bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11C‐doxepin in a placebo‐controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen
Authors: Tashiro Manabu , Mochizuki Hideki , Sakurada Yumiko , Ishii Kenji , Oda Keiichi , Kimura Yuichi , Sasaki Toru , Ishiwata Kiichi , Yanai Kazuhiko 
Published: December 2005

AimsThe strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second‐generation antihistamine and to compare it with that of ketotifen.MethodsEight healthy males (mean age 23.5 years‐old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C‐doxepin in a placebo‐controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined.ResultsH1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001).ConclusionIt is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders.Abbreviationshistamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood–brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)
Effect of rifampicin on the pharmacokinetics of pioglitazone
Authors: Jaakkola Tiina , Backman Janne T. , Neuvonen Mikko , Laitila Jouko , Neuvonen Pertti J. 
Published: December 2005

AimsThe effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans.MethodsIn a randomized, two‐phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M‐IV and M‐III into urine were measured up to 48 h.ResultsRifampicin decreased the mean total area under the plasma concentration‐time curve (AUC0−∞) of pioglitazone by 54% (range 20–66%; P = 0.0007; 95% confidence interval −78 to −30%) and shortened its dominant elimination half‐life (t1/2) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (Cmax) or time to peak (tmax) was observed. Rifampicin increased the apparent formation rate of M‐IV and shortened its tmax (P < 0.01). It also decreased the AUC0−∞ of M‐IV (by 34%; P = 0.0055) and M‐III (by 39%; P = 0.0026), shortened their t1/2 (M‐IV by 50%; P = 0.0008, and M‐III by 55%; P = 0.0016) and increased the AUC0−∞ ratios of M‐IV and M‐III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M‐IV/pioglitazone and M‐III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M‐XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M‐XI to pioglitazone by 240% (P = 0.0020).ConclusionsRifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.
The impact ofCYP2C8polymorphism and grapefruit juice on the pharmacokinetics of repaglinide
Authors: Bidstrup Tanja Busk , Damkier Per , Olsen Anette Kristensen , Ekblom Marianne , Karlsson Anders , Brøsen Kim 
Published: December 2005

AimsThe primary aim of the study was to investigate the possible effect of theCYP2C8*3allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose.MethodsThirty‐six healthy male subjects, genotyped forCYP2C8*3(11 genotyped asCYP2C8*1/*3, one asCYP2C8*3/*3 and24 asCYP2C8*1/*1), participated in a randomized, cross‐over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide.ResultsNeither the mean AUC0−∞(geometric mean ratio: 1.01; 95% CI: 0.93–1.1,P = 0.88) nor the meanCmax(geometric mean ratio: 1.05; 95% CI: 0.94–1.2,P = 0.35) of repaglinide were statistically significantly different in the group carrying theCYP2C8*3mutant allele compared with wild‐types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3‐hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75–0.87,P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC0−∞of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04–1.2,P = 0.0048), but had no statistically significant effect on thet1/2. There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg.ConclusionsThe pharmacokinetics of repaglinide in subjects carrying theCYP2C8*3mutant allele did not differ significantly from those in the wild‐types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.
Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation
Authors: Brunner M. , Ziegler S. , Di Stefano A. F. D. , Dehghanyar P. , Kletter K. , Tschurlovits M. , Villa R. , Bozzella R. , Celasco G. , Moro L. , Rusca A. , Dudczak R. , Müller M. 
Published: December 2005

AimsThe aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX®) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability.MethodsTwo phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of 153Sm‐labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco‐scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls.Results 153Sm‐labelled tablets reached the ascending colon after a mean ± SD 9.8 ± 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety‐six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased Cmax values from 1429 ± 1014 to 1040 ± 601 pg mL−1 (P = 0.028) and AUC values from 14 814 ± 11 254 to 13 486 ± 9369 pg h−1 mL−1 (P = 0.008). Mean residence time and tmax increased by 12–29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide.ConclusionsMMX®‐budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.
Grassland yield declined by a quarter in 5 years of free‐air ozone fumigation
Authors: VOLK MATTHIAS , BUNGENER PATRICK , CONTAT FRANÇOIS , MONTANI MYRTA , FUHRER JÜRG 
Published: December 2005

AbstractThe sensitivity of seminatural grasslands to ozone (O3) pollution is not well known, in spite of the important function of these common ecosystems for agriculture and nature conservation. A 5‐year field experiment was carried out at a rural, mid‐elevation site at Le Mouret (Switzerland) to investigate the effect of elevated O3 on yield and species composition of a permanent, extensively managed, species‐rich old pasture. Using a free‐air fumigation system, circular plots of 7 m diameter were exposed to either ambient air (control plots) or to air containing O3 of approximately 1.5 × ambient concentrations. The resulting accumulated O3 exposure over the threshold of 40 ppb for one season ranged from 13.3 to 59.5 ppm h in the elevated O3 plots, and from 1.0 to 20.7 ppm h in the control plots. Subplots in each ring were harvested three times each year, and harvested biomass was separated into functional groups (FGs) (grasses, legumes, forbs). Productivity in both treatments decreased over time, but the yield of O3‐exposed plots decreased faster than that of the control plots, with the reduction being twice as large by the end of the fifth season. Compared with the ambient air control, loss in annual dry matter yield was 23% after 5 years. The change in annual biomass production because of O3 stress was accompanied by a change in the fractions of FGs, with the legume fraction showing a strong negative response. Such long‐term effects of O3 stress could have negative implications for the maintenance of biological diversity in rural landscapes across large areas of Europe. The results from this first long‐term experiment show that a moderately elevated O3 level reduces the productivity of intact grasslands during a 5‐year exposure under real field conditions.
The effects of maternal exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin on testicular steroidogenesis in infantile male rats
Authors: HAAVISTO T. E. , MYLLYMÄKI S. A. , ADAMSSON N. A. , BROKKEN L. J. S. , VILUKSELA M. , TOPPARI J. , PARANKO J. 
Published: December 2005

SummaryExposure of adult male animals to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) decreases serum androgen concentrations. Reduction in androgen levels after maternal exposure has also been reported, but these results have not been reproduced. We have earlier shown that TCDD stimulates rather than inhibits testosterone synthesis in the prenatal rat testis. The aim of the present study was to elucidate in utero‐induced effects of TCDD on testicular steroidogenesis in the 14‐day‐old infant rats. At that time the foetal Leydig cell population is still the prevailing source of androgens. Pregnant Sprague–Dawley dams were given a single oral dose of TCDD (0, 0.04, 0.2, or 1.0 μg/kg) on day 13 of pregnancy. On postnatal day 14, the body weight of male offspring was reduced after exposure to 1.0 μg/kg TCDD (from 33.9 ± 1.66 g to 31.6 ± 2.67 g). Relative testis weight, plasma testosterone, luteinizing hormone and follicle‐stimulating hormone levels remained unaltered in all exposure groups. Moreover, in ex vivo incubations, testosterone and cAMP production was not affected. StAR protein level in the freshly isolated testes was increased in the 0.2 μg/kg group, and seminiferous cord diameter in the 0.04 μg/kg group. The present study confirms our earlier findings in in utero TCDD‐exposed foetal testis indicating that maternal TCDD exposure does not negatively influence the developmental testosterone production of foetal type Leydig cells in rats.
Prochloraz: an imidazole fungicide with multiple mechanisms of action
Authors: VINGGAARD ANNE MARIE , HASS ULLA , DALGAARD MAJKEN , ANDERSEN HELLE RAUN , BONEFELD‐JØRGENSEN EVA , CHRISTIANSEN SOFIE , LAIER PETER , POULSEN METTE ERECIUS 
Published: December 2005

SummaryProchloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America within gardening and agriculture. Screening studies have shown that prochloraz elicits multiple mechanisms of action in vitro, as it antagonizes the androgen and the oestrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts as an antiandrogen in the Hershberger assay by reducing weights of reproductive organs, affecting androgen‐regulated gene expressions in the prostate and increasing luteinizing hormone levels. In order to investigate the developmental effects of prochloraz, pregnant Wistar dams were dosed perinatally with 30 mg/kg prochloraz. Results showed that prochloraz significantly reduced plasma and testicular testosterone levels in gestational day 21 male foetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. In male pups a significant increase in nipple retention was found, and the weight of the bulbourethral glands was decreased. Behavioural studies showed that the activity level and sweet preference of adult males were significantly increased, indicating that exposure during gestation and lactation causes permanent effects in adulthood. Overall, these results indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis. Thus, a novel endocrine disruptor has been identified that is mechanistically interesting as it elicits dual mechanisms of action and acts as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. That a fungicide with such effects is so widely used is a cause for concern, and its use should be reduced, thereby minimizing the risk of human exposure.
Bio‐social determinants of fertility
Authors: KOHLER HANS‐PETER , RODGERS JOSEPH LEE , MILLER WARREN B. , SKYTTHE AXEL , CHRISTENSEN KAARE 
Published: December 2005

SummaryThis paper reviews several studies that investigated the potential role of genetic factors in determining fertility outcomes. Our review demonstrates convincingly that fertility contains genetic variance; that is, differences between humans in their genetic make‐up affects their fertility outcomes and fertility‐related behaviours. This finding is robust using both heritabilities and coefficients of genetic variation, and using both direct measures of fertility outcomes and also fertility precursors like fecundity, marriage, fertility expectations and attempts to get pregnant (proception). Moreover, genetic variance can change over short periods of time or across educational levels, specifically for females, and the relevance of genetic variance seems to increase during times of increasing reproductive choice.
Examining intention to control preschool children's sugar snacking: a study of carers in Uganda
Authors: ÅSTRØM A. N. , KIWANUKA S. N. 
Published: December 2005

Summary. Aim. The aims of this study were to investigate parents’ intention to control their children's sugar consumption and whether that behaviour is reported to occur in 3–5‐year‐old preschool children according to sociodemographics and attitudinal factors derived from the Theory of Planned Behaviour (TPB).Design. Some 589 children aged 3–5 years (51% boys, response rate = 85%) attending nursery schools in Kampala Central (urban) and Nakawa (suburban), Uganda, were examined clinically for dental caries. A questionnaire to assess sociodemographic factors, sugar intake and the constructs of the TPB was completed by their parents’/caregivers in face‐to‐face interviews.Results.  Analyses of variance revealed more positive attitudes and stronger intention to control children's intake of sugared snacks in highly as compared to less highly educated parents. Independent of educational level, parents having children with caries perceived themselves to have less control over their child’ intake of sugared snacks and perceived them to be more susceptible to tooth decay compared to parents of children without caries. In multiple linear regression, the TPB provided a significant prediction of intention with attitude (b = 0·16, P < 0·001), subjective norms (b = 0·18, P < 0·001) and perceived barriers (b = 0·11, P = 0·01), significant and reported sugar intake with attitudes (b = −0·10, P = 0·02), and perceived susceptibility (b = 16, P < 0·001) all significant.Conclusion.  The TPB components predict parental intention to control sugar snacking and whether that behaviour occurs in preschool children. The strengths of parents’ attitudes and reported level of child sugar snacking varied between diverse socioeconomic family groups. Implications for oral health education are discussed.
Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder
Authors: Frazier Jean A , Breeze Janis L , Makris Nikos , Giuliano Anthony S , Herbert Martha R , Seidman Larry , Biederman Joseph , Hodge Steven M , Dieterich Megan E , Gerstein Emily D , Kennedy David N , Rauch Scott L , Cohen Bruce M , Caviness Verne S 
Published: December 2005

Objective:  Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD.Methods:  Thirty‐two youths with DSM‐IV BPD (mean age 11.2 ± 2.8 years) and 15 healthy controls (HC) (11.2 ± 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral‐based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with α = 0.05.Results:  Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group.Conclusions:  Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.
Are the arginine vasopressin V1a receptor microsatellites related to hypersexuality in children with a prepubertal and early adolescent bipolar disorder phenotype?
Authors: Geller Barbara , Tillman Rebecca , Badner Judith A , Cook Edwin H 
Published: December 2005

Objective:  To examine family‐based transmission of the number of 5′ flanking arginine vasopressin V1a receptor (AVPR1A) microsatellites, which include [(GATA)14] and complex [(CT)4‐TT‐(CT)8‐(GT)24] repeats, in probands with a prepubertal and early adolescent bipolar disorder phenotype (PEA‐BP). Preferential transmission of the number of AVPR1A microsatellite repeats to hypersexual and uninhibited people‐seeking probands was hypothesized, based on reports from preclinical work in the literature.Methods:  Probands were 83 participants in an ongoing controlled study of PEA‐BP. The PEA‐BP phenotype was defined by DSM‐IV mania with at least one of the cardinal symptoms of mania (elation and/or grandiosity) to avoid diagnosing mania only by symptoms that overlapped with those for attention‐deficit hyperactivity disorder (ADHD). Comprehensive assessment of the probands included separate Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH‐U‐KSADS) interviews of parents about their children and of children about themselves. Hypersexuality and uninhibited people‐seeking were assessed from the corresponding WASH‐U‐KSADS items. Microsatellite genotyping of the AVPR1A repeats was conducted using fluorescently labeled primers and detected by laser‐induced fluorescence. Alleles were determined with the assistance of semi‐automated allele‐calling software. There were 32 complete, biological trios (28 informative families) for the GATA repeat and 34 complete, biological trios (30 informative families) for the complex repeat. Data were analyzed using case–control and family‐based association methods.Results:  Preferential transmission of AVPR1A GATA or complex repeats was not significant for hypersexuality or uninhibited people‐seeking, using the transmission disequilibrium test. Similarly, case–control analyses found no significant associations between hypersexuality or uninhibited people‐seeking and the number of AVPR1A GATA or complex repeats. For p < 0.05, there was about 80% power to detect odds ratios of 5.0 and 4.0 (in the family‐based analyses) and 3.5 and 2.6 (in the case–control analyses), for allele frequencies of 0.1 and 0.5, respectively.Conclusion:  Preferential transmission of AVPR1A to hypersexual or uninhibited people‐seeking probands was not supported.
Review and meta‐analysis of the phenomenology and clinical characteristics of mania in children and adolescents
Authors: Kowatch Robert A , Youngstrom Eric A , Danielyan Arman , Findling Robert L 
Published: December 2005

Objective:  Using predetermined criteria for study quality and methods, a literature review and meta‐analysis of seven reports about pediatric bipolar disorder (BPD) was conducted to determine if there is a consistent picture of the phenomenology and clinical characteristics of BPD in children and adolescents.Methods:  Searches were conducted in MedLine and PsycINFO using the terms mania, BPD, children and adolescents, and was limited to published articles in peer‐reviewed journals. Seven reports were selected that met the following criteria: a systematic method for the elicitation and reporting of symptoms and clinical characteristics of subjects; subjects were interviewed by a trained researcher or clinician; ages 5–18 years; use of a diagnostic system, either DSM or RDC for categorization; a consensus method for the establishment of the diagnosis of BPD.Results:  Most DSM‐IV symptoms of mania were common in the children and adolescents with BPD with the most common symptoms being increased energy, distractibility, and pressured speech. On average, four of five bipolar cases also showed threshold levels of irritable mood and grandiosity, and more than 70% of all cases showed elated/euphoric mood, decreased need for sleep, or racing thoughts. Roughly 69% of cases also showed poor judgment, whereas only half of bipolar cases demonstrated flight of ideas, and slightly more than one‐third showed hypersexuality or psychotic features.Conclusions:  The clinical picture that emerges is that of children or adolescents with periods of increased energy (mania or hypomania), accompanied by distractibility, pressured speech, irritability, grandiosity, racing thoughts, decreased need for sleep and euphoria/elation.