R)). The thickness of the posterior column of the fornix and the thickness of the mamillary bodies were also measured. RESULTS: We found 10 cases of ipsolateral hippocampal sclerosis, 6 cases of ipsolateral atrophy of the mamillary body and 4 cases of ipsolateral atrophy of the fornix. We did not find any atrophy of the cingulate gyrus. CONCLUSION: Hippocampal sclerosis can be associated with lesions of limbic lobe structures (fornix and mamillary body), excluding the cingulate gyrus.

Adult↗

PubMed2001

Mechanistic studies on the reversible metabolism of rofecoxib to 5-hydroxyrofecoxib in the rat: evidence for transient ring opening of a substituted 2-furanone derivative using stable isotope-labeling techniques.

Rofecoxib is a potent and highly selective cyclooxygenase-2 inhibitor used for the treatment of osteoarthritis and pain. Following administration of [4-(14)C]rofecoxib to intact rats, the plasma C(max) (at approximately 1 h) was followed by a secondary C(max) (at approximately 10 h), which was not observed in bile duct-cannulated rats. Following administration of [4-(14)C]5-hydroxyrofecoxib to intact or bile duct-cannulated rats, radiolabeled rofecoxib was detected in plasma, and once again a secondary C(max) for rofecoxib was observed (at approximately 10 h), which occurred only in the intact animals. These results indicate that reversible metabolism of rofecoxib to 5-hydroxyrofecoxib occurs in the rat and that the process is dependent upon an uninterrupted bile flow. Studies on the contents of the gastrointestinal tract of rats showed that conversion of 5-hydroxyrofecoxib to parent compound occurs largely in the lower intestine. Treatment of rats with [5-(18)O]5-hydroxyrofecoxib, followed by liquid chromatography-tandem mass spectrometry analyses of plasma samples, confirmed that 5-hydroxyrofecoxib undergoes metabolism to the parent drug, yielding [1-(18)O]rofecoxib, [2-(18)O]rofecoxib, and unlabeled rofecoxib. Similarly, treatment with [1,2-(18)O(2)]rofecoxib afforded the same three isotopic variants of rofecoxib. These findings are consistent with a metabolic sequence involving 5-hydroxylation of rofecoxib, biliary elimination of the corresponding glucuronide, and deconjugation of the glucuronide in the lower gastrointestinal tract. Reduction of the 5-hydroxyrofecoxib thus liberated yields a hydroxyacid that cyclizes spontaneously to regenerate rofecoxib, which is reabsorbed and enters the systemic circulation. This sequence represents a novel form of enterohepatic recycling and reflects the susceptibility of 5-hydroxyrofecoxib, as well as rofecoxib itself, to reversible 2-furanone ring opening under in vivo conditions.

Animals↗