bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV‐1‐infected patients
Authors: Kappelhoff Bregt S. , Huitema Alwin D. R. , Crommentuyn Kristel M. L. , Mulder Jan W. , Meenhorst Pieter L. , Van Gorp Eric C. M. , Mairuhu Albert T. A. , Beijnen Jos H. 
Published: July 2005

AimsThe aim of this study was to develop and validate a population pharmacokinetic model of ritonavir, used as an antiviral agent or as a booster, in a large patient population and to identify factors influencing its pharmacokinetics.MethodsAmbulatory HIV‐1‐infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, the Netherlands, who were being treated with a ritonavir‐containing regimen were included. During regular visits, blood samples were collected for the determination of ritonavir plasma concentrations and several clinical chemistry parameters. Furthermore, complete pharmacokinetic curves were available in some patients. Single and multiple compartment models with zero‐order and first‐order absorption, with and without absorption lag‐time, with linear and nonlinear elimination were tested, using nonlinear mixed effect modelling (NONMEM). Pharmacokinetic parameters and interindividual, interoccasion and residual variability were estimated. In addition, the influence of several factors (e.g. patient characteristics, comedication) on the pharmacokinetics of ritonavir was explored.ResultsFrom 186 patients 505 ritonavir plasma concentrations at a single time‐point and 55 full pharmacokinetic profiles were available, resulting in a database of 1228 plasma ritonavir concentrations. In total 62% of the patients used ritonavir as a booster of their protease inhibitor containing antiretroviral regimen. First order absorption in combination with one‐compartment disposition best described the pharmacokinetics of ritonavir. Clearance, volume of distribution and absorption rate constant were 10.5 l h−1 (95% prediction interval (95% PI) 9.38–11.7), 96.6 l (95% PI 67.2–121) and 0.871 h−1 (95% PI 0.429–1.47), respectively, with 38.3%, 80.0% and 169% interindividual variability, respectively. The interoccasion variability in the apparent bioavailability was 59.1%. The concomitant use of lopinavir resulted in a 2.7‐fold increase in the clearance of ritonavir (P value < 0.001). No patients characteristics influenced the pharmacokinetics of ritonavir.ConclusionsThe pharmacokinetic parameters of ritonavir were adequately described by our population pharmacokinetic model. Concomitant use of the protease inhibitor lopinavir strongly influenced the pharmacokinetics of ritonavir. The model has been validated and can be used for further investigation of the interaction between ritonavir and other protease inhibitors.
Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain
Authors: Lennernäs B. , Hedner T. , Holmberg M. , Bredenberg S. , Nyström C. , Lennernäs H. 
Published: July 2005

AimsIt is estimated that two‐thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated.MethodsEleven Caucasian patients (seven male and 4 female, aged 34–75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double‐blind, cross‐over trial, consisting of three 1‐day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 µg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography‐mass spectrometry/mass spectrometry (LC‐MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire.ResultsThe data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 µg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted Cmax (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400–100µg) in dose adjusted AUC from the three‐period crossover analysis was −0.016 min·ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25–40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. tmax increased from 39.7 ± 17.4 to 48.7 ± 26.3 and 56.7 ± 24.6 min for the 100, 200 and 400 µg doses, respectively. Adverse events were few and did not increase with increasing dose.ConclusionWith this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8–11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.
Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes
Authors: Glaeser H. , Drescher S. , Eichelbaum M. , Fromm M. F. 
Published: July 2005

AimsTo investigate the potential induction by rifampicin of intestinal CYP2C8, CYP2C9, CYP2D6 and CYP3A4 using preparations of human enterocytes.MethodsUsing a multilumen perfusion catheter shed human enterocytes were collected from 6 healthy subjects before and after 10 days of 600 mg day−1 oral rifampicin administration. The protein expression of CYP2C8, CYP2C9, CYP2D6 and CYP3A4 as well as that of CYP3A4 mRNA was determined using Western blotting and RT‐PCR, respectively.ResultsCYP3A4 mRNA expression in shed enterocytes increased from 74.6 ± 44.2 to 143.2 ± 68.4 a.u. (P < 0.05, 95% CI: 21.8–115.3). Expression of CYP2C8 and CYP2C9 increased from 5.1 ± 0.9 to 10.4 ± 2.3 pmol mg−1 protein (P < 0.01, 95% CI: 2.8–7.7) and from 4.2 ± 1.4 to 5.7 ± 1.1 pmol mg−1 protein (P < 0.01, 95% CI: 0.6–2.4), respectively. No significant difference in CYP2D6 expression before and during rifampicin intake was observed. Rifampicin administration also resulted in a significant induction of CYP3A4 protein (34.1 ± 10.7 vs. 113.9 ± 31.1 pmol mg−1 protein (P < 0.001, 95% CI: 51.8–107.6)). Ex vivo incubation of enterocyte homogenates with verapamil resulted in a significantly increased production of the metabolites formed via CYP3A4 (D‐617: 125.9 ± 118.8 vs. 277.2 ± 145.5 pmol min−1 mg−1 protein (P < 0.05, 95% CI: 30.1–272.5); norverapamil: 113.0 ± 57.9 vs. 398.4 ± 148.2 pmol min−1 mg−1 protein (P < 0.05, 95% CI: 47.2–523.6)).ConclusionOur findings indicate that shed enterocytes are a useful tool to study the expression, regulation and function of drug metabolizing enzymes. Induction of intestinal CYP2C8 and CYP2C9 might contribute in part to rifampicin – mediated drug interactions, in addition to their hepatic counterparts and intestinal and hepatic CYP3A4.
A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first‐pass hepatic extraction
Authors: Gordi Toufigh , Xie Rujia , Huong Nguyen V. , Huong Dinh X. , Karlsson Mats O. , Ashton Michael 
Published: July 2005

AimsPrevious studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time‐dependent pharmacokinetics of artemisinin in healthy subjects.MethodsTwenty‐four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two‐compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction.ResultsArtemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half‐life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non‐linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first‐pass extraction.ConclusionArtemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the time‐course of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.
A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma
Authors: Houghton C. M. , Woodcock A. A. , Singh D. 
Published: July 2005

AimsWe  have  compared  the  ability  of  plethysmography  (sGaw),  impulse  oscillometry (IOS) and spirometry (FEV1, MMEF) to detect bronchodilation in response to an anticholinergic.MethodsIOS (R5, R20, X5, RF), sGaw and spirometry were measured in 12 healthy subjects and 12 asthmatics. Variability was assessed by performing two measurements, 30 min apart and the effect of increasing the number of readings for each sGaw measurement was also studied. Ipratropium bromide (IB) 10, 20, 100 and 200 µg was administered and the sensitivity of the methods compared by determining the lowest dose that caused changes greater than variability.ResultsIn healthy subjects significant changes (P ≤ 0.05) occurred at 10 µg for FEV1 (mean [95% CI]; 1.3%[0.3–2.3]), R5 (mean [95% CI]; −7.9%, [−13.2–2.6]) and R20 (mean [95% CI], −6.4%, [−11.4–1.4]). No significant change was detected when the mean of 3 sGaw readings was used, but with 10 readings significant change was observed at 20 µg; (mean increase [95% CI] 15.2%[8.3–22.1]). In asthmatics significant changes (P ≤ 0.05) occurred with IB 10 µg for sGaw (mean [95% CI] 25.6%[11.1–40.1]), R5 (mean [95% CI]−11.3%, [−15.5–7.2]), RF (mean [95% CI] 11.7%[6.1–16.3]), FEV1 (mean [95% CI] 5.1%[2.6–7.7]) and MMEF (mean [95% CI] 12.3%[2.3–22.2]).ConclusionIOS and spirometry are more sensitive than sGaw in healthy subjects, but the sensitivity of sGaw improved when the number of readings was increased. The most sensitive method for assessing bronchodilation in asthmatics was sGaw.
Mothers’ voice: a qualitative study on feeding children with cerebral palsy
Authors: Sleigh G. 
Published: July 2005

AbstractBackground  Around one third of children with cerebral palsy have severe difficulty eating and drinking and are at risk of undernourishment. A gastrostomy feeding tube may be offered as a way of providing nourishment as it bypasses the main physical difficulties. For the families feeding and concerns about the method of feeding affect many areas of their daily life but we know little about what the experience is actually like. This study aimed to explore mothers’ experience of feeding children with cerebral palsy.Methods  Ten principal carers for children with cerebral palsy and severe eating difficulty were interviewed. Four of the children, one girl and three boys aged 2.5 to 4.5 years were being fed solely by mouth and six children, three girls and three boys, aged 4.5 years to 15 years and 10 months, were fed via a gastrostomy feeding tube. Long, loosely structured tape recorded interviews were transcribed and manually analysed using a phenomenological approach. This involved extracting and coding each relevant phrase that contained meaning; then through sequential stages of ordering and reduction into themes the invariant meanings were uncovered. The transcripts were analysed in two groups, oral and gastrostomy feeding, in an identical manner.Results  Phenomenological analysis resulted in two prose accounts that described in depth the essence of the experience. The accounts were mutually informative. Both groups treasured feeding by mouth suggesting that support for oral feeding should be given a higher priority. The accounts explained why some professional encounters added to families’ stress and why consistency of care is so important. The study gives insight about the kinds of support families find helpful.Conclusions  This study should help those involved to understand the families’ predicament better and so make a contribution towards providing more appropriate support.
Feeding practices in 105 counties of rural China
Authors: Wang X. , Wang Y. , Kang C. 
Published: July 2005

AbstractBackground  China has the largest population in the world with more than 70% of the people living in rural areas. Over 34% of children under the age of 5 years are responded to show moderate or severe growth stunting, so United Nations International Children's Emergency Fund and Chinese Ministry of Health conducted this large‐scale survey in China. This study aimed to learn the feeding practice, to find the problems in child‐feeding practice and to provide evidence for the government to develop an approach to child malnutrition in rural China.Methods  A structured  questionnaire  was  used  to  survey  21 036  mothers  of  children  with  age  of 0–24 months.Results  Of the 20 915 children, 98.22% were breastfeeding and 24.36% were exclusively breastfeeding. The proportion of children with weekly protein intake was 78.47%. Among the infants under 4 months, the risk of pneumonia in the group of exclusive breastfeeding was 1.69%, while in the group of non‐exclusive breastfeeding was 3.63%, showing a statistically significant difference between the two groups. The risk of diarrhoea in the group of exclusive breastfeeding and in the group of non‐exclusive breastfeeding among the infants under 4 months was 24.37% and 40.86%, respectively, also showing a statistically significant difference between the two groups. For children with age 4–6 months, the complementary feeding contributed to a higher prevalence of diarrhoea, but not pneumonia.Conclusions  The breastfeeding was very common, but the exclusive breastfeeding was quite low and the exclusive breastfeeding for children under the age of 4 months decreased the risks of pneumonia and diarrhoea. For children with age 4–6 months, the exclusive breastfeeding could decrease the risk of diarrhoea, too. Protein intake was insufficient for children in rural China. The rural people lacked health knowledge and were greatly influenced by traditional feeding practices.
Young adolescents’ perceptions of peer sexual behaviours: the role of television viewing
Authors: Eggermont S. 
Published: July 2005

AbstractObjective  To investigate whether young adolescents’ perceptions of peers’ sexual activity is related to the amount of television viewing, and whether this relationship may be moderated by young adolescents’ pubertal development.Methods  This study used a sample of 12‐ and a sample of 15‐year‐olds; 2127 respondents in a targeted sample of nine schools in Flanders (the Dutch‐speaking part of Belgium), completed a questionnaire with questions about their television viewing behaviour, the estimated prevalence of given sexual activities in peers, and self‐reports on pubertal development and sexual experience.Results  In the sample of 12‐year‐olds, results demonstrated that a quadratic regression equation provides the best description for the relationship between television viewing and perceptions of peer sexual behaviours, indicating that the ‘effect’ of television only starts off after a level of about 45 h of television viewing per week. Further exploration showed that this relationship remains significant when controlling for gender and sexual experience, and is stronger at more advanced levels of pubertal development. In the sample of 15‐year‐olds, linear and unmoderated relationships were found. Irrespective of their pubertal status, gender, or level of sexual experience, television viewing is related to higher expectations of peers’ sexual activities.Conclusion  Concerns about the impact of television viewing on sexual health should not be limited to older adolescents. This research has identified 12‐year‐olds who display a higher level of pubertal development and generally spend much time with television viewing as a category of viewers‐at‐risk.
The secular trends in height and weight of Turkish school children during 1993–2003
Authors: Simsek F. , Ulukol B. , Baskan Gulnar S. 
Published: July 2005

AbstractBackground  Secular changes in growth and development can be considered as the changing pattern of somatic development of children in a particular population from one generation to another. Developing countries, which have many changes in socio‐economical conditions, reveal various trends in growth. The aims of this study were to analyse growth trends in weight and height of Turkish children from a school in Ankara over the period 1993–2003 with 10‐year time interval, and to determine the relation between secular trends.Methods  Anthropometric measurements of 1214 children and adolescents (611 boys and 603 girls) aged between 7 and 15 years from Ankara, Turkey, obtained cross sectionally in 2003 were compared with measurements of 867 school children (451 boys and 416 girls) from a previous study which had been obtained in the same primary school in 1993. For 7–15 years of age the increments of weight and height were determined, and analysed statistically.Results  In 2003 survey boys and girls were taller and heavier than their peers from previous study in all age groups. For all cohorts in boys from 7 to 15 years, weight increments between 2.7 and 6.3 kg/decade and height increments between 1.7 and 5.5 cm/decade were demonstrated. For girls in the same cohorts, weight increments between 2.8 and 6.5 kg/decade and height increments between 1.8 and 5.7 cm/decade were indicated. Both weight and height increments suggest an upward displacement of growth curves in this interval of 10 years.Conclusion  A significant secular increase in weight and height measurements were found in 7–15‐year‐old boys and girls in Ankara. These secular increases can be explained with improvements in social and health indicators that reflect the overall health status of the population. The secular increases in growth of Turkish school children may reveal updates of growth standards.
Depressive symptoms in mothers of pre‐school children Effects of deprivation, social support, stress and neighbourhood social capital
Authors: Reading Richard 
Published: July 2005

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Mulvaney C &
Kendrick D.
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2005
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Background  Depressive symptoms in mothers of young children can have serious consequences for the health of the child. In particular, children whose mothers are experiencing depressive symptoms are at significantly greater risk of poisoning and accidental injury. A mother's risk of developing depressive symptoms has been shown to be related to socio‐economic disadvantage, high levels of stress and a perceived lack of social support. Residents who perceive their neighbourhoods to be of low social capital are more likely to report poor mental health. The aim of this study was to investigate the relationship between maternal depressive symptoms, deprivation, social support, stress and neighbourhood social capital in a group of mothers living in deprived areas of Nottingham, UK.Design and setting  A postal questionnaire at entry to a randomized controlled trial (RCT) assessed socio‐demographic characteristics and a second questionnaire, 21 months later, assessed depressive symptoms, perceived lack of social support, self‐reported stress and individual‐level assessment of neighbourhood social capital.Participants  A total of 846 mothers of young children living in deprived areas in Nottingham, UK, enrolled in the control group of an RCT.Results  One‐third of mothers reported high levels of depressive symptoms. Neighbourhood‐level deprivation and receiving means‐tested benefits were independently associated with maternal depressive symptoms. A lack of social support and high levels of self‐reported stress were also strongly associated with depressive symptoms. Individual‐level assessment of neighbourhood social capital was not associated with depressive symptoms amongst mothers after adjusting for self‐reported stress.Conclusions  Neighbourhood‐ and individual‐level variables of deprivation and psychological distress are more important than mothers’ assessment of the social capital of the neighbourhood in which she lives in determining the risk of depressive symptoms. Interventions aimed at supporting mothers of young children may be more effective at reducing the risks of depressive symptoms and consequent risks to the child's health than interventions aimed at improving a neighbourhoods’ social capital.
End of life care: a discursive analysis of specialist palliative care nursing
Authors: Skilbeck Julie K. , Payne Sheila 
Published: July 2005

Aim.  The aim of this paper is to consider alternative approaches to service delivery for patients with chronic life‐limiting illnesses other than cancer. It will also discuss the issues that arise when considering specialist palliative care services within a broader public health context in the United Kingdom.Background.  Contemporary specialist palliative care in the United Kingdom can be said to have two main client groups: the majority are people with a diagnosis of cancer, and a minority are those with a number of other chronic illnesses. From the evidence to date, patients dying from chronic, non‐malignant disease experience a considerable number of unmet needs in terms of symptom control and psychosocial support. Although debates in the literature over the last decade have challenged the focus of specialist palliative care services on patients with a cancer diagnosis, only a minority of those with other chronic illnesses receive specialist palliative care services.Discussion.  Current models of specialist palliative care may not be the most appropriate for addressing the complex problems experienced by the many patients with a non‐cancer diagnosis. We suggest that care should be structured around patient problems, viewing specialist palliative care as a service for those with complex end of life symptoms or problems. A role for innovative nurse‐led care is proposed.Conclusion.  Reframing the approach to specialist palliative care in the United Kingdom will require great effort on the part of all health and social care professionals, not least nurses. Critical and creative thinking are prerequisites to the development of new models of working. We suggest that a more coherent approach to research and education is required, in particular strategies that explore how patients and nurses can work together in exploring experiences of illness in order to develop more proactive approaches to care.