bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and immunological characterization of a novel timothy grass (Phleum pratense) pollen allergen, Phl p 11
Authors: Marknell DeWitt Å. , Niederberger V. , Lehtonen P. , Spitzauer S. , Sperr W. R. , Valent P. , Valenta R. , Lidholm J.
Published: October 2002

Background Allergy to grass pollen is typically associated with serum IgE antibodies to group 1 and/or group 5 allergens, and additionally often to one or several less prominent allergens. Most of the grass pollen allergens identified to date have been characterized in detail by molecular, biochemical and immunological methods, timothy grass being one of the most thoroughly studied species. However, a 20‐kDa allergen frequently recognized by IgE antibodies from grass pollen allergics has so far escaped cloning and molecular characterization.

Objective To clone and characterize the 20 kDa timothy grass pollen allergen Phl p 11.

Methods Phl p 11 cDNA was cloned by PCR techniques, utilizing N‐terminal amino acid sequence obtained from the natural allergen. Phl p 11 was expressed as a soluble fusion protein in Escherichia coli, purified to homogeneity and used for serological analysis and to study Phl p 11 specific induction of histamine release from basophils and skin reactivity in sensitized and control subjects.

Results Phl p 11 cDNA defined an acidic polypeptide of 15.8 kDa with homology to pollen proteins from a variety of plant species and to soybean trypsin inhibitor. The sequence contained one potential site for N‐linked glycosylation. Serological analysis revealed that recombinant Phl p 11 shared epitopes for human IgE antibodies with the natural protein and bound serum IgE from 32% of grass pollen‐sensitized subjects (n = 184). Purified recombinant Phl p 11 elicited skin reactions and dose‐dependent histamine release from basophils of sensitized subjects, but not in non‐allergic controls.

Conclusion As the first representative of group 11 grass pollen allergens, Phl p 11 has been cloned and produced as a recombinant protein showing allergenic activity. One‐third of grass pollen‐sensitized subjects showed specific IgE reactivity to recombinant Phl p 11, corresponding in magnitude to a significant proportion of specific IgE to grass pollen extract.
House dust mites and their allergens at selected locations in the homes of house dust mite‐allergic patients
Authors: Sidenius K. E. , Hallas T. E. , Brygge T. , Poulsen L. K. , Mosbech H.
Published: October 2002

Background Knowledge of the occurrence of house dust mites (HDM) and their allergens in domestic locations is important when planning intervention.

Objective The aim of this study was to describe the distribution of HDMs and their allergens before intervention in multiple locations in the homes of newly diagnosed HDM‐allergic patients with a known high Der 1 concentration in their mattress dust.

Methods Dust was collected from ten locations in the homes of eight HDM‐allergic patients. Dust was analysed for allergen content with ELISAs for Der f 1, Der p 1 and Der m 1; and HDM were counted. Total allergen concentrations (µg Der 1/g dust) were expressed as the sum of Der f 1, Der p 1 and Der m 1.

Results On mattresses the median concentration was 86 µg Der 1/g dust (range 30–288) and 188 mites/g dust (range 12–1910). Der 1 exceeded 10 µg/g dust in mattresses (8/8), duvets/pillows (3/8), a bedroom carpet (1/1), a living room carpet (1/6), upholstered furniture (2/8) and a curtain (1/5). Uncarpeted floors, upholstered furniture, bookshelves and walls had significantly lower Der 1 concentration than the mattresses. The relative contribution of Der p 1, Der f 1 or Der m 1 to Der 1 was related to homes, rather than to the location. Der m 1 only occurred in minute amounts.

Conclusion For HDM intervention, our results indicate that priority should be given to the removal of allergens from mattresses, and in addition from carpets, duvets/pillows and upholstered furniture. Dust from walls, uncarpeted floors, bookshelves and curtains appear to contribute insignificantly to the domestic HDM allergen load.
The accuracy of the diagnosis of suspected paracetamol (acetaminophen) hypersensitivity: results of a single‐blinded trial
Authors: Kvedariene V. , Bencherioua A. M. , Messaad D. , Godard P. , Bousquet J. , Demoly P.
Published: October 2002

Background Hypersensitivity to paracetamol (acetaminophen) is rare and very few clinical data are available in the literature.

Materials and methods Eighty‐four patients (28 males and 56 females, 5–70 years old) with a suspicion of paracetamol hypersensitivity were referred to our drug allergy clinic between May 1996 and May 2000. The reaction had occurred 1–96 months prior to the consultation. Single‐blinded placebo‐controlled oral challenges were carried out in 82 patients, under strict hospital surveillance.

Results Most of the patients experienced skin eruptions 82/84 (97.6%), with 10 cases of anaphylactic shock (11.9%). Twenty‐six (30.9%) reactions were immediate (occurring within the first hour after drug intake), 53 (63.1%) non‐immediate and five could not remember. Oral provocation tests (OPT) demonstrated drug hypersensitivity in 11 patients only. The two patients not tested (due to a history of life‐threatening reaction) were included in the positive group. Thus, 13 (15.5%) patients had paracetamol hypersensitivity and 71 (84.5%) had not. All the 13 positive patients had skin eruptions, five with anaphylactic shock. 9/13 had immediate reactions. Using OPT, 10 out of 11 had the same clinical reaction but more delayed. In both groups, whether hypersensitive to paracetamol or not: atopy was similar (7/13–53.8% and 31/71–43.7%), sex ratio was not different (M/F 0.3 and 0.5), 3/13 (23.1%) and 0/71 (0%) had aspirin/ibuprofen hypersensitivity.

Conclusion The clinical history of paracetamol (acetaminophen) hypersensitivity is rarely sufficient to set a firm diagnosis and only OPT can confirm this. Careful OPT reproduces the same symptoms (not more severe in our hands) with the same or slightly more delayed chronology. Atopy and sex are not risk factors.
Effect of ozone and nitrogen dioxide on the permeability of bronchial epithelial cell cultures of non‐asthmatic and asthmatic subjects
Authors: Bayram H. , Rusznak C. , Khair O. A. , Sapsford R. J. , Abdelaziz M. M.
Published: October 2002

Background Although epidemiological as well as in vivo exposure studies suggest that ozone (O3) and nitrogen dioxide (NO2) may play a role in airway diseases such as asthma, the underlying mechanisms are not clear.

Objective Our aim was to investigate the effect of O3 and NO2 on the permeability of human bronchial epithelial cell (HBEC) cultures obtained from non‐atopic non‐asthmatic (non‐asthmatics) and atopic mild asthmatic (asthmatics) individuals.

Methods We cultured HBECs from bronchial biopsies of non‐asthmatics and asthmatics, and exposed these for 6 h to air, 10 to 100 parts per billion (p.p.b.) O3, or to 100 to 400 p.p.b. NO2, and assessed changes in electrical resistance (ER) and movement of 14C‐BSA across the cell cultures.

Results Although exposure to either O3 or NO2 did not alter the permeability of HBEC cultures of non‐asthmatics, 10 to 100 p.p.b. O3 and 400 p.p.b. NO2 significantly decreased the ER of HBEC cultures of asthmatics, when compared with exposure to air. Additionally, 10, 50 and 100 p.p.b. O3 led to a significant increase in the movement of 14C‐BSA across asthmatic HBEC cultures, after 6 h of exposure (medians = 1.73%; P < 0.01, 1.50%; P < 0.05 and 1.53%, P < 0.05, respectively), compared with air exposed cultures (median = 0.89%). Similarly, exposure for 6 h to both 200 and 400 p.p.b. NO2 significantly increased the movement of 14C‐BSA across asthmatic HBEC cultures, when compared with air exposure. A comparison of data obtained from the two study groups demonstrated that 10 to 100 p.p.b. O3‐ and 200 to 400 p.p.b. NO2‐induced epithelial permeability was greater in cultures of asthmatics compared with non‐asthmatics.

Conclusion These results suggest that HBECs of asthmatics may be more susceptible to the deleterious effects of these pollutants. Whether in patients with asthma the greater susceptibility of bronchial epithelial cells to O3 and NO2 contributes to the development of the disease, or is a secondary characteristic of this condition, remains to be determined.
Use of a chimeric ELISA to investigate immunoglobulin E antibody responses to Der p 1 and Der p 2 in mite‐allergic patients with asthma, wheezing and/or rhinitis
Authors: Trombone A. P. F. , Tobias K. R. C. , Ferriani V. P. L. , Schuurman J. , Aalberse R. C. , Smith A. M. , Chapman M. D. , Arruda L. K.
Published: October 2002

Background Sensitization to indoor allergens, particularly to dust mites, is a strong risk factor for asthma in children and adults. Assessment of sensitization is carried out using in vivo and in vitro tests to detect specific IgE antibodies.

Objective To investigate IgE antibody responses to mites in patients with asthma, wheezing and/or rhinitis, using chimeric ELISA to measure specific IgE antibodies to mite allergens Der p 1 and Der p 2.

Methods Specific IgE antibodies to Der p 1 and Der p 2 were quantified by chimeric ELISA, and compared with IgE to Dermatophagoides pteronyssinus (Dpt) measured using the CAP system (Pharmacia). A panel of sera from 212 patients with asthma, wheezing and/or rhinitis and 11 controls was analysed.

Results There was a significant correlation between IgE to Dpt measured by CAP and IgE to Der p 1 (r = 0.81, P < 0.001), Der p 2 (r = 0.79, P < 0.001) and combined Der p 1 and Der p 2 (r = 0.86, P < 0.001). Seventy per cent of all patients had IgE to Dpt, and of those, 76.5% had IgE to Der p 1, 79.2% had IgE to Der p 2 and 83.1% had IgE to Der p 1 and Der p 2 combined. Considering the cut‐off level of 2 IU/mL of IgE to either Der p 1 or Der p 2, the predictive value for a positive IgE to Dpt by CAP was greater than 95%.

Conclusions The chimeric ELISA allowed accurate quantification of IgE antibodies to Dpt allergens Der p 1 and Der p 2, and it could be useful for studying immune responses to mites in patients with asthma and/or rhinitis.
Relationship between allergic rhinitis, disturbed cognitive functions and psychological well‐being
Authors: Kremer B. , Den Hartog H. M. , Jolles J.
Published: October 2002

Background Symptomatic allergic rhinitis reduces quality of life as a result of the symptoms experienced and possibly as a result of impaired psychological well‐being and cognitive functioning. Few investigations have measured cognitive functions objectively and it remains uncertain whether allergic rhinitis leads to an objective reduction in cognitive functions.

Objective To evaluate the relationship between symptomatic allergic rhinitis, cognitive functions and psychological well‐being. Differences between subjective and objective cognitive impairments were evaluated.

Methods The cognitive functions (working memory, memory retrieval, speed of information processing and flexibility of information processing) and psychological well‐being of 26 patients with symptomatic allergic rhinitis and 36 healthy controls matched for intelligence, education, age and sex were compared. The influence of education, intelligence, sex and age was considered.

Results Overall, psychological well‐being was significantly impaired in the patient group, as shown by higher scores in feelings of insufficiency, complaints of somatization, sleep disturbances and depressive feelings, whereas cognitive function was not.

Conclusions Allergic rhinitis was related to significantly impaired psychological well‐being and to perceived impaired cognitive functioning. However, no significant objective impairment of cognitive functioning was found. Allergic patients may temporarily put more effort into sustaining performance, resulting in earlier exhaustion, which is not noticed during assessment but which impairs psychological well‐being.
The relation between accommodative facility and general binocular dysfunction
Authors: Garcı´a Ángel , Cacho Pilar , Lara Francisco , Megı´as Ramón
Published: October 2002

This study was designed to evaluate the relation between accommodative facility and accommodative and binocular dysfunctions. We determined whether failure to achieve 8 cycles per minute of binocular accommodative facility or 11 cycles per minute of monocular accommodative facility tends to be associated with these dysfunctions. Forty eight subjects, ages 10–30 years were examined and classified into four groups: 13 subjects with accommodative dysfunctions, 11 patients with binocular dysfunctions, 12 subjects with accommodative and binocular dysfunctions and 12 control subjects with refractive errors but no accommodative or binocular anomalies. Monocular and binocular accommodative facility was conducted using ±2.00 D flip lenses. In general, statistical analysis indicates that subjects with binocular and accommodative (ocular motor) anomalies performed significantly poorer than subjects of normal group on monocular and binocular facility tests. Monocular accommodative facility results showed more information about the dysfunction of the patient compared with the results of the binocular accommodative facility. In general data supported a relation between reduced accommodative facility and a general binocular dysfunction (accommodative or binocular) which demonstrates the importance of the accommodative facility test in diagnosing an accommodative or binocular anomaly.
The practical near acuity chart (PNAC) and prediction of visual ability at near1
Authors: Wolffsohn James S. , Cochrane Anthea L.
Published: October 2002

Objective: To improve on present reading chart designs, providing a quick and accurate method to measure the near acuity threshold, of particular importance with low vision patients.

Design: The Practical Near Acuity Chart (PNAC) uses a single paragraph with 3 simple related words on each line (12 lower case letters). The line print size decreases in a logMAR progression (N80‐N5).

Methods: The time taken to measure near acuity of 53 subjects aged 9–91 years with the PNAC and Bailey–Lovie near chart was recorded and compared to their distance acuity (Bailey–Lovie chart), contrast sensitivity (Melbourne Edge Test) and ability to read extracts of newsprint.

Results: There was no difference in near acuity threshold using related or un‐related words. There was a high correlation (r=0.97) between near acuity measured with the PNAC and Bailey–Lovie charts. However, the time taken to measure near acuity was significantly faster with the PNAC (32±2 s vs 76±4 s, p<0.001). Near acuity measured with either chart was highly correlated (p<0.001) to distance acuity (r=0.74), contrast sensitivity (r=0.62) and ability to read newsprint (r=0.87). The PNAC was shown to have high test‐reliable (r=0.99).

Conclusions: The PNAC offers a quick but accurate way to measure near acuity and shows a high degree of correlation with distance acuity, contrast sensitivity and the ability to read newsprint.
Precision of autokeratometry expressed as confidence ellipses in Euclidian 2‐space
Authors: Naeser Kristian , Guo Suping
Published: October 2002

A number of studies have examined the repeatability or precision of keratometers. All studies have found exceptionally high precision in keratometry of the spherically equivalent proportion, while the joint variation in astigmatic direction and magnitude barely has been explored. The purpose of this study was to examine the simultaneous variation in astigmatic direction and magnitude between two single autokeratometries, using a Nidek ARK 2000‐S autokeratorefractometer.

A single autokeratometry was performed on two occasions on 50 right eyes of patients with cataracts. The precision was defined as the paired difference between these two measurements. Each net astigmatism was transformed to polar values, and uni‐ and bivariate polar value analysis was performed.

Precision of autokeratometry, expressed as a mean difference and a 95% confidence area, was calculated as a confidence ellipse in Euclidian 2‐space. The accompanying net astigmatisms with confidence perimeters were derived by point‐for‐point transformation from polar values.

Clinical variability may overwhelmingly be attributed to patient‐related factors and only to a small degree to autokeratometry itself. Clinicians should know the precision of their keratometers, both for daily use and in the planning and dimensioning of scientific studies. Our results indicate that a minimum number of 25 eyes in each group is necessary in order to detect a difference of 0.25 diopters in surgically induced astigmatism between two surgical techniques. Precision of keratometry can only be determined from polar values or similar entities and never by the use of net astigmatisms.
Evidence that a gender difference in intraocular pressure is present from childhood
Authors: Pointer Jonathan S.
Published: October 2002

Routine assessment of intraocular pressure (IOP) is usually confined to the clinical population aged over 40 years, i.e., to those individuals considered to be most at‐risk of developing glaucoma. Published IOP data collected from assumed non‐glaucomatous adult subjects have shown a gender difference in this parameter, with human females recording a consistently higher value than age‐matched males. A recent study has also demonstrated that a diurnal variation in IOP can be recorded in adults across normal consulting hours. IOP material is presented here, as collected in the early afternoon (14.00–14.59 hours) from n=140 school children aged ≥9<12 years. It is complemented by previously published data, also recorded between 14.00–14.59, from n=100 middle‐aged adults aged 40–59 years, and n=102 mature adults aged over 60 years. Analysis of these three data sets indicates that a non‐statistically significant gender difference in mean IOP (female>male) is present from childhood; it also suggests that, for either gender, the absolute mean level of IOP remains little altered from childhood into and throughout adulthood. However the physiological basis for these observations remains obscure.
Corneal shape of Hong Kong‐Chinese⋆
Authors: Cheung Sin‐wan , Cho Pauline , Douthwaite William
Published: October 2002

Corneal asphericity (the p‐value, p) and apical corneal radius (r0) were calculated for 63 Hong Kong‐Chinese (39 male and 24 female), using the Topographic Modeling System (TMS‐1). The values of p and r0 in, and between, the two principal meridians were compared, and the effects of refractive error and gender were also investigated. The mean±SD r0 and p along the flattest meridian of the right eye were 7.82±0.26 mm and 0.78±0.12 respectively. The mean±SD r0 and p along the steepest meridian of the right eye were 7.64±0.26 mm and 0.83±0.15 respectively. Meridional variations were found in r0 and in p. There was no correlation between p and r0 along the two principal meridians. p was not significantly correlated to the refractive error but r0 was. Our results agree with previous findings that while males have longer r0 than females, their p are not significantly different.
A prospective, randomized clinical trial of universal WBC reduction
Authors: Dzik W.H. , Anderson J.K. , O'Neill E.M. , Assmann S.F. , Kalish L.A. , Stowell C.P.
Published: October 2002

BACKGROUND : Recipient exposure to allogeneic donor WBCs results in transfusion complications for selected populations of recipients. Whether or not WBC reduction should be universally applied is highly controversial.

STUDY DESIGN AND METHODS : In a general hospital, a randomized, controlled clinical trial of conversion to universal WBC reduction was conducted. Patients (11%) with established medical indications for WBC‐reduced blood were not eligible. All other patients who required transfusion were assigned at random to receive either unmodified blood components or stored WBC‐reduced RBCs and platelets. Analysis for each patient was restricted to the first hospitalization.

RESULTS : All eligible patients (n = 2780) were enrolled. Three specified primary outcome measures were not different between the two groups: 1) in‐hospital mortality (8.5% control; 9.0% WBC‐reduced; OR, 0.94 [95% CI, 0.72‐1.22]; p = 0.64); 2) hospital length of stay (LOS) after transfusion (median number of days, 6.4 for control and 6.3 for WBC‐reduced; p = 0.21); and 3) total hospital costs (median, $19,500 for control and $19,200 for WBC‐reduced, p = 0.24). Secondary outcomes (intensive care LOS, postoperative LOS, antibiotic usage, and readmission rate) were not different between the two groups. Subgroup analysis based on patient age, sex, amount of blood transfused, or category of surgical procedure showed no effect of WBC reduction. Patients who received WBC‐reduced blood had a lower incidence of febrile reactions (p = 0.06).

CONCLUSION : A beneficial effect of conversion from selective to universal WBC reduction was not demonstrated.
Circulation and hemostatic function of autologous fresh, liquid‐preserved, and cryopreserved baboon platelets transfused to correct an aspirin‐induced thrombocytopathy
Authors: Valeri C. Robert , MacGregor Hollace , Giorgio Albert , Ragno Gina
Published: October 2002

BACKGROUND : The survival of fresh and preserved platelets has been used primarily to determine their therapeutic effectiveness. The function of the fresh and preserved platelets has been difficult to assess. In stable thrombocytopenic patients, platelet function of fresh and preserved allogeneic platelets is evaluated by the reduction in bleeding time. In this study of healthy male baboons, both the survival and function of autologous fresh, liquid‐preserved, and cryopreserved platelets in the correction of an aspirin‐induced thrombocytopathy was evaluated.

STUDY DESIGN AND METHODS
: Five healthy male baboons were studied on eight occasions over a 4‐year period. To produce a prolonged bleeding time, the baboon was administered 325 mg of aspirin 18 hours before receiving autologous transfusion. The fresh, liquid‐preserved, and previously frozen washed platelets were labeled with
111
In‐oxine before autologous transfusion. The autologous, nonaspirinated platelets' ability to reduce the aspirin‐induced prolonged bleeding time and increase the shed blood thromboxane B
2 level at the template bleeding time site was studied.

RESULTS
: Platelets stored at 22°C for 48 hours had in vivo recovery values similar to those platelets stored for 18 hours, and they significantly reduced the bleeding time and increased the shed blood thromboxane level after transfusion. Platelets stored at 22°C for 72 hours had in vivo recovery values similar to those platelets stored for 18 hours, but the bleeding time was not corrected after transfusion, although there was a significant increase in the shed blood thromboxane B
2 level. The cryopreserved platelets significantly reduced the bleeding time and significantly increased the shed blood thromboxane level after transfusion. Cryopreserved platelets had better in vivo survival and function than the 5‐day liquid‐stored platelets.

CONCLUSIONS : The survival of autologous fresh, liquid‐preserved, or cryopreserved platelets did not correlate with their function to reduce an increased bleeding time in baboons treated with aspirin.
Lessons learned from a phase III population pharmacokinetic study of cariporide in coronary artery bypass graft surgery
Authors: Weber Willi , Harnisch Lutz , Jessel Andreas
Published: October 2002

Background

Cariporide (HOE642) is a recently developed inhibitor of the myocardial sodium‐hydrogen exchange system. The clinical effects of sodium‐hydrogen exchange inhibition in patients at high risk for myocardial cell necrosis were investigated in the GUARDIAN trial (n = 11,590 patients). Although the trial did not show a significant benefit of cariporide over placebo in the overall population, a 25% relative risk reduction in the primary end point of death or myocardial infarction (12.1% for the highest tested cariporide dose of 120 mg 3 times a day versus 16.2% for placebo; P = .03) was observed in the subpopulation of patients who underwent bypass surgery.

Objective

Our objective was to identify an optimal dosing regimen that might offer increased protection during the period of highest risk.

Methods

A population pharmacokinetic model of cariporide was developed with use of data from phase I studies. After adequate predictability was shown for the patients in the pharmacokinetic substudy of the GUARDIAN trial (n = 269 patients), the model was used to predict the individual pharmacokinetic profile in the remaining patients. These predicted concentrations were used to calculate the mean concentration during the period of coronary artery bypass graft surgery (the acute risk period in patients who receive coronary artery bypass grafts), and this mean concentration was used as predictor variable in a time‐to‐event analysis.

Results

A mixture of two Weibull functions adequately described the time course of the observed sum of the acute and chronic hazard rate. The calculated mean concentration during the period of surgery was an adequate predictor for the probability of an event in the acute risk period. The estimated minimal effective mean concentration was 0.5 mg/L.

Conclusions

A dosing regimen with a loading dose of an infusion of 120 mg/h for 1 hour followed by an infusion of 20 mg/h for 47 hours should achieve stable exposure above the estimated minimal effective concentration in more than 95% of patients during and after coronary artery bypass graft surgery.

Clinical Pharmacology & Therapeutics (2002) 71, 457–467; doi: 10.1067/mcp.2002.124078
Pharmacokinetics and electrocardiographic effects of a new controlled‐release form of flecainide acetate: Comparison with the standard form and influence of the CYP2D6 polymorphism
Authors: Tennezé Laurent , Tarral Eliane , Ducloux Nicole , Funck‐Brentano Christian
Published: October 2002

Objectives

Our objectives were study the single‐ and repeated‐dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled‐release form offlecainide acetate compared with the immediate‐release form and to examine the influence of CYP2D6 activity.

Methods

Twenty‐four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate‐release and controlled‐release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration.

Results

The controlled‐release formulation had sustained‐release properties, with a significantly lower maximum concentration (Cmax) and delayed time to reach Cmax. Compared with the immediate‐release formulation, the relative bioavailability of the controlled‐release formulation at steady state was 0.85 ± 0.17 and0.89 ± 0.17 for the 100‐mg/day and 200‐mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximumand minimum QRS increases were not significantly different for either the immediate‐release or the controlled‐release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated withmean plasma concentration for both forms (pooled data; P < .001). The 95% confidence interval for this regression was 26% narrower for the controlled‐release form thanfor the immediate‐release form. Flecainide‐induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity.

Conclusions

Flecainide‐induced QRS prolongation did not differ between the newcontrolled‐release form and the immediate‐release form. Flecainide plasma concentrations associated with the new controlled‐release form predicted QRS prolongation with less variability compared with the immediate‐release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.

Clinical Pharmacology & Therapeutics (2002) 72, 112–122; doi: 10.1067/mcp.2002.125946
Risk factors for antituberculous chemotherapy‐induced hepatotoxicity in Japanese pediatric patients
Authors: Ohkawa Katsushito , Hashiguchi Masayuki , Ohno Keiko , Kiuchi Chikako , Takahashi Setsuko , Kondo Shinya , Echizen Hirotoshi , Ogata Hiroyasu
Published: October 2002

Objective

Our objective was to clarify risk factors associated with the development of severe hepatotoxicity during antituberculosis chemotherapy in Japanese children.

Methods

In a retrospective analysis in a 350‐bed referral children's hospital in a metropolitan area, the medical charts of all pediatric patients who received antituberculosis chemotherapy between January 1995 and November 1999 were surveyed. Univariate and multivariate analyses were performed to find any demographic parameters (ie, sex, age, height, and body weight), clinical characteristics (ie, nutritional or developmental status, co‐infection with hepatitis viruses [B or C] or human immunodeficiency virus, presence of extrapulmonary tuberculosis, or medical history of liver disease), or individual antituberculosis agents used that would be associated with the likelihood of development of severe hepatotoxicity during antituberculous chemotherapy. Severe hepatotoxicity (definedas an elevation of ALT and AST levels that were greater than 5 times the respective reference values) was attributed to the chemotherapy when it developed in children with normalpretreatment values for these parameters and no other potential causes were identified. Those who had abnormal ALT or AST values before treatment were excluded from analysis.

Results

Among the 117 patients surveyed (58 males and 59 females; age range, 0to 16 years), 18 were excluded from the analysis because of abnormal baseline ALT and ASTvalues. Severe hepatotoxicity developed in 8 of the 99 eligible children, and all 8 of those children were younger than 5 years old. The univariate analysis revealed that the children in whom hepatotoxicity developed were significantly (P < .05) younger, were predominantly male, had extrapulmonary tuberculosis, and were given pyrazinamide more often than those who had no hepatotoxicity. However, the multivariate logistic regression analysis revealed that only age and the administration of pyrazinamide would have a significant contribution (P < .05) to the development of severe hepatotoxicity, with odds ratios of 143 (95% confidence interval, 4.2 to 4934.9) and 0.60 (95% confidenceinterval, 0.39 to 0.90), respectively: the estimated probability of development of hepatotoxicity in a typical pediatric patient at 1, 5, and 10 years receiving pyrazinamide withrifampin (INN, rifampicin) and isoniazid would be 0.95, 0.72, and 0.16, respectively.

Conclusions

This study indicated that intensive monitoring of hepatotoxicity should be performed for younger children (<5 years) receiving pyrazinamide for antituberculosis chemotherapy.

Clinical Pharmacology & Therapeutics (2002) 72, 220–226; doi: 10.1067/mcp.2002.126175
Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19
Authors: Kim Kyoung‐Ah , Shon Ji‐Hong , Park Ji‐Young , Yoon Young‐Ran , Kim Min‐Jung , Yun Doo‐Hee , Kim Moon‐Kyung , Cha In‐June , Hyun Myung‐Ho , Shin Jae‐Gook
Published: October 2002

Objective

To evaluate the enantioselective disposition of lansoprazole in relation to the genetic polymorphism of CYP2C19.

Methods

A single oral dose of racemic lansoprazole (30 mg) was administered to6 extensive metabolizers and 6 poor metabolizers whose genotypes were determined by use of polymerase chain reaction‐restriction fragment length polymorphism. The pharmacokineticparameters were estimated from the plasma concentrations of lansoprazole racemate, its enantiomers, and metabolites, which were measured for 24 hours after drug administration. The unbound fraction of lansoprazole enantiomers was determined by means of ultrafiltrationof fresh human serum spiked with racemic lansoprazole.

Results

The plasma concentrations of R(+)‐lansoprazole were consistently higher than those of the S(−)‐enantiomer in both extensive and poor metabolizers of CYP2C19, and the meanarea under the plasma concentration‐time curve of the (+)‐ and (−)‐enantiomersshowed 4.3‐ and 5.8‐fold differences between poor and extensive metabolizers, respectively. The (+)/(−) ratios of lansoprazole clearance were not significantly different betweenpoor and extensive metabolizers (0.19 ± 0.07 and 0.05 ± 0.08, respectively). The values for volume of distribution of the (−)‐enantiomer were 3‐ and 10‐fold greater, respectively, than those of the (+)‐enantiomer in poor and extensive metabolizers, which was related to a 2‐fold higher unbound fraction of the (−)‐enantiomer.

Conclusions

The effect of CYP2C19 genetic polymorphism on the enantioselectivedisposition of lansoprazole seems to be less significant than the effect on omeprazole and pantoprazole. The disposition of lansoprazole enantiomers appears to be influenced by enantioselective protein binding and by enantioselective metabolism of lansoprazole.

Clinical Pharmacology & Therapeutics (2002) 72, 90–99; doi: 10.1067/mcp.2002.126176
A target‐mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans
Authors: Eppler Stephen M. , Combs Daniel L. , Henry Timothy D. , Lopez John J. , Ellis Stephen G. , Yi Joo‐Hee , Annex Brian H. , McCluskey Edward R. , Zioncheck Thomas F.
Published: October 2002

Background

The Vascular Endothelial Growth Factor (VEGF) in Ischemiafor Vascular Angiogenesis (VIVA) trial was a double‐blind, placebo‐controlled, phase II clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of combinedintracoronary and intravenous infusions of recombinant human vascular endothelial growth factor (rhVEGF165) for therapeutic angiogenesis. This study describes the use of a mechanism‐based model to characterize the nonlinear kinetics observed after intravenous administration of rhVEGF165. The model predicts that rhVEGF165 distribution occurs through both saturable binding to high‐affinity receptors and reversible interactions with low‐affinity binding sites.

Methods

In this trial, rhVEGF165 was administered to patients with coronary artery disease at a dose rate of 17 or 50 ng/kg/min by means of intracoronary infusion for 20 minutes, followed by three 4‐hour intravenous infusions on days 3, 6, and 9. Pharmacokinetic samples and blood pressure measurements were collected at baseline, during infusion, and for 6 hours after infusion.

Results

The plasma clearance, steady‐state volume of distribution, and terminal half‐life after a 4‐hour intravenous infusion of rhVEGF165 at the high dose were 19.1 ± 5.7 mL/min/kg, 960 ± 260 mL/kg, and 33.7 ± 13 minutes, respectively. The duration of hypotension that occurred after rhVEGF165 administration appeared to be related to the model‐predicted VEGF165 concentration associated with the high‐affinity receptor compartment.

Conclusions

This mechanism‐based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF165 dose regimens that may aid in optimization of drug delivery for future clinical trials.

Clinical Pharmacology & Therapeutics (2002) 72, 20–32; doi: 10.1067/mcp.2002.126179
Pharmacokinetics of valganciclovir and ganciclovir in renal impairment
Authors: Czock David , Scholle Cornelia , Rasche Franz Maximilian , Schaarschmidt Dieter , Keller Frieder
Published: October 2002

Background

Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects.

Methods

A total of 44 patients were included—18 with mild, medium, or severe renal impairment; 6 with end‐stage renal disease who were on long‐term hemodialysis;8 HIV/CMV‐positive patients with normal renal function; and 12 healthy subjects serving as controls. Valganciclovir and ganciclovir serum concentrations were measured after oral administration of 900 mg of valganciclovir. Pharmacokinetic parameters were estimated by means of noncompartmental and compartmental methods.

Results

After oral administration of the prodrug valganciclovir, ganciclovir bioavailability was 60% and ganciclovir concentrations were higher (maximum concentration [Cmax], 8.5 μg/mL versus 5.8 μg/mL) and appeared later (time to maximum concentration [Tmax], 4.3 versus 2.0 hours) in patients with severe renal impairment compared with healthy subjects. The elimination half‐life (t1/2)of ganciclovir was longer in patients with renal failure (t1/2 of 68.1 hours in patients with end‐stage renal disease compared with 3.5 hours in healthy subjects). Ganciclovir clearance was correlated with creatinine clearance (r = 0.975). Hemodialysis removed 50% of ganciclovir. We observed no differences in pharmacokinetics between HIV/CMV‐positive patients and healthy subjects. A 2‐compartment model with zero‐order input and first‐order elimination proved to be the most appropriate model for ganciclovir after oral administration of valganciclovir.

Conclusions

The dosage of valganciclovir has to be adjusted to the degree of renal impairment. Dosage adjustment is not necessary for HIV/CMV‐positive patients.

Clinical Pharmacology & Therapeutics (2002) 72, 142–150; doi: 10.1067/mcp.2002.126306
Peripheral prostanoid levels and nonsteroidal anti‐inflammatory drug analgesia: Replicate clinical trials in a tissue injury model
Authors: Gordon Sharon M. , Brahim Jaime S. , Rowan Janet , Kent Allison , Dionne Raymond A.
Published: October 2002

Background

Nonsteroidal anti‐inflammatory drug (NSAID) analgesia is generally attributed to peripheral suppression of cyclooxygenase (COX) enzymes, leading to decreased products of the arachidonic acid cascade. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia aftersystemic or local NSAID administration in a clinical model of tissue injury.

Methods

Subjects in two replicate clinical trials had one or two mandibular third molars removed and a microdialysis probe implanted at the surgical site for measurement of immunoreactive prostaglandin E2 (PGE2) or immunoreactive thromboxane B2 (TxB2) and pain measured concurrently. In the first study, ketorolac tromethamine (INN, ketorolac) was administered at pain onset in a 30‐mg intramuscular dose, a 1‐mg intramuscular dose, or a 1‐mg submucosal dose at the extraction site in comparison with placebo. In the second study, subjects received either ketorolac tromethamine 30 mg by the intravenous route or placebo at pain onset.

Results

PGE2 was detectable in the first postoperative sample, decreased over the next hour, and then increased significantly coincident with the onset of postoperative pain. Administration of 30 mg ketorolac tromethamine produced parallel decreases in pain, PGE2 levels, and TxB2 levels at the surgical site. Administration of 1 mg ketorolac tromethamine intramuscularly or directly at the surgical site was analgesic but without measurable effects on PGE2 levels.

Conclusion

The temporal profile of PGE2 and TxB2 in the immediate postoperative period is consistent with constitutive COX‐1 initially, followed by an increase in PGE2 resulting from expression of COX‐2. The temporal association between NSAID analgesia and decreased prostanoids at the site of injury is consistent with a dual COX‐1/COX‐2 peripheral site of action. The analgesic effects of 1 mg ketorolac tromethamine without a reduction in PGE2 at the site of injury suggests an additional central site for NSAID analgesia.

Clinical Pharmacology & Therapeutics (2002) 72, 175–183; doi: 10.1067/mcp.2002.126501
Sense of Belonging as a Buffer Against Depressive Symptoms
Authors: Sargent Judy , Williams Reg Arthur , Hagerty Bonnie , Lynch-Sauer Judith , Hoyle Kenneth
Published: October 2002

BACKGROUND: Lack of a sense of belonging has been shown to be associated with loneliness, emotional distress, psychosocial disturbance, and mental illness. Conversely, sense of belonging was found to correspond with psychosocial health.

OBJECTIVE: The purpose of this study was to determine the buffering effect of sense of belonging against the development of depression.

STUDY DESIGN: This study used a comparative design. The sample consisted of 443 Navy recruits in basic training who were divided into depressed and control groups based on depressive symptoms. The groups were then further stratified based on risk factors: a personal history of abuse and family histories of mental illness, alcohol, and drug abuse.

RESULTS: The results refuted a significant buffering effect of sense of belonging against the development of depressive symptoms in several of the subgroups. However, sense of belonging significantly buffered those with a family history of alcohol abuse against developing depressive symptoms.

CONCLUSION: Sense of belonging is a concept that has important implications for psychosocial well being. Interventions that enhance sense of belonging will be useful in the treatment and primary prevention of depression.
Systemic Vascular Disease in Male B6C3F1 Mice Exposed to Particulate Matter by Inhalation: Studies Conducted by the National Toxicology Program
Authors: Moyer Carolyn F. , Kodavanti Urmila P. , Haseman Joseph K. , Costa L. , Nyska Abraham
Published: October 2002

Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate-matter-induced inflammation and vascular disease, a 2-phase retrospective study was conducted. Phase one included the review of heart, lung, and kidney tissues from high-dose and control male B6C3F1 mice exposed by inhalation to 9 particulate compounds for a 2-year period. The results showed that high-dose males developed significantly increased incidences of coronary and renal arteritis over controls in 2 of the 9 studies (indium phosphide and cobalt sulfate heptahydrate), while marginal increases in arteritis incidence was detected in 2 additional studies (vanadium pentoxide and gallium arsenide). In contrast, arteritis of the muscular arteries of the lung was not observed. Morphological features of arteritis in these studies included an influx of mixed inflammatory cells including neutrophils, lymphocytes, and macrophages. Partial and complete effacement of the normal vascular wall architecture, often with extension of the inflammatory process into the periarterial connective tissue, was observed. Phase 2 evaluated the heart, lung, kidney, and mesentery of male and female B6C3F1 mice from the 90-day studies of the 4 compounds demonstrating arteritis after a 2-year period. The results showed arteritis did not develop in the 90-day studies, suggesting that long-term chronic exposure to lower-dose metallic particulate matter may be necessary to induce or exacerbate arteritis.
Vascular Effects of GI262570X (PPAR-γ agonist) in the Brown Adipose Tissue of Han Wistar Rats: A Review of 1-month, 13-week, 27-week and 2-year Oral Toxicity Studies
Authors: Elangbam Chandikumar S. , Brodie Thomas A. , Roger Brown H. , Nold James B. , Raczniak Timothy J. , Tyler Ronald D. , Lightfoot Ruth M. , Wall Henry G.
Published: October 2002

We describe and discuss microscopic findings in the brown adipose tissue (BAT) blood vessels of Han Wistar rats treated with GI262570X, a peroxisome proliferator-activated receptor- γ agonist (PPAR- γ agonist) by oral gavage for 28 days, 13 weeks, 27 weeks, and 2 years. Review of these studies revealed a consistent vascular change, consisting of multifocal fatty infiltration in the BAT of treated rats. A similar vascular change was not seen in other vessels or organs. Microscopically, fatty infiltration was characterized primarily by round, clear vacuoles within the tunica media and/or tunica adventitia of small and medium-sized arteries and arterioles. Occasionally, these vacuoles had peripherally located nuclei and morphologically resembled adipocytes, suggesting a well-characterized PPAR effect (ie, differentiation of stem cells or preadipocytes into mature adipocytes). However, administration of GI262570X up to 2 years failed to induce more severe or progressive lesions in the blood vessels of rat BAT and, in particular, did not result in induction of any atherosclerotic-like lesions or foam cell infiltration. At the longer exposure, there was an apparent reduction of severity and/or incidence, indicating a possible adaptive response. These results suggest that the possibility of generating atherosclerotic-like lesions through prolonged treatment of GI262570X (PPAR- γ agonist) is highly unlikely in rats.
“Have You Seen This?” Peliosis Hepatis
Authors: Edwards Richard , Colombo Tina , Greaves Peter
Published: October 2002

Peliosis hepatis, characterized by the presence of blood-filled spaces within hepatic parenchyma, developed in C57B1 mice implanted subcutaneously with melanoma cells 23 days previously. The peliosis was associated with dilated hepatic sinusoids that were lined by prominent, proliferating endothelial cells. The development of peliosis hepatis was completely abrogated when melanoma growth was inhibited by administration of dexamethasone. These features support the concept that peliosis hepatis can be induced by a circulating tumor-derived endothelial growth factor such as vascular endothelial growth factor.
Endocardial Myxomatous Change in Harlan Sprague-Dawley Rats (Hsd:S—D) and CD-1 Mice: Its Microscopic Resemblance to Drug-Induced Valvulopathy in Humans
Authors: Elangbam Chandikumar S. , Colman Karyn A. , Lightfoot Ruth M. , Tyler Ronald D. , Wall Henry G.
Published: October 2002

A full assessment of all heart valves in rats and mice is often impractical and is usually not performed in routine toxicity studies, largely due to an inevitable inconsistency of histological sampling. The majority of reported heart valve changes involve the examination of a single, semirandom section through the heart and the valvulopathy occurring with age or induced by xenobiotics may have been generally underestimated in mice and rats. Here we describe the incidence and microscopic features of endocardial myxomatous change (EMC) in Hsd:S—D rats and CD-1 mice. EMC was common and widespread in both CD-1 mice and Hsd:S—D rats (188 of 220 rats and 96 of 215 mice were affected by EMC). Microscopically, EMC consisted of focal or segmental thickening of valves, primarily due to the presence of fibromyxoid tissue in the subendocardium. Occasionally, fibrin or thrombi deposits and collection of neutrophils or mononuclear cells were observed. These microscopic features were similar to those seen in valvular disease in humans induced by fenfluramine-phentermine (fen-phen), ergot alkaloids (ergotamine, methysergide), and carcinoid syndrome. The mitral valve in rats and pulmonary valve in mice were most frequently affected. An association between murine progressive cardiomyopathy (MPC) and EMC was noted only in rats, suggesting that there may be a possible relationship between MPC and EMC. However, additional research is needed to confirm a relationship between EMC and MPC in rats and/or mice.