bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo regulation of inducible NO synthase in immune-mediated liver injury in mice
Authors: Koerber Kerstin , Sass Gabriele , Kiemer Alexandra K. , Vollmar Angelika M. , Tiegs Gisa
Published: March 2003

Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A). Here we investigated the in vivo effects of tumor necrosis factor (TNF)-α and/or interferon (IFN)-γ, two mediators of con A-induced liver injury, the TNF receptor (TNFR) usage leading to iNOS expression, and its connection with nuclear factor κB (NF-κB) activation. In conclusion, iNOS expression in vivo is dependent on both TNF-α and IFN-γ. Although con A-induced liver injury depends on both TNFR1 and TNFR2, TNF-dependent iNOS expression is mediated exclusively by TNFR1 and requires NF-κB activation.
Differential expression of intestinal trefoil factor in biliary epithelial cells of primary biliary cirrhosis
Authors: Kimura Yasuhiko , Leung Patrick S. C. , Kenny Thomas P. , Van De Water Judy , Nishioka Mikio , Giraud Andrew S. , Neuberger James , Benson Gordon , Kaul Rashmi , Ansari Aftab A. , Coppel Ross L. , Gershwin Eric M.
Published: March 2003

Intestinal trefoil factor (ITF) promotes epithelial cell migration and mucosal restitution during inflammation. We used real-time quantitative PCR, in situ nucleic acid hybridization, and immunohistochemistry to study the expression of the ITF gene and protein expression in the liver of primary biliary cirrhosis (PBC) and controls. There were significantly higher levels of ITF messenger RNA (mRNA) in PBC liver compared with primary sclerosing cholangitis (PSC) (P < .05) or normal controls (P < .001) and also higher in hepatitis C virus (HCV) liver (P < .05) and cryptogenic cirrhosis (P < .01) compared with normal controls. However, only in PBC was there a significant difference between small (interlobular and bile ductules) and large (intrahepatic and septal) bile ducts. Using in situ hybridization, the highest levels of ITF gene expression were localized to the large bile ducts in PBC. This differential expression of ITF was also noted at the protein level. Thus, in PBC, although 92% of large bile ducts expressed the ITF protein, only 2% of small bile ducts (P < .0001) expressed ITF. In contrast, in control livers, 34% of large bile ducts and 13% of small bile ducts expressed ITF. ITF protein is absent in small bile ducts in all stages of PBC. In conclusion, the expression of ITF may play an important role in bile duct damage. In small bile ducts, ITF production in response to damage is absent, making such cells vulnerable to damage and providing a thesis for the selective loss of small, but not large, bile ducts in PBC.
PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival
Authors: Coutant Alexandre , Rescan Claude , Gilot David , Loyer Pascal , Guguen-Guillouzo Christiane , Baffet Georges
Published: March 2003

Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.
Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS
Authors: Damink Steven W. M. Olde , Jalan Rajiv , Redhead Doris N. , Hayes Peter C. , Deutz Nicolaas E. P. , Soeters Peter B.
Published: March 2003

Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.
Southeast Asian patients with chronic hepatitis C: The impact of novel genotypes and race on treatment outcome
Authors: Dev Anouk T. , McCaw Rhonda , Sundararajan Vijaya , Bowden Scott , Sievert William
Published: March 2003

Hepatitis C virus (HCV) genotype and other host and viral factors influence treatment outcome in chronic HCV infection. We evaluated the effect of race and genotype on interferon and ribavirin treatment outcome in 70 Southeast Asian (SEA) and 50 white patients. Genotype was based on the 5’ untranslated region (5’UTR) with a commonly used line probe assay (INNO-LiPA HCV II) that may mistype genotype 7, 8, or 9 as 1b. HCV core region sequencing resulted in reclassification of 8 genotype 1 and 25 genotype 1b SEA subjects as genotype 7, 8, or 9. Twenty-six SEA genotype 7, 8, and 9 (79%) and 10 SEA true genotype 1b (59%) patients achieved a sustained virologic response (SVR) compared with 15 (34%) white genotype 1b patients. Logistic regression analysis showed that SEA patients with genotype 7, 8, or 9 were more likely to achieve a SVR than white genotype 1b patients (OR 16.56; 95%CI 4.16, 65.91) as were SEA true genotype 1b patients compared with white genotype 1b patients (OR 4.63; 95%CI 1.19, 18.04). In conclusion, a proportion of SEA patients classified by INNO-LiPA as genotype 1b were in reality genotype 7, 8, or 9. In comparison with white genotype 1b patients, both SEA genotype 1b and SEA genotype 7, 8, and 9 patients showed a significantly greater SVR. HCV core sequencing was necessary to determine genotype accurately in persons potentially exposed to HCV genotypes 7, 8, or 9. This study also supports the concept that race and ethnicity are important determinants of treatment outcome in HCV infected patients.
Quantitative evaluation of altered hepatic spaces and membrane transport in fibrotic rat liver
Authors: Hung Daniel Y. , Chang Ping , Cheung Kee , Winterford Clay , Roberts Michael S.
Published: March 2003

Four animal models were used to quantitatively evaluate hepatic alterations in this study: (1) a carbon tetrachloride control group (phenobarbital treatment only), (2) a CCl4-treated group (phenobarbital with CCl4 treatment), (3) an alcohol-treated group (liquid diet with alcohol treatment), and (4) a pair-fed alcohol control group (liquid diet only). At the end of induction, single-pass perfused livers were used to conduct multiple indicator dilution (MID) studies. Hepatic spaces (vascular space, extravascular albumin space, extravascular sucrose space, and cellular distribution volume) and water hepatocyte permeability/surface area product were estimated from nonlinear regression of outflow concentration versus time profile data. The hepatic extraction ratio of 3H-taurocholate was determined by the nonparametric moments method. Livers were then dissected for histopathologic analyses (e.g., fibrosis index, number of fenestrae). In these 4 models, CCl4-treated rats were found to have the smallest vascular space, extravascular albumin space, 3H-taurocholate extraction, and water hepatocyte permeability/surface area product but the largest extravascular sucrose space and cellular distribution volume. In addition, a linear relationship was found to exist between histopathologic analyses (fibrosis index or number of fenestrae) and hepatic spaces. The hepatic extraction ratio of 3H-taurocholate and water hepatocyte permeability/surface area product also correlated to the severity of fibrosis as defined by the fibrosis index. In conclusion, the multiple indicator dilution data obtained from the in situ perfused rat liver can be directly related to histopathologic analyses.
Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure
Authors: Leonis Mike A. , Toney-Earley Kenya , Degen Sandra J. F. , Waltz Susan E.
Published: March 2003

The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK−/− mice display marked protection compared with control Ron TK+/+ mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK−/− mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK−/− mice. Paradoxically, treatment of Ron TK−/− mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) α, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-α production) and interferon (IFN)-γ (a TNF-α sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-α. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.
Isozyme‐specific induction of low‐dose aspirin on cytochrome P450 in healthy subjects
Authors: Chen Xiao‐Ping , Tan Zhi‐Rong , Huang Song‐Lin , Huang Zheng , Ou‐Yang Dong‐Sheng , Zhou Hong‐Hao
Published: March 2003

Objective

This study was designed to define the effect of low‐dose aspirin administration on the activity of cytochrome P450 (CYP) in normal human subjects.

Methods

Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy male volunteers. A modified 5‐drug cocktail procedure consisting of caffeine, mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A, respectively. The activities were assessed on 4 occasions including at baseline, after 7 and 14 daily doses of aspirin, and at 7 days after discontinuation of aspirin. Concentrations of parent drugs and corresponding metabolites in biologic samples were assayed by reversed‐phase HPLC.

Results

Both 7‐day and 14‐day aspirin intake increased the activity of CYP2C19 significantly, as indicated by 4‐hydroxymephenytoin urinary recovery (P < .001). Induction of low‐dose aspirin on CYP2C19 was time‐dependent. CYP3A activity indices increased moderately but significantly by both 7‐day and 14‐day aspirin treatment (P < .05), but the percentage changes in CYP3A activity indices were not significant. Low‐dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo activity by either 7‐day or 14‐day treatment.

Conclusions

The effect of low‐dose aspirin on CYPs was enzyme‐specific. Both 7‐day and 14‐day low‐dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low‐dose aspirin on CYP3A activity awaits further confirmation. When low‐dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy.

Clinical Pharmacology & Therapeutics (2003) 73, 264–271; doi: 10.1067/mcp.2003.14
Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites
Authors: Chalon Stephan A. , Desager Jean‐Pierre , DeSante Karl A. , Frye Reginald F. , Witcher Jennifer , Long Amanda J. , Sauer John‐Michael , Golnez Jean‐Luc , Smith Brian P. , Thomasson Holly R. , Horsmans Yves
Published: March 2003

Background and Objectives

Atomoxetine is a treatment for attention‐deficit/hyperactivity disorder and is primarily eliminated via cytochrome P4502D6 (CYP2D6). The pharmacokinetics of atomoxetine and its primary metabolites were investigated in 10 adults with hepatic impairment (6 moderate, 4 severe) and 10 age‐ and sex‐matched control subjects, all being genotyped as CYP2D6 extensive metabolizers.

Methods

A single oral 20‐mg dose of atomoxetine was given. Multiple blood samples were collected for 48 hours in healthy subjects and for 120 hours in patients. Urine was collected up to 24 hours. Before atomoxetine administration (10–20 days), sorbitol clearance and debrisoquin (INN, debrisoquine) metabolic ratio were determined as markers of hepatic blood flow and CYP2D6 activity, respectively.

Results

The systemic clearance of atomoxetine was significantly reduced in those with hepatic impairment compared with controls, thereby resulting in increased exposure (area under the concentration‐time curve from time 0 to infinity, 1.58 versus 0.85 μg · h−1 · mL−1; P = .035) but no change in maximum concentration. Mean 4‐hydroxyatomoxetine area under the concentration‐time curve from time 0 to time t and maximum concentration were increased approximately 7‐fold and 2‐fold, respectively (P = .0001 and P = .0056, respectively). For the glucuronide conjugate of 4‐hydroxyatomoxetine, the mean half‐life was longer and the mean area under the concentration‐time curve from time 0 to infinity and the maximum concentration were lower (P = .0028, P = .003, and P = .0001, respectively). The sorbitol clearance was lower and the debrisoquin metabolic ratio was higher, reflecting reduced hepatic blood flow and decreased CYP2D6 activity, respectively. Decreased atomoxetine clearance in patients with hepatic impairment was clearly correlated with decreased CYP2D6 activity and decreased hepatic blood flow. Mean atomoxetine plasma protein binding was lower in patients with hepatic impairment compared with controls (96.5% versus 98.7%, P = .0008). Atomoxetine was well tolerated in the 2 populations.

Conclusion

For patients with attention‐deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.

Clinical Pharmacology & Therapeutics (2003) 73, 178–191; doi: 10.1067/mcp.2003.25
Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol
Authors: Lilja Jari J. , Backman Janne T. , Laitila Jouko , Luurila Harri , Neuvonen Pertti J.
Published: March 2003

Objectives

Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the β‐adrenergic receptor‐blocking agent celiprolol in healthy volunteers.

Methods

In a randomized 3‐phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later.

Results

During the itraconazole phase, the mean area under the plasma concentration‐time curve from 0 to 33 hours [AUC(0–33)] of celiprolol was 80% greater (P < .05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0–33) and peak plasma concentration values of celiprolol were reduced to about 13% (P < .001) and 5% (P < .001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P < .05) and decreased by 85% by grapefruit juice (P < .001). Hemodynamic variables did not differ between the phases.

Conclusions

Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole‐celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P‐glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice‐celiprolol interaction is probably of clinical relevance.

Clinical Pharmacology & Therapeutics (2003) 73, 192–198; doi: 10.1067/mcp.2003.26
P‐glycoprotein‐mediated intestinal and biliary digoxin transport in humans
Authors: Drescher Siegfried , Glaeser Hartmut , Mürdter Thomas , Hitzl Monika , Eichelbaum Michel , Fromm Martin F.
Published: March 2003

Background and Aims

Intestinal transport by P‐glycoprotein is a recently recognized determinant of drug disposition. However, direct measurements of transporter‐mediated drug elimination into isolated segments of human small intestine are lacking.

Methods

Using a recently developed intestinal perfusion catheter, we perfused in healthy volunteers two 20‐cm jejunal segments with and without the P‐glycoprotein inhibitor quinidine before and during administration of the P‐glycoprotein inducer rifampin (INN, rifampicin).

Results

Within 3 hours after intravenous administration of digoxin (1 mg), perfusate samples were collected. We found that 0.45% ± 0.24% and 0.83% ± 0.60% of the digoxin dose were eliminated into a jejunal segment and into bile, respectively. Perfusion of the isolated segment with quinidine reduced intestinal digoxin elimination (0.23% ± 0.08%, P = .031). During rifampin, intestinal digoxin elimination was 0.80 ± 0.59 (P = .383). Enterocyte P‐glycoprotein content correlated with the area under the plasma concentration‐time curve of digoxin (Spearman nonparametric correlation coefficient [rS] = −0.73, P = .003) and digoxin nonrenal clearance (rS = 0.52,
P = .056), as well as with intraluminal and plasma concentrations of quinidine (rS = 0.55, P = .041 and rS = −0.67, P = .009, respectively).

Conclusion

Using segmental intestinal perfusion, we provide direct evidence that intestinal P‐glycoprotein mediates substantial drug elimination after intravenous administration from the systemic circulation into the gut lumen and prevents entry of luminally administered P‐glycoprotein substrates into the enterocytes. These data also highlight the relative importance of direct intestinal drug secretion in comparison with drug elimination through bile.

Clinical Pharmacology & Therapeutics (2003) 73, 223–231; doi: 10.1067/mcp.2003.27
Cisapride: A potential model substrate to assess cytochrome P4503A4 activity in vivo
Authors: Lowry Jennifer A. , Kearns Gregory L. , Abdel‐Rahman Susan M. , Nafziger Anne N. , Khan Irim S. , Kashuba Angela D. M. , Schuetz Erin G. , Bertino Joseph S. , van den Anker John N. , Leeder J. Steven
Published: March 2003

Objectives

Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 “probe.” As well, we evaluated whether cisapride was transported by P‐glycoprotein.

Methods

Bidirectional transport assays were conducted in LLC‐PK1 cells and the derivative cell line L‐MDR1 to determine whether cisapride was a substrate for P‐glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15 mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma concentrations were quantitated from repeated after‐dosing blood samples by HPLC with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry detection for cisapride and norcisapride. Pharmacokinetic parameters were determined by noncompartmental methods. Both linear and nonlinear regression analyses were used to examine the association between the apparent plasma clearance of midazolam and cisapride and the cisapride/norcisapride plasma concentration ratios.

Results

Although not a substrate for P‐glycoprotein, cisapride inhibited P‐glycoprotein with an apparent inhibition constant (Ki) of 16.1 μmol/L. Linear correlations between cisapride clearance and both intravenous and oral midazolam clearance (P = .01, r2 = 0.43 and P = .001, r2 = 0.46, respectively) were found. Cisapride/norcisapride plasma concentration ratios at 8 hours (P = .001, r2 = 0.90) and 12 hours (P = .001, r2 = 0.96), as well as cisapride plasma concentrations at these time points, were shown to accurately predict the area under the plasma concentration versus time curve for cisapride.

Conclusions

CYP3A4 activity reflected by the total body clearance after oral administratioin of cisapride should be independent of transport by P‐glycoprotein. Concordance between the pharmacokinetics for cisapride and midazolam support the applicability of oral cisapride as a pharmacologic substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a single‐point determination to reflect the area under the plasma concentration versus time curve and the plasma clearance of cisapride and, as well, total CYP3A4 activity in vivo.

Clinical Pharmacology & Therapeutics (2003) 73, 209–222; doi: 10.1067/mcp.2003.29
Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin
Authors: Hamzeh Fayez M. , Benson Constance , Gerber John , Currier Judith , McCrea Jackie , Deutsch Paul , Ruan Ping , Wu Hulin , Lee Jin , Flexner Charles ,   for the AIDS Clinical Trials Group 365 Study Team
Published: March 2003

Background

Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens.

Methods

Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 AM or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus‐infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 AM for 14 days. Twenty‐four‐hour pharmacokinetic sampling was performed at the end of each 14‐day study period.

Results

Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration‐time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration‐time curve values of rifabutin and 25‐desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 AM or staggered by 4 hours.

Conclusions

Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25‐desacetyl rifabutin concentrations is not known.

Clinical Pharmacology & Therapeutics (2003) 73, 159–169; doi: 10.1067/mcp.2003.3
Disposition and miotic effects of oral alfentanil: A potential noninvasive probe for first‐pass cytochrome P4503A activity
Authors: Kharasch Evan D. , Hoffer Christine , Walker Alysa , Sheffels Pamela
Published: March 2003

Background and Objectives

Systemic clearance of the opioid alfentanil after intravenous administration is an excellent in vivo probe for hepatic cytochrome P4503A (CYP3A) activity and drug interactions. Alfentanil effect (miosis) is a surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics may be a suitable noninvasive probe for hepatic CYP3A. Oral alfentanil might be a probe for first‐pass CYP3A activity; however, it is not used clinically, and oral alfentanil disposition is unknown. This investigation evaluated the disposition and miotic effects of oral alfentanil.

Methods

Ten healthy volunteers were studied in a dose‐escalation fashion, receiving 23, 30, 43, and 75 μg/kg oral alfentanil on different days. Dark‐adapted pupil diameter was measured at the time of venous blood sampling. Alfentanil was quantified by liquid chromatography‐mass spectrometry. Plasma concentrations of alfentanil and pupil diameter change versus time data were analyzed by noncompartmental modeling.

Results

Alfentanil was rapidly absorbed (time to maximum concentration [Tmax], 0.7 ± 0.5 hour). Mean values for area under the plasma concentration‐time curve extrapolated to infinity (AUC∞) (27 ± 14, 38 ± 22, 57 ± 31, and 105 ± 59 ng · h · mL−1) and maximum concentration (16 ± 8, 23 ± 16, 31 ± 18, and 50 ± 22 ng/mL) were linear with dose, although there was considerable interindividual variability. Tmax, elimination half‐life (1.0 ± 0.2 hours), total body clearance after oral administration (20 ± 18 mL · kg−1 · min−1), and dose‐normalized AUC∞ were independent of dose. Dose‐dependent alfentanil disposition was mirrored by commensurate changes in clinical effect, although miosis was variable and not detectable in all subjects at the lowest dose. Mean miosis AUC (AUEC) and peak miosis were log‐dose linear. Effect half‐life (1.3 ± 0.9 hours) was similar to plasma half‐life.

Conclusion

Oral alfentanil is rapidly absorbed, exhibits linear and dose‐independent kinetics, and undergoes substantial first‐pass metabolism. Oral alfentanil may be a suitable probe for first‐pass CYP3A activity. Alfentanil effect (miosis) may be an acceptable surrogate for plasma alfentanil concentrations. Oral alfentanil effect may be a noninvasive surrogate for conventional pharmacokinetics. Further studies are warranted to determine whether oral alfentanil and alfentanil effect kinetics may be a suitable noninvasive in vivo probe for first‐pass CYP3A activity.

Clinical Pharmacology & Therapeutics (2003) 73, 199–208; doi: 10.1067/mcp.2003.30
Effect of single and repeated oral doses of telithromycin on cardiac QT interval in healthy subjects
Authors: Démolis Jean‐Louis , Vacheron Françoise , Cardus Stéphane , Funck‐Brentano Christian
Published: March 2003

Background

Telithromycin is the first member of a new class of antimicrobials—the ketolides. The main objective of this study was to assess the effect of various oral doses of telithromycin on QT interval during single and repeated administrations.

Methods

Seventeen men and 17 women participated in double‐blind, placebo‐controlled, crossover studies. Of these subjects, 18 (9 men and 9 women) received single and repeated oral doses of telithromycin (800 mg daily), clarithromycin (500 mg twice daily), or placebo (protocol 1). The other 16 subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of telithromycin or placebo (protocol 2). At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT intervals were measured within a wide range of R‐R intervals in each subject.

Results

ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo. The greatest effect observed during any study period was a mean (±SD) change in QT‐interval duration of 4.2 ± 15.2 ms (ie, +1.2% ± 4.0%, P not significant) at R‐R = 1000 ms after repeated doses of 800 mg telithromycin. Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12‐lead electrocardiograms did not differ across treatment groups, including placebo.

Conclusions

Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort. Telithromycin did not prolong QT‐interval duration when administered to healthy young male and female subjects.

Clinical Pharmacology & Therapeutics (2003) 73, 242–252; doi: 10.1067/mcp.2003.4
Do Micrometastases Detected with Cytokeratin Immunoperoxidase Reactivity Affect the Treatment Approach to Neck in Supraglottic Cancers?
Authors: Kocatürk Sinan , Yilmazer Demet , Önal Binnur , Erkam Ünsal , Ürünal Bilge
Published: March 2003

OBJECTIVES

The aim of this study was to determine the occult lymph node metastasis rates with immunoperoxidase staining for cytokeratin in supraglottic larynx cancers and to assess our approach to the neck.

STUDY DESIGN

Twenty‐two patients who had squamous cell carcinoma in the supraglottic region and no histopathologic metastasis in the neck who had their cancer detected with the use of hematoxylineosin were included in the study. All of the specimens were reevaluated with the use of immunoperoxidase staining for cytokeratin.

RESULTS

Micrometastatic disease (pN1) has been detected in 3 patients (13.61%) in whom no metastasis was detected with routine histopathologic examination.

CONCLUSION AND SIGNIFICANCE

Results suggest that the occult metastasis rates are higher than those detected with routine hematoxylin‐eosin staining. However, because it is accepted that neck dissection alone has adequate therapeutic efficiency in pN1 patients, the detected 13.61% rate of micrometastases has not changed our treatment plan in the neck.
Headache after Removal of Vestibular Schwannoma Via the Retrosigmoid Approach: A Long‐Term Follow‐Up‐Study
Authors: Schaller Bernhard , Baumann Ariane
Published: March 2003

OBJECTIVE

Our goal was to study the occurrence and source of origin of postcraniotomy headache syndrome after removal of vestibular schwannoma via the retrosigmoid approach.

METHODS

A retrospective chart analysis was conducted of all patients with headache at 3 months after removal of vestibular schwannoma from January 1981 through March 1997 and with a minimum of 24 months of follow‐up. Diagnosis was made according to the headache classification and was graded using the HARNER scale. Recovery outcome was compared in selected groups of patients with and without headache. A descriptive statistical analysis was used to analyze differences between groups.

RESULTS

Of the patients who underwent retrosigmoid craniotomy for removal of vestibular schwannomas, 52 of 155 patients (34%) reported having severe headache of requiring medication every day and/or feeling incapacitated 3 months after surgery. Headache was more prevalent in those who had the bone flap replaced (94% versus 27%), if there was duraplastic or direct dura closure (0% versus 100%). Laboratory‐proven aseptic meningitis, most likely due to the use of fibrin glue and drilling of posterior aspect of the internal auditory canal, was mainly associated with postoperative headache (81% versus 2%). In 75% of these cases, calcifications along the brainstem had been noted.

CONCLUSION

The origin of postoperative headaches after retrosigmoid vestibular schwannoma resections is not yet fully understood. Different factors may play a role in preventing or reducing headache: dural adhesions to nuchal muscles or to subcutaneous tissues and dural tension in the case of direct dural closure may explain postoperative headache from dural tension. Intradural drilling and the use of fibrin glue may be the source of aseptic meningitis as the etiology of persistent postoperative headache. Prevention of postoperative headache may include the replacement of bone flap at the end of surgery, duraplastic instead of direct dural closure, and prevention of the use of fibrin glue or extensive drilling of the posterior aspect of internal auditory canal.
Study of Some “Intrinsic Risk Factors” that Can Enhance an Iatrogenic Injury of the External Branch of the Superior Laryngeal Nerve
Authors: Furlan Julio Cesar , Cordeiro Anói Castro , Brandã Lenine Garcia
Published: March 2003

OBJECTIVE

This study evaluates some “intrinsic risk factors” for a surgical injury of the external branch of superior laryngeal nerve (EBSLN) based on its anatomic relationship with the thyroid gland.

STUDY DESIGN AND SETTING

Seventy‐two neck dissections were performed in 36 fresh human adult cadavers. Every EBSLN was dissected and categorized using Cernea's classification. All data regarding gender, ethnicity, stature, side of the neck, and volume of hemi thyroid were collected and statistically analyzed by the χ2–test and analysis of variance.

RESULTS

Although no statistical differences were observed between genders (P = 0.3770), ethnicities (P = 0.9780) or sides of the neck (P = 0.2523), statistical significance was reached regarding the nerve type when the groups were divided by stature (P = 0.0006) and glandular volume (P = 0.0007).

CONCLUSION

Individual stature and volume of the hemi thyroid gland are probably involved in risk of the surgical EBSLN injury.

SIGNIFICANCE

Surgeons should be aware of these anatomic findings in order to obtain a good voice‐related outcome in the thyroidectomies.
Nonattended Home Automated Continuous Positive Airway Pressure Titration: Comparison with Polysomnography
Authors: Woodson B. Tucker , Saurejan Adrian , Brusky Laura T. , Han Joseph K.
Published: March 2003

OBJECTIVE

Automatic adjusting nasal continuous positive airway pressure titration (APAP) has been introduced as an alternative method of establishing pressures for patients with sleep apnea. The performance and accuracy of APAP in nonattended home environment are controversial. This study assessed APAP polysomnographic outcomes and accuracy in a nonattended home environment.

STUDY DESIGN AND SETTING

We conducted a retrospective consecutive case series of 24 consecutive patients who had nonattended APAP and simultaneous full polysomnography (PSG).

RESULTS

APAP was tolerated and reduced obstructive Apnea‐Hypopnea Index (AHI) to < 10 events/h in all patients. Mean AHI decreased from 38.4 (21.2) to 5.9 (6.6) events/h. Central apneas worsened in one patient. A therapeutic pressure was determined in 91% of patients. Autoset accurately measured residual AHI compared with PSG (R = 0.77, P < 0.001). APAP overestimated the AHI by 1.4 events/h.

CONCLUSIONS

Nonattended APAP is successful in many patients in determining a therapeutic positive pressure setting. Reported AHI via Autoset is similar to that of PSG.

SIGNIFICANCE

APAP reduces AHI and is tolerated in a nonattended environment.
Child Abuse and the Otolaryngologist: Part I
Authors: Crouse C. D. , Faust R. A.
Published: March 2003

Nearly 1 million infants and children are neglected and abused yearly in the United States, with a greater than 1% resulting mortality rate. One half of these children are seen by physicians for abuse‐related injuries, and nearly 75% have injuries of the head and neck. Physicians, however, account for reporting only 11% of all cases. As experts trained in diseases and injuries of the head and neck, otolaryngologists are particularly well positioned to recognize abuse in the clinic and in the emergency room and during other consultations. We present an overview of child abuse definitions, risk factors, and legal obligations of the physician. We also review the manifestations of child abuse within the head and neck, with particular attention to the role of the otolaryngologist. We briefly discuss some conditions that may be mistaken for abuse and suggest a practical protocol for management of suspected cases in the clinic.
Harmonic Scalpel Tonsillectomy in Children: A Randomized Prospective Study
Authors: Willging J. Paul , Wiatrak Brian J.
Published: March 2003

OBJECTIVE

In this randomized prospective study, we evaluated postoperative morbidity after use of the Harmonic Scalpel (HS), an ultrasonic dissector coagulator (Ethicon Endo‐Surgery Inc, Cincinnati, OH), or conventional electrocautery (EC) during tonsillectomy.

STUDY DESIGN AND SETTINGS

Pediatric subjects at 2 sites were randomized and underwent tonsillectomy. Intraoperative blood loss and operation duration were recorded. Postoperative parameters and complications were recorded.

RESULTS

One hundred seventeen subjects completed the study. For the HS group, mean operative time was significantly longer (P < 0.001), but intraoperative blood loss was equivalent (P = 1.000). HS subjects slept soundly on postoperative days 1, 2, 3, and 14 (P = 0.041, 0.013, 0.022, and 0.038, respectively, compared with EC group). Mean postoperative pain scores trended lower for HS subjects on postoperative days 2, 3, and 4.

CONCLUSION

The use of the HS in pediatric tonsillectomy showed no increase in intraoperative or postoperative blood loss compared with the use of EC, and HS provided possible clinical advantages over EC in patient comfort.

SIGNIFICANCE

Tonsillectomy subjects in the HS group showed a statistically significant ability to sleep soundly, suggesting that the subjects experienced less pain. These data correlate with the observed decrease in pain scores.
Viscoelastic Properties of Rabbit Vocal Folds after Augmentation
Authors: Hertegård Stellan , Dahlqvist Åke , Laurent Claude , Borzacchiello Assunta , Ambrosio Luigi
Published: March 2003

BACKGROUND

Vocal fold function is closely related to tissue viscoelasticity. Augmentation substances may alter the viscoelastic properties of vocal fold tissues and hence their vibratory capacity.

OBJECTIVES

We sought to investigate the viscoelastic properties of rabbit vocal folds in vitro after injections of various augmentation substances.

STUDY DESIGN AND SETTING

Polytetrafluoroethylene (Teflon), cross‐linked collagen (Zyplast), and cross‐linked hyaluronan, hylan b gel (Hylaform) were injected into the lamina propria and the thyroarytenoid muscle of rabbit vocal folds. Dynamic viscosity of the injected vocal fold as a function of frequency was measured with a Bohlin parallelplate rheometer during small‐amplitude oscillation.

RESULTS

All injected vocal folds showed a decreasing dynamic viscosity with increasing frequency. Vocal fold samples injected with hylan b gel showed the lowest dynamic viscosity, quite close to noninjected control samples. Vocal folds injected with polytetrafluoroethylene showed the highest dynamic viscosity followed by the collagen samples.

CONCLUSIONS

The data indicated that hylan b gel in short‐term renders the most natural viscoelastic properties to the vocal fold among the substances tested. This is of importance to restore/preserve the vibratory capacity of the vocal folds when glottal insufficiency is treated with injections.
Genetic Core Competencies: Exploring the Implications for Psychiatric Nursing
Authors: Pestka Elizabeth
Published: March 2003

Psychiatric nurses need to become knowledgeable about the basics of genetics and then keep up-to-date with the rapid explosion of genetics information and applications to clinical practice. The Human Genome Project has produced a map of the human genome composed of all the genetic information that makes up a human being. As a result, focus has been on genetic-related research, and a significant amount of media attention has been directed to the findings. This article provides information that psychiatric nurses need to move into the genetic era of health care, to be able to respond to questions, and to provide supportive care to patients.
Innovative real estate financing in Germany – a financial desert?
Authors: Iblher Felix , Lucius Dominik I.
Published: March 2003

Innovative financing instruments are well‐known in Anglo‐American real estate finance markets. This study is the first to analyse the use and structure of the innovative financing instruments in Germany. Based on a survey addressed to German banks offering real estate financing, instrument‐ and bank‐type specific patterns and reimbursement schemes are examined. While the research shows that innovative instruments are not yet widely used in Germany, banks possess experience in mezzanine capital, project and joint venture financing and are optimistic regarding the future development of demand for these instruments.
The role of investment and finance in real estate education and research throughout the world
Authors: Schulte Karl‐Werner
Published: March 2003

Investigates the role of investment and finance in real estate education and researches the programs of the conferences of the American Real Estate Society (ARES), the European Real Estate Society (ERES), held in the years 1999, 2000 and 2001, and the program of the International Real Estate Society (IRES) World Congress 2001. To give a structure to the different topics of hundreds of papers, the interdisciplinary approach is taken as a framework visualised by the “House of real estate economics”. The paper comes to the conclusion that real estate investment and finance play an important role which is supposed to decrease in the future.
Shape reconstruction by genetic algorithms and artificial neural networks
Authors: Xiyu Liu , Mingxi Tang , Hamilton Frazer John
Published: March 2003

This paper presents a new surface reconstruction method based on complex form functions, genetic algorithms and neural networks. Surfaces can be reconstructed in an analytical representation format. This representation is optimal in the sense of least‐square fitting by predefined subsets of data points. The surface representations are achieved by evolution via repetitive application of crossover and mutation operations together with a back‐propagation algorithm until a termination condition is met. The expression is finally classified into specific combinations of basic functions. The proposed method can be used for CAD model reconstruction of 3D objects and free smooth shape modelling. We have implemented the system demonstration with Visual C++ and MatLab to enable real time surface visualisation in the process of design.
Three improved neural network models for air quality forecasting
Authors: Wang Wenjian , Xu Zongben , Weizhen Lu Jane
Published: March 2003

Artificial neural networks (ANN) are appearing as alternatives to traditional statistical modeling techniques in many scientific disciplines. However, the inherent drawbacks of neural networks such as topology specification, undue training expense, local minima and training unpredictability will overlay their merits in engineering applications, especially. In this paper, adaptive radial basis function (ARBF) network and improved support vector machine (SVM) are presented in atmospheric sciences. The principle component analysis (PCA) technique is employed to the ARBF network as well, namely, ARBF/PCA network for the convenience of expression and comparison, so as to fasten the learning process. Comparing with traditional neural network models, the proposed models can automatically determine the size of network and parameters, fasten the learning process and achieve good generalization performances in prediction of pollutant level. The simulation results based on a real‐world data set demonstrate the effectiveness and robustness of the proposed methods.
The importance of internal aspects in quality improvement
Authors: Llopis Juan , José Tarí Juan
Published: March 2003

The adoption of ISO 9000 has been justified in terms of the many benefits it generate, although problems may also arise. Such advantages and disadvantages lead to different reasons for seeking certification. Based on these reasons, this paper analyzed the influence of internal motivation for seeking certification with level of quality management and performance in order to determinate whether internal aspects are more important than external aspects. For this purpose, a factor analysis (to identify reasons) and a cluster analysis (to establish significant differences among the groups in order to study the relation between reasons for seeking certification and level of quality management and performance) have been performed on the answers supplied by 106 certified firms in the Alicante area (eastern Spain). It is part of a wider research process, aimed at analyzing quality practices in certified firms by using quality management elements.
Using the QFD concept to resolve customer satisfaction strategy decisions
Authors: Chien Te‐King , Su Chao‐Ton
Published: March 2003

To achieve higher operating performance, many enterprises have implemented customer satisfaction (CS) activities. However, after collecting massive amounts of data, most enterprises still cannot make effective CS decisions. There are two factors involved in the difficulty in CS decisions. When collecting data, enterprises have trouble covering the wide scope of customer demands. Furthermore, it is difficult to prioritize the collected elements. The purpose of this article is therefore to modify the traditional quality function deployment (QFD) methodology and propose using “strategy value” as an effective decision basis for CS activities. The use of “strategy value” can strongly supplement the lack of “importance” and “performance” in the traditional analysis. A case study involving an enterprise's strategy decisions is used to analyze the proposed concepts and methodology. The results from this study will facilitate enterprises achieving more effective CS strategy decisions and generally increase the probability for CS success rates among enterprises.