Search

Secondary prevention of lung cancer by screening a high-risk population with low-dose CT (LDCT) of the chest has been shown to save lives. Our Institution offered a free screening program in 2013. The program was promoted through flyers, radio programs, face-to-face information sessions, and a multidisciplinary lung symposium. A lung navigator confirmed the eligibility of patients according to National Lung Screening Trial (NLST) criteria. Data were, prospectively, collected over a 12-month period using Lung-RADs (Lung Imaging Reporting and Data System). After one year, an online survey was sent out to all primary care and referring physicians in the network. One hundred and sixty-nine patients were found to be eligible for screening. Sixty-five per cent were black, 44 per cent white, 9 per cent Hispanic, and 6 per cent were Asian. Sixty per cent patients were referred by their physician. Thirty-one were Lung-RADs 1 (18.3%), 116 were Lung-RADs 2 (68.6%), 16 were Lung-RADs 3 (9.5%), and six were Lung-RADs 4 (3.6%). At the end of the study period, the survey showed that 100 per cent of the providers were aware of the screening program but 15 per cent never referred a patient. Time constraints and requirement for precertification were cited as potential barriers to referral. Twenty-six per cent of providers were unaware that LDCT was recommended by the U.S. Preventive Services Task Force on par with colonoscopy and mammography. The NLST showed that screening with LDCT could reduce lung cancer mortality by 20 per cent. Significant concerns exist about the generalizability of these results and the applicability of screening programs in the community.

This contribution describes the synthesis and characterization of a perylene diimide (PDI)-based n-type semiconductor and its application to organic photovoltaic (OPV) devices having inverted architecture. Films of N,N′-bis(3-trimethoxysilylpropyl)-1,6,7,12-tetrachloroperylene-3,4,9,10-tetracarboxyldiimide (Cl4PSi2) and blends of this material with various polymers are solution-deposited on tin-doped indium oxide (ITO) substrates as interfacial layers (IFLs). The organic IFL described in this work is based on the air- and light-stable PDI core, annealed at low temperatures compatible with flexible substrates, and crosslinks in air for compatibility with device fabrication. Morphological, optical, and electrochemical analysis of these IFL films demonstrate predominantly smooth surfaces and HOMO and LUMO energies of ∼4.5 and 7.0 eV, respectively, which are ideal for accepting electrons and blocking holes in inverted devices. A cationic silane species is added to the Cl4PSi2at an optimum ∼2–5 wt % to reduce IFL series resistance and enhance device performance. Also, a short light soaking procedure is necessary for completed devices to achieve high fill factors in current density–voltage analysis, a phenomenon previously only observed for inverted devices having an n-type inorganic IFL.

Design of physical installations and sampling procedures for ground-water monitoring networks, particularly for detection and analysis of possible contaminants, is a topic of great scientific and practical interest at the present time. Recent practice in the design of monitoring networks associated with known contaminant sources sometimes includes an array of monitoring wells with long well screens (up to 50 feet or more). Numerical experiments with a detailed three-dimensional ground-water flow model indicate that significant wellbore flow can occur in contaminant monitoring wells with long well screens that are embedded in homogeneous aquifers with very small vertical head differences in the aquifer. This ``short circuiting'' of flow through boreholes should exist at some level on all scales. Consideration of the general flow pattern within the borehole, the flow pattern in the aquifer adjacent to the borehole, and the process of obtaining water samples from the borehole suggests that in many situations the practice of installing long well screens in contaminant monitoring wells should be abandoned.

In the field of organic electronics, which includes organic light emitting diodes (OLEDs) and organic photovoltaics (OPVs), there is a need for solution processable materials with low work functions. These materials would serve an important role by modifying the Fermi level at electron injecting (OLEDs) and electron collecting (OPVs) electrodes to improve performance. Certain reduced complexes of transition metals (e.g. Ru and Os) are capable of satisfying the aforementioned criteria. On the cyclic voltammetry time-scale [FeL3]2+ complexes, where L = 2,2'-bipyridine-type ligands, exhibit a series of one-electron, reversible reductions at very similar negative potentials to what is observed for Ru and Os analogs. These similarities are significant because iron would afford an earth-abundant alternative to the higher atomic weight congeners when considering potential applications of these reduced materials. However, in contrast to the analogous Ru and Os complexes, when reduced to the formal [FeL3]0 form, this formally zero-valent complex undergoes a slow decomposition to form Fex0 nanoparticles in non-polar solvent (hexane or toluene). When the bipyridine ligand is appended with long-straight-chain hydrocarbon tails, these particles remain dispersed in solution and are apparently capped with the lipophilic ligand.

Disordered nanohole arrays were formed in silver films by colloidal lithography techniques and characterized for their surface-plasmon activity. Careful control of the reagent concentration, deposition solution ionic strength, and assembly time allowed generation of a wide variety of nanohole densities. The fractional coverage of the nanospheres across the surface was varied from 0.05−0.36. Electrical sheet resistance measurements as a function of nanohole coverage fit well to percolation theory indicating that the electrical behavior of the films is determined by bulk silver characteristics. The transmission and reflection spectra were measured as a function of coverage and the results indicate that the optical behavior of the films is dominated by surface plasmon phenomena. Angle-resolved transmission and reflection spectra were measured, yielding insight into the nature of the excitations taking place on the metal films. The tunability of the colloidal lithography assembly method holds much promise as a means to generate customized transparent electrodes with high surface plasmon activity throughout the visible and NIR spectrum over large surface areas.

Pentacene, a model organic semiconductor, is shown to couple with surface plasmon (SP) active silver nanohole films to produce enhanced excited-state absorption. In addition, the dynamics of triplet formation and decay on a subpicosecond time scale are altered due to the coupling of the excited state with the resonant SP, possibly involving the interplay between singlet fission and triplet−triplet annihilation. Shifting the resonance of the SP with respect to the pentacene excitations and introducing a dielectric spacer between pentacene and metal lead to changes in the spectra and dynamics that can be explained qualitatively. These results are compared with recent literature reports of molecule/plasmon hybridization and are placed in context with efforts to utilize SPs for enhanced solar energy conversion.

ABSTRACTFrancisella tularensisis a facultative intracellular pathogen and the etiologic agent of tularemia. It is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. Bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. The goal of this study was to delete the four primary acid phosphatases (Acps) from Francisella novicidaand examine the interactions of mutant strains with macrophages, as well as the virulence of these strains in mice. We constructed F. novicidamutants with various combinations of acpdeletions and showed that loss of the four Acps (AcpA, AcpB, AcpC, and histidine acid phosphatase [Hap]) in an F. novicidastrain (ΔABCH) resulted in a 90% reduction in acid phosphatase activity. The ΔABCH mutant was defective for survival/growth within human and murine macrophage cell lines and was unable to escape from phagosome vacuoles. With accumulation of Acp deletions, a progressive loss of virulence in the mouse model was observed. The ΔABCH strain was dramatically attenuated and was an effective single-dose vaccine against homologous challenge. Furthermore, both acpAand hapwere induced when the bacteria were within host macrophages. Thus, the Francisellaacid phosphatases cumulatively play an important role in intracellular trafficking and virulence.

Francisella tularensis is a facultative intracellular pathogen and the etiologic agent of tularemia. It is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. Bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. The goal of this study was to delete the four primary acid phosphatases (Acps) from Francisella novicida and examine the interactions of mutant strains with macrophages, as well as the virulence of these strains in mice. We constructed F. novicida mutants with various combinations of acp deletions and showed that loss of the four Acps (AcpA, AcpB, AcpC, and histidine acid phosphatase [Hap]) in an F. novicida strain (ABCH) resulted in a 90% reduction in acid phosphatase activity. The ABCH mutant was defective for survival/growth within human and murine macrophage cell lines and was unable to escape from phagosome vacuoles. With accumulation of Acp deletions, a progressive loss of virulence in the mouse model was observed. The ABCH strain was dramatically attenuated and was an effective single-dose vaccine against homologous challenge. Furthermore, both acpA and hap were induced when the bacteria were within host macrophages. Thus, the Francisella acid phosphatases cumulatively play an important role in intracellular trafficking and virulence.

A clinical retrospective study was conducted.

The number of travellers undertaking long-distance flights has continued to increase. Such flights are associated with travel fatigue and jet lag, the symptoms of which are considered here, along with their similarities, differences, and causes. Difficulties with jet lag because of sleep loss and decreased performance are emphasised. Since jet lag is caused mainly by inappropriate timing of the body clock in the new time zone, the pertinent properties of the body clock are outlined, with a description of how the body clock can be adjusted. The methods, both pharmacological and behavioural, that have been used to alleviate the negative results of time-zone transitions, are reviewed. The results form the rationale for advice to travellers flying in different directions and crossing several time zones. Finally, there is an account of the main problems that remain unresolved.

Nanoaperture arrays in a silver film were quantitatively evaluated, for the first time, to determine the absolute Raman scattering enhancement factors as a function of aperture lattice spacing using a nonresonant analyte. The arrays, with 200 nm diameter apertures and varying spacing in a 50 nm thick silver film, resulted in an average area-corrected SERS enhancement factor of (6 ± 3) × 107for 514.5 nm excitation. Comparison between theory and experiment provided critical insight into the magnitude and origin of enhancement in these nanoaperture arrays as a function of lattice spacing. The measured enhancement factor was attributed to two distinct sources:? a factor of 105from nm scale roughness associated with the Ag film in the absence of the nanoapertures and a factor of 6 × 102associated with plasmons localized near the aperture edges.

Exercise causes body temperature to rise and the resulting heat stored becomes a factor limiting exercise performance in hot conditions. Loss of heat by evaporative processes leads to hypohydration which itself can eventually impair performance. This review focuses on thermoregulatory and behavioural processes during sustained exercise in the heat.

The Haemophilus influenzae P4 lipoprotein (hel) is a potential component of a nontypeable H. influenzae otitis media vaccine. Since P4 is known to be an enzyme, nonenzymatically active forms of recombinant P4 are required. After site-directed mutagenesis of the hel gene, three of the mutated proteins were shown to be vaccine candidates.

ABSTRACTThe Haemophilus influenzaeP4 lipoprotein (hel) is a potential component of a nontypeable H. influenzaeotitis media vaccine. Since P4 is known to be an enzyme, nonenzymatically active forms of recombinant P4 are required. After site-directed mutagenesis of the helgene, three of the mutated proteins were shown to be vaccine candidates.

The optimal treatment of “unstable” thoracolumbar injuries remains controversial. Studies have shown the advantages of direct anterior decompression of thoracolumbar injuries along with supplemental posterior instrumentation as a combined or staged procedure. Others have also shown success in decompression as a single-stage anterior procedure, largely limited to two-column (anterior and middle) injuries. A retrospective review of all available clinical and radiographic data was used to classify unstable three-column thoracolumbar fractures according to the Association for the Study of Internal Fixation (AO) classification system. This was conducted to evaluate the efficacy of stand-alone anterior decompression and reconstruction of unstable three-column thoracolumbar injuries, utilizing current-generation anterior spinal instrumentation.

The intermediary metabolism of Haemophilus influenzae strain Rd KW20 was studied by a combination of protein expression analysis using a recently developed direct proteomics approach, mutational analysis, and mathematical modeling. Special emphasis was placed on carbon utilization, sugar fermentation, TCA cycle, and electron transport of H. influenzae cells grown microaerobically and anaerobically in a rich medium. The data indicate that several H. influenzae metabolic proteins similar to Escherichia coli proteins, known to be regulated by low concentrations of oxygen, were well expressed in both growth conditions in H. influenzae. An in silico model of the H. influenzae metabolic network was used to study the effects of selective deletion of certain enzymatic steps. This allowed us to define proteins predicted to be essential or non-essential for cell growth and to address numerous unresolved questions about intermediary metabolism of H. influenzae. Comparison of data from in vivo protein expression with the protein list associated with a genome-scale metabolic model showed significant coverage of the known metabolic proteome. This study demonstrates the significance of an integrated approach to the characterization of H. influenzae metabolism.

Notation analysis has now gained wide use in the assessment of competitive football play. Computer-aided methods have largely replaced the use of hand-notation systems. Whilst a hand-notation approach has been adopted previously in assessing injury-risk in football, the recording and analysing of events with injury potential are time-consuming. In this report, a computerised system of notating incidents in the game is described. Key incidents are monitored with respect to degree of injury potential, location and other factors. The use of the system is illustrated by comparing home and away performances in Premier League matches between Manchester United and Liverpool F.C. The system has advantages in speed and accuracy of handling data related to injury and injury risk.

Haemophilus influenzaelipoprotein e(P4) is a member of the DDDD phosphohydrolase superfamily and mediates heme transport. Each of the aspartate residues of the signature motif is required for phosphomonoesterase activity, as none of the e(P4) single D mutants (D64A, D66A, D181N, and D185A) possessed detectable phosphomonoesterase activity. These results suggest that the signature motif is essential to the phosphomonoesterase activity of lipoprotein e(P4). When assessed for phosphomonoesterase‐dependent heme transport activity in Escherichia coli hemAstrains, plasmids containing D181N and D185A retained heme transport as indicated by aerobic growth while D64A and D66A did not. We conclude that phosphomonoesterase activity is not required for heme transport.

This study was undertaken to define the αvβ3binding affinity and specificity of the low-molecular-weight nonpeptide integrin antagonist, SM256. SM256 demonstrated high potency (IC50, 0.057 ± 0.030 nM) in inhibiting vitronectin binding to purified human αvβ3receptors. Additionally, SM256 inhibited αvβ3-mediated human umbilical vein endothelial cell (HUVEC) or 293/β3 (β3-transfected cell line) adhesion to fibrinogen with IC50values of 0.0054 ± 0.0058 and 0.0023 ± 0.0012 μM,respectively. SM256 demonstrated a relatively high degree of specificity for human αvβ3-mediated functions as compared with other human integrins including αvβ5(IC50, 0.92 ± 0.69 μM), αIIbβ3(IC50, 0.72 ± 0.07 μM), α4/β1(IC50, >100 μM) and α5/β1(IC50, 2.3 ± 2.1 μM). SM256 demonstrated different degree of species specificity in blocking αvβ3-mediated cellular adhesion with relatively higher affinity to dog (IC50, 0.005 ± 0.002 μM), rabbit (IC50, 0.021 ± 0.01 μM), mouse (IC50, 0.035 ± 0.01 μM), and pig (IC50, 0.41 ± 0.24 μM) endothelial or smooth-muscle cell αvβ3-mediated adhesion. Additionally, SM256 demonstrated high degree of αvβ3specificity as compared with αvβ5, α5β1, or αIIbβ3-mediated binding in these species. SM256 is a potent αvβ3antagonist with high affinity and specificity for αvβ3-mediated functions. Additionally, a comparable αvβ3affinity for SM256 was demonstrated with endothelial cells obtained from various species (dog, mouse, rabbit, and pig) as compared with that from human.

Acid phosphatases capable of inhibiting the respiratory burst of neutrophils have been identified in certain intracellular pathogens. Here we evaluate the role of AcpA, a respiratory burst‐inhibiting acid phosphatase of Francisella, in the virulence and intracellular growth of this organism. An F. novicida acpAnull mutant was created and found to exhibit wild‐type growth kinetics in both cell‐line and inflammatory mouse macrophages. The acpAmutant also shows wild‐type replication in the spleens of experimentally infected mice. These data suggest that AcpA is not essential for the intracellular growth or virulence of F. novicida.

A major new survey program, the Medicare Beneficiary Health Status Registry (MBHSR), has been proposed to improve the monitoring of the health status of Medicare beneficiaries. The MBHSR would collect data by mail with telephone follow up of nonrespondents to permit economical assessment of a total Registry of approximately 200,000 Medicare beneficiaries, approximately 54,000 of whom would be surveyed in any given year. (Surveys would be conducted of samples of new enrollees who would be reinterviewed every five years.)

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and ³H-SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 μg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 ng/mL was obtained at the 2.0 μg/kg dose. Pooling individual concentration–time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig at the 0.5 μg/kg dose. The 2.0 μg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non-plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists. Copyright © 1999 John Wiley & Sons, Ltd.

Haemophilus influenzaeis a common inhabitant of the upper respiratory tract and can cause serious infections of mucosal surfaces. Results from recent studies indicate that this pathogen possesses copious amounts of surface-localized phosphomonoesterase activity mediated by the bacterial lipoprotein e(P4). While the enzyme has previously been purified to apparent homogeneity, purification of large amounts of protein has been prevented by presence of N-terminal lipid modification. Recombinant DNA technology was employed to simultaneously replace the N-terminal lipid modification signal sequence with one for protein secretion without such modification and to place expression of the protein under the control of the T7-inducible promoter. Results from this work show that high levels of phosphomonoesterase activity were achieved after IPTG induction and purified to apparent homogeneity after two chromatography steps. Consistent with loss of the N-terminal lipid modification, the recombinant enzyme was easily extracted from the bacterial membrane and partitioned within the matrix of gel filtration chromatography resin while retaining a denatured molecular weight similar to that of wild-type e(P4). Results from physicochemical characterization suggest that the recombinant protein was similar to wild-type protein in SDS–PAGE-derived molecular weight, primary structure, substrate specificity, pH optimum, and sensitivity or resistance to various inhibitors. Acquisition of sufficient amounts of recombinant P4 was a prelude for studies to elucidate the structure and function of this unusual phosphomonoesterase.

Two groups of healthy subjects were studied indoors, first while living normally for 8 days (control section) and then for 18 × 27h "days" (experimental section). This schedule forces the endogenous (body clock-driven) and exogenous (lifestyle-driven) components of circadian rhythms to run independently. Rectal temperature and wrist movement were measured throughout and used as markers of the amplitude of the circadian rhythm, with the rectal temperature also "purified" by means of the activity record to give information about the endogenous oscillator. Results showed that, during the experimental days, there were changes in the amplitude of the overt temperature rhythm and in the relative amounts of out-of-bed and in-bed activity, both of which indicated an interaction between endogenous and exogenous components of the rhythm. However, the amplitude and the amount of overlap were not significantly different on the control days (when endogenous and exogenous components remained synchronized) and those experimental days when endogenous and exogenous components were only transiently synchronized; also, the amplitudes of purified temperature rhythms did not change significantly during the experimental days in spite of changes in the relationship between the endogenous and exogenous components. Neither result offers support for the view that the exogenous rhythm alters the amplitude of oscillation of the endogenous circadian oscillator in humans.

Fourteen ambulatory subjects, varying in their amount of habitual physical activity, were studied for 24h during a total of 25 "typical" days. Rectal temperature was recorded every 6 minutes, an activity diary was filled in every half hour, and wrist activity and heart rate were monitored every minute. Actimetry and heart rate data generally showed close parallelism with each other and with the masking effects on body temperature. Psychological stressors such as public speaking produced a greater effect on heart rate and body temperature than on wrist movement, while typing produced high values for wrist movement, but affected heart rate and temperature much less. When data for the circadian rhythm of body temperature were purified, the diary, actimetry, and measurement of heart rate were all useful in reducing masking effects, but the present evidence indicates that heart rate can be more successful than actimetry-as judged by the closeness of the purified data to a sinusoid. This superiority of heart rate monitoring over wrist activity as a method of purification might be because core temperature can be increased by stressor-induced thermogenesis, as well as by physical activity, and because wrist movement can, with some activities, give an inaccurate estimate of the factors that contribute to whole-body thermogenesis.

Nine healthy female subjects were studied when exposed to the natural light-dark cycle, but living for 17 "days" on a 27h day (9h sleep, 18h wake). Since the circadian endogenous oscillator cannot entrain to this imposed period, forced desynchronization between the sleep/activity cycle and the endogenous circadian temperature rhythm took place. This enabled the effects of activity on core temperature to be assessed at different endogenous circadian phases and at different stages of the sleep/activity cycle. Rectal temperature was measured at 6-minute intervals, and the activity of the nondominant wrist was summed at 1-minute intervals. Each waking span was divided into overlapping 3h sections, and each section was submitted to linear regression analysis between the rectal temperatures and the total activity in the previous 30 minutes. From this analysis were obtained the gradient (of the change in rectal temperature produced by a unit change in activity) and the intercept (the rectal temperature predicted when activity was zero). The gradients were subjected to a two-factor analysis of variance (ANOVA) (circadian phase/ time awake). There was no significant effect of time awake, but circadian phase was highly significant statistically. Post hoc tests (Newman-Keuls) indicated that gradients around the temperature peak were significantly less than those around its trough. The intercepts formed a sinusoid that, for the group, showed a mesor (±SE) of 36.97 (±0.12) and amplitude (95% confidence interval) of 0.22°C (0.12°C, 0.32°C). We conclude that this is a further method for removing masking effects from circadian temperature rhythm data in order to assess its endogenous component, a method that can be used when subjects are able to live normally. We suggest also that the decreased effect of activity on temperature when the endogenous circadian rhythm and activity are at their peak will reduce the possibility of hyperthermia.

The effects of hormone deficiency at the menopause on muscle strength was examined in 10 healthy middle-aged women (1-3 years post-menopause) in a longitudinal trial over 39 weeks. Performance was compared with that of age-matched females (n = 11) taking a course of hormone replacement therapy (HRT). Muscle strength of the quadriceps was measured isometrically at 90° of knee flexion and at angular velocities of 1.05, 2.09 and 3.13 rad/s using an isokinetic dynamometer. Hand grip strength was assessed by means of a portable dynamometer. Measurements were taken every 13 weeks for 39 weeks. Significant decreases in isometric strength (-10%) and dynamic leg strength at 1.05 rad/s (-9%) were found in the post-menopausal women over 39 weeks. There was no change in strength in the HRT group. There were also no changes in leg strength at higher angular velocities or in grip strength for either the post-menopausal group or those taking HRT. While HRT preserved muscle strength, there was no evidence of a strengthening effect on skeletal muscle within this short period of treatment. A rapid loss of leg strength occurs post-menopausally in hormone-depleted women. HRT may offer protection against muscle weakness, although the hormone responsible for regulating strength is not evident using this model.

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H‐SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography‐mass spectrometry (LC‐MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 μg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 ng/mL was obtained at the 2.0 μg/kg dose. Pooling individual concentration–time data yielded a systemic clearance of 1.42 mL/min/kg, Vssof 0.24 L/kg, and a terminal half‐life of 2.8 h in the guinea pig at the 0.5 μg/kg dose. The 2.0 μg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non‐plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitrostudies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitroplatelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists. Copyright © 1999 John Wiley & Sons, Ltd.