bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations
Authors: Itagaki Fumio , Homma Masato , Yuzawa Kenji , Nishimura Masuhiro , Naito Shinsaku , Ueda Nobuhiko , Ohkohchi Nobuhiro , Kohda Yukinao 
Published: July 2004

Abstract
The aim of this study was to investigate the effects of the proton pump inhibitors (PPIs), lansoprazole and rabeprazole, on tacrolimus pharmacokinetics in healthy volunteers with mutations in the cytochrome P450 (CYP) 2C19 gene (CYP2C19). An open-label crossover study was performed with 19 healthy subjects. Tacrolimus (2 mg) was administered orally with and without lansoprazole (30 mg per day for 4 days) or rabeprazole (10 mg per day for 4 days). Blood concentrations of tacrolimus were determined before and 1, 2, 4 and 8 h after dosing. Genotyping for CYP2C19 was conducted by a polymerase chain reaction-restriction fragment length polymorphism method. Coadministration of lansoprazole significantly decreased the oral tacrolimus clearance, resulting in an increase in the area under the blood concentration-time curve (AUC0–8) (control vs with lansoprazole: 29.7 ± 3.5 vs 44.1 ± 5.0 ng h mL−1, P&lt;0.05). Large individual variation was observed in the effects of lansorazole on tacrolimus AUC0–8 owing to CYP2C19 genotype status. The percent change for tacrolimus AUC0–8 in subjects with and without CYP2C19 mutant alleles was 81% and 29%, respectively. Coadministration of rabeprazole also increased the mean AUC0–8 of tacrolimus, but the difference was not statistically significant. These observations suggest that drug interaction between tacrolimus and lansoprazole occurs in subjects with higher lansoprazole blood concentrations corresponding to CYP2C19 genetic status. In contrast, rabeprazole has minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status.
Lack of effect of proteinase-activated receptor-2 (PAR-2) deletion on the pathophysiological changes produced by lipopolysaccharide in the mouse: comparison with dexamethasone
Authors: Kazerani Hamid Reza , Plevin Robin , Kawagoe Junichi , Kanke Toru , Furman Brian L 
Published: July 2004

Abstract
This study tested the hypothesis that activation of proteinase-activated receptor-2 (PAR-2) contributes towards the pathophysiology of lipopolysaccharide (LPS)-induced shock in the mouse. The effects of LPS on plasma glucose, biochemical markers of hepatic, renal and pancreatic exocrine function and lung content of myeloperoxidase (MPO) were examined in homozygous PAR-2 knockout mice (PAR-2 -/-) and genetically equivalent, homozygous PAR-2 +/+ mice. The effect of LPS was also examined in normal mice receiving dexamethasone (10 mg kg−1, i.p.) or saline as a positive control. At six hours after intraperitoneal injection, LPS (40 mg kg−1) produced an increase in rectal temperature, hypoglycaemia and elevations in serum concentrations of alanine aminotransferase (ALT), creatinine and lipase, as well as an increase in lung MPO content. Dexamethasone treatment reduced LPS-induced hypoglycaemia and elevation of serum ALT concentrations but did not modify elevations in serum creatinine and lipase concentrations or the increase in lung MPO content. The changes in serum concentrations of glucose, ALT, creatinine and lipase produced by LPS in PAR-2 -/- mice were not different from those seen in wild-type or PAR-2 +/+ mice. These data suggest that activation of PAR-2 may not play a pivotal role in LPS-induced multi-organ dysfunction.
Comparative assessment of ocular tissue distribution of drug-related radioactivity after chronic oral administration of 14C-levofloxacin and 14C-chloroquine in pigmented rats
Authors: Tanaka Makoto , Takashina Hideo , Tsutsumi Shuichiro 
Published: July 2004

Abstract
Fluoroquinolones have been reported to have a high affinity for melanin. The ocular tissue distribution and accumulation of radioactivity was compared after repeated oral administration of 14C-levofloxacin and 14C-chloroquine at daily doses of 20 mg (0.054 mmol) kg−1 and 28 mg (0.054 mmol) kg−1, respectively, in pigmented rats for 84 days. The mean serum level at 24 h following each dose of 14C-levofloxacin was almost constant in the range of 0.33–0.45 nmol equiv mL−1 after the 14th dose and thereafter. The melanin-containing ocular tissues, such as iris ciliary body and stratum pigment chorioides sclera, showed a much higher concentration of radioactivity than other non-pigmented ocular tissues. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 126.47 and 74.91 nmol equiv g−1, and gradually increased with increasing dose number, reaching 1261.81 and 447.45 nmol equiv g−1 after the 84th dose, which was ca. 10 and 6 times higher, respectively, than after the 1st dose. The mean serum level following each dose of 14C-chloroquine was almost constant in the range 0.51–0.87 nmol equiv mL−1 after the 7th dose and thereafter. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 572.10 and 709.41 nmol equiv g−1, and gradually increased with increasing dose number, reaching 33 317.92 and 12 322.90 nmol equiv g−1 after the 84th dose, which was ca. 58 and 17 times higher, respectively, than after the 1st dose. The concentration in aqueous humour, cornea, lens, vitreous body and retina after the 84th dose was 1.84, 6.33, 0.48, 5.60 and 11.42 nmol equiv g−1 for 14C-levofloxacin and 18.84, 264.99, 27.26, 158.43 and 1020.89 nmol equiv g−1 for 14C-chloroquine (ca. 10, 42, 57, 28 and 89 times higher, respectively, than for 14C-levofloxacin). Especially, the concentration in the retina was markedly higher after 14C-chloroquine administration than after 14C-levofloxacin administration. The concentration and the extent of accumulation of radioactivity not only in melanin-containing ocular tissues but also in other non-pigmented ocular tissues, such as retina, after chronic oral administration of 14C-levofloxacin once daily for 84 days were much lower than those after multiple dosing with 14C-chloroquine under the same conditions. These results indicate that levofloxacin would have a much lower risk for ocular toxicity than chloroquine after chronic dosing.
Concentration dependency of modulatory effect of amlodipine on P-glycoprotein efflux activity of doxorubicin — a comparison with tamoxifen
Authors: Darvari Ramin , Boroujerdi Mehdi 
Published: July 2004

Abstract
Modulators of P-glycoprotein (P-gp) can enhance or limit the permeability of a number of therapeutic agents that are considered substrates of this efflux pump protein. The modulatory effect of amlodipine (4-dihydropyridine calcium antagonist) on P-gp efflux activity has not been fully elucidated. We have studied the concentration dependency of its modulatory effect and compared it qualitatively with tamoxifen (a non-esteroid anti-estrogen). The investigation was conducted on transmembrane efflux of doxorubicin at a fixed concentration of 5 μm across a Caco-2 monolayer in the presence of various concentrations of amlodipine or tamoxifen. The maximum flux of doxorubicin from basolateral to apical (ba) occurred at 4.5 μm amlodipine and at 0.02 μm tamoxifen. At higher concentrations, the apical to basolateral (ab) flux and the net flux of doxorubicin (ba — ab) declined steadily in a concentration-dependent manner. We analysed the observed net flux data by fitting different mathematical models to the data. A composite sigmoidal Emax/Imax (stimulatory/inhibitory) model was found to be the most appropriate to define the system. The observed and calculated parameters supported the modulatory role of both compounds and clearly indicated that the stimulation and inhibition of transmembrane efflux occurred simultaneously in the presence of amlodipine or tamoxifen. It was concluded that amlodipine, similar to tamoxifen, modulated the transporter-dependent transmembrane flux of the P-gp substrate in a concentration-dependent manner.
Ethanol inhibits in-vitro metabolism of nifedipine, triazolam and testosterone in human liver microsomes
Authors: Patki Kiran C , Greenblatt David J , von Moltke Lisa L 
Published: July 2004

Abstract
Although extended exposure to ethanol induces CYP3A metabolism in-vivo, the acute effects of ethanol on CYP3A metabolism have not been fully evaluated in-vitro. We assessed the effect of ethanol on CYP3A-mediated biotransformation using human liver microsomes in-vitro with three prototypic CYP3A-mediated reactions: nifedipine to oxidized nifedipine, triazolam to its 1-hydroxy (1-OH TRZ) and 4-hydroxy (4-OH TRZ) metabolites, and testosterone to 6β-hydroxytestosterone (6β-OH TST). Ethanol inhibited metabolism of nifedipine (oxidized nifedipine IC50 3 mg dL−1, where the IC50 value is the inhibitor concentration corresponding to a 50% reduction in metabolite formation velocity), triazolam (1-OH TRZ IC50 1.1 mg dL−1, 4-OH TRZ IC50 2.7 mg dL−1) and testosterone (6β-OH TST IC50 2.4 mg dL−1). The inhibitory potency of ethanol was similar for the three substrates representing the three hypothetical CYP3A substrate categories. The IC50 values obtained were lower than clinically relevant blood alcohol concentrations. In conclusion, ethanol is an inhibitor of human CYP3A metabolism and may contribute to clinically important interactions.
Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds — implications for pharmacokinetics of selected substrates
Authors: Abou El Ela Amal , Härtter Sebastian , Schmitt Ulrich , Hiemke Christoph , Spahn-Langguth Hildegard , Langguth Peter 
Published: July 2004

Abstract
The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levome-promazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand displacement assay with [3H]talinolol as radioligand and transport — as well as transport inhibition — studies of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers. In addition, the physicochemical descriptors log P and Δlog P were determined to test potential correlations between transporter affinity and lipophilicity parameters. All of the tested antipsychotics showed affinity to P-gp albeit their IC50 values (concentration of competitor that displaced 50% of the bound radioligand) differed by a factor exceeding 1000, when compared using the transport inhibition assay. From the group of P-gp substrates, amisulpride and fluphenazine were selected for in-vivo drug-drug interaction studies in rats to demonstrate the in-vivo relevance of the in-vitro findings. Compounds were administered by intraperitoneal injection either alone or in combination with 50 mg kg−1 ciclosporin. The concentration versus time profiles for both drugs were followed in serum as well as in brain tissues. Significant differences between the treatments with the antipsychotic alone versus the combination of antipsychotic with ciclosporin were found for amisulpride. The distribution of amisulpride to the brain was increased and systemic serum levels were likewise increased indicating decreased systemic clearance for the combination regimen. For fluphenazine, systemic levels with and without co-administraton of ciclosporin were comparable while higher brain-to-serum concentration ratios were found after co-administration of ciclosporin. The findings are explained on the basis of the limited contribution of P-gp-mediated transport to the elimination of fluphenazine and to a direct effect with respect to its distribution into the brain.
Parameters of drug antagonism: re-examination of two modes of functional competitive drug antagonism on intraocular muscles
Authors: Patil Popat N 
Published: July 2004

Abstract
There are two distinct kinetic functional pharmacological procedures by which the equilibrium affinity constant, KB, of a competitive reversible blocker is obtained. The classical method on an organ system requires the study of the parallel displacement of the agonist concentration-response curve in the presence of the blocker. In the second method, the agonist-evoked functional mechanical response is reduced to half by the blocker IC50 (the concentration required for 50% inhibition). In relation to these parameters the role of the ionization constant pKa and liposolubility log Pc or log D of blockers was examined. On the ciliary muscle from human eye, IC50/KB ratios for (±)-atropine, its quaternary analogue (±)-methylatropine, (-)-scopolamine, (±)-cyclopentolate, (-)-tropicamide, (±)-oxybutynin and pirenzepine were 15, 23, 4.4, 2.6, 1.66, 1.46 and 1.71, respectively. The ratios on the iris sphincter were comparable with those of ciliary muscle. When compared with large proportions of ionized molecules with water soluble properties of (±)-atropine and (±)-methylatropine, relatively high amounts of un-ionized and/or with greater partitioning of all other blockers in the lipoid barrier co-related well to low IC50/KB ratios, as predicted by the classical theory of competitive drug antagonism. It was hypothesized that due to receptor biophase access, the reduction of the mechanical response of the agonist by the highly ionized water-soluble antagonist at IC50 represented time-distorted “pseudo-equilibrium” estimation, where a higher concentration of the blocker was needed. On the other cholinergic effectors, like that of rat anococcygeus muscle or frog rectus abdominus muscle, IC50/KB ratios of respective blockers atropine or (+)-tubocurarine and hexamethonium were close to 1. Thus physicochemical properties, which affect the distribution coefficient log D and the tissue morphology (where asymmetric distribution of receptors may occur), appeared to be a critical factor in the analysis of the affinity parameters of the competitive reversible blocker. On the intraocular muscles, two functional pharmacological procedures for obtaining KB and IC50 values were not kinetically equivalent.
Comparative evaluation of the powder properties and compression behaviour of a new cellulose-based direct compression excipient and Avicel PH-102
Authors: Reus-Medina M , Lanz M , Kumar V , Leuenberger H 
Published: July 2004

Abstract
This study compares the compression behaviour of a new cellulose-based tableting excipient, hereinafter referred to as UICEL-A/102, and Avicel PH-102, a commercial direct compression excipient commonly referred to as microcrystalline cellulose (MCC). UICEL-A/102 shows the cellulose II lattice, while Avicel PH-102 belongs to the cellulose I polymorphic form. The median particle diameters of UICEL-A/102 and Avicel PH-102 fractions used in the study were 107 and 97 μm, respectively. Compared with Avicel PH-102, UICEL-A/102 was more dense; the relative poured and tapped densities were: 0.277 and 0.327 (vs 0.195 and 0.248 for Avicel PH-102), respectively. The true density, Ptrue, of the two materials was comparable (∼1.56g cm−3). The slopes of the in-die and out-of-die Heckel curves for Avicel PH-102 were steeper than for UICEL-A/102. The relative density versus applied pressure plot was in good agreement with the modified Heckel equation. The out-of-die and in-die minimal pressure susceptibility (χpmin) values calculated were 3.36 times 10−3 and 8.09 times 10−3 MPa−1 for UICEL-A/102 and 8.00 times 10−3 and 16.12 times 10−3 MPa−1 for Avicel PH-102, respectively. The elastic recovery profiles showed UICEL-A/102 to be more elastic than Avicel PH-102. In conclusion, UICEL-A/102 and Avicel PH-102 differ in their compression behaviour under pressure. The different polymorphic forms could provide a possible explanation.
A comparison of topical formulations for the prevention of human schistosomiasis
Authors: Cooper E , Iqbal A , Bartlett A , Marriott C , Whitfield P J , Brown M B 
Published: July 2004

Abstract
Recently, a dimeticone formulation has been shown to be effective at preventing Schistosoma cercariae infecting skin, while DEET (N,N-diethyl-m-toluamide), a highly effective insecticide, has been shown to have activity against cercariae. Seven formulations, 3 containing DEET, were prepared and applied to excised human skin in Franz cells for 1 h. Schistosoma cercariae were applied for 30 min at 1 and 24 h, and the number that penetrated the skin calculated (n = 9). DEET could not be incorporated into the dimeticone formulation, yet it remained the most effective at preventing cercarial penetration, both 1 and 24 h after application. The ointments that contained DEET did prevent penetration but their mode of action was due to the toxicity of DEET against the cercariae. The persistence of the protection afforded by the dimeticone formulation after washing suggests that the formulation may be interacting with the stratum corneum to prevent cercarial recognition of skin.
Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells
Authors: Kitagawa Shuji , Nabekura Tomohiro , Kamiyama Shizu 
Published: July 2004

Abstract
We studied the effects of tea catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG) on the P-glycoprotein (P-gp) function in multidrug-resistant P-gp over-expressing KB-C2 cells. EC did not have any effects on cellular accumulation of P-gp substrates, rhodamine-123 and daunorubicin, but the other catechins increased the accumulation in the order of EGC&lt;ECG&lt;EGCG. The effects of EGCG were larger than those of verapamil and quercetin. Since these catechins inhibited the efflux of P-gp substrates, the elevation of substrate accumulation seemed to be induced by the inhibition of the efflux transporter. The results showed that the inhibitory effects of the catechins did not depend on their total hydrophobicity, but significantly depended on their chemical structure. The presence of the galloyl moiety on the C-ring markedly increased the n-octanol/PBS partition coefficients of the catechins and their activity on P-gp. On the other hand, the presence of the trihydric pyrogallol group as the B-ring decreased the partition coefficients but increased the activity on P-gp, compared with the action of the corresponding catechins with a dihydric catechol B-ring.
Inhibition of in-vitro simvastatin metabolism in rat liver microsomes by bergamottin, a component of grapefruit juice
Authors: Goff-Klein N Le , Klein L , Hérin M , Koffel J-C , Ubeaud G 
Published: July 2004

Abstract
Grapefruit juice can modify the pharmacokinetic parameters of many drugs, in particular simvastatin, an orally active cholesterol-lowering agent. The exact components in grapefruit juice responsible for drug interactions are not perfectly known. However, it seems that bergamottin, a furocoumarin derivative, is one of the main active components within grapefruit juice. The objective of this paper was to quantify and to characterize in-vitro the inhibitory effect of bergamottin on simvastatin metabolism by using rat and human liver microsomes. In rat liver microsomes, the incubation conditions (± NADPH) of bergamottin were found to influence its inhibiting capacity. In co-incubation with simvastatin, the Ki value (the equilibrium dissociation constant for the enzyme-inhibitor complex) was higher (Ki = 174±36 μm) than in pre-incubation (Ki =45±6 μm and 4±2μm, without and with NADPH, respectively). It thus seems that the pre-incubation of bergamottin (in particular with NADPH) increases its inhibiting capacity on simvastatin metabolism. Bergamottin metabolism study in rat liver microsomes showed the formation of two metabolites that were CYP-450 dependent. In contrast, in human liver microsomes, the incubation conditions of bergamottin did not influence its inhibiting capacity of simvastatin metabolism (Ki = 34±5 μm, Ki = 22±5 μm, Ki = 27±11 μm in co-incubation and pre-incubation without and with NADPH, respectively). In rat and man, bergamottin was found to be a mixed-type inhibitor of simvastatin hepatic metabolism. However, in rat, bergamottin was partially a mechanism-based inhibitor by involvement of either bergamottin alone or one of its metabolites. The results highlight the importance of validating in-vitro models to help verify the suitability of the in-vitro model for predicting the nature and degree of metabolic drug interactions.
Inhibition of human cytochromes P450 by components of Ginkgo biloba
Authors: von Moltke Lisa L , Weemhoff James L , Bedir Erdal , Khan Ikhlas A , Harmatz Jerold S , Goldman Peter , Greenblatt David J 
Published: July 2004

Abstract
The extraction, isolation and characterization of 29 natural products contained in Ginkgo biloba have been described, which we have now tested for their in-vitro capacity to inhibit the five major human cytochrome P450 (CYP) isoforms in human liver microsomes. Weak or negligible inhibitory activity was found for the terpene trilactones (ginkgolides A, B, C and J, and bilobalide), and the flavonol glycosides. However 50% inhibitory activity (IC50) was found at concentrations less than 10 μg mL−1 for the flavonol aglycones (kaempferol, quercetin, apigenin, myricetin, tamarixetin) with CYP1A2 and CYP3A. Quercetin, the biflavone amentoflavone, sesamin, as well as (Z,Z)-4,4′-(1,4-pentadiene-1,5-diyl)diphenol and 3-nonadec-8-enyl-benzene-1,2-diol, were also inhibitors of CYP2C9. The IC50 of amentoflavone for CYP2C9 was 0.019 μg mL−1 (0.035 μm). Thus, the principal components of Ginkgo biloba preparations in clinical use (terpene trilactones and flavonol glycosides) do not significantly inhibit these human CYPs in-vitro. However, flavonol aglycones, the biflavonol amentoflavone and several other non-glycosidic constituents are significant in-vitro inhibitors of CYP. The clinical importance of these potential inhibitors will depend on their amounts in ginkgo preparations sold to the public, and the extent to which their bioavailability allows them to reach the CYP enzymes in-situ.
“You have shown me my end”: Attitudes toward presymptomatic testing for familial amyotrophic lateral sclerosis
Authors: Fanos Joanna H. , Gelinas Deborah F. , Miller Robert G. 
Published: July 2004

AbstractAmyotrophic lateral sclerosis (ALS) is a lethal degenerative motor neuron disease. Approximately, 5–10% of cases of ALS are familial (FALS), inherited primarily as an autosomal dominant trait. Recently, mutations in Cu/Zn superoxide dismutase (SOD1) have been identified; 15–20% of familial cases carry this mutation, providing a marker for diagnosis, carrier testing, and prenatal detection. We assessed understanding of genetics of FALS in relatives of patients cared for at the Forbes Norris MDA/ALS Research Center in San Francisco. A total of 25 participants completed a questionnaire and semistructured interview. Of these, 60% would have gene testing for themselves; 36% believed testing of children or adolescents was a good idea. Overall knowledge of genetics of FALS was limited. Also, 24% of respondents understood the inheritance pattern of FALS; 64% were aware that not all individuals who had the gene would show symptoms in their lifetime. Families were confused about whether they would receive results from linkage studies. We recommend that: (1) physicians refer relatives of newly diagnosed individuals for genetic counseling and possibly psychological counseling; (2) investigators ensure that participants comprehend the purpose of gene identification is for research, not disclosure of individual results; (3) families be helped to understand how to keep abreast of medical and genetic advances; (4) following the model of Huntington disease (HD), consensus guidelines for FALS genetic counseling and testing be developed. © 2004 Wiley‐Liss, Inc.