bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Microbleeds as a Risk Factor for Subsequent Intracerebral Hemorrhages Among Patients With Acute Ischemic Stroke
Authors: Fan Yu Hua , Zhang Lei , Lam Wynnie W.M. , Mok Vincent C.T. , Wong Ka Sing
Published: September 2003

Background and Purpose—

Cerebral microbleeds (MBs) detected by gradient-echo MRI are considered evidence of advanced microangiopathy with potential for further bleeding. The goal of this study was to determine whether the presence of MBs is a risk factor for subsequent intracerebral hemorrhage among patients with acute ischemic stroke.

Methods—

We prospectively examined patients hospitalized with acute cerebral infarction with gradient-echo T2*-weighted MRI for the presence of MBs. We recorded demographics, medical history, and stroke severity. Patients were then followed up for the development of stroke, other vascular events, and death.

Results—

One hundred twenty-one consecutive patients with a mean age of 67.96±10.97 years were recruited. MBs were present in 43 patients (35.5%). During follow-up of 27.15±11.68 months, 16 patients had recurrent stroke. There was no difference between patients with or without MB for the development of ischemic stroke (5 and 6 respectively,
P
=0.841). However, 4 patients (9.3%) with MBs and 1 patient (1.3%) without an MB had intracerebral hemorrhage during follow-up (
P
=0.053). Of the 5 patients who developed subsequent intracerebral hemorrhages, 3 were treated with aspirin and 2 with anticoagulation. Two of the intracerebral hemorrhages occurred in the site where asymptomatic MBs were found at baseline.

Conclusions—

MBs appear to be a risk factor for subsequent intracerebral hemorrhage among patients with ischemic stroke in this small cohort of Chinese stroke patients. A large cohort study is required to confirm this observation.
Are Patients With Acutely Recovered Cerebral Ischemia More Unstable?
Authors: Johnston S. Claiborne , Easton J. Donald
Published: September 2003

Background and Purpose—

Recent studies suggest that the short-term risk of stroke may be greater after transient ischemic attack (TIA) than after stroke.

Methods—

We compared risks of neurological deterioration in those with and without TIA in the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator (tPA) trial, a randomized trial of intravenous tPA given within 3 hours of onset of cerebral ischemia, after excluding those with cerebral hemorrhage and those dying before 90 days of causes other than new ischemic stroke. TIA was defined as a National Institutes of Health Stroke Scale (NIHSS) score of zero at 24 hours. We chose subsequent deterioration as our outcome, defined as a worsening on the NIHSS at 90 days compared with 24 hours, so that episodes of new ischemia that may have been attributed to other causes would be included.

Results—

Of 498 subjects meeting entry criteria, 40 (8%) had TIA. Subsequent deterioration occurred in 30% of those with TIA and 10% of others (
P
=0.001, Fisher exact test). In multivariable models with adjustment for age, sex, ethnicity, 24-hour NIHSS score, tPA administration, presumed stroke subtype, and baseline systolic blood pressure, temperature, and glucose, TIA was an independent predictor of subsequent deterioration (odds ratio, 5.0; 95% CI, 2.0 to 12.5;
P
=0.001). Subsequent deterioration was not associated with tPA treatment, and there was no interaction between tPA administration, TIA, and subsequent deterioration. Lesser degrees of substantial acute recovery were also associated with greater risk of subsequent deterioration.

Conclusions—

Patients with TIA may be a greater risk of subsequent neurological deterioration from causes other than hemorrhage. Substantial acute recovery may be an indicator of greater instability more broadly.
From Oral Practice to Written Record in Ramesside Deir el-Medina
Authors: Haring Ben
Published: September 2003

The thousands of hieratic ostraca and papyri from the Ramesside settlement of necropolis workmen at Deir el-Medina include many texts about private business and legal matters. The majority of standard formulas in these records did not develop before the first half of the 20th dynasty, whereas most of the formulas current in administrative texts of the necropolis already existed in the 19th dynasty. The later increase in and formalization of private and legal texts suggest that writing became only gradually popular in village life. Studies of similar processes in anthropological and historical literature help to explain this development in an exceptionally literate village community. Parmi les milliers des ostraca et des papyrus hiératiques du village des ouvriers de la nécropole de Deir el-Medina, de l'époque ramesside, on trouve un grand nombre de textes relatifs aux affaires privées et juridiques. La plupart de ces textes comprennent des formules standardisées datant de la première moitié de la 20ième dynastie, tandis que la majorité des formules habituelles dans les textes administratifs de la nécropole existaient déjà plus tôt. L'accroissement et la formalisation tardifs des textes privés et juridiques suggère que l'écriture ne se répandait que lentement dans le village. Les études de procès similaires dans la littérature anthropologique et historique nous aident à expliquer ce dévéloppement dans une communauté exceptionellement lettrée.
The Jewish Merchants in the Light of Eleventh-Century Geniza Documents
Authors: Gil Moshe
Published: September 2003

This article deals with various aspects of trade in the 11th century as attested by documents written by Jewish merchants, or regarding them, found in the Cairo Geniza. The following topics are discussed: (a) Partnership; it seems that all transactions were carried out by way of partnership, each party acting in a different locality, and dealing with imports and exports from one country to the other. (b) The methods of accounting, based on regular reports between partners. (c) The ways of marketing the goods. (d) The payments, and matters of credit, price reductions, etc. (e) Disputes between merchants, and the ways of settling them, an oath being the most conclusive argument. (f) The nature and functions of a kind of leader of the merchants, wakīl al-tujjār. Cet article traite de différents aspects du commerce au 11ème siècle, tels qu'ils sont attestés dans les documents écrits par des marchands juifs, ou dans des documents qui les concernent, préservés dans la Geniza du Caire. Les points principaux en sont : (a) L'association; il semble que toutes les transactions s'effectuaient par l'intermédiaire d'associés, chacun des associés agissant dans une localité différente et pratiquant en commerce d'importations et d'exportations d'un pays à l'autre. (b) Les systèmes de comptabilité qui étaient fondés sur des comptes-rendus réguliers échangés entre les associés. (c) Les méthodes de vente. (d) Les modes de payement, de crédit, les réductions de prix, etc. (e) Les conflits entre les marchands et les actions entreprises pour les résoudre. (f) Les fonctions du wakīl al-tujjār, le "chef des marchands".
Colonial Misunderstanding of an Efficient Peasant Institution: Land Settlement and Mushā Tenure in Mandate Palestine, 1921-47
Authors: Nadan Amos
Published: September 2003

The accepted wisdom is that the mushā in Palestine was an archaic system that blocked any chance of development, since no one had any inducement to improve his land. But this study of the mushā, as part of a set of institutions, contradicts that wisdom. The mushā in Palestine was an efficient, dynamic economic institution that facilitated investment. There was no need for land reform, which only proved destructive to the economy of the fallāhīn. It nullified the advantages inherent in the system and, unexpectedly, facilitated the transfer of lands from Arabs to Jews. La vision généralement admise est que le mushā en Palestine était un système archaïque qui faisait obstacle à toute perspective de développement, puisque personne n'était incité à améliorer sa terre. Mais notre étude du mushā contredit cette vision. Le mushā en Palestine était une institution économique efficace et dynamique qui facilitait l'investissement. La réforme foncière qui abolit le mushā a été destructrice pour l'économie des fallāhīn. La réforme a annulé les avantages inhérents au système et, de façon inattendue, a facilité le transfert de terres des Arabes aux Juifs.
On Cultural Conceptualisations
Authors: Sharifian Farzad
Published: September 2003

This paper first elaborates on the notions of conceptualisation and cultural conceptualisations. Cultural conceptualisations enable the members of a cultural group to think, so to speak, in one mind. These conceptualisations are not equally imprinted in the minds of people but are rather represented in a distributed fashion across the minds in a cultural group. Two major kinds of cultural conceptualisations are cultural schemas and cultural categories. These group-level conceptualisations emerge from and act as the locus for the interactions between people from the same cultural background. The members negotiate and renegotiate these conceptualisations across generations. The paper employs the notion of 'distributed representation' in presenting a model of cultural conceptualisations. It then provides examples of such conceptualisations and discusses how they may be instantiated in various artefacts, such as discourse. The paper also proposes a general framework for the identification of cultural conceptualisations, based on the adoption of an ethnographic approach towards the analysis of discourse. Examples from Australian Aboriginal cultural conceptualisations are provided throughout the paper.
The Role of Control in Attributing Intentional Agency to Inanimate Objects
Authors: Barrett Justin , Johnson Amanda Hankes
Published: September 2003

Previous research into the perception of agency has found that objects in twodimensional displays that move along non-inertial-looking paths are frequently attributed intentional agency, including beliefs and desires. The present experiment re-addressed this finding using a tangible, interactive, electromagnetic puzzle. The experimental manipulation was whether or not participants controlled the electromagnet that moved the marbles along unexpected trajectories. Thirty-one college undergraduates participated. Participants who lacked control over the movement of the marbles were significantly more likely to attribute agency to the marbles. Participants in control of the display rarely attributed intentional agency to the marbles. Implications are discussed for the identification of agents in the real world.
The Common Land Model
Authors: Dai Yongjiu , Zeng Xubin , Dickinson Robert E. , Baker Ian , Bonan Gordon B. , Bosilovich Michael G. , Denning A. Scott , Dirmeyer Paul A. , Houser Paul R. , Niu Guoyue , Oleson Keith W. , Schlosser C. Adam , Yang Zong-Liang
Published: September 2003

The Common Land Model (CLM) was developed for community use by a grassroots collaboration of scientists who have an interest in making a general land model available for public use and further development. The major model characteristics include enough unevenly spaced layers to adequately represent soil temperature and soil moisture, and a multilayer parameterization of snow processes; an explicit treatment of the mass of liquid water and ice water and their phase change within the snow and soil system; a runoff parameterization following the TOPMODEL concept; a canopy photo synthesis-conductance model that describes the simultaneous transfer of CO2 and water vapor into and out of vegetation; and a tiled treatment of the subgrid fraction of energy and water balance. CLM has been extensively evaluated in offline mode and coupling runs with the NCAR Community Climate Model (CCM3). The results of two offline runs, presented as examples, are compared with observations and with the simulation of three other land models [the Biosphere-Atmosphere Transfer Scheme (BATS), Bonan's Land Surface Model (LSM), and the 1994 version of the Chinese Academy of Sciences Institute of Atmospheric Physics LSM (IAP94)].
THE USE OF SPANISH HISTORICAL ARCHIVES TO RECONSTRUCT CLIMATE VARIABILITY
Authors: Herrera Ricardo García , García Rolando R. , Prieto M. Rosario , Hernández Emiliano , Gimeno Luis , Díaz Henry F.
Published: September 2003

Spanish historical archives contain a vast store of information about Spain and its former colonies in America and Asia. Some searches for climate-related information within these archives have been undertaken recently, but they have been by no means exhaustive. This paper discusses the principal archives and shows, by means of several examples, that they exhibit a high potential for inferring past climate over a wide range of timescales and geographical areas. Extraction of such information is often time consuming, and requires a combination of archival, historical, and climatological expertise, and the development of individualized methodologies to fit each situation and type of data. In spite of these difficulties, the archives can be particularly useful in many cases where there are no alternative sources of climate data. Thus, the complexities of the multidisciplinary effort required should not discourage other researchers from undertaking similar studies.
The Sydney 2000 World Weather Research Programme Forecast Demonstration Project: Overview and Current Status
Authors: Keenan T. , Joe P. , Wilson J. , Collier C. , Golding B. , Burgess D. , May P. , Pierce C. , Bally J. , Crook A. , Seed A. , Sills D. , Berry L. , Potts R. , Bell I. , Fox N. , Ebert E. , Eilts M. , O'Loughlin K. , Webb R. , Carbone R. , Browning K. , Roberts R. , Mueller C.
Published: September 2003

The first World Weather Research Programme (WWRP) Forecast Demonstration Project (FDP), with a focus on nowcasting, was conducted in Sydney, Australia, from 4 September to 21 November 2000 during a period associated with the Sydney 2000 Olympic Games. Through international collaboration, nine nowcasting systems from the United States, United Kingdom, Canada, and Australia were deployed at the Sydney Office of the Bureau of Meteorology (BOM) to demonstrate the capability of modern forecast systems and to quantify the associated benefits in the delivery of a real-time nowcast service. On-going verification and impact studies supported by international committees assisted by the WWRP formed an integral part of this project. A description is given of the project, including component systems, the weather, and initial outcomes. Initial results show that the nowcasting systems tested were transferable and able to provide valuable information enhancing BOM nowcasts. The project provided for unprecedented interchange of concepts and ideas between forecasters, researchers, and end users in an operational framework where they all faced common issues relevant to real time nowcast decision making. A training workshop sponsored by the World Meteorological Organization (WMO) was also held in conjunction with the project so that other member nations could benefit from the FDP.
Galantamine Population Pharmacokinetics in Patients with Alzheimer's Disease: Modeling and Simulations
Authors: Piotrovsky Vladimir , Van Peer Achiel , Van Osselaer Nancy , Armstrong Martin , Aerssens Jeroen
Published: September 2003

Galantamine is a reversible, competitive inhibitor of acetylcholinesterase and an allosteric modulator of nicotinic acetylcholine receptors. It is cleared by renal and hepatic mechanisms, including metabolism by the CYP 450 2D6 and 3A4 isoenzymes. The authors estimated the population pharmacokinetics of galantamine using nonlinear mixed‐effects modeling as implemented in NONMEM software. Data from 15 clinical studies (1089 individuals, 7480 concentration measurements in total) were used to examine the effect of body size, demographic characteristics, and concomitant disease status on galantamine pharmacokinetic parameters. Galantamine clearance was shown to decrease with age and increase with body weight and creatinine clearance of individuals. Median clearance in male and female patients with Alzheimer's disease (AD) was 14.8 and 12.4 L/h, respectively. The dissimilarity was related to the body weight difference, not to the real gender effect. Metabolic clearance was reduced by 60% in patients with moderate or severe hepatic dysfunction (Pugh score 7 or higher). Simulations were performed to assess the impact of hepatic impairment and renal insufficiency on peak plasma concentration of galantamine. Simulations confirmed the need for slower dose titration in patients with hepatic impairment: 4 mg daily during 1 week followed by 4, 8, and 12 mg bid, with each dose level during 1 week compared to the standard titration scheme 4–8–12–16 mg bid. However, no significant differences between plasma levels in AD patients with and without severe renal insufficiency were found. CYP 450 2D6 genotype also influenced galantamine clearance but not to the extent that dose adjustment is required.
Ensuring Supplies of Quality Diethylcarbamazine Citrate (DEC)
Authors: Kitler Mary Ellen , Zagaria Nevio
Published: September 2003

In 1997, the World Health Organization (WHO) made a commitment to eliminate lymphatic filariasis. The WHO Global Program to Eliminate Lymphatic Filariasis (WHO‐FIL) needed a reliable supply of diethylcarbamazine citrate (DEC) of known acceptable quality at an affordable price, so in August 1999, it started the DEC Project. Today's standards required development of a modern stability‐indicating assay method for DEC and for DEC tablet dissolution. ADD Advanced Drug Delivery Technologies (Switzerland) developed a high‐pressure liquid chromatography assay, which was independently validated and is in the United States Pharmacopoeia 25 (2002). After a global search, the project found that almost all existing and potential DEC active pharmaceutical ingredient (API) and tablet manufacturers are in low‐income countries. The project constructed an audit team to conduct on‐site audits to assess good manufacturing practices according to European Union standards. National/state inspectors accompany the audit team. The team prequalified one DEC API manufacturer and three DEC tablet manufacturers. The project plans to increase the number of prequalified DEC manufacturers. Now, WHO‐FIL only purchases from prequalified manufacturers. Consolidation of several national program DEC requirements into a limited international competitive bid reduced the price for DEC tablets between 30% and 45%, compared to previous small‐scale WHO purchases.
The COX‐2 Selective Inhibitor, Valdecoxib, Does Not Impair Platelet Function in the Elderly: Results of a Randomized Controlled Trial
Authors: Leese Philip T. , Recker David P. , Kent Jeffrey D.
Published: September 2003

The effects of the new cyclooxygenase (COX)‐2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65–85 years) in this 7.5‐day, randomized, single‐center, double‐blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2–4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX‐1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern.
Evaluation of the Cohort Size in Phase I Dose Escalation Trials Based on Laboratory Data
Authors: Buöen Camilla , Holm Sture , Thomsen Mikael S.
Published: September 2003

A survey of Phase I dose escalation trials published since 1995 shows that there is great disparity in all aspects of the design of the studies, and the cohort sizes range from 2 to 16 subjects with a great variety in the distribution between active and placebo‐treated subjects. This study investigates the impact of the cohort size on Type I error and power in Phase I dose escalation trials based on laboratory data, with the hospitalization‐induced increase in hepatic enzyme levels taken into consideration. The power of a Phase I dose escalation trial is very low, and only events with a very high probability of occurrence are detectable with acceptable power. For studies with cohort sizes smaller than 6 active subjects, there is much to gain with the inclusion of 1 extra subject, but for more than 10 subjects, little is gained by increasing the cohort size. With increasing cohort sizes, the probability of spontaneous non‐drug‐related events also increases, and this background rate needs to be considered when evaluating the trial.
Effect of Unilateral Nephrectomy on the Pharmacokinetics of Atenolol in Humans
Authors: Drozdzik Marek , Domanski Leszek , Wojcicki Jerzy , Pudlo Artur , Machoy Piotr
Published: September 2003

Unilateral nephrectomy is a common surgical procedure and involves functional adaptation of the remaining kidney. There is a paucity of data addressing whether drugs eliminated predominantly through the urinary tract, such as atenolol, can be effectively handled by unilaterally nephrectomized patients. This study was carried out in 28 subjects 1 month (10 subjects) and 1 year (10 subjects) after unilateral nephrectomy, as well as in 8 healthy volunteers who were administered atenolol as a single oral dose of 100 mg. Pharmacokinetic parameters of atenolol were calculated using a one‐compartment open model. It was revealed that atenolol blood serum concentrations were significantly elevated in nephrectomized patients as compared with the control subjects, especially 1 month after the surgery. Patients nephrectomized 1 month prior to the study were characterized by an increase in AUC by 43% (p < 0.05), reduction of Λz by 36% (p<0.001) and CLT by 27% (p < 0.001), and prolongation of t1/2 by 60% (p < 0.001) in comparison with healthy volunteers. The values of atenolol pharmacokinetic parameters in patients 1 year after unilateral nephrectomy did not differ significantly as compared to the controls. However, a trend indicating an impaired elimination was noted. A decrease in Λz by 16%, prolongation of t1/2 by 32%, and reduction of CLT by 32% were observed. The results suggest that unilateral nephrectomy impairs elimination of atenolol and possibly other drugs predominantly eliminated via the kidney.
Isoniazid‐Induced Anaphylaxis
Authors: Crook Michael J.
Published: September 2003

Anaphylaxis from isoniazid is a possible side effect to this commonly prescribed antibiotic. The case reported here illustrates that clinicians should be aware of this potentially fatal drug reaction.
Pharmacokinetics and Pharmacodynamics of Intrathecal Ziconotide in Chronic Pain Patients
Authors: Wermeling Daniel , Drass Michael , Ellis David , Mayo Martha , McGuire Dawn , O'Connell Damian , Hale Victoria , Chao Stella
Published: September 2003

The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48‐hour period following intrathecal (IT) administration (1, 5, 7.5, or 10 μg) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24‐hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half‐life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose‐related analgesia was observed. Pharmacokinetic‐pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1‐hour IT infusion.
Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active Iron‐Chelating Agent in Patients with Transfusion‐Dependent Iron Overload Due to β‐Thalassemia
Authors: Galanello Renzo , Piga Antonio , Alberti Daniele , Rouan Marie‐Claude , Bigler Hilde , Séchaud Romain
Published: September 2003

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion–dependent iron overload in chronic anemias. In this randomized, double‐blind study, patients with transfusion‐dependent β‐thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half‐life of 11 to 19 hours was found for ICL670, supporting once‐daily oral administration. AUC0–24h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0–24 h of ICL670 and the iron complex exceeded specific threshold values at the 40‐ and 80‐mg/kg dose levels.
Interaction Study between Digoxin and a Preparation of Hawthorn (Crataegus oxyacantha)
Authors: Tankanow Roberta , Tamer Helen R. , Streetman Daniel S. , Smith Scott G. , Welton Janice L. , Annesley Thomas , Aaronson Keith D. , Bleske Barry E.
Published: September 2003

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorn's beneficial effects in the treatment of heart failure. However, these components may also affect P‐glycoprotein function and cause interactions with drugs that are P‐glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0‐∞, Cmax‐Cmin, Cmin, and renal clearance for the D group were 79 ± 26 mcg•h/L, 1.4 ± 0.7mcg/L, 0.84 ± 0.2 mcg/L, and 74 ± 10 mL/min versus 73 ± 20 mcg•h/L, 1.1 ± 0.1 mcg/L, 0.65 ± 0.2 mcg/L, and 81 ± 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, maybe coadministered safely.
Correlation of Antifactor Xa Concentrations with Renal Function in Patients on Enoxaparin
Authors: Chow Sheryl L. , Zammit Kimberly , West Kathleen , Dannenhoffer MaryAnne , Lopez‐Candales Angel
Published: September 2003

Enoxaparin is a low molecular weight heparin (LMWH) that has been shown to be effective in deep vein thrombosis, pulmonary embolism, and unstable angina. Because renal function plays an important role in the clearance of LMWH, the authors sought to investigate the effect of renal function on enoxaparin. This prospective multiple‐dose study evaluated 18 patients with varying degrees of renal function initiated on enoxaparin 1 mg/kg subcutaneously every 12 hours. Peak blood levels of anti‐Xa concentrations were obtained 4 ± 0.5 hours postdose after receiving at least three doses of enoxaparin. The median antifactor Xa levels were higher in patients with creatinine clearance (CLCr) ≤ 30 mL/min compared to CLCr ≥ 31 mL/min (1.34 IU/mL vs. 0.91 IU/mL, respectively, p < 0.05). A linear correlation was established between creatinine clearance and anti‐Xa concentrations (p < 0.0005). On the basis of the data, the authors believe that a dose adjustment is necessary in patients receiving repeated doses of enoxaparin with CLCr ≤ 30 mL/min.
Model Appropriateness and Population Pharmacokinetic Modeling
Authors: Ette Ene I. , Williams Paul J. , Kim Yong Ho , Lane James R. , Liu Mei‐Jen , Capparelli Edmund V.
Published: September 2003

The purpose of this study was to define model appropriateness, identifying the individual elements thereof, and to set out a framework within which model appropriateness could be determined for population pharmacokinetic (PPK) models. Model appropriateness was defined by stating the problem to be solved, with the intended use of the model being the pivotal event. The elements of model appropriateness were identified with the type of model (descriptive vs. predictive) determining which elements of model appropriateness need to be executed. An example is presented to show how model appropriateness is determined for the optimal application of PPK models. It was determined that PPK models are developed to solve problems. Model appropriateness depends on identifying the problem, as well as stating the intended use of the model, and requires evaluation of the model for goodness of fit, reliability, and stability if intended for descriptive purposes; for predictive models, validation would be an additional requirement. Descriptive models are used to explain variability in the pharmacokinetics (PK) of a drug, while predictive models are developed to extrapolate beyond the immediate study population. For those models used for predictive purposes, strong assumptions are made about the relationship to the underlying population from which the data were collected. As an example of determining model appropriateness, a PPK model for 5‐fluorocytosine was developed, using NONMEM, version IV. The model was evaluated and validated by the process of percentile bootstrapping. From the PPK model, the range of expected serum concentrations based on two widely used dosing methods (Sanford and the University of California at San Diego [UCSD]) was simulated (Pharsight Trial Designer software). These results indicated that the UCSD method performed well and has the advantage of recommending convenient dosing intervals. In conclusion, considering and applying the principles of model appropriateness to PPK models will result in models that can be applied for their intended use with confidence. Model appropriateness was efficiently established and determined to address the problem of comparing competing dosing strategies.
Drug Interaction Potential of Soy Extract and Panax Ginseng
Authors: Anderson Gail D. , Rosito Gina , Mohustsy Michael A. , Elmer Gary W.
Published: September 2003

To determine if soy extract or Panax ginseng increases the urinary excretion of the 6‐β‐hydroxycortisol/cortisol ratio as a marker of cytochrome P450 (CYP) 3A enzyme induction, subjects received a soy extract containing 50 mg isoflavones twice daily (n = 20) or Panax ginseng 100 mg standardized to 4% ginsenosides twice daily (n = 20) for 14 days. Neither Panax ginseng nor soy extract significantly altered the urinary 6‐β‐OH‐cortisol/cortisol ratio, suggesting that unlike St. John's wort, they are not CYP3A inducers. Studies in vitro using human liver microsomes were performed to determine the effect of soy extract on probe substrates of CYP and UDP glucuronosyltransferase (UGT). Unhydrolyzed soy extract produced very little inhibition of CYP1A2, CYP2A6, and CYP2D6 and a trend of activation of CYP3A4. Hydrolyzed soy extract showed inhibition of all of the CYPs tested, particularly CYP2C9 and CYP3A4. UGT2B15 was the only UGT significantly inhibited. Even though both soy extract and ginseng have been shown to activate CYP3A4 in vitro, there is a lack of an in vitro correlation with the in vivo effects.
Characterization of Etoricoxib, a Novel, Selective COX‐2 Inhibitor
Authors: Dallob Aimee , Hawkey Christopher J. , Greenberg Howard , Wight Nicholas , De Schepper Paul , Waldman Scott , Wong Peggy , DeTora Lisa , Gertz Barry , Agrawal Nancy , Wagner John , Gottesdiener Keith
Published: September 2003

Etoricoxib is a potent selective COX‐2 inhibitor in man. Ex vivo whole‐blood assays assessed COX‐2 inhibition after oral administration of etoricoxib in single (5–500 mg) and multiple (25–150 mg) once‐daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2 synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of etoricoxib 120 mg qd on the COX‐1‐mediated antiplatelet effects of low‐dose aspirin (ASA) was also assessed. The mean (time)–weighted average inhibition (WAI) of lipopolysaccharide (LPS)–stimulated PGE2(COX‐2 assay) versus placebo was dose related after single (range: 3.1%–99.1%) and multiple doses (range: 52.5%–96.7%). PGE2 remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS‐stimulated PGE2 showed a strong relationship with etoricoxib plasma concentrations; ex vivo, IC50 was almost identical to in vitro. Multiple dosing of etoricoxib (up to 150 mg qd) showed no important effects on serum TXB2, bleeding time, or platelet aggregation (COX‐1‐mediated effects). The nonselective nonsteroidal anti‐inflammatory (NSAID) naproxen significantly inhibited (∼78%) ex vivo prostaglandin synthesis in gastric mucosa; etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low‐dose ASA, as assessed by serum TXB2 and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, etoricoxib is a potent selective inhibitor of COX‐2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.
Influence of Drugs Interacting with CYP3A4 on the Pharmacokinetics, Pharmacodynamics, and Safety of the Prandial Glucose Regulator Repaglinide
Authors: Hatorp Vibeke , Hansen Kristian T. , Thomsen Mikael S.
Published: September 2003

The object of this study was to analyze drug interactions between repaglinide, a short‐acting insulin secretagogue, and five other drugs interacting with CYP3A4: ketoconazole, rifampicin, ethinyloestradiol/levonorgestrel (in an oral contraceptive), simvastatin, and nifedipine. In two open‐label, two‐period, randomized crossover studies, healthy subjects received repaglinide alone, repaglinide on day 5 of ketoconazole treatment, or repaglinide on day 7 of rifampicin treatment. In three open‐label, three‐period, randomized crossover studies, healthy subjects received 5 days of repaglinide alone; 5 days of ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine alone; or 5 days of repaglinide concomitant with ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. Compared to administration of repaglinide alone, concomitant ketoconazole increased mean AUC0‐∞ for repaglinide by 15% and mean Cmax by 7%. Concomitant rifampicin decreased mean AUC0‐∞ for repaglinide by 31% and mean Cmax by 26%. Concomitant treatment with CYP3A4 substrates altered mean AUC0–5h and mean Cmax for repaglinide by 1% and 17% (ethinyloestradiol/levonorgestrel), 2% and 27% (simvastatin), or 11% and 3% (nifedipine). Profiles of blood glucose concentration following repaglinide dosing were altered by less than 8% by both ketoconazole and rifampicin. In all five studies, most adverse events were related to hypoglycemia, as expected in a normal population given a blood glucose regulator. The safety profile of repaglinide was not altered by pretreatment with ketoconazole or rifampicin or by coadministration with ethinyloestradiol/levonorgestrel. The incidence of adverse events increased with coadministration of simvastatin or nifedipine compared to either repaglinide or simvastatin/nifedipine treatment alone. No clinically relevant pharmacokinetic interactions occurred between repaglinide and the CYP3A4 substrates ethinyloestradiol/levonorgestrel, simvastatin, or nifedipine. The pharmacokinetic profile of repaglinide was altered by administration of potent inhibitors or inducers, such as ketoconazole or rifampicin, but to a lesser degree than expected. These results are probably explained by the metabolic pathway of repaglinide that involves other enzymes than CYP3A4, reflected to some extent by a small change in repaglinide pharmacodynamics. Thus, careful monitoring of blood glucose in repaglinide‐treated patients receiving strong inhibitors or inducers of CYP3A4 is recommended, and an increase in repaglinide dose may be necessary. No safety concerns were observed, except a higher incidence in adverse events in patients receiving repaglinide and simvastatin or nifedipine.
Furosemide Pharmacokinetics and Pharmacodynamics following Gastroretentive Dosage Form Administration to Healthy Volunteers
Authors: Klausner Eytan A. , Lavy Eran , Stepensky David , Cserepes Eva , Barta Miklos , Friedman Michael , Hoffman Amnon
Published: September 2003

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage form (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate‐release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled‐release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.
Selection of the First‐Time Dose in Humans: Comparison of Different Approaches Based on Interspecies Scaling of Clearance
Authors: Mahmood Iftekhar , Green Martin David , Fisher J. Edward
Published: September 2003

The authors describe four approaches to selecting a safe starting dose for humans in clinical drug trials based on interspecies scaling of clearance. Human clearance was predicted by scaling for 10 example drugs for which animal clearance values were available in the literature. The predicted human clearance values were then used to select the estimated starting dose in humans. These doses were then compared with the actual doses given to humans during clinical trials. All four approaches used to estimate the first‐time dose in humans provided values that were within the dose range given to humans from Phases I to III. This work demonstrates that animal pharmacokinetic data can be used to estimate a suitable human starting dose, provided the data have been obtained from a dose that produces no adverse effects.
Pharmacokinetics of Oral Ibuprofen in Premature Infants
Authors: Sharma Pramod Kumar , Garg Santosh Kumar , Narang Anil
Published: September 2003

Patent ductus arteriosus (PDA) is a frequent complication in premature infants. So far, intravenous indomethacin is the standard mode of medical therapy in such patients but carries a risk of frequently occurring side effects. Ibuprofen, another nonsteroidal anti‐inflammatory drug, has also been shown to be efficacious in closing ductus with lesser adverse effects after parenteral administration. However, limited data are available on the pharmacokinetics of intravenous ibuprofen in this population. Nonavailability of parenteral preparation and lack of information regarding pharmacokinetic disposition of ibuprofen in this subgroup of the population led the authors to conduct this pharmacokinetic study with oral ibuprofen. Twenty premature infants with a gestational age of 30.45 ± 0.33 weeks and a birth weight of 1262.5 ± 55.4 g (values given as mean ± SEM) admitted to the neonatal unit were enrolled in this study. Ibuprofen was administered in a single oral dose of 10 mg/kg between 4 and 72 hours postnatally, and blood samples were collected through an indwelling vascular catheter at time 0 and 1, 2, 4, 8, 12, and 24 hours. Ibuprofen plasma concentrations were assayed by high‐performance liquid chromatography. There was a large interindividual variability observed for plasma concentrations, elimination half‐life (t1/2) (15.72 ± 3.76 h), and area under the plasma concentration‐time curve (AUC0‐∞) (402.60 ± 79.67 μg•h/mL) in these babies. Variables such as gestational age, birth weight, and sex did not affect ibuprofen pharmacokinetics significantly (p > 0.05). Moreover, no correlation could be found between elimination half‐life and gestational age (r = 0.02). Ibuprofen pharmacokinetics showed a wide variability in premature infants. The results of the present study warrant revising the oral dosage schedule to achieve comparable plasma concentrations of ibuprofen associated with successful closure of ductus, as reported in earlier studies.
Efficacy of Dichloroacetate as a Lactate‐Lowering Drug
Authors: Stacpoole Peter W. , Nagaraja Nelamangala V. , Hutson Alan D.
Published: September 2003

Dichloroacetate (DCA) decreases blood, cerebral spinal fluid, and intracellular lactate concentrations by activating the mitochondrial pyruvate dehydrogenase enzyme complex. The authors reviewed the efficacy of this investigational drug in the treatment of acquired or congenital forms of lactic acidosis from data in 40 English‐language publications. The hypolactatemic effect of DCA occurs over a broad range of pretreatment lactate concentrations and is directly related to the baseline lactate level. The maximum lactate‐lowering effect of the drug is dependent on its dose but independent of time following its administration. Recent clinical studies of acquired lactic acidosis suggest that DCA could be rapidly effective in reducing this risk factor of mortality in patients with mild hyperlactatemeia.
Pharmacokinetics of Sumatriptan Nasal Spray in Adolescents
Authors: Christensen Michael L. , Mottern Robin K. , Jabbour J. T. , Fuseau Eliane
Published: September 2003

Sumatriptan is a potent and selective vascular 5‐HT1 receptor agonist effective for the treatment of migraine. In adults, intranasal sumatriptan is well absorbed and tolerated. The authors evaluated the pharmacokinetics and tolerability of a single dose of 20 mg intranasal sumatriptan in healthy adolescent migraineurs ages 12 to 17 years, administered outside of migraine attack. Serum sumatriptan levels were measured by high‐performance liquid chromatography (HPLC) with electrochemical detection in serial samples collected over 8 hours. Physical exam, vital signs, clinical laboratory tests, and electrocardiogram measurements were monitored to assess safety and tolerability. A total of 16 subjects (10 males and 6 females) had pharmacokinetic data that could be analyzed, 2 withdrew from the study 30 and 60 minutes after dosing following the loss of venous access for blood sampling, and a bioanalysis failure resulted in loss of data from 3 subjects. Noncompartmental pharmacokinetic parameters (geometric mean and 95% confidence interval) for the remaining 16 subjects were as follows: Cmax was 13.9 (11.0, 17.6) ng/mL, AUC∞ was 57.3 (47.6, 69.0) ng/mL•, and t1/2 was 2.0 (1.8, 2.3) hours. Population pharmacokinetic analysis for all subjects (n = 21) showed that clearance and volume of distribution increase slightly with age and body size, but the changes were minimal and would not warrant dose adjustment: CL/F was 316 L (coefficient of variance [CV] = 25%) and Vd/F was 1070 L (CV = 46%). Sumatriptan was well tolerated with only minor adverse events reported, which all resolved spontaneously. The pharmacokinetic parameters in these adolescent subjects were similar to those previously reported in adults, suggesting that adolescents should be dosed similar to adults.
Medication Errors: An Analysis Comparing PHICO's Closed Claims Data and PHICO's Event Reporting Trending System (PERTS)
Authors: Benjamin David M. , Pendrak Robert F.
Published: September 2003

Clinical pharmacologists are all dedicated to improving the use of medications and decreasing medication errors and adverse drug reactions. However, quality improvement requires that some significant parameters of quality be categorized, measured, and tracked to provide benchmarks to which future data (performance) can be compared. One of the best ways to accumulate data on medication errors and adverse drug reactions is to look at medical malpractice data compiled by the insurance industry. Using data from PHICO insurance company, PHICO's Closed Claims Data, and PHICO's Event Reporting Trending System (PERTS), this article examines the significance and trends of the claims and events reported between 1996 and 1998. Those who misread history are doomed to repeat the mistakes of the past. From a quality improvement perspective, the categorization of the claims and events is useful for reengineering integrated medication delivery, particularly in a hospital setting, and for redesigning drug administration protocols on low therapeutic index medications and “high‐risk” drugs. Demonstrable evidence of quality improvement is being required by state laws and by accreditation agencies. The state of Florida requires that quality improvement data be posted quarterly on the Web sites of the health care facilities. Other states have followed suit. The insurance industry is concerned with costs, and medication errors cost money. Even excluding costs of litigation, an adverse drug reaction may cost up to $2500 in hospital resources, and a preventable medication error may cost almost $4700. To monitor costs and assess risk, insurance companies want to know what errors are made and where the system has broken down, permitting the error to occur. Recording and evaluating reliable data on adverse drug events is the first step in improving the quality of pharmacotherapy and increasing patient safety. Cost savings and quality improvement evolve on parallel paths. The PHICO data provide an excellent opportunity to review information that typically would not be in the public domain. The events captured by PHICO are similar to the errors and “high‐risk” drugs described in the literature, the U.S. Pharmacopeia's MedMARx Reporting System, and the Sentinel Event reporting system maintained by the Joint Commission for the Accreditation of Healthcare Organizations. The information in this report serves to alert clinicians to the possibility of adverse events when treating patients with the reported drugs, thus allowing for greater care in their use and closer monitoring. Moreover, when using high‐risk drugs, patients should be well informed of known risks, dosage should be titrated slowly, and therapeutic drug monitoring and laboratory monitoring should be employed to optimize therapy and minimize adverse effects.