bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of azole antifungals ketoconazole and fluconazole on the pharmacokinetics of dexloxiglumide
Authors: Jakate Abhijeet S. , Roy Partha , Patel Alpita , Abramowitz Wattanaporn , Persiani Stefano , Wangsa Julie , Kapil Ram 
Published: October 2005

AimsDexloxiglumide is a new CCK1 receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9. The objectives of these two separate randomized, two‐period, two‐treatment crossover studies were to investigate the effects of steady‐state ketoconazole, a model CYP3A4 inhibitor (Study 1), and steady‐state fluconazole, a model CYP2C9 inhibitor (Study 2), on the pharmacokinetics of dexloxiglumide in healthy subjects.MethodsPlasma samples were analysed for dexloxiglumide and its primary metabolites: O‐demethyl dexloxiglumide (ODM; Study 1 and 2) and dexloxiglumide carboxylic acid (DCA; Study 2).ResultsFollowing ketoconazole coadministration, dexloxiglumide Cmax increased by 32% (90% confidence intervals (CI) 112–154), with unchanged ODM Cmax; AUC of dexloxiglumide and ODM increased by 36% (90% CI 124–140 and 128–142, respectively). No changes were observed in dexloxiglumide or ODM t½. Fluconazole coadministration caused a 77% increase (90% CI 154–204) in dexloxiglumide Cmax, no change in ODM Cmax and a 32% decrease (90% CI 62–75) in DCA Cmax. Fluconazole coadministration resulted in a 2.5‐fold increase (90% CI 235–267) in dexloxiglumide AUC, 40% increase (90% CI 136–156) in ODM AUC and an 18% decrease (90% CI 82–94) in DCA AUC. The t½ of all three analytes increased by approximately 2‐fold with fluconazole coadministration (P‐value < 0.05).ConclusionsKetoconazole caused a minimal increase while fluconazole caused a moderate increase in dexloxiglumide systemic exposure with no change in the adverse event profile of dexloxiglumide.
Fluvoxamine impairs single‐dose caffeine clearance without altering caffeine pharmacodynamics
Authors: Culm‐Merdek Kerry E. , Von Moltke Lisa L. , Harmatz Jerold S. , Greenblatt David J. 
Published: October 2005

BackgroundCoadministration of fluvoxamine impairs the clearance of caffeine and prolongs its elimination half‐life, which is attributable to inhibition of CYP1A2 by fluvoxamine. The clinical importance of this interaction is not established.AimTo evaluate the effects of fluvoxamine on the kinetics and dynamics of single doses of caffeine.MethodsSeven healthy subjects received single 250 mg doses of caffeine (or matching placebo) together with fluvoxamine (four doses of 100 mg over 2 days) or with matching placebo in a double‐blind, four‐way crossover study. For 24 h after caffeine or placebo administration, plasma caffeine and fluvoxamine concentrations were determined. Psychomotor performance, sedation, and electroencephalographic (EEG) ‘beta’ frequency activity were also assessed.ResultsFluvoxamine significantly reduced apparent oral clearance of caffeine (105vs.9.1 mL min−1,P < 0.01; mean difference: 95.7 mL min−1, 95% CI: 54.9–135.6), and prolonged its elimination half‐life (4.9vs.56 h,P < 0.01; mean difference: 51 h, 95% CI: 26–76). Caffeine produced CNS‐stimulating effects compared with placebo. However, psychomotor performance, alertness, or EEG effects attributable to caffeine were not augmented by coadministration of fluvoxamine.ConclusionsFluvoxamine greatly impaired caffeine clearance, but without detectable changes in caffeine pharmacodynamics. However, this study does not rule out possible adverse effects due to extensive accumulation of caffeine with daily ingestion in fluvoxamine‐treated individuals.
Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients
Authors: Dansirikul C. , Duffull S. B. , Morris R. G. , Tett S. E. 
Published: October 2005

AimTo explore relationships between sirolimus dosing, concentration and clinical outcomes.MethodsData were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann–Whitney U‐tests).ResultsSeveral patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day−1, and sirolimus concentration greater than 12 µg l−1. No relationship was shown for PLT and dichotomized sirolimus dose or concentration.ConclusionsGiven this relationship between sirolimus concentration and effect, linked population pharmacokinetic–pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.
Trimethoprim–sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant recipients
Authors: Böttiger Ylva , Brattström Christina , Bäckman Lars , Claesson Kerstin , Burke James T. 
Published: October 2005

AimsThe influence of the trimethoprim–sulphamethoxazole combination on the steady‐state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients.MethodsFifteen kidney transplant recipients were treated with sirolimus 8–23 mg m−2 in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and Cmax were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg).ResultsOn day 6, the mean (95% confidence interval) whole blood sirolimus AUC(0−24 h) was 1040 (846, 1234) ng ml−1 and mean Cmax was 109 (88, 129) ng ml−1. Corresponding values on day 7 were AUC(0−24 h) 1060 (826, 1293) ng ml−1 and Cmax mean 107 (87, 127)  ng ml−1.  The  mean  difference  in  the  dose‐corrected  AUC(0−24 h)  was  0.40% (−9.4, +10).ConclusionsA single dose of trimethoprim–sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.
Suicide and self‐harm following prescription of SSRIs and other antidepressants: confounding by indication
Authors: Didham Rebecca C. , McConnell Doug W. , Blair Hayden J. , Reith David M. 
Published: October 2005

AimTo identify the incidence and risk of suicide and self harm, among patients prescribed antidepressant drugs.MethodsA retrospective cohort study, with nested case control, of patients identified from a nonrandom sample of general practices in New Zealand from 1996 to 2001. A total of 57 361 patients who received a prescription for a single antidepressant were identified from the RNZCGP Research Unit Database. Suicides within 120 days of a prescription were identified from the New Zealand National Mortality Database and self‐harm events within 120 days of a prescription were identified from the New Zealand Hospital discharge database.Results26 suicides and 330 episodes of self‐harm were identified within 120 days of an antidepressant prescription. On univariate analysis the association, expressed as OR (95% CI), between selective serotonin reuptake inhibitors (SSRIs) and self harm and suicide were 2.26 (1.27–4.76) and 1.92 (0.77–4.83), respectively. When corrected for the confounding effects of age, gender and depression/suicidal ideation there was an association between SSRIs and self harm, OR 1.66 (95% CI 1.23–2.23), but not for suicide, 1.28 (0.38–4.35). Paroxetine was a significant risk factor for suicide on univariate analysis, 4.23 (1.19–14.95), but not when corrected for age, gender and depression/suicidal ideation, 2.76 (0.30–24.87).ConclusionsAge, gender and pre‐existing depression/suicidal ideation are important confounders in observational studies of the association between antidepressants and suicide or self harm.
Prediction ofin vivodrug–drug interactions fromin vitrodata: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant
Authors: Brown Hayley S. , Ito Kiyomi , Galetin Aleksandra , Houston J. Brian 
Published: October 2005

AimsSuccess of the quantitative prediction of drug–drug interactions via inhibition of CYP‐mediated metabolism from the inhibitor concentration at the enzyme active site ([I]) and thein vitroinhibition constant (Ki) is variable. The aim of this study was to examine the impact of the fraction of victim drug metabolized by a particular CYP (fmCYP) and the inhibitor absorption rate constant (ka) on prediction accuracy.MethodsDrug–drug interaction studies involving inhibition of CYP2C9, CYP2D6 and CYP3A4 (n = 115) were investigated. Data onfmCYPfor the probe substrates of each enzyme andkavalues for the inhibitors were incorporated intoin vivopredictions, alone or in combination, using either the maximum hepatic input or the average systemic plasma concentration as a surrogate for [I]. The success of prediction (AUC ratio predicted within twofold ofin vivovalue) was compared using nominal values offmCYP = 1 andka = 0.1 min−1.ResultsThe incorporation offmCYPvalues intoin vivopredictions using the hepatic input plasma concentration resulted in 84% of studies within twofold ofin vivovalue. The effect ofkavalues alone significantly reduced the number of over‐predictions for CYP2D6 and CYP3A4; however, less precision was observed compared with thefmCYP. The incorporation of bothfmCYPandkavalues resulted in 81% of studies within twofold ofin vivovalue.ConclusionsThe incorporation of substrate and inhibitor‐related information, namelyfmCYPandka, markedly improved prediction of 115 interaction studies with CYP2C9, CYP2D6 and CYP3A4 in comparison with [I]/Kiratio alone.
Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation
Authors: Brunner Martin , Dehghanyar Pejman , Seigfried Bernd , Martin Wolfgang , Menke Georg , Müller Markus 
Published: October 2005

AimsThe study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN“ 50 mg enteric coated tablets.MethodsDiclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14‐day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days. In vivo microdialysis in subcutaneous and muscle tissues was performed immediately after the final doses from both treatments on day 4, and 48 h later. Plasma samples were taken simultaneously.ResultsThe relative bioavailability of diclofenac in subcutaneous adipose and skeletal muscle tissue was substantially higher after topical compared with oral dosing (324% and 209%, respectively) whereas relative plasma bioavailability was 50‐fold lower. Plasma Cmax values were approximately 250‐fold lower after topical compared with oral drug administration (i.e. median values = 4.89 ng mL−1; 95% CI: 3.37–7.68 and 1240 ng mL−1; 95% CI: 787–1389 ng mL−1). Both treatments were well tolerated.ConclusionsOwing to its favourable penetration characteristics and low systemic availability, MIKA Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.
Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice
Authors: Yamashita Namiko , Osato Motomi , Huang Liqun , Yanagida Masatoshi , Kogan Scott C. , Iwasaki Masayuki , Nakamura Takuro , Shigesada Katsuya , Asou Norio , Ito Yoshiaki 
Published: October 2005

SummaryHaploinsufficiency of RUNX1/AML1 is associated with familial platelet disorder with a predisposition to acute myeloid leukaemia (FPD/AML), but the causal relationship remains to be addressed experimentally. Mice heterozygous for the Runx1 null mutation, Runx1+/−, are considered to be genetically comparable with human FPD/AML patients but do not develop spontaneous leukaemia. To induce additional genetic alterations, retroviral insertional mutagenesis was employed with the use of BXH2 mice, which develop myeloid leukaemia because of the random integration of retrovirus present in the mouse. Heterozygous disruption of Runx1 in BXH2 mice resulted in a shortening of the latency period of leukaemia. In addition, BXH2‐Runx1+/− mice exhibited more marked myeloid features than control mice. Moreover, the c‐Kit gene, mutated in human RUNX leukaemias, was recurrently activated in BXH2‐Runx1+/− mice, and a colony‐forming assay revealed synergism between the Runx1+/− status and c‐KIT overexpression. In conclusion, the BXH2‐Runx1+/− system is a promising mouse model to investigate the mechanism of leukaemogenesis in FPD/AML.
Managing the risk of transmission of variant Creutzfeldt Jakob disease by blood products
Authors: Ludlam Christopher A. , Turner Marc L. 
Published: October 2005

SummaryWhereas plasma‐derived clotting factor concentrates now have a very good safety record for not being infectious for lipid enveloped viruses, concern has arisen about the possibility that prion diseases might be transmitted by blood products. There is epidemiological evidence that classical sporadic Creutzfeld Jakob disease (CJD) is not transmitted by blood transfusion. There is now good evidence that the abnormal prion associated with variant CJD can be transmitted by transfusion of fresh blood components and infect recipients. To reduce the risk of the pathological prion in the UK infecting recipients of clotting factor concentrates, these are now only manufactured from imported plasma collected from countries where there has not been bovine spongiform encephalopathy (BSE) in cattle and the risk of variant CJD in the population is, therefore, considered negligible. The safety of these concentrates is also enhanced because prion protein is, to an appreciable extent, excluded by the manufacturing process from the final product. To help reduce the chance of prion transmission by fresh blood products, donations are leucodepleted, there is increasing use of imported fresh frozen plasma (especially for treating children) and potential donors, who have been recipients of blood since 1980 (the beginning of the BSE epidemic in cattle) are deferred.
Erythropoietin levels in the different clinical forms of hereditary spherocytosis
Authors: Rocha S. , Costa E. , Catarino C. , Belo L. , Castro E. M. B. , Barbot J. , Quintanilha A , Santos‐Silva A. 
Published: October 2005

SummaryErythropoietin (EPO), the main growth factor responsible for the regulation of red blood cell production, may be overproduced when blood loss or haemolysis occurs. Patients with mild hereditary spherocytosis (HS) are able to maintain normal haemoglobin concentration, whereas typical and severe HS patients develop an anaemic state. Splenectomy usually reverses anaemia. We aimed to clarify the role of EPO in the response to enhanced spherocyte destruction, and to look for a linkage with the broad clinical spectra of HS. EPO levels, reticulocyte count and production index (RPI), other parameters used to classify HS and the protein deficiencies underlying HS were evaluated in previously diagnosed unsplenectomised (n = 24) and splenectomised (n = 10) patients presenting mild, typical or severe HS. A significant increase in EPO was observed in all unsplenectomised HS patients. In the mild form, a significant correlation of EPO with reticulocyte count and RPI was observed; however, this correlation disappeared in typical HS patients. Splenectomised HS patients presented a correction in EPO levels in all forms of HS, although the reticulocyte count and RPI sustained slightly higher values. Our data show HS as a disease linked to an overproduction of EPO, according to the severity of the disease; however, a disturbance in erythropoiesis seems to occur in typical HS. Moreover, splenectomy leads to a correction in the EPO levels.
Monitoring gastric lymphoma in peripheral blood by quantitative IgH allele‐specific oligonucleotide real‐time PCR and API2‐MALT1 PCR
Authors: Schreuder M. I. , Hoeve M. A. , Groothuis L. , Boot H. , Boerrigter L. H. , de Jong D. , Veenendaal R. A. , Jansen J. H. , van Krieken J. H. J. M. 
Published: October 2005

SummaryGastric extranodal marginal zone lymphoma (EMZL) often shows prolonged localised disease, but the present study demonstrated the presence of tumour cells in peripheral blood (PB) of low stage patients. We studied the presence of tumour cells in PB in gastric lymphoma patients harbouring or lacking t(11;18)(q21;q21), by real‐time immunoglobulin (Ig)H allele‐specific oligonucleotide‐polymerase chain reaction (ASO‐PCR) and API2‐MALT1 PCR. Tumour cells were exclusively detected in PB of t(11;18)(q21;q21)+‐EMZL patients. The presence of tumour cells in PB and gastric biopsy follow‐up samples showed a good correlation in these patients, suggesting clinical relevance for monitoring of tumour cells in PB of gastric t(11;18)(q21;q21)+‐EMZL patients.
Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH‐independent macronodular adrenal hyperplasia
Authors: Lee Sihoon , Hwang Ranjoo , Lee Junho , Rhee Yumie , Kim Dae Jung , Chung Ung‐il , Lim Sung‐Kil 
Published: October 2005

SummaryObjective  ACTH‐independent macronodular adrenal hyperplasia (AIMAH) is a rare and unusual cause of Cushing's syndrome, characterized by bilateral nodular adrenocortical hyperplasia and hypersecretion of cortisol. Familial AIMAH has rarely been reported. Recently, the aberrant expression of adrenal receptors for various ligands in AIMAH patients has become important in explaining the pathogenesis of AIMAH. In this study, we present the cases of two sisters who were affected with AIMAH.Patients and Measurements  Two sisters, aged 46 and 58, respectively, at the time of diagnosis, were found to have Cushing's syndrome due to AIMAH. We performed provocation tests with various materials and reverse transcription polymerase chain reaction (RT‐PCR) with their resected adrenal tissues to examine the hyper‐responsiveness to steroidogenesis and the overexpression of related receptors, respectively.Results  Provocation tests in vivo indicated that arginine vasopressin (AVP) promoted cortisol secretion through vasopressin V1a as well as V1b and V2 receptors. RT‐PCR analysis revealed an abnormal cDNA expression of vasopressin V1b and V2 receptors, none of which is known to be normally expressed in the adrenal glands.Conclusion  The expression of ectopic vasopressin V1b and V2 receptors may be involved in the aetiology of AIMAH, at least in the case of the sibling patients presented here.
Discoloration of polyvinyl chloride (PVC) tape as a proxy for water‐table depth in peatlands: validation and assessment of seasonal variability
Authors: BOOTH R. K. , HOTCHKISS S. C. , WILCOX D. A. 
Published: October 2005

Summary

Discoloration of polyvinyl chloride (PVC) tape has been used in peatland ecological and hydrological studies as an inexpensive way to monitor changes in water‐table depth and reducing conditions.
We investigated the relationship between depth of PVC tape discoloration and measured water‐table depth at monthly time steps during the growing season within nine kettle peatlands of northern Wisconsin. Our specific objectives were to: (1) determine if PVC discoloration is an accurate method of inferring water‐table depth in Sphagnum‐dominated kettle peatlands of the region; (2) assess seasonal variability in the accuracy of the method; and (3) determine if systematic differences in accuracy occurred among microhabitats, PVC tape colour and peatlands.
Our results indicated that PVC tape discoloration can be used to describe gradients of water‐table depth in kettle peatlands. However, accuracy differed among the peatlands studied, and was systematically biased in early spring and late summer/autumn. Regardless of the month when the tape was installed, the highest elevations of PVC tape discoloration showed the strongest correlation with midsummer (around July) water‐table depth and average water‐table depth during the growing season.
The PVC tape discoloration method should be used cautiously when precise estimates are needed of seasonal changes in the water‐table.
p63 correlates with both BRCA1 and cytokeratin 5 in invasive breast carcinomas: further evidence for the pathogenesis of the basal phenotype of breast cancer
Authors: Ribeiro‐Silva A , Ramalho L N Z , Garcia S B , Brandão D F , Chahud F , Zucoloto S 
Published: October 2005

Aims:  To study the expression of p63, cytokeratin (CK) 5 and CK8/18 in invasive ductal carcinomas and their relationship with BRCA1 and other pathological and immunohistochemical features of clinical significance.Methods and results:  Immunohistochemistry with the antibodies p63, CK5, CK8/18, BRCA1, oestrogen receptor, progesterone receptor, p53, c‐erbB‐2 and Ki67 was performed in 102 formalin‐fixed paraffin‐embedded samples of invasive ductal carcinomas. The CK5+ cases were submitted to a double‐immunolabelling study with p63. There was a strong relationship between CK5 and p63 expression and both markers were associated with hormonal receptor‐negative high‐grade carcinomas with high proliferative rate. Furthermore, there was coexpression of CK5 and p63 in neoplastic cells, indicating that p63, like CK5, is a marker of the basal phenotype of breast cancer. There was a strong relationship between reduced expression of BRCA1 with both p63 and CK5 expression as well as an inverse correlation between p63 and CK8/18 expression, suggesting that loss of p63 expression is required for the transition between a basal to a luminal phenotype of breast carcinoma.Conclusions:  Since p63 is thought to be a marker of stem cells and may act as an oncogene, our data support the idea that BRCA1 acts as stem cell regulator.
The optimization of the formulation for a chocolate cake containing inulin and yacon meal
Authors: Moscatto Janaina Andrea , Borsato Dionisio , Bona Evandro , de Oliveira Antonio Sérgio , de Oliveira Hauly Maria Celia 
Published: October 2005

SummaryThe research aimed at determining, using surface response methodology, an optimal chocolate cake formulation when wheat flour was partially replaced with inulin and/or yacon meal. The yacon meal used in the formulation was prepared by using tuberous roots of yacon (Polymnia sonchifolia Poepp. & Endl.). The optimization indicated that a formulation with 20% of the wheat flour replaced with yacon meal, 153 mL of water and no inulin showed the best values for hardness (3.638 N), cohesiveness (0.691) and specific volume (1.86 cm3 g−1). A formulation with 40% of the wheat flour replaced with yacon meal, 6% replaced with inulin and containing 126 mL of water showed similar values to the optimized formulation for the three responses mentioned earlier but, in addition, it had a greater content of fructooligosaccharides and inulin. Consequently, both formulations may give useful functional foods with physical parameters comparable with the control formulation.