Preliminary Analysis of Simple Novelty Search.

Novelty search is a powerful tool for finding diverse sets of objects in complicated spaces. Recent experiments on simplified versions of novelty search introduce the idea that novelty search happens at the level of the archive space, rather than individual points. The sparseness measure and archive update criterion create a process that is driven by a two measures: 1) spread out to cover the space while trying to remain as efficiently packed as possible, and 2) metrics inspired by k Nearest Neighbor theory. In this paper, we generalize previous simplifications of novelty search to include traditional population (µ,λ) dynamics for generating new search points, where the population and the archive are updated separately. We provide some theoretical guidance regarding balancing mutation and sparseness criteria and introduce the concept of saturation as a way of talking about fully covered spaces. We show empirically that claims that novelty search is inherently objectiveless are incorrect. We leverage the understanding of novelty search as an optimizer of archive coverage suggest several ways to improve the search, and we demonstrate one simple improvement-generate some new points directly from the archive rather than the parent population.

Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya.

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in 13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups. These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373).

2013 multistate outbreaks of Cyclospora cayetanensis infections associated with fresh produce: focus on the Texas investigations.

The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0-∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.

Impact of lymphocyte and monocyte recovery on the outcomes of allogeneic hematopoietic SCT with fludarabine and melphalan conditioning.

We have recently shown that lymphocyte and monocyte recovery by day +100 are associated with survival post myeloablative allogeneic hematopoietic transplant for acute leukemia. We hypothesized that lymphocyte and monocyte recovery would have a similar impact on survival in the reduced intensity setting. To test this hypothesis, we analyzed clinical data from 118 consecutive fludarabine/melphalan-conditioned patients by correlating peripheral blood absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) at days +15, +30, +60 and +100 with the outcomes. Multivariate analysis revealed that day +100 AMC (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.07-0.73, P=0.01) and mild chronic GVHD (RR 0.09, 95% CI 0.005-0.43, P=0.008) were independently associated with survival. To explore whether the patterns of lymphocyte and monocyte recovery had a prognostic value, we performed unsupervised hierarchical clustering on the studied hematopoietic parameters and identified three patient clusters, A-C. Patient clusters A and B both had improved OS compared with cluster C (77.8 months vs not reached vs 22.3 months, respectively, P<0.001). No patient in cluster C had a day +100 AMC >300. Both severe acute GVHD and relapse occurred more frequently in cluster C. Our data suggest that patients with low AMC by day +100 post fludarabine/melphalan-conditioned allogeneic hematopoietic SCT may be at risk for poor outcomes.

SNP genotyping defines complex gene-flow boundaries among African malaria vector mosquitoes.

Mosquitoes in the Anopheles gambiae complex show rapid ecological and behavioral diversification, traits that promote malaria transmission and complicate vector control efforts. A high-density, genome-wide mosquito SNP-genotyping array allowed mapping of genomic differentiation between populations and species that exhibit varying levels of reproductive isolation. Regions near centromeres or within polymorphic inversions exhibited the greatest genetic divergence, but divergence was also observed elsewhere in the genomes. Signals of natural selection within populations were overrepresented among genomic regions that are differentiated between populations, implying that differentiation is often driven by population-specific selective events. Complex genomic differentiation among speciating vector mosquito populations implies that tools for genome-wide monitoring of population structure will prove useful for the advancement of malaria eradication.

Discovery of potent and selective histamine H3 receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold.

A novel series of potent histamine H(3) receptor inverse agonists based on the 3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one scaffold has been discovered. Several compounds display high selectivity over other histamine receptor subtypes and have favorable physicochemical properties, low potential for CYP450 enzyme inhibition and high metabolic stability in microsomal preparations. (R)-2-Cyclopropylmethyl-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (8t) showed good in vivo efficacy after per os application in an acute rat dipsogenia model of water intake.

Evolution of sensory complexity recorded in a myxobacterial genome.

Myxobacteria are single-celled, but social, eubacterial predators. Upon starvation they build multicellular fruiting bodies using a developmental program that progressively changes the pattern of cell movement and the repertoire of genes expressed. Development terminates with spore differentiation and is coordinated by both diffusible and cell-bound signals. The growth and development of Myxococcus xanthus is regulated by the integration of multiple signals from outside the cells with physiological signals from within. A collection of M. xanthus cells behaves, in many respects, like a multicellular organism. For these reasons M. xanthus offers unparalleled access to a regulatory network that controls development and that organizes cell movement on surfaces. The genome of M. xanthus is large (9.14 Mb), considerably larger than the other sequenced delta-proteobacteria. We suggest that gene duplication and divergence were major contributors to genomic expansion from its progenitor. More than 1,500 duplications specific to the myxobacterial lineage were identified, representing >15% of the total genes. Genes were not duplicated at random; rather, genes for cell-cell signaling, small molecule sensing, and integrative transcription control were amplified selectively. Families of genes encoding the production of secondary metabolites are overrepresented in the genome but may have been received by horizontal gene transfer and are likely to be important for predation.

The cooperative coevolutionary (1+1) EA.

Coevolutionary algorithms are variants of traditional evolutionary algorithms and are often considered more suitable for certain kinds of complex tasks than noncoevolutionary methods. One example is a general cooperative coevolutionary framework for function optimization. This paper presents a thorough and rigorous introductory analysis of the optimization potential of cooperative coevolution. Using the cooperative coevolutionary framework as a starting point, the CC (1+1) EA is defined and investigated from the perspective of the expected optimization time. The research concentrates on separability, a key property of objective functions. We show that separability alone is not sufficient to yield any advantage of the CC (1+1) EA over its traditional, non-coevolutionary counterpart. Such an advantage is demonstrated to have its basis in the increased explorative possibilities of the cooperative coevolutionary algorithm. For inseparable functions, the cooperative coevolutionary set-up can be harmful. We prove that for some objective functions the CC (1+1) EA fails to locate a global optimum with overwhelming probability, even in infinite time; however, inseparability alone is not sufficient for an objective function to cause difficulties. It is demonstrated that the CC (1+1) EA may perform equal to its traditional counterpart, and may even outperform it on certain inseparable functions.

Advanced glycation end-products pentosidine and N epsilon-carboxymethyllysine are elevated in serum of patients with osteoporosis.

OBJECTIVE: To investigate serum levels of the advanced glycation end-products (AGEs) pentosidine and N epsilon-carboxymethyllysine (CML) in patients classified into different osteoporosis subgroups according to histomorphometric data. METHOD: Serum samples were obtained from 116 osteoporotic patients (34 men, 82 women) classified by bone histomorphometry into subgroups with high turnover (HTO, n = 32), low turnover (LTO, n = 39), normal turnover (NTO, n = 9) and cellular uncoupled osteoporosis (CUO, n = 36). Pentosidine was measured by high-performance liquid chromatography, and CML by a competitive enzyme-linked immunoassay. RESULTS: The entire osteoporosis group had significantly higher pentosidine and CML serum concentrations than healthy subjects. In contrast to healthy subjects, no correlation between levels of AGEs and age could be found. In subgroups characterized by increased bone resorption (HTO, CUO), serum pentosidine correlated significantly with the histomorphometric marker reflecting osteoclast activity/bone resorption (eroded surface as a percentage of trabecular surface). Moreover, in CUO a strong correlation between pentosidine and the mineral apposition rate was found. Surprisingly, in HTO the levels of CML and percentage of eroded surface were significantly negatively correlated. CONCLUSION: AGE-modified proteins may be a cause of disturbed bone remodelling in osteoporosis. Our findings do not support the alternative hypothesis that increased AGEs in serum indicate only a more intensive releasing of AGEs in circumstances of increased bone resorption.

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design.

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d x 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d x 5. The recommended Phase II dose i s 4.3mg/m2/d x 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8-8.4 mg/m2/d x 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation.

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.

A novel linear amphipathic beta-sheet cationic antimicrobial peptide with enhanced selectivity for bacterial lipids.

All known naturally occurring linear cationic peptides adopt an amphipathic alpha-helical conformation upon binding to lipids as an initial step in the induction of cell leakage. We designed an 18-residue peptide, (KIGAKI)3-NH2, that has no amphipathic character as an alpha-helix but can form a highly amphipathic beta-sheet. When bound to lipids, (KIGAKI)3-NH2 did indeed form a beta-sheet structure as evidenced by Fourier transform infrared and circular dichroism spectroscopy. The antimicrobial activity of this peptide was compared with that of (KIAGKIA)3-NH2, and it was better than that of GMASKAGAIAGKIAKVALKAL-NH2 (PGLa) and (KLAGLAK)3-NH2, all of which form amphipathic alpha-helices when bound to membranes. (KIGAKI)3-NH2 was much less effective at inducing leakage in lipid vesicles composed of mixtures of the acidic lipid, phosphatidylglycerol, and the neutral lipid, phosphatidylcholine, as compared with the other peptides. However, when phosphatidylethanolamine replaced phosphatidylcholine, the lytic potency of PGLa and the alpha-helical model peptides was reduced, whereas that of (KIGAKI)3-NH2 was improved. Fluorescence experiments using analogs containing a single tryptophan residue showed significant differences between (KIGAKI)3-NH2 and the alpha-helical peptides in their interactions with lipid vesicles. Because the data suggest enhanced selectivity between bacterial and mammalian lipids, linear amphipathic beta-sheet peptides such as (KIGAKI)3-NH2 warrant further investigation as potential antimicrobial agents.

Electroencephalography correlates in tinnitus.

This study was conducted in an attempt to determine whether the quantitative electroencephalograph activity differs between normal control subjects and subjects suffering from tinnitus. Results indicated that male tinnitus patients as a group had a significantly reduced average total power as compared to control subjects. This finding contrasted with female tinnitus patients, who as a group had a higher average total power as compared to normal female control subjects. Topographical maps (control value-tinnitus value) indicate that with male patients, the frontocentral regions of the brain show the greatest difference. For the female tinnitus patients, the brain regions most affected are the central, parietal, temporal, and occipital regions.

Cryptophycin 1 cellular levels and effects in vitro using L1210 cells.

Cryptophycin 1 is a natural product that was initially isolated from blue-green algae which has shown potent broad spectrum antitumor activity in preclinical in vitro and in vivo models. The drug strongly binds to tubulin and disrupts microtubule assembly for more than 24 hours after its removal. We evaluated cell survival, intracellular levels and inhibition of macromolecular synthesis in L1210 cells following exposure to cryptophycin 1 in vitro. Cell survival was strongly inhibited following drug exposure for either 1 or 4 hours. Intracellular drug levels were minimally affected by temperature (4 degrees C versus 37 degrees C) or exposure times up to 1 hour. However, extracellular drug concentration in culture media and increasing cell numbers did affect the concentration of intracellular drug levels in a nearly proportional manner. The synthesis of DNA and RNA was inhibited less than 5%, while protein synthesis inhibition was near 30%. Thus, none of the macromolecules were inhibited enough to explain the inhibition of tumor cell growth.

Preclinical pharmacokinetic, antitumor and toxicity studies with CI-994 (correction of CL-994) (N-acetyldinaline).

CI-994, a substituted benzamide derivative, is a compound that showed solid tumor selectivity for a variety of solid tumor models compared to L1210 leukemia. Due to its lack of aqueous solubility, it requires oral administration. Female B6D2F1 mice were treated with CI-994 once daily by oral administration of 50 mg/kg for 14 days. Following treatment mice were evaluated for pharmacodynamic effects as well as the pharmacokinetic behavior of CI-994 and the de-acetylated derivative dinaline. Mice samples (plasma, urine, feces) were analyzed using solid phase extraction, reverse phase HPLC and ultraviolet detection. The plasma distribution and elimination half-lives for CI-994 were 51 minutes and 9.4 hours, respectively, on D-1; 31 minutes and 3.4 hours, respectively on D-14. The apparent plasma distribution and elimination half-lives for dinaline were 27 minutes and 2.4 hours, respectively, on D-1; 40 minutes and 7.3 hours, respectively on D-14. The CI-994 AUC on D-1 and D-14 were 2879 and 2407 micrograms/ml x minutes, respectively; while the dinaline AUC on D-1 and D-14 were 87 and 92 micrograms/ml x minutes, respectively. Urinary excretion for CI-994 and dinaline was higher on D-14, while the fecal excretion was the same on both days. The Colon #38 tumor growth in treated mice was reduced to 22% of that observed in the controls by D-19. The levels of all blood cells were reduced in the treated mice when compared to controls and the total WBC was the most affected (median 38%). Recovery to pretreatment levels occurred quickly following treatment cessation. Phase I evaluation of chronic oral administration of CI-994 is currently ongoing.

Pharmacokinetic studies in mice of two new thioxanthenones (183577 and 232759) that showed preferential solid tumor activity.

Two new thioxanthenones, 183577 and 232759, have rekindled interest in the development of representatives from this class of structures as useful anticancer agents. Although the mechanism of action is unknown, both compounds demonstrated a similar spectrum of solid tumor selectivity. 232759 was selected for clinical development because it showed no hepatotoxicity in preliminary studies, whereas 183577 showed hepatotoxicity but only at the maximum tolerated dose (MTD). The limiting toxicity for the clinical candidate was myelosuppression in preliminary studies. Plasma and tissue drug levels, as well as protein binding, were studied in mice using optimal administration times at the MTD for each drug (for 183577, this was a 4-h infusion at 1350 mg/m2 and for 232759, it was a 5-min injection at 240 mg/m2), as well as at one-half the MTD for the clinical candidate. The drugs were 96-100% bound by plasma proteins. The peak drug concentrations, half-life, and area under the concentration-time curve in plasma for 183577 were 3483 ng/ml, 465 min, and 2018 microgram/ml. min, respectively. The peak drug concentration, half-life, and area under the concentration-time curve in plasma for 232759 were 5257 ng/ml, 44 min, and 276 microgram/ml. min, respectively, at the MTD and 2810 ng/ml, 40 min, and 110 microgram/ml. min at one-half the MTD. In all instances of simultaneous measurements, drug concentrations were equal or higher in tissues than they were in plasma. Unlike the plasma and kidney concentrations of 183577, the liver concentrations did not show a declining trend over the 8-h observation period. Declines in plasma, liver, kidney, and tumor levels of 232759 were detected over the 8-h observation period. The sustained high 183577 concentration in liver is believed to be responsible for its prolonged half-life and hepatotoxicity. Evidence for metabolism of the parent drugs was based on the finding of additional peaks on the high-pressure liquid chromatography tracings. Future studies will focus on identification and antitumor studies of these presumed metabolites in hopes of a better understanding of the solid tumor activity profiles and toxic effects of these compounds.

Three-dimensional structure of human cytomegalovirus protease.

Herpesviruses encode a serine protease that specifically cleaves assembly protein. This protease is critical for replication, and represents a new target for antiviral drug design. Here we report the three-dimensional structure of the protease from human cytomegalovirus (hCMV) at 2.27 angstroms resolution. The structure reveals a unique fold and new catalytic strategy for cleavage. The monomer fold of the enzyme, a seven-stranded beta-barrel encircled by a chain of helices that form the carboxy terminus of the molecule, is unrelated to those observed in classic serine proteases such as chymotrypsin and subtilisin. The serine nucleophile at position 132 is activated by two juxtaposed histidine residues at positions 63 and 157. Dimerization, which seems to be necessary for activity, is observed in the crystals. Correlations of the structure with the sequences of herpesvirus proteases suggest that dimerization may confer specificity and recognition in substrate binding.

Preclinical anticancer activity of cryptophycin-8.

Cryptophycin-8 was prepared by the conversion of the epoxide group on cryptophycin-1 to a chlorohydrin. In the studies reported here, cryptophycin-8 was evaluated for preclinical activity against subcutaneous tumors of both mouse and human origin. At the highest non-toxic single course treatment, the following results were obtained (Table A). Cryptophycin-8 was less potent than cryptophycin-1 by approximately 4-fold; however, it was both more water soluble and had greater therapeutic efficacy, as demonstrated by % T/C, tumor cell log kill values, range of dose effectiveness and host cures.

Identification and antitumor activity of a reduction product in the murine metabolism of pyrazoloacridine (NSC-366140).

PURPOSE: Pyrazoloacridine (PZA) is a newly developed anticancer agent currently undergoing clinical trials. Its mode of action has not been elucidated but the presence in its chemical structure of a 5-nitro functional group and its activity against oxygen-deficient cancerous cells argue in favor of enzymatic nitro reduction as a possible pathway for its antitumor activity. In order to assess the involvement of the nitro functionality in PZA activity, as well as to determine other metabolic products, a pharmacological and chemical study of PZA was designed. METHODS: Urine and stool samples were collected from mice before and after treatment with PZA. Samples were fractionated using chromatographic methods and then evaluated using mass spectrometry (MS). One of the characterized metabolites was synthesized and tested in vitro and in vivo for anticancer activity. RESULTS: One major fraction from mouse stool was initially characterized by MS as the 5-aminopyrazoloacridine (5-APZ). This compound was chemically synthesized by catalytic hydrogenation of PZA was stabilized as the hydrochloride salt. 5-APZ was marginally cytotoxic in vitro and was inactive in vivo against a tumor cured by PZA (Panc 03). CONCLUSIONS: Bioreduction of the nitro group to an amine compound from PZA represents a pathway in the metabolic sequence of PZA. The inactivity of the chemically generated amine product does not provide conclusive evidence that this pathway is not involved in the cytotoxicity of PZA because other intermediates in the nitro reduction pathway may have a role in the activity of PZA. In particular, the hydroxylamine derivative of PZA could give answers to the involvement of this pathway in PZA cytotoxicity.

Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4, 5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials1.

Pharmacokinetic studies that consisted of measuring the plasma drug profile, tissue drug distribution, and elimination in urine and feces were performed in female C57BL/6 x DBA/2 (hereafter called B6D2F1) and male B6D2F1A/2 and C57BL/6 x CH3 (hereafter called B6C3F1) mice following treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140). This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its in vivo toxicity profile that was predictable based on drug dose and schedule of administration. The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targets for its acute and sub-acute toxic effects. Plasma samples from three to four mice per time point were pooled, and then individual tissue samples from the same mice were collected at specified times following treatment. All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography. The acute dose-limiting toxicity was neurological and occurred immediately after treatment at 300 mg/m2. The peak plasma level range at the acute maximum tolerated dose was 1040-1283 ng/ml. Thus, peak plasma levels <1000 ng/ml were the acute toxicity target. Variations in the area under the plasma drug concentration x the time curve were observed that did not appear to be related to sex or age. The previously defined subacute dose-limiting toxicity was myelosuppression that occurred at a maximum tolerated dose of 600 mg/m2 (300 mg/m2 x 2) in B6D2F1 females. Thus, the area under the plasma drug concentration x the time curve in B6D2F1 females at this dose (1048 microg/ml x min) was the area under the plasma drug concentration x the time curve target. Drug levels were detected at 60 min following treatment in all tissues examined with a plasma:tissue ratio as high as 1:500. The organs with the highest levels were kidney, pancreas, liver, lung, and brain. Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly different between males and females. Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related differences, with male urinary drug excretion being higher than female urinary drug excretion. The drug was >/=95% protein bound. Preliminary evidence for drug metabolism was found in urine and feces and will be further explored.