bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide
Authors: Bidstrup Tanja Busk , Bjørnsdottir Inga , Sidelmann Ulla Grove , Thomsen Mikael Søndergård , Hansen Kristian Tage 
Published: August 2003

Aims  To identify the principal human cytochrome P450 (CYP) enzyme(s) responsible for the human in vitro biotransformation of repaglinide. Previous experiments have identified CYP3A4 as being mainly responsible for the in vitro metabolism of repaglinide, but the results of clinical investigations have suggested that more than one enzyme may be involved in repaglinide biotransformation.Methods  [14C]‐Repaglinide was incubated with recombinant CYP and with human liver microsomes (HLM) from individual donors in the presence of inhibitory antibodies specific for individual CYP enzymes. Metabolites, measured by high‐performance liquid chromatography (HPLC) with on‐line radiochemical detection, were identified by liquid chromatography‐mass spectrophotometry (LC‐MS) and LC‐MS coupled on‐line to a nuclear magnetic resonance spectrometer (LC‐MS‐NMR).Results  CYP3A4 and CYP2C8 were found to be responsible for the conversion of repaglinide into its two primary metabolites, M4 (resulting from hydroxylation on the piperidine ring system) and M1 (an aromatic amine). Specific inhibitory monoclonal antibodies against CYP3A4 and CYP2C8 significantly inhibited (> 71%) formation of M4 and M1 in HLM. In a panel of HLM from 12 individual donors formation of M4 and M1 varied from approximately 160–880 pmol min−1 mg−1 protein and from 100–1110 pmol min−1 mg−1 protein, respectively. The major metabolite generated by CYP2C8 was found to be M4. The rate of formation of this metabolite in HLM correlated significantly with paclitaxel 6α‐hydroxylation (rs = 0.80; P = 0.0029). Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0‐OH). The rate of formation of M4 in CYP2C8 SupersomesTM was 2.5 pmol min−1 pmol−1 CYP enzyme and only about 0.1 pmol min−1 pmol−1 CYP enzyme in CYP3A4 SupersomesTM. The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6β‐hydroxylation (rs = 0.90; P = 0.0002). Three other metabolites were identified, namely, M0‐OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 SupersomesTM was 1.6 pmol min−1 pmol−1 CYP enzyme but in CYP2C8 Super‐somesTM it was only approximately 0.4 pmol min−1 pmol−1 CYP enzyme.Conclusions  The results confirm an important role for both CYP3A4 and CYP2C8 in the human in vitro biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug‐drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited.
Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6
Authors: Ohnuma Tohru , Shibata Nobuto , Matsubara Yoichiro , Arai Heii 
Published: August 2003

Aims  The cytochrome P‐450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6*10A producing a decrease of enzyme activity were screened in a large number of Japanese psychiatric subjects (n = 111) in order to investigate whether these mutated alleles affected the plasma concentration of haloperidol.Methods  Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method was performed to identify the CYP2D6*10A and CYP2D6*2 genotypes in subjects who had been taking haloperidol. For the screening of duplicated active CYP2D6 gene, allele‐specific long PCR was performed. Plasma concentration of haloperidol was measured by the enzyme immunoassay, and expressed as ‘plasma concentration dose ratio’ to normalize individual differences.Results  The plasma concentration–dose ratio showed large interindividual differences of approximately 18‐fold. PCR‐RFLP methods revealed that 29 (26.1%), 10 (9.0%), 39 (35.1%), 0 (0%), seven (6.3%) and 26 (23.4%) cases possessed the CYP2D6 genotypes *1/*1, *1/*2, *1/*10A, *2/*2, *2/*10A and *10 A/*10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration–dose ratio between the groups classified by CYP2D6*10A and *2 genotypes (Kruskal–Wallis test; P = 0.37), even in those cases whose daily doses were lower than 20 mg (n = 90, P = 0.91). Subjects having duplicated genes (n = 6) did not show significant differences of plasma concentration–dose ratio by comparison with subjects who had no duplicated genes (Mann–Whitney U‐test; P = 0.80).Conclusions  Gene duplication, and the common Japanese mutation CYP2D6*10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.
Pharmacodynamic characterization of the interaction between the glycoprotein IIb/IIIa inhibitor YM337 and unfractionated heparin and aspirin in humans
Authors: Graff Jochen , Klinkhardt Ute , Westrup Dagmar , Kirchmaier Carl M. , Breddin Hans Klaus , Harder Sebastian 
Published: August 2003

Aims  To investigate the pharmacodynamic interaction of unfractionated heparin (UFH) and acetylic salicylic acid (ASA) on YM337, a monoclonal humanized antibody of the platelet GPIIb/IIIa receptor.Methods  In a randomized, placebo‐controlled study three treatment groups each with six healthy volunteers received the following medication: group 1, ASA (3 days) + UFH + YM337 (placebo); group 2, ASA (placebo) + UFH (placebo) + YM337; group 3, ASA + UFH + YM337. Assessments were made over 24 h and included bleeding time (BT), ADP (20 µm)‐ and collagen (5 µg ml−1)‐induced platelet aggregation and PAC1 and CD62 expression measured by flow cytometry.Results  In group 3 BT was prolonged to 35 [median, 16–45 min (1,3 quartile)] after UFH administration, increasing to 45 [median, 42–45 min (1,3 quartile)] after YM infusion (6 h). BT remained elevated to 26 [median, 14–45 min (1,3 quartile)] at 24 h, while groups 1 and 2 returned to normal values. Collagen‐induced aggregation was 73% [median, 70–80% (1,3 quartile)] under YM337 alone, 79% [median, 72–80% (1,3 quartile)] under ASA + UFH and reduced only in group 3 to 24% [median, 18–29% (1,3 quartile)]. In both groups receiving active YM337, PAC1 expression showed a reduction to < 20% after 6 h of infusion. CD62 expression was not significantly affected by any treatment.Conclusion  UFH and YM337 have strong synergistic effects on BT, while coadministration of ASA strongly augments inhibitory effects of YM337 on collagen‐induced platelet aggregation.
Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids
Authors: Hesselink Dennis A. , Ngyuen Hien , Wabbijn Marike , Gregoor Peter J. H. Smak , Steyerberg Ewout W. , Van Riemsdijk Iza C. , Weimar Willem , Van Gelder Teun 
Published: August 2003

Aims  To evaluate the effect of corticosteroids on tacrolimus pharmacokinetics.Methods  In a randomized trial, kidney transplant recipients were treated with tacrolimus and mycophenolate mofetil with either daclizumab (n = 31) or 3 months of prednisone (n = 34). Tacrolimus dose‐adjusted predose concentrations (C0) at month 1–6 were compared between both groups and within the corticosteroid group before and after prednisone withdrawal.Results  At month 1 the tacrolimus dose‐adjusted C0 in the corticosteroid group was 83 ± 8 vs 119 ± 17 ng ml−1 mg−1 kg−1 in the daclizumab group. The tacrolimus dose‐adjusted C0 within the corticosteroid group at month 1 and 2 was 42% and 29% lower compared with month 4 (P < 0.001).Conclusions  A higher tacrolimus dose is required to reach target concentrations when used in combination with corticosteroids.
Identification of a novel splice‐site mutation in the CYP1A2 gene
Authors: Allorge Delphine , Chevalier Dany , Lo‐Guidice Jean‐Marc , Cauffiez Christelle , Suard Françoise , Baumann Pierre , Eap Chin B. , Broly Franck 
Published: August 2003

Aims  To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71‐year‐old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug.Methods  The nucleotide sequence of the 7 exons, exon‐intron boundaries and 5′‐flanking region of the CYP1A2 gene was analysed by direct sequencing.Results  Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians.Conclusions  This is the first report of a splice‐site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.
Allele and genotype frequency of CYP2C19 in a Tamilian population
Authors: Adithan C. , Gerard N. , Vasu S. , Rosemary J. , Shashindran C. H. , Krishnamoorthy R. 
Published: August 2003

Aims  To investigate the frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 alleles and CYP2C19 genotypes in a Tamilian population.Methods  The study was conducted in 112 unrelated healthy human volunteers. DNA was extracted from leucocytes and analyzed by the PCR‐RFLP protocol. The PCR product was digested with restriction enzymes (SmaI and BamH1) and then separated electrophoretically using polyacrylamide gel.Results  The frequencies of the CYP2C19*1, *2 and *3 alleles were 0.598 [95% confidence interval (CI) 0.507, 0.689], 0.379 (95% CI, 0.350,0.407) and 0.022 (95% CI −0.005, 0.049), respectively. The distribution of CYP2C19*1/*1,*1/*2, *1/*3, *2/*2 and *2/*3 genotypes were 0.295 (95% CI, 0.210, 0.379), 0.580 (95% CI, 0.488, 0.671), 0.027 (95% CI −0.003, 0.057), 0.080 (95% CI 0.030, 0.130) and 0.018 (95% CI −0.006, 0.042), respectively.Conclusions  The distribution of CYP2C19*1/*1 in the Tamilian population is lower than that in Caucasians, Africans and the North Indian population. The CYP2C19*1/*2 is significantly higher in Tamilians when compared with other populations. The CYP2C19*1/*3 allele, which was not reported in the North Indian and Caucasian populations has been identified in 2.7% of the Tamilian population.
The effect of ketoconazole and diltiazem on oestrogen metabolism in postmenopausal women after single dose oestradiol treatment
Authors: Annas Anita , Carlström Kjell , Alván Gunnar , AL‐Shurbaji Ayman 
Published: August 2003

Aims  The effect of the CYP3A4 inhibitors ketoconazole and diltiazem on the pharmacokinetics of oestrone was studied in six healthy postmenopausal women after treatment with a single oral dose of oestradiol.Methods  Plasma oestrone concentrations were measured following the administration of 1) oestradiol, 2) oestradiol and ketoconazole and 3) oestradiol and diltiazem.Results  Treatment with ketoconazole increased the AUC of oestrone (+ 4029 nmol l−1 h; 95% CI on the difference: 1588, 6471) and its Cmax (+ 306 nmol l−1; 95% CI on the difference: 117, 496). The AUC and Cmax of oestrone tended to increase on treatment with diltiazem although this did not reach the level of statistical significance.Conclusions  The small increase in the plasma concentrations of oestrone formed from 17β‐oestradiol during co‐administration with ketoconazole is unlikely to be clinically significant.
Factors affecting family‐centred service delivery for children with disabilities
Authors: Law M. , Hanna S. , King G. , Hurley P. , King S. , Kertoy M. , Rosenbaum P. 
Published: August 2003

AbstractBackground  The provision of family‐centred services (FCS) emphasizes a partnership between parents and service providers so that families are involved in every aspect of services for their child. There is evidence that providing FCS is associated with improvements in parents’ satisfaction with services, decreased parental stress, and positive child outcomes.Methods  The purpose of this study was to examine factors that are most important in determining parent perceptions of the family centredness of care and parent satisfaction with service. A cross‐sectional survey was completed by 494 parents, 324 service providers, and 15 CEOs from 16 organizations delivering children's rehabilitation services. Analyses were completed using a structural equation modelling approach.Results  Survey return rates ranged from 77 to 94%. Findings indicate that the principal determinants of parent satisfaction with services are the family‐centred culture at the organization and parent perceptions of FCS. Parent satisfaction with services was also influenced by the number of places where services were received and the number of health and development problems experienced by their child.Conclusion  Parent satisfaction with services is strongly influenced by the perception that services are more family centred, fewer places where services were received and fewer health and development problems for their child. Ways in which organizations can improve satisfaction through carrying out family‐centred behaviours are discussed.
Social patterning and prediction of parent‐reported behaviour problems at 3 years in a cohort study
Authors: Spencer N. , Coe C. 
Published: August 2003

AbstractObjective  To study the determinants of parent‐reported behaviour problems at 3 years and the value of behaviour problems reported at 8 and 18 months as predictors of behaviour at 3 yearsStudy design  A whole year birth cohortSetting  CoventryMain outcomes  Parent‐reported behaviour problems at 3 yearsParticipants A total of 2580 infants were enrolled into the Coventry Cohort Study at the birth visit by their family health visitor. Data on parent‐reported behaviour at all three ages (8 months, 18 months and 3 years) were available on 775 infants.Results  Living in rented accommodation [adjusted OR 2.38 (95% CI 1.36, 4.21); OR, odds ratio; CI, confidence intervals] and living in a smoking household [adjusted OR 2.47 (95% CI 1.53, 3.99)] were independently associated with parent‐reported behaviour problems at 3 years after controlling for other sociodemographic variables in logistic regression. The risk of behaviour problems at 3 years was increased in those reporting behaviour problems at 8 months [OR 3.77 (95% CI 1.73, 8.20)] and 18 months [OR 5.84 (95% CI 3.34, 10.23)] after adjustment for sociodemographic variables and other health problems. Behaviour at 8 months as a predictor of behaviour at 3 years had a sensitivity of 13.9%, a specificity of 95.7%, a positive predictive value of 32.6%, and positive and negative likelihood ratios of 3.23 and 0.90. For behaviour at 18 months, the sensitivity was 35.6%, the specificity 92.9%, the positive predictive value 42.9%, and positive and negative likelihood ratios 5.01 and 0.69.Conclusions  Parent‐reported behaviour problems at 8 and 18 months are highly specific but not particularly sensitive as predictors of behaviour problems at 3 years. Assuming the availability of an effective early intervention, use of a question such as that in the Warwick Child Health and Morbidity Profile at 8 and 18 months will identify, respectively, 21% and 36% of children at risk of parent‐reported behaviour problems at 3 years.
Intentional communicative behaviours of Turkish‐speaking children with normal and delayed language development
Authors: Topbaş S. , Maviş İ. , Erbaş D. 
Published: August 2003

AbstractBackground  Language profiles may predict whether children with slower language development will catch up to their peers by overcoming this transient phenomenon or will be at risk for persistent language disorders. The research of the last decade has focused on this topic. Some researchers have emphasized the significance of developing communicative intentions, which provide a potential predictor of later language competence. In Turkey, children with slower language development may not be diagnosed partly because of the lack of sufficient standardized assessment/evaluation tools, educational and therapeutic media, and qualified speech‐language therapists. In devising appropriate evaluation instruments, it is necessary to examine cross‐linguistic variation in early language acquisition. The purpose of this study therefore is to observe, describe and assess early communicative behaviours of 15–36 months old Turkish‐speaking children by using a functional communicative approach.Methods  The research was designed within a qualitative‐descriptive paradigm, involving qualitative data collection, observation and data analysis procedures. A total of 16 children, eight typically developing and eight language delayed, served as subjects. The classification system used in this study for coding children's communicative intentions was mostly based upon a system used by Dore (1977). Each variable was referred to as one of three intentional categories: regulating behaviours (request for object, request for action and protest), social interaction (direct attention, greeting and acknowledgement) and joint attention (comment/statement, asking for information and responding). A non‐parametric Mann–Whitney U‐test was carried out to verify the descriptive measures in comparing the delayed and normal group performance.Results  As expected, the mode of expressing communicative intentions varied as a function of age for both groups. Children with normal language development were observed to express intentions within the category of joint attention more frequently whereas the children with delayed language expressed intentions related to the variables of regulating behaviours and social interaction.
Use of an interactive game to increase food acceptance – a pilot study
Authors: Gillis L. 
Published: August 2003

AbstractBackground  Techniques to improve food selection in healthy children with long standing food refusal are limited. The use of educational games has been successful in getting children to increase knowledge in healthy eating, but it is uncertain whether this translates into behaviour change. Therefore the purpose of this study was to test the use of an interactive food game to increase food acceptance in healthy‐weight school‐age children with chronic food refusal.Methods  Children attended an outpatient clinic and played an interactive game with a therapist and one parent during which non‐preferred foods were consumed. Weekly recording of food consumption occurred with diet analysis by a Registered Dietitian three times during a 1‐year time span.Results  The children increased their repertoire of foods and had a more balanced intake. The changes in intake were incorporated into their daily meal patterns in the home setting and were maintained for 1 year.Conclusions  An interactive food game is a successful tool for increasing food variety in healthy children with chronic food refusal. As this report included only three subjects, the results will be used for subsequent work on this topic.
A clinical evaluation of ophthalmic assessment in children with sensori‐neural deafness
Authors: Guy R. , Nicholson J. , Pannu S. S. , Holden R. 
Published: August 2003

AbstractBackground  Since 1991, children with sensori‐neural deafness and their families within Southern Derbyshire have been supported by a multiagency approach to their diagnosis and management.Results  One hundred and twenty‐two children were seen at the Child Development Centre for an holistic assessment, and 110 of these children have had an ophthalmic assessment, of whom 48 (43.6%) were found to have ophthalmic abnormalities. These included 43 children (39.1%) with refractive errors, ranging from mild to severe. Of 82 children with uncomplicated deafness, 26 (31.7%) had refractive errors. The prevalence of ophthalmic problems was higher than the prevalence in hearing school children in the literature and in local pre‐school children. There were six cases of Usher syndrome. Twenty‐one children had more than one eye defect. The findings indicate that deaf and hearing impaired children are two to three times more likely to develop ophthalmic abnormalities than their hearing peers, which makes early detection of paramount importance. An important local outcome has been the establishment of guidelines for ophthalmic assessment to include assessment of vision and screening for Usher syndrome by electro‐physiological testing at aged 7 years and above. Screening has been completed to date in 78 children with congenital sensori‐neural deafness.Conclusions  Sensitive and efficient ophthalmic assessment and management are essential for all deaf and hearing impaired children and national guidelines need to be established for both assessment of vision and screening for Usher syndrome, based on further evaluated research.
Black South African children's understanding of health and illness: colds, chicken pox, broken arms and AIDS
Authors: Peltzer K. , Promtussananon S. 
Published: August 2003

AbstractPurpose  To examine the understanding of both health and illness (colds, broken arms, chicken pox, AIDS) in the same black South African childrenMethod  The sample included 60 children (30 were 5‐year‐olds and 30 were 9‐year‐olds) selected by simple random sampling from a rural primary school. They were interviewed, using a semi‐structured interview schedule, about their understanding of health issues and their exposure to learning about health or sickness.Results  Differences across age in children's expressed understanding of health and illnesses were found. The 9‐year‐olds were more likely to give objective signs of chicken pox and AIDS than the 5‐year‐olds. They also knew more about objective symptoms of colds, chicken pox and AIDS, and were more likely to mention non‐observable signs of colds and broken arms. Although there were no differences between the two age groups regarding ‘knowing’ strategies for avoiding illnesses, the older children had a more accurate knowledge about preventive measures than the younger children. The understanding of AIDS followed the same developmental sequence reported for children's understanding of general physical illness.Conclusion  The results have implications for the creation of developmentally appropriate and effective health and AIDS education curricula for primary and elementary grades.