bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Coadministration of Fluoxetine on Cisapride Pharmacokinetics and QTc Intervals in Healthy Volunteers
Authors: Zhao Qinying , Wojcik Mary Ann , Parier Jean‐Loup , Pesco‐Koplowitz Luana
Published: June 2004

Study Objective. To evaluate the effect of fluoxetine on the pharmacokinetics and cardiovascular safety of cisapride at steady state in healthy men.

Design. Open‐label, three‐phase, sequential study.

Setting. Clinical research center.

Subjects. Twelve healthy male volunteers.

Interventions. Each subject was treated according to the following sequence: baseline; phase 1 (days 1–6): cisapride 10 mg 4 times/day; washout (days 7–13); phase 2 (days 14–44): fluoxetine 20 mg/day; and phase 3 (days 45–52): cisapride 10 mg 4 times/day (days 45–51) plus fluoxetine 20 mg/day (days 45–52).

Measurements and Main Results. Blood samples were drawn and 12‐lead electrocardiograms performed at specified time points after the last morning dose of cisapride in phases 1 and 3. Blood samples also were taken before morning doses on the 3rd, 4th, and 5th days of phases 1 and 3. Electrocardiograms were done at baseline and on the last day of the washout period and phase 2. Coadministration of fluoxetine significantly decreased cisapride plasma concentrations. There were no clinically significant changes in corrected QT intervals during administration of cisapride alone or with fluoxetine. Cisapride was well tolerated when administered alone or with fluoxetine.

Conclusion. Cisapride can be administered safely to patients receiving low therapeutic dosages of fluoxetine.
Relative Bioavailability of Lamotrigine Chewable Dispersible Tablets Administered Rectally
Authors: Birnbaum Angela K. , Kriel Robert L. , Im Yoonsun , Remmel Rory P.
Published: June 2004

Study Objective. To determine the relative bioavailability of lamotrigine (LTG) chewable dispersible tablets after rectal administration.

Design. Two‐period, crossover study with a 2‐week washout between dosing periods.

Setting. Clinical research center.

Patients. Twelve healthy adult volunteers.

Intervention. One hundred milligrams of a LTG chewable dispersible tablet was administered by oral and rectal routes.

Measurements and Main Results. Plasma samples were collected before and up to 120 hours after drug administration. The samples were analyzed for LTG by high‐performance liquid chromatography, and the relative bioavailability was determined. Drug concentrations were lower after rectal than after oral administration. The relative bioavailability (F = AUCrectal/AUCoral) was 0.52 ± 0.23 (SD).

Conclusion. Drug prepared from LTG chewable dispersible tablets is absorbed rectally, although not to the same extent as when given orally. Rectal administration of suspension of these tablets can be an acceptable route of administration.
Lack of Effect of a Single Dose of Ketoconazole on the Pharmacokinetics of Citalopram
Authors: Gutierrez Marcelo , Abramowitz Wattanaporn
Published: June 2004

Study Objective. To determine whether the pharmacokinetics of the antidepressant citalopram are affected by ketoconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4.

Design. Single‐center, double‐blind, randomized, three‐way crossover trial.

Setting. Research facility.

Participants. Eighteen healthy male and female volunteers.

Intervention. Subjects received three treatments with a 14‐day washout period: single dose of ketoconazole 200 mg plus placebo, single dose of citalopram 40 mg plus placebo, and single dose of ketoconazole 200 mg plus single dose of citalopram 40 mg.

Measurements and Main Results. Pharmacokinetic parameters were determined after each treatment. The pharmacokinetic profile of citalopram administered alone was essentially identical to that when administered with ketoconazole. Similarly, the pharmacokinetics of the metabolite desmethylcitalopram were unaltered by ketoconazole.

Conclusion. No changes in pharmacokinetics of citalopram were observed after coadministration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors may be administered safely with citalopram. Furthermore, no adjustment of citalopram dosage should be necessary in most patients who receive the drug in combination with a CYP3A4 inhibitor.
The Pharmacokinetics of Subcutaneous Enoxaparin in End‐Stage Renal Disease
Authors: Brophy Donald F. , Wazny Lori D. , Gehr Todd W. B. , Comstock Thomas J. , Venitz Jürgen
Published: June 2004

Study Objective. To evaluate the pharmacokinetics of enoxaparin in end‐stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range.

Design. Prospective, single‐dose pharmacokinetic study.

Setting. University‐affiliated general clinical research center.

Patients. Eight nonthrombosed patients with ESRD requiring hemodialysis.

Intervention. All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours.

Measurements and Main Results. The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple‐dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2‐fold prolongation in antifactor Xa activity half‐life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single‐dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady‐state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady‐state concentrations within the therapeutic range.

Conclusions. Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.
Evaluation and Survey of Intravenous Vitamin K1 for Treatment of Coagulopathy in Critically Ill Patients
Authors: MacLaren Robert , Wilson S. Jo‐Anne , Campbell Amanda , Anderson David , Rocker Graeme
Published: June 2004

Study Objectives. To determine patient factors associated with coagulopathy, to assess variables affecting response to vitamin K1, to describe vitamin K1‐associated adverse reactions, and to survey Canadian tertiary care hospitals about vitamin K1 practice patterns in their intensive care units (ICUs).

Design. Retrospective chart audit and prospective survey.

Setting. Medical‐surgical ICU with a 23‐bed complement in a tertiary care, university‐affiliated hospital, and 47 Canadian tertiary care hospitals.

Patients. Forty‐eight critically ill patients with nonconsumptive coagulopathies.

Intervention. Intravenous vitamin K1 utilization over 4 months.

Measurements and Main Results. The only independent risk factor for elevated baseline international normalized ratios (INRs) was Acute Physiologic and Chronic Health Evaluation (APACHE) II score (r2 = 0.51, p<0.05). The INR values decreased after two doses of vitamin K1 10 mg for patients grouped as a whole (2.14 ± 0.96 to 1.61 ± 0.62, p<0.0001) and when patients were stratified according to APACHE II scores below 23 (1.83 ± 0.44 to 1.34 ± 0.18, p<0.05). The INRs were not significantly reduced for patients with APACHE II scores of 23 or greater (2.44 ± 1.23 to 1.82 ± 0.66). No variables were associated with response, and adverse events were not observed. Of 47 Canadian tertiary care hospitals surveyed, 27 (55%) responded. Twenty‐four (89%) indicated that vitamin K1 was administered intravenously, and no adverse events resembling anaphylaxis were reported.

Conclusion. Administration of two doses of intravenous vitamin K1 10 mg was associated with reversal of coagulopathies, but variable responses may be expected for patients with high APACHE II scores. Randomized, placebo‐controlled studies are necessary to confirm the effectiveness of vitamin K1.
Improved Health‐Related Quality of Life with SSRIs and other Antidepressants
Authors: Taylor A. Thomas , Spruill William J. , Longe R. Leon , Wade William E. , Wagner Peggy J.
Published: June 2004

Study Objective. To document the health‐related quality of life (HRQOL) of depressed patients receiving antidepressant drugs.

Design. Cross‐sectional study.

Setting. Community pharmacy‐based setting.

Patients. Fifty‐seven depressed patients.

Intervention. Independent pharmacist members of the Community Pharmacists Research Network in Georgia administered the Medical Outcomes Study 36‐Item Short‐Form Health Survey (SF‐36) to subjects.

Measurements and Main Results. Sixty‐one percent of patients were treated with a selective serotonin reuptake inhibitor (SSRI) and 38.6% were treated with a non‐SSRI. Those receiving SSRIs scored higher on the mean physical (PCS) and mental (MCS) health summary scores of the SF‐36 than those not receiving the drugs. No significant differences were seen in PCS or MCS scores of men and women.

Conclusion. Community pharmacists documented better HRQOL in patients receiving SSRIs than in those given other antidepressants.
Implications of Cytochrome P450 2C9 Polymorphism on Warfarin Metabolism and Dosing
Authors: Redman Andrea R.
Published: June 2004

Warfarin is an anticoagulant available as a racemic mixture. The R‐ and S‐isomers differ with respect to relative plasma concentrations, clearance, potency, sites of metabolism, and cytochrome P450 (CYP) isoenzymes responsible for metabolism. S‐Warfarin, the more potent isomer, is metabolized primarily by CYP2C9. Genetic polymorphisms resulting from single amino acid substitutions reduce the metabolic capability of 2C9. A reduction in warfarin metabolism due to genetic polymorphism may explain the increased warfarin response and bleeding episodes in some patients. Clinical studies showed an increased plasma level of S‐warfarin, decreased clearance of S‐warfarin, increased frequency of bleeding, and prolongation of hospitalization in patients with variant CYP2C9 alleles. Adverse outcomes associated with warfarin possibly could be avoided by identifying patients with variant alleles before therapy and starting therapy at low dosages.
Photosensitivity Associated with Fluorouracil, Prochlorperazine, and Topical Tretinoin
Authors: Birner Ann M. , Meyer Louise P.
Published: June 2004

A woman newly diagnosed with colon cancer began chemotherapy with fluorouracil and leucovorin. Chemotherapy was given daily for 5 days with prochlorperazine premedication and was well tolerated. The patient continued her previous drug regimen during and after chemotherapy, which consisted of hormone replacement therapy, chloroquine, insulin, multivitamin, and tretinoin topical cream. Several days after the end of the first cycle of chemotherapy she experienced a dramatic photosensitivity reaction. Tretinoin application was discontinued, and she recovered. All other drugs remained unchanged. The patient was treated with five additional cycles of chemotherapy. She did not experience the reaction with any potentially photosensitizing agents again; only when the specific sequence and drug combination was administered in the first cycle.
Comparison of Length of Hospital Stay for Patients with Known or Suspected Methicillin‐ResistantStaphylococcusSpecies Infections Treated with Linezolid or Vancomycin: A Randomized, Multicenter Trial
Authors: Li Zhiming , Willke Richard J. , Pinto Lionel A. , Rittenhouse Brian E. , Rybak Michael J. , Pleil Andreas M. , Crouch Charles W. , Hafkin Barry , Glick Henry A.
Published: June 2004

Study Objective.To compare hospital length of stay (LOS), weekly discharges, and days of antibiotic treatment with linezolid (intravenous with oral follow‐up) and vancomycin (intravenous only).

Design.Multinational, randomized, phase III trial.

Settings.Hospitals in North America, Latin America, and Europe.

Patients.Four hundred sixty hospitalized patients with infections of known or suspected methicillin‐resistantStaphylococcusspecies.

Intervention.Administration of linezolid or vancomycin.

Measurements and Main Results.For linezolid recipients, median LOS was 5 and 8 days shorter (p=0.05 and 0.003) in the complicated skin and soft tissue infection intent‐to‐treat (230 patients) and clinically evaluable (144) samples, and slightly but not significantly shorter in the overall intent‐to‐treat (460) and clinically evaluable (254) samples. In all samples, linezolid recipients had more discharges in the first week of treatment and fewer days of intravenous therapy than vancomycin recipients.

Conclusion.Our results support linezolid's ability to reduce medical resource use.
Risk Assessment for Antimicrobial Agent‐Induced QTc Interval Prolongation and Torsades de Pointes
Authors: Owens Robert C.
Published: June 2004

Over the past several years a multitude of new pharmaceutical agents have been released to the market. Several of them were withdrawn altogether or their use severely restricted to certain indications due to unexpected adverse events, including fatalities. Progress in developing new compounds clearly has surpassed our technology, in some cases, to measure and predict certain toxicities. Prolongation of the QT interval, which may lead to potentially life‐threatening ventricular arrhythmias such as torsades de pointes, is one example. Regulatory agencies such as the Food and Drug Administration are increasing standards by which drugs are evaluated for cardiac toxicity related to QT interval prolongation. It is imperative that clinicians be knowledgeable of the risk factors for QT prolongation and avoid the use of culpable agents in patients at risk for QT prolongation.
Clinical Use of New Antithrombotic Therapies for Medical Management of Acute Coronary Syndromes
Authors: Wiggins Barbara S. , Wittkowsky Ann K. , Nappi Jean M.
Published: June 2004

Prevention and management of acute coronary syndromes (ACS) are focal points of interest among health care providers. Acute coronary syndromes is an all‐encompassing term that refers to unstable angina, non‐Q wave myocardial infarction, and Q wave myocardial infarction. These syndromes are usually the result of atherosclerotic plaque rupture leading to thrombus formation in a coronary artery. Heparin and aspirin are traditional antithrombotic treatments. They typically are administered with antiischemic therapies and often with fibrinolytic agents for patients with ST segment elevation associated with acute myocardial infarction. Although aspirin and heparin are important, they have significant limitations that have prompted development of newer antithrombotic approaches. Adenosine diphosphate inhibitors have been evaluated as either alternatives or adjunctive treatment to aspirin. Glycoprotein IIb‐IIIa receptor inhibitors, low‐molecular‐weight heparins, and direct thrombin inhibitors have been studied as concurrent therapy with, or as alternatives to, heparin.
Does Prophylaxis against Atrial Fibrillation after Cardiac Surgery Reduce Length of Stay or Hospital Costs?
Authors: Reddy Prabashni
Published: June 2004

Atrial fibrillation (AF) is common after cardiac surgery and may result in stroke, need for permanent pacemaker, hemodynamic instability, and sustained AF. Studies determining the effect of prophylaxis against AF in cardiac surgery on length of stay (LOS) and hospital cost were reviewed. A MEDLINE search from January 1966–November 2000 was conducted using the medical subject heading (MeSH) “atrial fibrillation.” The search was limited to clinical trials in the English language. In five of the seven studies reviewed, the frequency of postoperative AF was significantly reduced with prophylactic amiodarone or sotalol. In only one study were LOS and costs significantly reduced. Whereas there is strong evidence that prophylactic drug therapy reduces the frequency of postoperative AF, there is little evidence of an economic advantage. Future studies are warranted that examine costs beyond initial hospitalization; compare prophylaxis administered selectively to high‐risk patients with prophylaxis administered universally; and compare prophylaxis with the combination of rate control and anticoagulation with cardioversion if AF persists.
Comparison of Preoperative Skin Preparation Products
Authors: Armstrong Edward P. , Patrick Kristin L. , Erstad Brian L.
Published: June 2004

We compared application, drying, and removal times as well as user satisfaction of four preoperative skin preparation products. All products were applied to 25 subjects, allowed to dry, and removed. Operating room personnel who applied the products were asked to complete a user‐satisfaction survey. Application and drying times were longest with the povidone iodine paint and scrub product (p<0.05). That product had the highest rating for overall user satisfaction. Cost‐minimization analysis revealed that although alcohol‐containing products had lower overall costs, savings may not outweigh associated safety risks.
Improving Blood Pressure Control in a Pharmacist‐Managed Hypertension Clinic
Authors: Vivian Eva M.
Published: June 2004

Objective. To determine whether pharmaceutical care provided by a pharmacist‐managed hypertension clinic results in better treatment outcomes when compared with traditional health care from a primary care physician.

Design. Prospective, controlled study.

Setting. Veterans Affairs Medical Center, Philadelphia, Pennsylvania.

Patients. Fifty six patients with essential hypertension; 27 were randomly assigned to the intervention group and 29 to the control group.

Intervention. Patients in the intervention group were scheduled monthly to meet with a clinical pharmacist who made appropriate changes in prescribed drugs, adjusted dosages, and provided drug counseling in accordance with the hypertension guidelines in the sixth report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Patients in the control group received standard care from their physicians. The study period was 6 months.

Measurements and Main Results. Treatment outcomes were measured by changes in compliance, blood pressure, and patient satisfaction. The Short Form‐36 health survey and a patient satisfaction survey were used to measure changes in patient satisfaction, and a compliance evaluation survey measured compliance. Twenty‐one (81%) patients in the intervention group attained their blood pressure goal of below 140/90 mm Hg at the completion of the study versus only eight (30%) in the control group (p<0.0001). Of 11 patients with diabetes in the intervention group, 10 (91%) attained their blood pressure goal (< 130/80 mm Hg) versus only two (12 %) of 16 patients with diabetes in the control group (p<0.0001). No significant differences in patient satisfaction or compliance were reported between the intervention and control groups.

Conclusions. Pharmaceutical care improves blood pressure control and results in more patients with hypertension reaching their blood pressure goal.
Compliance with National Guidelines in Patients with Diabetes in a Family Practice Clinic
Authors: Kirk Julienne K. , Poirier Jessica E. , Mattox Michelle G. , Thomas Perry M. , Michielutte Robert
Published: June 2004

Study Objective. To assess whether clinicians are treating patients with both type 2 diabetes and hyperlipidemia according to national goals for blood pressure, low‐density lipoprotein cholesterol (LDL), and glucose levels.

Design. Retrospective chart review.

Setting. University‐based family medicine teaching practice.

Patients. One hundred twenty‐four patients with both type 2 diabetes and hyperlipidemia.

Measurements and Main Results. Sixty‐nine patients (58%) met the National Cholesterol Education Program Adult Treatment Panel II's goals for LDL (< 130 mg/dl for primary prevention and < 100 mg/dl for secondary prevention). Only 47 patients (38%) were in compliance with national standards for both systolic and diastolic blood pressures. The mean hemoglobin A1c (A1C) level was 8.6%; 27 patients (21.8%) had A1C levels below 7%.

Conclusion. A high percentage of patients in our family practice clinic met their goals for reducing lipid levels, but more aggressive therapy is necessary to attain glucose and blood pressure goals. Data from this study emphasize the need for understanding which factors influence clinicians' treatment decisions.
Key Articles and Guidelines Relative to Intensive Care Unit Pharmacology
Authors: Erstad Brian L. , Jordan Ché J. , Thomas Michael C.
Published: June 2004

Compilations of key articles and guidelines in a particular clinical practice area are useful not only to clinicians who practice in that area, but to all clinicians. We compiled pertinent articles and guidelines pertaining to drug therapy in the intensive care unit setting from the perspective of an actively practicing critical care pharmacist. This document also may serve to stimulate other experienced clinicians to undertake a similar endeavor in their practice areas.
Pharmaceutical Considerations in Aerosol Drug Delivery
Authors: Kuhn Robert J.
Published: June 2004

Aerosolized drug delivery has been used for over 50 years, but its quality and scope continue to increase. Three factors affect this form of drug delivery: the nebulizer, the compressor, and the actual drug preparation. As technology and knowledge improve, this delivery system also improves. Patients with cystic fibrosis, in particular, can benefit significantly from this form of therapy.
Optimizing Drug Therapy in Patients with Cardiovascular Disease: The Impact of Pharmacist‐Managed Pharmacotherapy Clinics in a Primary Care Setting
Authors: Geber Jean , Parra David , Beckey Nick P. , Korman Lisa
Published: June 2004

We evaluated the effectiveness of pharmacist‐managed pharmacotherapy clinics in implementing and maximizing therapy with agents known to reduce the morbidity and mortality associated with cardiovascular disease. This was a retrospective chart review of 150 patients who were treated for coronary artery disease in primary care clinics. Appropriate treatment of hypercholesterolemia occurred in 96% of patients referred to a clinical pharmacy specialist, compared with 68% of those followed by primary care providers alone (p>0.0001). Eighty‐five percent and 50%, respectively, achieved goal low‐density lipoprotein (LDL) values below 105 mg/dl (p>0.0001). Appropriate therapy with aspirin or other antiplatelet or anticoagulant drugs was prescribed in 97% and 92%, respectively (p=0.146). As appropriate therapy with these agents was high in both groups, the ability to detect a difference between groups was limited. Among patients with an ejection fraction below 40%, appropriate therapy with an angiotensin‐converting enzyme inhibitor or acceptable alternative was 89% and 69%, respectively (p>0.05). Twenty‐seven cardiac events were documented in the clinical pharmacy group, versus 22 in the primary care group (p=0.475). Despite the relatively high percentage of patients reaching goal LDL in the primary care group, referral to clinical pharmacy specialists resulted in statistically significant increases in the number of patients appropriately treated for hypercholesterolemia and achieving goal LDL.
Effectiveness of a Pharmacist‐Based Smoking‐Cessation Program and Its Impact on Quality of Life
Authors: Zillich Alan J. , Ryan Melody , Adams Aimee , Yeager Bryan , Farris Karen
Published: June 2004

We conducted a prospective, open‐label trial to evaluate the effectiveness of a pharmacist‐based, comprehensive, smoking‐cessation program with 31 self‐referred subjects. A secondary goal was to measure changes in health‐related quality of life (HRQOL) during the cessation attempt. The program consisted of weekly, 1‐hour group sessions over 12 weeks. It incorporated nicotine replacement therapy (patch, gum) with extensive behavior modification counseling. Trained pharmacists served as program facilitators. Smoking cessation was chemically verified at 3 and 6 months by exhaled carbon monoxide. The patients' HRQOL was measured using the smoking‐cessation quality of life questionnaire at baseline, 2 weeks, and 1, 2, 3, and 6 months. Chemically verified abstinence rates at 3 and 6 months were 42% (13 patients) and 26% (8 patients), respectively. Among patients who quit, vitality, mental health, and self‐control significantly improved during the 3‐month program. Six‐month cessation rates were modest, although HRQOL improved within 3 months of abstinence.
Rhabdomyolysis Associated with Cerivastatin: Six Cases within 3 Months at One Hospital
Authors: Lucas Robert A. , Weathersby B. Blake , Rocco Vito K. , Pepper J. Michael , Butler Kerry L.
Published: June 2004

Rhabdomyolysis is an uncommon complication associated with 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors. We observed six cases of cerivastatin‐associated rhabdomyolysis: two patients developed acute renal failure requiring hemodialysis, and one patient died. Four of the patients had impaired renal function, and five were prescribed drugs with the potential to interact with cerivastatin. Also, five of the six patients presented with symptoms of rhabdomyolysis 3–4 weeks after starting cerivastatin therapy.
Filtration of flocculated suspensions under declining pressure
Authors: Martin A. D.
Published: June 2004

The modeling of gravity driven batch filtration is dicussed in which the slurry is considered to comprise a flocculated suspension. The gravity belt thickener and the sludge drying bed are commonly employed devices to which this model may be applied. In both devices, the slurry is applied to a filter medium through which the filtrate passes under the influence of the hydraulic head of the slurry. The solids are retained on the filter and accumulate in up to 3 distinct zones. A fourth zone of clear liquor may also exist above the solids zones. As the filtration process proceeds, the hydraulic head declines because of the discharge of filtrate. A model of this filtration process is developed together with methods for its solution. The model links the filtration rate to the physical properties of the slurry through constitutive relationships for the permeability and compressive yield stress. 2004 American Institute of Chemical Engineers AIChE J, 50:1418–1430, 2004
Measurement and prediction of the ultrafiltration of whey protein
Authors: Davey M. , Landman K. , Perera J. M. , Stevens G. W. , Lawrence N. D. , Iyer M.
Published: June 2004

Ultrafiltration of proteins and other compressible material is characterized by a significant transmembrane pressure and is often limited by the formation of a fouling layer. This study examines the compressive rheology of such fouling layers. A model is proposed that can be used to predict the performance of filtration processes where there is significant pressure drop across the clean membrane and the filtration rate is limited by fouling during the filtration cycle. The information required for the model can in principle be obtained from simple centrifuge tests and the clean membrane pressure drop. The model can be used to optimize the cycle times, pressures, and other operating parameters of the ultrafiltration process. The model was tested on the ultrafiltration of whey protein concentrate and shown to describe the experimental data. © 2004 American Institute of Chemical Engineers AIChE J, 50: 1431–1437, 2004
The dysbindin gene in major depression: An association study
Authors: Zill Peter , Baghai Thomas C. , Engel Rolf , Zwanzger Peter , Schüle Cornelius , Eser Daniela , Behrens Stefanie , Rupprecht Rainer , Möller Hans‐Jürgen , Ackenheil Manfred , Bondy Brigitta
Published: June 2004

The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin‐binding‐protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin‐associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24–41]; Brambilla et al. [2003: Mol Psychiatry 8:721–737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results. © 2004 Wiley‐Liss, Inc.
Congenital malformations in offspring of Hispanic and African‐American women in California, 1989–1997
Authors: Carmichael Suzan L. , Shaw Gary M. , Kaidarova Zhanna
Published: June 2004

BACKGROUND

Little is known about risks of most specific birth defects among infants born to U.S.‐born and foreign‐born Hispanic or African‐American women.

METHODS

Using data from a large population‐based registry, we explored risks of selected congenital malformation phenotypes in offspring of U.S.‐born and foreign‐born Hispanic and African‐American women, relative to non‐Hispanic white women, in California. Approximately 2.2 million live births and stillbirths occurred during the ascertainment period, 1989–1997. Information on maternal racial‐ethnic background and other covariates was obtained from birth certificate and fetal death files.

RESULTS

Adjusted relative risks (ARRs) for the 20 groupings of malformations designated by three‐digit British Pediatric Association (BPA) codes ranged from 0.6 (genital organ malformations, among infants born to foreign‐born Hispanics) to 1.7 (anencephaly, also among infants born to foreign‐born Hispanics). Grouping by four‐digit BPA codes revealed that among infants born to U.S.‐born Hispanics, 46 of the ARRs were ≤0.8 and 12 were ≥1.3; among infants born to foreign‐born Hispanics, 75 of the ARRs were ≤0.8 and 15 were ≥1.3; and among infants born to African‐American women, 45 ARRs were ≤0.8 and 25 were ≥1.3. For each racial‐ethnic group of women, the observed variability in risks covered most organ systems.

CONCLUSIONS

Although the results suggested that (in comparison with non‐Hispanic whites) each racial‐ethnic group was more likely to have reduced risk for specific defects (rather than elevated risk), in general, the range of the relative risks was comparatively narrow. Birth Defects Research (Part A), 2004. © 2004 Wiley‐Liss, Inc.
A common ABCC2 promoter polymorphism is not a determinant of the risk of spina bifida
Authors: Jensen Liselotte E. , Wall Amelia M. , Cook Michelle , Hoess Katy , Thorn Caroline F. , Whitehead Alexander S. , Mitchell Laura E.
Published: June 2004

BACKGROUND

There is compelling evidence that the risk of spina bifida, a malformation of the caudal neural tube, is associated with maternal and/or embryonic disturbances in folate/homocysteine metabolism. Hence, functional variants of genes that influence folate/homocysteine metabolism constitute a biologically plausible group of candidate risk factors for spina bifida and other neural tube defects. One such candidate is ABCC2, the gene encoding ABCC2, (a.k.a. canalicular multispecific organic anion transporter [cMOAT], multidrug resistance related protein 2 [MRP2]), a member of the ABC transporter family that effluxes natural folates and anti‐folate drugs such as methotrexate.

METHODS

The association between the risk of spina bifida and both the maternal and embryonic ABCC2 C(–24)T genotype was evaluated by using the transmission disequilibrium test and log‐linear modeling.

RESULTS

These analyses provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic ABCC2 C(–24)T genotype.

CONCLUSIONS

The results of the present analyses suggest that the C(–24)T variant of the ABCC2 gene is not a major determinant of spina bifida risk. Birth Defects Research (Part A), 2004. © 2004 Wiley‐Liss, Inc.
Immunocytochemical localization of polyamines during attachment and spreading of retinal pigment epithelial and intestinal epithelial cells
Authors: Johnson Dianna A. , Sharma Rajesh K. , Allan Katherine , Ray Ramesh , Johnson Leonard R.
Published: June 2004

In order to form and maintain a protective barrier for photoreceptors, the retinal pigment epithelium relies on integrin signaling and related pathways to form adhesion complexes, undergo cell spreading, and establish a confluent cellular monolayer. Polyamines are multifunctional polycations that are essential for cell attachment and spreading, although their exact mechanisms of action are as yet unclear. We report new immunocytochemical evidence suggesting that in the cells of retinal pigment epithelium and also the intestinal epithelium, polyamines are present in a population of intracellular vesicles that appear transiently during initial stages of cell spreading. In newly attached cells with minimal spreading, the vesicles are seen near the nucleus, whereas in more highly spread cells, the vesicles are localized to the plasma membrane, near, but not precisely co‐localized with an enzyme marker for adhesion complexes, focal adhesion kinase. We also observe pronounced nuclear staining in newly attached cells that have not spread, whereas this staining is decreased in cells that have spread. Nuclear staining has been previously reported in other cell types and has been attributed to DNA binding of polyamines, which is known to stabilize chromatin structure. We hypothesize that the appearance of polyamine vesicles near focal adhesions of cells undergoing attachment and spreading may reflect the mechanism by which polyamine pools are targeted to appropriate interaction sites necessary for the assembly of adhesion complexes. Alternatively, the vesicles could represent the mechanism by which polyamines are removed from the nucleus and possibly released from the cell. Cell Motil. Cytoskeleton 58:269–280, 2004. © 2004 Wiley‐Liss, Inc.
Folate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studies
Authors: Kim Young‐In
Published: June 2004

Folate, a water‐soluble B vitamin and cofactor in one‐carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer (CRC). Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with CRC risk. Collectively, these studies suggest an ∼ 40% reduction in the risk of CRC in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose‐dependent protective effect of folate supplementation. However, animal studies also have shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote, rather than suppress, colorectal carcinogenesis. These animal studies, in conjunction with clinical observations, suggest that folate possesses dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect, whereas folate supplementation has a promoting effect on the progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these studies suggest that the optimal timing and dose of folate intervention must be established for safe and effective chemoprevention in humans. Folate is an important factor in DNA synthesis, stability, and integrity, the repair aberrations of which have been implicated in colorectal carcinogenesis. Folate may also modulate DNA methylation, which is an important epigenetic determinant in gene expression (an inverse relationship), in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. A mechanistic understanding of how folate status modulates colorectal carcinogenesis further strengthens the case for a causal relationship and provides insight into a possible chemopreventive role of folate. Environ. Mol. Mutagen. 44:10–25, 2004. © 2004 Wiley‐Liss, Inc.
Goeldi's monkeys: A primate paradox?
Authors: Porter Leila M. , Garber Paul A.
Published: June 2004

“A primate with the skull of aCallicebus, the mandible and feet of a marmoset and the tail and teeth ofPseudocebus[=Cebus] ….” (Riberio, 1941 as cited in Hershkovitz1p. 866). Goeldi's monkeys are the least understood species of platyrrhine. The monkeys' small body size, black coloration, tendency to forage in the low forest understory, and cryptic nature, make them difficult to observe in the wild. Until recently, they had never been the focus of a long‐term field study and as a result, little was known of the monkeys' behavior and ecology. Goeldi's monkeys comprise only one recognized species,Callimico goeldii, and have an unusual suite of anatomical and reproductive traits. These traits have created considerable confusion for taxonomists and physical anthropologists.
Inverse expression of dihydrodiol dehydrogenase and glutathione‐S‐transferase in patients with esophageal squamous cell carcinoma
Authors: Wang Liang‐Shun , Chow Kuan‐Chih , Wu Yu‐Chung , Lin Tze‐Yi , Li Wing‐Yin
Published: June 2004

We investigated the significances of the expressions of dihydrodiol dehydrogenase (DDH) and glutathione‐S‐transferase (GST) in patients with esophageal squamous cell carcinoma (ESCC). By using immunohistochemistry, we measured expressions of DDH, GST, COX‐2, nm23‐H1, HER‐2/neu and mdr‐1 in 145 patients with ESCC. Expression of DDH was confirmed by immunoblotting and reverse transcription‐polymerase chain reaction. Relation between DDH expression and clinicopathological parameters was analyzed by statistical analysis. Difference of survivals between different groups was compared by a log rank test. DDH overexpression was detected in 66.9% of pathological sections (97/145) and in 41.6% of metastatic lymph nodes (37/89). The nucleotide sequencing of DNA fragments from 16 tumorous specimens showed that the major isoform was DDH2 for ESCC. GST expression, however, was only detected weakly in 24 patients (16.6%). For patients with ESCC, DDH overexpression was positively correlated with smoking habit, tumor stage, number of metastatic lymph nodes, lymphovascular invasion and COX‐2 expression, and inversely correlated with GST and nm23‐H1 expressions, but not related to mdr‐1 or HER‐2/neu expressions. As compared to DDH overexpressed group, patients with low DDH expression had significantly lower incidence of tumor recurrences and better survival (p = 0.026). Using univariate analysis, prognostic factors included tumor stage, number of metastatic lymph nodes, cell differentiation, lymphovascular invasion and expressions of DDH and nm23‐H1. Multivariate analysis showed significant correlation of tumor stage, number of metastatic lymph nodes and nm23‐H1 expression with patient's survival. In conclusion, inverse expressions of DDH and GST may be associated with carcinogenesis and disease progression for ESCC patients, but their biological function and pathophysiological regulation in tumors require additional studies. © 2004 Wiley‐Liss, Inc.
Evaluation of a selectively oncolytic adenovirus for local and systemic treatment of cervical cancer
Authors: Bauerschmitz Gerd J. , Kanerva Anna , Wang Minghui , Herrmann Isabell , Shaw Denise R. , Strong Theresa V. , Desmond Renee , Rein Daniel T. , Dall Peter , Curiel David T. , Hemminki Akseli
Published: June 2004

Treatment options for disseminated cervical cancer remain inadequate. Here, we investigated a strategy featuring Ad5‐Δ24RGD, an oncolytic adenovirus replication‐competent selectively in cells defective in the Rb‐p16 pathway, such as most cervical cancer cells. The viral fiber contains an αvβ3 and αvβ5 integrin‐binding RGD‐4C motif, allowing coxsackie‐adenovirus receptor‐independent infection. These integrins have been reported to be frequently upregulated in cervical cancer. Oncolysis of cervical cancer cells was similar to a wild‐type control in vitro. In an animal model of cervical cancer, the therapeutic efficacy of Ad5‐Δ24RGD could be demonstrated for both intratumoral and intravenous application routes. Biodistribution was determined following intravenous administration to mice. Further preclinical safety data were obtained by demonstrating lack of replication of the agent in human peripheral blood mononuclear cells. These results suggest that Ad5‐Δ24RGD could be useful for local or systemic treatment of cervical cancer in patients with disease resistant to currently available modalities. © 2004 Wiley‐Liss, Inc.
Signaling pathways required for matrix metalloproteinase‐9 induction by betacellulin in head‐and‐neck squamous carcinoma cells
Authors: O‐charoenrat Pornchai , Wongkajornsilp Adisak , Rhys‐Evans Peter H. , Eccles Suzanne A.
Published: June 2004

The mechanisms by which c‐erbB‐dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c‐erbB autocrine and/or paracrine stimulation upregulates MMP‐9 but has no effect on the related gelatinase, MMP‐2. BTC, a major c‐erbB ligand, has the ability to efficiently activate all c‐erbB receptors and to bind directly to EGFR and c‐erbB‐4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c‐erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c‐erbB receptor signaling to the regulation of MMP‐9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN‐006 and Detroit‐562, BTC treatment resulted in rapid tyrosine phosphorylation of all c‐erbB receptors whereas both endogenous MMP‐9 and BTC‐stimulated MMP‐9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC‐dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK‐1/ERK pathway occurred via all 4 c‐erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC‐induced MMP‐9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF‐κB, BAY 11‐7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP‐9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC‐γ. Taken together, our data show that BTC induces MMP‐9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells. © 2004 Wiley‐Liss, Inc.
Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice
Authors: Irie Masaki , Homma Sadamu , Komita Hideo , Zeniya Mikio , Kufe Donald , Ohno Tsuneya , Toda Gotaro
Published: June 2004

We attempted to prevent spontaneous development of liver tumors by s.c. inoculation with DCs loaded with syngeneic HCC cells in C3H/HeNCrj mice. A new cell line, MIH‐2, was established from an HCC that had developed spontaneously in a C3H/HeNCrj mouse. Bone marrow–derived DCs were loaded with irradiated MIH‐2 cells by treatment with PEG. Fluorescence microscopy and flow‐cytometric analysis showed that about 45% of PEG‐treated DCs and MIH‐2 cells (DC/MIH‐2) were DCs loaded with MIH‐2 cells. Thirteen‐month‐old mice received inoculations of DC/MIH‐2 (9 × 105/mouse) 4 times at 6‐day intervals and were killed at 16 months of age to assess liver tumors. The incidence of liver tumors in these mice was significantly lower than that in mice not receiving inoculations (p < 0.05) but similar to that in 13‐month‐old mice (the age at which inoculation started), indicating that inoculation inhibited the development of new tumors. Splenocytes from inoculated mice, but not those from uninoculated mice, showed cytotoxic activity against MIH‐2 cells. Cytotoxic activity was not elicited by CD4+ T cells, CD8+ T cells, or DX5+ cells isolated from splenocytes but was elicited by adherent cells, identified as CD11b+ macrophages. CD4+ T cells, but not CD8+ T cells, from inoculated mice produced IFN‐γ by incubation with DC/MIH‐2. Cytotoxicity by splenocytes was attenuated by anti‐IFN‐γ antibody. Immunization with DCs loaded with syngeneic HCC cells induces CD4+ T cells that produce IFN‐γ by response to antigen of HCC, which would lead to macrophage activation to kill liver tumor cells at an early stage. © 2004 Wiley‐Liss, Inc.
Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma
Authors: Coon Steven W. , Savera Adnan T. , Zarbo Richard J. , Benninger Michael S. , Chase Gary A. , Rybicki Benjamin A. , Van Dyke Daniel L.
Published: June 2004

Loss of heterozygosity (LOH) in chromosomal regions that harbor tumor suppressor genes from tumor tissue may lead to decreased survival time in cancer patients with squamous cell carcinoma of the head and neck (HNSCC). We studied 8 regions frequently lost in HNSCC in 150 patients having a primary diagnosis of HNSCC. Tumor and normal tissue DNA were genotyped for microsatellite repeat markers in 8 unlinked chromosomal regions. The association between LOH and death from HNSCC was investigated, weighted by number of informative markers per region and adjusted for age at diagnosis, self‐reported race, tumor stage and current smoking status. LOH at 3 chromosomal regions were independently associated with reduced survival. A greater risk for cancer mortality was observed for LOH at chromosomal regions 3p24.3‐p14.3 (p = 0.02), 8p21.3‐p11.21 (p = 0.02) and 9p24.2‐p21.2 (p = 0.03). In these regions, LOH at one or more markers was observed in 66.9%, 43.3% and 60.6% of patients, respectively. Survival times were significantly shorter for those with LOH at marker NEFL on 8p21.2 (relative risk = 6.15; p = 0.0002) and at D9S126 on 9p21.2 (relative risk = 5.96; p = 0.0003). Our results indicate that LOH at several chromosomal sites may offer additional independent prognostic information beyond traditional indicators such as tumor stage and age. © 2004 Wiley‐Liss, Inc.