bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDR1 gene polymorphisms and disposition of the P‐glycoprotein substrate fexofenadine
Authors: Drescher Siegfried , Schaeffeler Elke , Hitzl Monika , Hofmann Ute , Schwab Matthias , Brinkmann Ulrich , Eichelbaum Michel , Fromm Martin F. 
Published: March 2003

Aims  The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P‐glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P‐glycoprotein substrate digoxin. Using fexofenadine, a known P‐glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans.Methods  Ten Caucasian subjects homozygous for the wild‐type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P‐glycoprotein function was assessed using efflux of the P‐glycoprotein substrate rhodamine 123 from CD56+ cells.
Results
Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,∞) CC vs TT: 3567.1±1535.5 vs 3910.1±1894.8 ng ml−1 h, NS; 95% CI on the difference −1364.9, 2050.9). In contrast, P‐glycoprotein function was significantly decreased in CD56+ cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6±7.2% vs 61.1±12.3%, P<0.05; 95% CI on the difference 5.6, 25.5).
Conclusions
In spite of MDR1 genotype‐dependent differences in P‐glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P‐glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.
Topographic pharmaco‐EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers
Authors: Riba Jordi , Anderer Peter , Morte Adelaida , Urbano Gloria , Jané Francesc , Saletu Bernd , Barbanoj Manel J. 
Published: March 2003

Aims  Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian‐based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N‐dimethyltryptamine (DMT), and β‐carboline alkaloids with MAO‐inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self‐assessment instruments. In the present study the cerebral bioavailability and time‐course of effects of ayahuasca were assessed in humans by means of topographic quantitative‐electroencephalography (q‐EEG), a noninvasive method measuring drug‐induced variations in brain electrical activity.Methods  Two doses (one low and one high) of encapsulated freeze‐dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg−1 body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double‐blind crossover placebo‐controlled clinical trial. Nineteen‐lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS).Results  Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose‐dependent increases in all subscales of the HRS, and in significant and dose‐dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were −20.20±15.23 µV2 and −2.70±2.21 µV2 for total power and theta power, respectively. Relative power decreased in the delta (−1.20±1.31% after 120 min at P3) and theta (−3.30±2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta‐3 (1.00±0.88% after 90 min at P3) and beta‐4 (0.30±0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15–30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4–6 h after administration.Conclusions  The central effects of ayahuasca could be objectively measured by means of q‐EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q‐EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro‐serotonergic and pro‐dopaminergic drugs. The q‐EEG profile supports the role of 5‐HT2 and dopamine D2‐receptor agonism in mediating the effects of ayahuasca on the central nervous system.
Association between the N‐acetylation genetic polymorphism and bronchial asthma
Authors: Nacak Muradiye , Aynacioglu A. Sükrü , Filiz Ayten , Cascorbi Ingolf , Erdal M. Emin , Yilmaz Necat , Ekinci Erhan , Roots Ivar 
Published: March 2003

Aims  Since polymorphic N‐acetyltransferase 2 (NAT2) has been suggested as a susceptibility factor for atopic diseases, the study was undertaken to investigate whether an association exists between acetylation polymorphism and asthma patients with atopy.Methods  The frequencies of NAT2 alleles and genotypes were determined by PCR/RFLP in a total of 210 asthma patients (extrinsic (n = 108) and intrinsic (n = 102) asthmatics) and 240 control subjects. Presence of the NAT2*4 (wild‐type) allele defined a NAT2 genotype as rapid and combinations of mutant alleles NAT2*5 A, *5B, *5C, *6 A, and *7B as slow.Results  Genotypes coding for slow acetylation were detected in 70.4, 58.4 and 58.3% of extrinsic asthmatics, but intrinsic asthmatics and control subjects, respectively. The frequency of slow acetylators was higher among extrinsic asthmatics than intrinsic asthmatics, this difference did not reach statistical significance (odds ratio 1.02, 95% confidence interval 0.64, 1.63, P = 0.085). However, we found a relatively moderate, but significantly higher, increased frequency of slow acetylators among extrinsic asthma patients compared with control subjects (odds ratio 1.70, 95% confidence interval 1.04, 2.76, P = 0.042).Conclusions  This study shows an association between acetylation polymorphism and susceptibility to extrinsic asthma, but not to intrinsic asthma, suggesting a minor role of the NAT2 polymorphism in the development of atopic asthma.
Spatial distribution of 8‐methoxypsoralen penetration into human skin after systemic or topical administration
Authors: Grundmann‐Kollmann Marcella , Podda Maurizio , Bräutigam Lutz , Hardt‐Weinelt Katja , Ludwig Ralf J. , Geisslinger Gerd , Kaufmann Roland , Tegeder Irmgard 
Published: March 2003

Aims  Photochemotherapy employing psoralens combined with UVA irradiation (PUVA) is a standard therapy for a variety of dermatoses. Psoralens can be administered orally or topically in the form of bath or cream preparations. Recommendations for the time of UVA irradiation are mainly based on the time course of minimal phototoxic doses. However, the time course and depth of skin penetration of psoralens is not well characterized.Methods  We assessed the time course of 8‐MOP concentrations in horizontal epidermal and dermal skin sections in 10 patients undergoing oral (n = 3), cream (n = 4) and bath (n = 3) PUVA therapy. Punch biopsies (4 mm) were taken from ‘healthy’ skin sites. A highly sensitive LC‐MS‐MS method was employed for 8‐MOP analysis.Results  Epidermal concentrations following cream or bath were highest at the end of the application period (time zero) when irradiation is performed. At this time, 8‐MOP cream provided significantly higher epidermal concentrations (mean ± s.e. mean 128.0 ± 22.6 pg mm−3; 95% CI: 77.6, 178.4) than oral 8‐MOP (27.0 ± 25.3 pg mm−3; 95% CI: 29.3, 83.3 at 1 h; P = 0.025). Conversely, concentrations in the papillary dermis were significantly higher with oral 8‐MOP (20.2 ± 3.1 and 16.2 ± 2.2 pg mm−3 at 1 and 2 h, respectively) than with 8‐MOP cream (7.1 ± 2.8 and 8.4 ± 2.0 pg mm−3 time zero and 0.5 h, respectively; P = 0.020 and 0.045, respectively) or bath (8.8 ± 3.1 and 7.7 ± 2.2 pg mm−3; P = 0.050 and 0.039, respectively). The observed time courses of 8‐MOP concentrations correspond to time courses of photosensitivity found previously with the different treatment modalities.Conclusions  The higher epidermal 8‐MOP concentrations found after topical 8‐MOP may explain the lower UVA doses needed with the topical route. These results suggest that topical 8‐MOP may be superior in patients where the pathology is localized in the epidermis. In sclerosing diseases, which mainly affect the dermis oral PUVA might be advantageous because dermal concentrations are highest with this route of administration.
Faster absorption of ethanol and higher peak concentration in women after gastric bypass surgery
Authors: Klockhoff H. , Näslund I. , Jones A. W. 
Published: March 2003

AimsTo investigate the absorption, distribution and elimination of ethanol in women with abnormal gut as a result of gastric bypass surgery. Patients who undergo gastric bypass for morbid obesity complain of increased sensitivity to the effects of alcohol after the operation.MethodsTwelve healthy women operated for morbid obesity at least 3 years earlier were recruited. Twelve other women closely matched in terms of age and body mass index (BMI) served as the control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g kg−1body weight) as a bolus dose. The ethanol was diluted with orange juice to 20% v/v and finished in 5 min. Specimens of venous blood were taken from an indwelling catheter before drinking started and every 10 min for up to 3.5 h post‐dosing. The blood alcohol concentration (BAC) was determined by headspace gas chromatography.Results    The    maximum    blood‐ethanol    concentration    (Cmax)    was   0.741 ± 0.211 g l−1(± s.d.) in the operated group compared with 0.577 ± 0.112 g l−1in the controls (mean difference 0.164 g l−1, 95% confidence interval (CI) 0.021, 0.307). The median  time  to  peak  (tmax) was 10 min in the bypass patients compared with 30 min in controls (median difference −15 min (95% CI −10, −20 min). At 10 and 20 min post‐dosing the BAC was higher in the bypass patients (P < 0.05) but not at 30 min and all later times (P > 0.05). Other pharmacokinetic parameters of ethanol were not significantly different between the two groups of women (P > 0.05).Conclusions The higher sensitivity to ethanol after gastric bypass surgery probably reflects the more rapid absorption of ethanol leading to higherCmaxand earliertmax. The marked reduction in body weight after the operation might also be a factor to consider if the same absolute quantity of ethanol is consumed.
Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo
Authors: Wilkinson Ian B. , MacCallum Helen , Cockcroft John R. , Webb David J. 
Published: March 2003

Aims  To investigate the role of basal nitric oxide (NO) production in regulating large artery stiffness in vivo.Methods  Incremental doses of the NO synthase inhibitor L‐NG‐monomethyl arginine (LNMMA: 0.1, 0.3, 1.0 and 3.0 mg kg−1 min−1) or placebo were infused in eight healthy men. Arterial stiffness was assessed noninvasively by pulse wave analysis.Results  Compared with placebo, infusion of LNMMA led to a dose‐dependent increase in mean arterial pressure, peripheral vascular resistance, and aortic and systemic arterial stiffness. There was an accompanying reduction in heart rate and cardiac index. The highest dose of LNMMA resulted in an increase of 25% in AIx (95% confidence limits; 12, 38) and of 16 mmHg in mean arterial pressure (9, 23) compared with infusion of saline.Conclusions  These data indicate functional regulation of large artery stiffness in vivo by NO, and may provide new therapeutic strategies for cardiovascular risk reduction.
Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans
Authors: Kirchheiner Julia , Meineke Ingolf , Steinbach Nadine , Meisel Christian , Roots Ivar , Brockmöller Jürgen 
Published: March 2003

Aims The cytochrome P450 enzyme CYP2C9 catalyses the 4′‐hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50‐mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of diclofenac activity, the ex vivo formation of prostaglandin E2 and thromboxane B2, which reflects COX‐2 and COX‐1 activity, was measured.Methods Genotyping was performed in 516 healthy volunteers to obtain 20 participants with all allelic combinations of the two CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Diclofenac and 4′‐hydroxydiclofenac were quantified in plasma by reversed phase h.p.l.c. after oral intake of 50 mg diclofenac. Concentrations of thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) were measured by immunoassays.Results There was no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type (mean CL/F (95% CI) 20.5 (11, 30) l h−1 for *1/*1, 29.9 (19, 40) l h−1 for *1/*2, 30.0 (4, 56) l h−1 for *2/*2, 22.6 (12, 33) l h−1 for *1/*3, 23.5 (11, 37) l h−1 for *3/*3 and 37.3 (−15, 89) l h−1 in *2/*3). Furthermore, plasma concentrations of the metabolite 4′‐hydroxydiclofenac were not lower in carriers of the CYP2C9 low‐activity alleles *2 and *3 compared with carriers of the CYP2C9*1/*1 genotype. Marked diclofenac mediated inhibition of COX‐1‐ and COX‐2 activity was detected in all individuals independent of CYP2C9 genotype.Conclusions Polymorphisms of the CYP2C9 gene had no discernible effect on the pharmacokinetics and pharmacodynamics of diclofenac. The question of whether enzymes other than CYP2C9 play a major role in diclofenac 4′‐hydroxylation in vivo or whether 4′‐hydroxylation is not a rate‐limiting step in diclofenac elimination in vivo, or whether the effect of the CYP2C9 polymorphisms is substrate‐dependent, needs further investigation.
NAT2 and CYP1A2 phenotyping with caffeine: head‐to‐head comparison of AFMU vs. AAMU in the urine metabolite ratios
Authors: Nyéki Á , Buclin T. , Biollaz J. , Decosterd L. A. 
Published: March 2003

Aims  (i) To compare the phenotyping of healthy subjects for NAT2 and CYP1A2 activities with caffeine, by the simultaneous assay of the urinary metabolites AFMU and AAMU, and (ii) to ascertain whether NAT2 and CYP1A2 phenotyping is influenced by the use of AFMU or AAMU in the metabolite ratio.Methods  Thirty‐five healthy subjects (16 men, 19 women) participated to the study. Caffeine metabolite concentrations were measured in urine collected 8 h after 2.5 mg kg−1 caffeine intake using a new validated h.p.l.c. method. The metabolite ratios AFMU/1X, AFMU/(AFMU+1X+1U), AAMU/1X, AAMU/(AAMU+1X+1 U), and (AFMU+1U+1X)/17U, (AAMU+1U+1X)/17U were determined as indices of NAT2 and CYP1A2 activity, respectively.Results  Slow and rapid acetylators were similarly identified using the four NAT2 metabolite ratios in 139 out of 140 measurements. An appreciable amount of AAMU was present in urine that was immediately acidified and analysed. Consequently, the ratio using AFMU was lower than that using total AAMU following transformation of AFMU in basic conditions. The proportion of AFMU in urine analysed immediately expressed as AFMU/(AFMU+AAMU) ratio did not correlate with urine pH, but was a function of the acetylation phenotype, with a low intergroup variability (64 ± 3% and 32 ± 5%, for rapid and slow acetylators, respectively; P < 0.00001, anova). Regarding CYP1A2 activity, a good correlation (r = 0.99) was observed between the metabolite ratios calculated from AFMU and AAMU, although the ratios calculated from AFMU were proportionately and systematically lower P < 0.00001, paired t‐test, slope 1.2).Conclusions  This study demonstrates that both AFMU and AAMU can be used for NAT2 and CYP1A2 metabolite ratio determinations. The reported conversion of AFMU into AAMU is unlikely to explain the large amount of AAMU in urine that was acidified and analysed immediately after voiding. The results suggest that AAMU is formed not solely through a nonenzymatic hydrolysis in urine, but in vivo by a NAT2 phenotype‐dependent pathway.
Safety profile of rofecoxib as used in general practice in England: results of a prescription‐event monitoring study
Authors: Layton Deborah , Riley Jane , Wilton Lynda V. , Shakir Saad A. W. 
Published: March 2003

Aims A postmarketing Prescription‐Event Monitoring study was undertaken to monitor the safety of rofecoxib, a cyclo‐oxygenase (COX)‐2 selective inhibitor prescribed in primary care in England.Methods Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events.Results There were 15 268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other nonsteroidal anti‐inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton‐pump inhibitors, histamine‐2 antagonists), and age (≥ 65 years) modified the risk of having minor GI events. During treatment or within 1 month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon), 101 thromboembolic events, three reports of acute renal failure, one each of Stevens–Johnson syndrome, severe anaphylaxis and angio‐oedema.Conclusions Doctors should continue to prescribe NSAIDs including COX‐2 selective inhibitors with caution.
Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study
Authors: Rukwied R. , Lischetzki G. , Mcglone F. , Heyer G. , Schmelz M. 
Published: March 2003

AbstractWhile histamine is the crucial mediator of pruritus in type 1 allergic reactions, its role in atopic dermatitis (AD) is unclear. In this study, the role of mast cell mediators in protein extravasation and pruritus was evaluated using intradermal microdialysis. The microdialysis capillaries were used to apply the mast cell degranulating substance compound 48/80 (C48/80; 0·05%) or histamine (0·01%) and also to deliver H1-blockers (cetirizine, 200 μg mL−1) in nine AD patients and nine controls. Large pore size membranes (3000 kDa) enabled simultaneous analysis of protein extravasation. Itch sensation was measured psychophysically and weal and flare reaction were evaluated planimetrically. Protein extravasation induced by histamine and C48/80 was significantly reduced in AD patients. Blockade of H1-receptors by cetirizine significantly reduced C48/80-induced protein extravasation in AD patients and controls to an identical level. C48/80-induced pruritus was abolished by cetirizine in controls, whereas pruritus in AD patients was unchanged after H1 blockade. We conclude that mast cell mediators others than histamine are involved in C48/80-induced pruritus in AD patients. Whether the reduced capacity of AD patients to induce protein extravasation is of pathophysiological relevance for pruritus remains to be established.
Cost evaluation of the medical management of neurofibromatosis 1: a prospective study on 201 patients
Authors: Wolkenstein P. , Durand-Zaleski I. , Moreno J.C. , Zeller J. , Hemery F. , Revuz J. 
Published: March 2003

Abstract
Neurofibromatosis 1 (NF1) is associated with many internal complications as well as skin manifestations, and patients may require a variety of medical and surgical interventions. We aimed to assess the medical needs of NF1 patients, and to evaluate the financial cost of the resources used for them in relation to the severity of the disease. We conducted a prospective analysis on a cohort of 201 patients in our referral centre for adults. Severity of the disease was assessed. Therapeutic management was considered as multidisciplinary if it required more than three different specialists. Plastic and dermatological surgery procedures performed were recorded. Hospital costs were computed over a 3-year period and included all hospitalization days, clinic visits and procedures performed in all departments where the patients were admitted. One hundred and thirty-seven patients had at least one out-patient procedure or one hospitalization during the follow-up period. The mean cost per patient per year was £810 (median 240; range 0–13,860). Multidisciplinary procedures were more frequent in moderately and severely affected NF1 patients than in milder cases (P &lt; 0·0001); hence, the costs for moderate and severe cases were higher than for less severe groups (P = 0·005). Plastic and/or dermatological surgery was performed with the same frequency in the different severity groups (71%). Regardless of the presence of serious intractable complications, the patients’ priority is for treatment of the disfigurement due to the disease. The management of these patients can be considered relatively inexpensive from the viewpoint of the healthcare system.
Inverse immunostaining pattern for synthesized versus endocytosed alpha‐granule proteins in human bone marrow megakaryocytes
Authors: De Larouzière Vanina , Brouland Jean‐Philippe , Souni Fadila , Drouet Ludovic , Cramer Elisabeth 
Published: March 2003

The time of appearance and pattern of expression of several α‐granule proteins, von Willebrand factor (VWF), fibrinogen and immunoglobulins (Ig) were examined and compared in human bone marrow megakaryocytes (MK) using an immunocytochemical approach. VWF is synthesized by immature MK, whereas it has been shown that fibrinogen is incorporated from the plasma into α‐granules. The present study was undertaken in order to determine whether there are chronological and morphological differences in the expression of VWF and fibrinogen in vivo in human MK. Seven paraffin‐embedded biopsies of normal human bone marrow were labelled with specific antibodies for VWF and for fibrinogen, detected by the alkaline phosphatase anti‐alkaline phosphatase (APAAP) method, and analysed by immunomorphometry. We found a clear, statistically significant, difference in the labelling pattern of VWF and fibrinogen. The expression of other endocytosed α‐granule proteins, immunoglobulins G and A, was therefore studied in bone marrow MK from two patients with multiple myeloma, one with monoclonal IgG and one with monoclonal IgA. The immunostaining pattern was similar to that of fibrinogen and different from VWF, and characteristic of endocytosed α‐granule proteins.This study demonstrates that: (i) immunohistochemical staining of MK α‐granules proteins distinguishes the peripheral cockade distribution pattern of endocytosed protein from the perinuclear pattern of endogenously synthesized proteins; (ii) VWF is present in human bone marrow MK when fibrinogen is not yet detectable; (iii) VWF synthesis ceases while fibrinogen is still being incorporated; (iv) immunoglobulins can be detected in MK cytoplasm, with a staining pattern resembling that of fibrinogen.