Edentulism Predicts Cognitive Decline in the US Health and Retirement Cohort Study.

This longitudinal cohort study examines if 1) cognitive decline varies by birth cohort, adjusting for covariates, and 2) edentulism and nonuse of dental care predict 10-y cognitive decline (2008-2018). The Health and Retirement Study (HRS) features a representative sample of US adults over age 50. Eligibility criteria included having cognitive interview data available and responding to the question, "Have you lost all of your upper and lower natural permanent teeth?" at 2+ time points between 2006 and 2018. Use of dental care in the past 2 y was assessed. Linear mixed models for repeated measures estimated the trajectories of mean cognition over time for the birth cohorts, adjusted for baseline cognition, dentition status, dental care use, and covariates (demographic characteristics, health behaviors, and medical conditions). Cohort-by-time interaction terms were included to assess if cognitive decline varied by birth cohort. Ten-year change in cognition status (measured by HRS Cogtot27)-categorized as dementia (<7); cognitive impairment, not demented (7-11) 7≤Cogtot27<12; and normal (≥12)-was also investigated according to birth cohort, dentition status, and dental care use. Mean (SD) baseline age was 63.4 (10.1) y (n = 22,728). Older birth cohorts had greater cognitive decline than younger cohorts. Linear mixed-model estimates and 95% confidence intervals for protective factors for cognitive decline included higher baseline cognition (HRS Cogtot27) (0.49; 0.48-0.50), use of dental care in the past 2 y (0.17; 0.10-0.23), and covariates such as greater household wealth and being married. Risk increased with being edentulous (-0.42; -0.56 to -0.28), history of stroke or diabetes, less education, Medicaid recipient, current smoker, loneliness, and poor/fair self-rated health. Edentulism and irregular dental care are among important predictors of cognitive decline. Tooth retention and regular dental care throughout life appear to be important for maintaining oral and cognitive health.

Prediction Model Development and Validation of 12-Year Incident Edentulism of Older Adults in the United States.

INTRODUCTION: Edentulism affects health and quality of life. OBJECTIVES: Identify factors that predict older adults becoming edentulous over 12 y in the US Health and Retirement Study (HRS) by developing and validating a prediction model. METHODS: The HRS includes data on a representative sample of US adults aged >50 y. Selection criteria included participants in 2006 and 2018 who answered, "Have you lost all of your upper and lower natural permanent teeth?" Persons who answered "no" in 2006 and "yes" in 2018 experienced incident edentulism. Excluding 2006 edentulous, the data set (n = 4,288) was split into selection (70%, n = 3,002) and test data (30%, n = 1,286), and Monte Carlo cross-validation was applied to 500 random partitions of the selection data into training (n = 1,716) and validation (n = 1,286) data sets. Fitted logistic models from the training data sets were applied to the validation data sets to obtain area under the curve (AUC) for 32 candidate models. Six variables were included in all models (age, race/ethnicity, gender, education, smoking, last dental visit) while all combinations of 5 variables (income, alcohol use, self-rated health, loneliness, cognitive status) were considered for inclusion. The best parsimonious model based on highest mean AUC was fitted to the selection data set to obtain a final prediction equation. It was applied to the test data to estimate AUC and 95% confidence interval using 1,000 bootstrap samples. RESULTS: From 2006 to 2018, 9.7% of older adults became edentulous. The 2006 mean (SD) age was 66.7 (8.7) for newly edentulous and 66.3 (8.4) for dentate (P = 0.31). The baseline 6-variable model mean AUC was 0.740. The 7-variable model with cognition had AUC = 0.749 and test data AUC = 0.748 (95% confidence interval, 0.715-0.781), modestly improving prediction. Negligible improvement was gained from adding more variables. CONCLUSION: Cognition information improved the 12-y prediction of becoming edentulous beyond the modifiable risk factors of smoking and dental care use, as well as nonmodifiable demographic factors. KNOWLEDGE TRANSFER STATEMENT: This prediction modeling and validation study identifies cognition as well as modifiable (dental care use, smoking) and nonmodifiable factors (race, ethnicity, gender, age, education) associated with incident complete tooth loss in the United States. This information is useful for the public, dental care providers, and health policy makers in improving approaches to preventive care, oral and general health, and quality of life for older adults.

Topical Fluoride Effectiveness in High Caries Risk Adults.

This retrospective analysis of longitudinal data was developed to determine which types, combinations, and intensities of topical fluorides more effectively prevent new caries-related restorations and extractions in high caries risk adults. We included data from October 1, 2008, through June 30, 2018, from electronic dental and medical records and pharmacy database from the US Department of Veterans Affairs. Veterans who were eligible for continuing and comprehensive care, met the criteria of high caries risk (received 2 or more caries-related restorations within a 365-d period), and had 3 y of follow-up were included. Multivariable logistic regression models estimated the odds of caries-related treatment during the 1-y observation period, controlling for age, gender, race and ethnicity, illness burden (Selim comorbidity index), use of prescription medications, attendance at dental prophylaxis appointments, number of caries-related restorations during the index year, and time between first and last caries-related restoration during the index year. The study sample included 68,757 veterans, who were primarily male (91.5%), were White (73.6%), had a mean age of 59.2 ± 13.5 y, and had significant medical comorbidity as measured by the Selim index (3.7 ± 2.4 physical and 1.3 ± 1.2 mental diagnoses). They had 10.8 ± 6.3 prescription VA drug classes, took 0.6 ± 0.8 strong anticholinergic medications, and had 3.9 ± 2.6 teeth restored due to caries during the index year. Adjusted multivariable logistic regression models showed veterans who received a varnish or gel/rinse fluoride intervention versus no fluoride had an approximately 29% decreased odds of receiving caries-related treatment during the observation period (gel/rinse adjusted odds ratio [AOR] = 0.72; 95% confidence interval [CI], 0.67-0.76; varnish AOR = 0.71; 95% CI, 0.67-0.75). The receipt of a varnish and gel/rinse did not demonstrate statistically better odds than each intervention alone (AOR = 0.69; 95% CI, 0.64-0.75). A dose-response effect was observed. Two-plus applications of varnish versus none (AOR = 0.73; 95% CI, 0.69-0.77) and 2-plus applications of gel/rinse versus none (AOR = 0.71; 95% CI, 0.67-0.75) were more effective than 1 application of either modality versus none.

Abnormal lymphatic phenotype in a CRISPR mouse model of the human lymphedema-causing Connexin47 R260C point mutation.

Connexin proteins form gap junctions controlling exchange of ions and small molecules between cells and play an important role in movement of lymph within lymphatic vessels. Connexin47 (CX47) is highly expressed in lymphatic endothelial cells and CX47 missense mutations, i.e., R260C, cosegregate with primary lymphedema in humans. However, studies utilizing CX47 knockout mice have failed to demonstrate any lymphatic anomalies. To unravel the lymphatic consequences of expressing a mutant CX47 protein, we used CRISPR technology to create a mouse carrying a Cx47 missense mutation (Cx47R259C) equivalent to the human CX47R260C missense mutation associated with human primary lymphedema. Intradermal Evans Blue dye injection identified a 2-fold increase in regional lymph nodes in homozygous Cx47R259C mice compared to wildtype, particularly in the jugular region (4.8 ± 0.4 and 2.0 ± 0.0, respectively, p<0.01). Associated lymphatic channels were increased in Cx47R259C mice and mesenteric lymph reflux occurred in homozygous Cx47R259C mice but not in wildtype. Contractility of superficial cervical lymphatics, assessed by pressure myography, was reduced in homozygous Cx47R259C mice compared to wildtype. In conclusion, our data are the first to demonstrate a role for the Cx47 protein in lymphatic anatomy and function. This phenotype is similar to that found with other valve deficient mouse mutants, e.g., in Foxc2. Of significance, this study is the first to use CRISPR technology to develop a pre-clinical model of primary lymphedema and demonstrates the importance of distinguishing between lack of and presence of mutant protein when developing clinically relevant animal models for translation of pre-clinical findings.

Drive-noise tolerant optical switching inspired by composite pulses.

Electro-optic modulators within Mach-Zehnder interferometers are a common construction for optical switches in integrated photonics. A challenge faced when operating at high switching speeds is that noise from the electronic drive signals will effect switching performance. Inspired by the Mach-Zehnder lattice switching devices of Van Campenhout et al. [Opt. Express17(26), 23793 (2009).] and techniques from the field of Nuclear Magnetic Resonance known as composite pulses, we present switches which offer protection against drive-noise in both the on and off state of the switch for both the phase and intensity information encoded in the switched optical mode.

Optimizing Metabolic Pathways for the Improved Production of Natural Products.

Metabolic engineering strives to develop microbial strains that are capable of high-titer production of a variety of industrially significant pharmaceuticals, nutraceuticals, commodity, and high-value compounds. Despite extensive success with many proof-of-concept systems there is still the need for optimization to achieve industrially relevant titers, yields, and productivities. The field of metabolic pathway optimization and balancing has formed to address this need using a scientific and systematic approach. In this chapter, we aim to outline various pathway optimization and system balancing strategies while giving insights and tips into the systems and procedures that have demonstrated recent success in the peer-reviewed literature.

Insight into dopamine-dependent planning deficits in Parkinson's disease: A sharing of cognitive & sensory resources.

Cognitive and sensorimotor processes are both needed for successful planning of footsteps during complex gait situations, but the interaction between these factors during motor planning, as well as their response to dopaminergic treatment is poorly understood in Parkinson's disease (PD). In the current study, we evaluated walking and gaze behaviors of individuals with PD while planning an approach toward an obstacle to be stepped over. The obstacle clearance task was completed both ON and OFF dopaminergic medication by individuals with Parkinson's disease (n=20) and compared to healthy age-matched control participants (n=19), as well as with and without an auditory digit monitoring dual task. In this novel protocol of synchronized gaze and gait data collection, each trial was split into an early and late phase prior to the obstacle, providing a unique opportunity to examine dopamine-dependent planning deficits in PD. Interestingly, only patients in the OFF medication state showed greater deceleration in the late phase (i.e., just before the obstacle) (F(1,37)=45.42, p<0.001), as well as an increase in step time variability (also in this late phase) with the additional demands of a dual task (F(2,74)=3.49, p=0.035). Only gait deceleration between approaching phases improved with dopaminergic treatment (F(1,18)=59.20; p<0.001). Although groups showed different walking behaviors, gaze behaviors were the same for all participants, in that they planned for the obstacle more so in the early phase (p<0.05), and fixations were reduced across participants with the presence of the dual task (p<0.001). Surprisingly, the gaze behavior of the PD OFF group showed no interactions with phase or condition suggesting that the deceleration and increased variability when approaching an obstacle is the result of a greater demand for online sensory feedback that cannot be compensated for with visual strategies. We conclude that dopamine influences planning by limiting sensorimotor processing capacity, especially in the presence of increased cognitive demand in PD.

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

Sensorimotor learning in children and adults: Exposure to frequency-altered auditory feedback during speech production.

Auditory feedback plays an important role in the acquisition of fluent speech; however, this role may change once speech is acquired and individuals no longer experience persistent developmental changes to the brain and vocal tract. For this reason, we investigated whether the role of auditory feedback in sensorimotor learning differs across children and adult speakers. Participants produced vocalizations while they heard their vocal pitch predictably or unpredictably shifted downward one semitone. The participants' vocal pitches were measured at the beginning of each vocalization, before auditory feedback was available, to assess the extent to which the deviant auditory feedback modified subsequent speech motor commands. Sensorimotor learning was observed in both children and adults, with participants' initial vocal pitch increasing following trials where they were exposed to predictable, but not unpredictable, frequency-altered feedback. Participants' vocal pitch was also measured across each vocalization, to index the extent to which the deviant auditory feedback was used to modify ongoing vocalizations. While both children and adults were found to increase their vocal pitch following predictable and unpredictable changes to their auditory feedback, adults produced larger compensatory responses. The results of the current study demonstrate that both children and adults rapidly integrate information derived from their auditory feedback to modify subsequent speech motor commands. However, these results also demonstrate that children and adults differ in their ability to use auditory feedback to generate compensatory vocal responses during ongoing vocalization. Since vocal variability also differed across the children and adult groups, these results also suggest that compensatory vocal responses to frequency-altered feedback manipulations initiated at vocalization onset may be modulated by vocal variability.

Laparoscopic versus open surgery for complicated appendicitis: a randomized controlled trial to prove safety.

BACKGROUND: To date, no randomized control trial has been performed comparing open appendectomy (OA) to laparoscopic appendectomy (LA) in complicated appendicitis. A systematic review and meta-analysis in 2010 concluded LA is advantageous to OA with less surgical site sepsis in complicated appendicitis; however, the level of evidence is weak (level 3a). The aim of the study was to determine whether LA is safe in the treatment of complicated appendicitis. Primary outcome included all-cause mortality and procedure-related mortality; secondary outcomes included intra-operative duration, rates of wound sepsis and re-intervention, length of hospital stay and re-admission rates. METHODS: One hundred and fourteen patients were randomized prospectively to either OA or LA using a computer-generated blind method. Patients who were either less than 12 years of age, had previous abdominal surgery or were pregnant were excluded. A team of senior surgeons capable of doing both OA and LA performed all procedures. RESULTS: The intra-operative duration, the rate of wound sepsis, the number of re-operations, the length of hospital stay and the rate of re-admissions between the OA and LA groups did not differ statistically. CONCLUSION: Laparoscopic appendectomy is safe in complicated appendicitis. Current Control Trials (ISRCTN92257749).

Obinutuzumab for the treatment of chronic lymphocytic leukemia.

Obinutuzumab is a novel therapeutic anti-CD20 monoclonal antibody recently approved by the United States Food and Drug Administration (FDA) for use in combination with chlorambucil as first-line treatment of chronic lymphocytic leukemia (CLL). It is distinguished from other anti-B-lymphocyte antigen CD20 (anti-CD20) therapeutic antibodies in current clinical use by its type II properties and glycoengineered Fc region. In vitro these unique properties translate into higher rates of antibody-dependent cytotoxicity and direct cell death compared to rituximab, and obinutuzumab demonstrates improved efficacy in human lymphoma xenograft models and whole blood lymphocyte depletion assays. FDA approval was based upon results from a randomized phase III trial comparing treatment with single-agent chlorambucil to the combination of chlorambucil and either rituximab or obinutuzu-mab. The obinutuzumab arm resulted in higher rates of complete remission and significant improvements in progression-free survival versus either comparator regimen. The majority of patients in the obinutuzumab and chlorambucil arm finished all six planned treatment cycles, and therapy was well tolerated. Toxicities of obinutuzumab are similar to those of other anti-CD20 antibodies, although infusion-related reactions and neutropenia appear to be more common. This trial establishes chemoimmunotherapy with obinutuzumab and chlorambucil as an attractive treatment option for CLL patients, particularly those with comorbid medical illnesses or advanced age. Obinutuzumab remains under study in combination with both chemotherapy and novel agents for CLL and non-Hodgkin's lymphoma, where it is expected to find additional clinical applications.

The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody-drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro, depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

Removable dental prostheses and cardiovascular survival: a 15-year follow-up study.

OBJECTIVES: In previous studies, increasing number of teeth predicted better survival and the acute needs for dental treatment predicted mortality. We sought to investigate whether restored dentitions by various removable dental prostheses impact cardiovascular (CVD) longevity. METHODS: Kuopio Oral Health and Heart study was initiated as a cross-sectional investigation with 256 subjects with diagnosed coronary artery disease [CAD] and 250 age- and sex-matched controls without CAD in 1995-1996. The mean age of both groups was 61, 30% were females. We appended mortality follow-up records to the baseline data and formulated this 15-year follow-up study. We examined the relationship between various types of dental prostheses and cardiovascular mortality by proportional hazard regression analyses. We also explored their correlation to oral and systemic inflammatory markers such as asymptotic dental score and C-reactive protein. RESULTS: In a model adjusted for age, sex and smoking, groups having only natural teeth (NT), removable partial denture(s) [PD] and NT, a PD and a full denture [FD], and FD/FD or FD/NT demonstrated the following hazard ratios for mortality (95% confidence interval). NT both arches: 1.00 [reference]; PD and NT: 0.75 [0.22-2.56]; PD and FD: 1.99 [1.05-3.81]; and FD opposed by FD or NT: 1.71 [0.93-3.13], respectively [p for trend=0.05]. Although statistically not significant, those with PD and NT with mean a number of teeth [Nteeth] of 15.4 had better survival compared with those who had all NT [Nteeth=22.5]; while those who had FD and PD [Nteeth=6.5] had shorter longevity than those with FD/FD or FD/NT [Nteeth=3.5]. CONCLUSIONS: Although not all subgroups of dental prostheses reached significant relationship with CVD mortality, our study suggests that not only the number [quantity] of remaining teeth but their maintenance [quality] removing potential inflammatory foci, such as pericoronitis or retained root tips, may positively impact on cardiovascular survival.

Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma.

Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin's and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(-) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5-55 months), 7 patients relapsed (4 in the PET/CT(-) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30-0.85) vs 87% (95% CI: 0.57-0.97) in PET/CT(+) and PET/CT(-) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23-0.84) vs 100% in PET/CT(-) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.

ERP correlates of the magnitude of pitch errors detected in the human voice.

Auditory event-related potentials (ERP)s of the P1-N1-P2 complex are modulated when participants hear frequency-altered feedback (FAF) regarding their ongoing vocal productions. However, the relationship between feedback perturbation magnitudes and the resultant neural responses is at present unclear. In the present study, we exposed speakers to FAF of different magnitudes ranging from 0 to 400 cents. Vocal responses and P1-N1-P2-N2 ERPs were examined in an attempt to relate variation in the magnitude of the imposed feedback perturbation with variation in vocal and neural responses. Overall, vocal response magnitudes remained relatively consistent in response to smaller feedback perturbations (<250 cents), while larger feedback perturbations (>300 cents) resulted in decreased vocal response magnitudes. P1 amplitudes were found to increase in a non-specific manner in response to FAF. Conversely, N1 amplitudes displayed increased specificity: small feedback perturbations evoked one size of response, while larger feedback perturbations resulted in larger responses. The P2 component showed the most systematic amplitude modulation as feedback perturbation magnitude increased. A regression analysis highlighted the relationship between vocal response magnitude and P2 amplitude, with both vocal response magnitude and P2 amplitude increasing in response to perturbations between 50 and 250 cents, and then decreasing in response to larger perturbations. Although not generally observed in FAF studies, a robust N2 was also found; N2 amplitudes increased as stimulus magnitudes increased. The pattern of P1-N1-P2-N2 amplitude modulation in response to different magnitudes of FAF indicates that these components reflect processes involved in the detection and correction of unintended changes in auditory feedback during speech.

The absence of detectable fetal microchimerism in nontransgenic goats (Capra aegagrus hircus) bearing transgenic offspring.

Regulations for the disposal of genetically engineered animals are strict due to concern for their inappropriate introduction into the food chain, and of the possible public health and environmental impacts of these organisms. Nontransgenic animals that give birth to transgenic offspring are treated as if they are transgenic due to concern of fetal cells crossing the placental barrier and residing in the mother (fetal-maternal microchimerism). Determining whether or not fetal-fetal or fetal-maternal transfer of DNA or cells occurs during caprine gestation is critical to effectively protect the public without culling animals that pose no risk. Additionally, fetal-maternal transfer, should it exist in the goat, could contraindicate the rebreeding of nontransgenic dams due to the possible transfer of fetal cells from 1 pregnancy to the fetus of subsequent pregnancies. Fetal-maternal transfer in Capra hircus has not been reported in the literature, although it has been reported in another ruminant, Bos taurus. We examined blood from nontransgenic dams that carried transgenic offspring using a PCR method sensitive enough to detect the presence of a spider silk transgene to a 1:100,000 dilution. At this sensitivity, we did not detect the occurrence of fetal-maternal transfer in 5 nontransgenic dams. Likewise, fetal-fetal transfer was not observed from a transgenic to a nontransgenic twin in utero. To test tissue-specific expression of the silk transgene, proteins purified from standard necropsy tissue from a lactating transgenic dam were examined by Western blot analysis. Silk protein expression was only observed in mammary tissue consistent with the tissue specificity of the ß-casein promoter used in the transgenic construct. We report evidence collected from a limited caprine breeding pool against transfer of transgenes in utero from fetus to dam and fetus to fetus. In addition, we show evidence that the ß-casein promoter in our expression construct is not expressed ectopically as previously suggested. These results suggest that transgene transfer in utero does not occur, but further study is warranted with a larger sample group to confirm these results.

The disposition and metabolism of zibotentan (ZD4054): an oral-specific endothelin A receptor antagonist in mice, rats and dogs.

Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h. The main route of elimination was via the urine in dogs and female rats, but via the faeces in male rats and mice of both sexes. Zibotentan was moderately bound to plasma proteins of all species examined (55-95%), and widely distributed throughout all tissues with the highest concentrations seen in the organs of excretion. Zibotentan was moderately metabolised. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine.