Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment.     

Assessment of possible ecological risks and hazards of transgenic fish with implications for other sexually reproducing organisms

Transgenic technology is developing rapidly; however, consumers and environmentalists remain wary of its safety for use in agriculture. Research is needed to ensure the safe use of transgenic technology and thus increase consumer confidence. This goal is best accomplished by using a thorough, unbiased examination of risks associated with agricultural biotechnology. In this paper, we review discussion on risk and extend our approach to predict risk. We also distinguish between the risk and hazard of transgenic organisms in natural environments. We define transgene risk as the probability a transgene will spread into natural conspecific populations and define hazard as the probability of species extinction, displacement, or ecosystem disruption given that the transgene has spread. Our methods primarily address risk relative to two types of hazards: extinction which has a high hazard, and invasion which has an unknown level of hazard, similar to that of an introduced exotic species. Our method of risk assessment is unique in that we concentrate on the six major fitness components of an organism's life cycle to determine if transgenic individuals differ in survival or reproductive capacity from wild type. Our approach then combines estimates of the net fitness parameters into a mathematical model to determine the fate of the transgene and the affected wild population. We also review aspects of fish ecology and behavior that contribute to risk and examine combinations of net fitness parameters which can lead to invasion and extinction hazards. We describe three new ways that a transgene could result in an extinction hazard: (1) when the transgene increases male mating success but reduces daily adult viability, (2) when the transgene increases adult viability but reduces male fertility, and (3) when the transgene increases both male mating success and adult viability but reduces male fertility. The last scenario is predicted to cause rapid extinction, thus it poses an extreme risk. Although we limit our discussion to aquacultural applications, our methods can easily be adapted to other sexually reproducing organisms with suitable adjustments of terminology.     

Medicating the environment: assessing risks of pharmaceuticals to wildlife and ecosystems

Global pharmaceutical consumption is rising with the growing and ageing human population and more intensive food production. Recent studies have revealed pharmaceutical residues in a wide range of ecosystems and organisms. Environmental concentrations are often low, but pharmaceuticals typically are designed to have biological effects at low doses, acting on physiological systems that can be evolutionarily conserved across taxa. This Theme Issue introduces the latest research investigating the risks of environmentally relevant concentrations of pharmaceuticals to vertebrate wildlife. We take a holistic, global view of environmental exposure to pharmaceuticals encompassing terrestrial, freshwater and marine ecosystems in high- and low-income countries. Based on both field and laboratory data, the evidence for and relevance of changes to physiology and behaviour, in addition to mortality and reproductive effects, are examined in terms of the population- and community-level consequences of pharmaceutical exposure on wildlife. Studies on uptake, trophic transfer and indirect effects of pharmaceuticals acting via food webs are presented. Given the logistical and ethical complexities of research in this area, several papers focus on techniques for prioritizing which compounds are most likely to harm wildlife and how modelling approaches can make predictions about the bioavailability, metabolism and toxicity of pharmaceuticals in non-target species. This Theme Issue aims to help clarify the uncertainties, highlight opportunities and inform ongoing scientific and policy debates on the impacts of pharmaceuticals in the environment.     

Using molecular and ecological data to diagnose endangered populations of the puritan tiger beetle Cicindela puritana

Populations of the puritan tiger beetle Cicindela puritana in the eastern United States were found to be highly threatened at the Connecticut River, whereas several large populations on the western shore and newly discovered populations on the eastern shore of the Chesapeake Bay appeared to be less endangered. We assessed if the disjunct C. puritana subgroups are genetically distinct and therefore should be treated as separate units for conservation purposes. A total of 13 individuals from the Connecticut River and 27 individuals from the Chesapeake Bay were each analysed by sequencing of up to 837 base pairs of mitochondrial DNA per individual. Five different haplotypes could be distinguished. In a phylogenetic analysis of these DNA sequences that included four related Cicindela species as out-groups, haplotypes from the Chesapeake Bay represent a distinct clade. The conservation status of these populations was evaluated using a phylogenetic approach based on cladistic analysis and the framework of the phylogenetic species concept. According to this analysis, beetles from the Connecticut River and the Chesapeake Bay have to be considered as independent units. Populations from the eastern and western shore of Chesapeake Bay are not split in more than one unit using the same criteria, although they exhibited some degree of genetic subdivision. The results from the mtDNA analysis were corroborated by ecological parameters in that the Chesapeake Bay populations can be distinguished from all congeners by their different tat association.     

Downscaling patterns of complementarity to a finer resolution and its implications for conservation prioritization

Given species inventories of all sites in a planning area, integer programming or heuristic algorithms can prioritize sites in terms of the site's complementary value, that is, the ability of the site to complement (add unrepresented species to) other sites prioritized for conservation. The utility of these procedures is limited because distributions of species are typically available only as coarse atlases or range maps, whereas conservation planners need to prioritize relatively small sites. If such coarse‐resolution information can be used to identify small sites that efficiently represent species (i.e., downscaled), then such data can be useful for conservation planning. We develop and test a new type of surrogate for biodiversity, which we call downscaled complementarity. In this approach, complementarity values from large cells are downscaled to small cells, using statistical methods or simple map overlays. We illustrate our approach for birds in Spain by building models at coarse scale (50 × 50 km atlas of European birds, and global range maps of birds interpreted at the same 50 × 50 km grid size), using this model to predict complementary value for 10 × 10 km cells in Spain, and testing how well‐prioritized cells represented bird distributions in an independent bird atlas of those 10 × 10 km cells. Downscaled complementarity was about 63–77% as effective as having full knowledge of the 10‐km atlas data in its ability to improve on random selection of sites. Downscaled complementarity has relatively low data acquisition cost and meets representation goals well compared with other surrogates currently in use. Our study justifies additional tests to determine whether downscaled complementarity is an effective surrogate for other regions and taxa, and at spatial resolution finer than 10 × 10 km cells. Until such tests have been completed, we caution against assuming that any surrogate can reliably prioritize sites for species representation.     

A dominance‐based approach to map risks of ecological invasions in the presence of severe uncertainty

Aim Uncertainty has been widely recognized as one of the most critical issues in predicting the expansion of ecological invasions. The uncertainty associated with the introduction and spread of invasive organisms influences how pest management decision makers respond to expanding incursions. We present a model‐based approach to map risk of ecological invasions that combines two potentially conflicting goals: (1) estimating the likelihood of a new organism being established at a given locale and (2) quantifying the uncertainty of that prediction. Location Eastern and central Canada. Methods Our methodology focuses on the potential for long‐distance, human‐assisted spread of invasive organisms. First, we used a spatial simulation model to generate distributions of plausible invasion outcomes over a target geographical region. We then used second‐degree stochastic dominance (SSD) criteria to rank all geographical locations in the target region based on these distributions. We applied the approach to analyze pathways of human‐assisted spread (i.e., with commercially transported goods) of the emerald ash borer (EAB) (Agrilus planipennis Fairmaire), a major pest of ash trees in North America. Results The projected potential of the pest to establish at remote locations is significantly shaped by the amount of epistemic uncertainty in the model‐based forecasts. The estimates based on the SSD ranking identified major ‘crossroads’ through which the movement of the EAB with commercial transport is most likely to occur. The system of major expressways in Ontario and Quebec was confirmed as the primary gateway of the pest’s expansion throughout the Canadian landscape. Main conclusions Overall, the new approach generates more realistic predictions of long‐distance introductions than models that do not account for severe uncertainties and thus can help design more effective pest surveillance programmes. The modelling technique is generic and can be applied to assess other environmental phenomena when the level of epistemic uncertainty is high.     

Combining genetic and ecological data to assess the conservation status of the endangered Ethiopian walia ibex

Knowledge about the phylogenetic history, genetic variation and ecological requirements of a species is important for its conservation and management. Unfortunately, for many species this information is lacking. Here we use multiple approaches (phylogenetics, population genetics and ecological modelling) to evaluate the evolutionary history and conservation status of Capra walie , an endangered flagship species of wild goat endemic to Ethiopia. The analysis of mitochondrial cytochrome b and Y-chromosome DNA sequences suggests that C. walie forms a monophyletic clade with Capra nubiana , but potentially has been isolated for up to 0.8 million years from this closely related species. Microsatellite DNA analyses show that C. walie has very low genetic variation (mean heterozygosity=0.35) compared with other endangered mammals. This reduced variation likely derives from a prolonged demographic decline and small effective population size. Ecological niche modelling using the bioclimatic features of habitats occupied by C. walie , suggests ecological differences between C. walie and C. nubiana , and identifies the areas most suitable for future reintroductions of C. walie . The genetic and bioclimatic data suggest that C. walie is distinct and requires immediate conservation actions including genetic monitoring and reintroductions to establish independent populations. This study illustrates how combining noninvasive sampling along with genetic and ecological (bioclimatic) approaches can help assess conservation status of poorly known species.     

Guiding the prioritization of the most endangered and evolutionary distinct birds for new zoo conservation programs

Zoos have played a pivotal role in the successful reinforcement and reintroduction of species threatened with extinction, but prioritization is required in the face of increasing need and limited capacity. One means of prioritizing between species of equal threat status when establishing new breeding programs is the consideration of evolutionary distinctness (ED). More distinct species have fewer close relatives such that their extinction would result in a greater overall loss to the Tree of Life. Considering global ex situ holdings of birds (a group with a complete and well‐detailed evolutionary tree), we investigate the representation of at‐risk and highly evolutionarily distinct species in global zoo holdings. We identified a total of 2,236 bird species indicated by the Zoological Information Management System as being held in zoological institutions worldwide. As previously reported, imperiled species (defined as those possessing endangered or critically endangered threat status) in this database are less likely to be held in zoos than non‐imperiled species. However, we find that species possessing ED scores within the top 10% of all bird species are more likely to be held in zoos than other species, possibly because they possess unique characteristics that have historically made them popular exhibits. To assist with the selection of high priority ED species for future zoo conservation programs, we provide a list of imperiled species currently not held in zoos, ranked by ED. This list highlights species representing particular priorities for ex situ conservation planners, and represents a practical tool for improving the conservation value of zoological collections.     

Determining threatened species distributions in the face of limited data: Spatial conservation prioritization for the Chinese giant salamander (Andrias davidianus)

The purpose of this study was to determine whether limited occurrence data for highly threatened species can provide useful spatial information to inform conservation. The study was conducted across central and southern China. We developed a habitat suitability model for the Critically Endangered Chinese giant salamander (Andrias davidianus) based on one biotic and three abiotic parameters from single‐site locality records, which represent the only relevant environmental data available for this species. We then validated model quality by testing whether increased percentage of predicted suitable habitat at the county level correlated with independent data on giant salamander presence. We randomly selected 48 counties containing historical records which were distinct from, and independent of, the single‐site records used to develop the model, and 47 additional counties containing >50% predicted suitable habitat. We interviewed 2,812 respondents near potential giant salamander habitat across these counties and tested for differences in respondent giant salamander reports between counties selected using each method. Our model predicts that suitable giant salamander habitat is found widely across central and southern China, with counties containing ≥50% predicted suitable habitat distributed in 13 provinces. Counties with historical records contain significantly more predicted suitable habitat than counties without historical records. There are no statistical differences in any patterns of respondent giant salamander reports in surveyed counties selected from our model compared with the areas of known historical giant salamander distribution. A Chinese giant salamander habitat suitability model with strong predictive power can be derived from the restricted range of environmental variables associated with limited available presence‐only occurrence records, constituting a cost‐effective strategy to guide spatial allocation of conservation planning. Few reported sightings were recent, however, with most being over 20 years old, so that identification of areas of suitable habitat does not necessarily indicate continued survival of the species at these locations.     

RANKVET: A new ranking method for comparing and prioritizing the environmental risk of veterinary pharmaceuticals

In recent years veterinary medicinal products (VMPs) have been recognized as emerging contaminants, giving rise to concerns regarding their environmental impact. Due to the high number of utilized VMPs, it is necessary to develop tools (indicators) for ranking these compounds according to their environmental risk relevance. These indicators can be useful, for example, for setting up monitoring programmes, and more in general for risk management purposes. In this paper we propose a new scoring system method (RANKVET) that enables ranking the risk of VMPs for aquatic and terrestrial organisms. The procedure is fully based on the information required by the EU Directives and Regulations for marketing authorization of VMPs and Veterinary International Conference on Harmonization (VICH) guidelines. According to the latter, if the environmental risk assessment of a VMP indicates an unacceptable risk to the environment, i.e., the risk quotient (RQ) consisting of the ratio of Predicted Environmental Concentration (PEC) to Predicted No Effect Concentration (PNEC) is ≥1, then mitigation measures should be proposed by the applicant in order to reduce the risk to an acceptable level. If a risk mitigation measure does not fulfil the criteria mentioned above then the outcome of the risk assessment is that a serious risk for the environment exists. In accordance with Directive 2001/82/EC (as amended) this risk has to be weighed against the favourable aspects of a marketing authorization. The prioritization scheme is based on a quantitative approach and consist of different phases. First, for each VMP, PECs are calculated using simple exposure models and worst case assumptions. PNECs are calculated for non-target organisms representative of the considered ecosystems (soil or surface water). Then numerical scores are given to the calculated PEC/PNEC ratio. Finally, the obtained score is multiplied with a further score which is based on the relevance of the metabolic rate in animals. RANKVET can be applied for surface water and soil systems and for different farming methods (intensive or pasture) and treated species. As an example of its potential use we applied RANKVET to 48 VMPs largely utilized in Italy.     

Invasive alien plants and South African rivers: a proposed approach to the prioritization of control operations

1. A number of parallel initiatives in South Africa have been addressing the prioritization and management of invasive alien plant species, the prioritization of rivers for the conservation of biodiversity, and broad‐scale planning for water resource management. This paper has combined aspects of these approaches to develop a composite index of prioritization of quaternary catchments for alien plant control purposes. 2. We calculated, for each quaternary catchment, a simple composite index that combined estimates of (i) the number of invasive alien plant species present; (ii) the potential number of invasive alien plant species that would be present if they occupied the full range as determined by climatic envelope models; (iii) the degree of habitat loss in rivers; and (iv) the degree of water stress. Each of the four components contributed between one and four to the combined index, which had a range of values between four and 16. 3. We used a geographic information system to map the distribution of priority catchments for invasive alien plant control. Of the 1911 quaternary catchments in South Africa and Lesotho, just over one‐third (650) were in the highest priority category with an index of 13 or more. A relatively small proportion (273, or 14%) of the catchments had the maximum scores of 15 or 16. 4. The approach identified priority areas that have not currently been identified as such, and should provide decision makers with an objective and transparent method with which to prioritize areas for the control of invasive alien plants. We anticipate debate about the way in which components of the index are calculated, and the weight given to the different components, and that this will lead to the transparent evolution of the index. Improvements would also come about through the addition of a more comprehensive list of species, and through the addition of further components.     

Place prioritization for biodiversity reserve network design: a comparison of the SITES and ResNet software packages for coverage and efficiency

Abstract. The place prioritization problem in conservation biology is that of establishing a sequentially prioritized list of places on the basis of biodiversity content. Such a list can then be used to select reserve networks that are designed to be fully representative of the biodiversity of an area as efficiently as possible (for instance, with minimum area or cost). The usual goal is the representation of all chosen biodiversity surrogates up to or beyond a required target, or to the greatest available extent. The purpose of this paper is to compare the respective performances of two place prioritization software packages, SITES and ResNet, on four datasets (distributions of termite genera in Namibia, breeding bird species in the Falkland Islands/Islas Malvinas, vertebrate species in Texas and flora and fauna species that are at risk in Québec), to determine their respective merits. The two software packages implement radically different algorithms: SITES is based on a simulated annealing procedure for finding (local) optima; ResNet uses an algorithm based on rarity and complementarity. This analysis indicates that the rarity‐complementarity based algorithm of ResNet surpasses the simulated annealing approach of SITES with respect to time and completeness. SITES, however, contains other features that are useful in conservation planning. Ways in which the two packages can be used together effectively are suggested.     

Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain

L-Kynurenine and quinolinic acid are neuroactive L-tryptophan-kynurenine pathway metabolites of potential importance in pathogenesis and treatment of neurologic disease. To identify precursors of these metabolites in brain, [(2)H(3) ]-L-kynurenine was infused subcutaneously by osmotic pump into three groups of gerbils: controls, CNS-localized immune-activated, and systemically immune-activated. The specific activity of L-kynurenine and quinolinate in blood, brain and systemic tissues at equilibrium was then quantified by mass spectrometry and the results applied to a model of metabolism to differentiate the relative contributions of various metabolic precursors. In control gerbils, 22% of L-kynurenine in brain was derived via local synthesis from L-tryptophan/formylkynurenine versus 78% from L-kynurenine from blood. Quinolinate in brain was derived from several sources, including: local tissue L-tryptophan/formylkynurenine (10%), blood L-kynurenine (35%), blood 3-hydroxykynurenine/3-hydroxyanthranilate (7%), and blood quinolinate (48%). After systemic immune-activation, however, L-kynurenine in brain was derived exclusively from blood, whereas quinolinate in brain was derived from three sources: blood L-kynurenine (52%), blood 3-hydroxykynurenine or 3-hydroxyanthranilate (8%), and blood quinolinate (40%). During CNS-localized immune activation, > 98% of both L-kynurenine and quinolinate were derived via local synthesis in brain. Thus, immune activation and its site determine the sources from which L-kynurenine and quinolinate are synthesized in brain. Successful therapeutic modulation of their concentrations must take into account the metabolic and compartment sources.     

A new sequence data set of SSU rRNA gene for Scleractinia and its phylogenetic and ecological applications

Scleractinian corals (i.e. hard corals) play a fundamental role in building and maintaining coral reefs, one of the most diverse ecosystems on Earth. Nevertheless, their phylogenies remain largely unresolved and little is known about dispersal and survival of their planktonic larval phase. The small subunit ribosomal RNA (SSU rRNA) is a commonly used gene for DNA barcoding in several metazoans, and small variable regions of SSU rRNA are widely adopted as barcode marker to investigate marine plankton community structure worldwide. Here, we provide a large sequence data set of the complete SSU rRNA gene from 298 specimens, representing all known extant reef coral families and a total of 106 genera. The secondary structure was extremely conserved within the order with few exceptions due to insertions or deletions occurring in the variable regions. Remarkable differences in SSU rRNA length and base composition were detected between and within acroporids (Acropora, Montipora, Isopora and Alveopora) compared to other corals. The V4 and V9 regions seem to be promising barcode loci because variation at commonly used barcode primer binding sites was extremely low, while their levels of divergence allowed families and genera to be distinguished. A time‐calibrated phylogeny of Scleractinia is provided, and mutation rate heterogeneity is demonstrated across main lineages. The use of this data set as a valuable reference for investigating aspects of ecology, biology, molecular taxonomy and evolution of scleractinian corals is discussed.     

Automated culture of aquatic model organisms: shrimp larvae husbandry for the needs of research and aquaculture

Modern research makes frequent use of animal models, that is, organisms raised and bred experimentally in order to help the understanding of biological and chemical processes affecting organisms or whole environments. The development of flexible, reprogrammable and modular systems that may help the automatic production of ‘not-easy-to-keep’ species is important for scientific purposes and for such aquaculture needs as the production of alive foods, the culture of small larvae and the test of new culture procedures. For this reason, we planned and built a programmable experimental system adaptable to the culture of various aquatic organisms, at different developmental stages. The system is based on culture cylinders contained into operational tanks connected to water conditioning tanks. A programmable central processor unit controls the operations, that is, water changes, temperature, light irradiance, the opening and closure of valves for the discharge of unused foods, water circulation and filtration and disinfection systems, according to the information received by various probes. Various devices may be set to modify water circulation and water changes to fulfil the needs of given organisms, to avoid damage of delicate structures, improve feeding performances and reduce the risk of movements over the water surface. The results obtained indicate that the system is effective in the production of shrimp larvae, being able to produce Hippolyte inermis post-larvae with low mortality as compared with the standard operation procedures followed by human operators. Therefore, the patented prototype described in the present study is a possible solution to automate and simplify the rearing of small invertebrates in the laboratory and in production plants.     

Center for the evaluation of risks to human reproduction--the first five years

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) was established by the NTP and the National Institute of Environmental Health Sciences (NIEHS) in 1998 to address the impact of chemical exposures on human reproductive and developmental health and to serve as an environmental and reproductive health resource for government agencies and the general public. The purpose of this report is to provide an overview of the Center activities and a summary of NTP conclusions on chemicals evaluated during this time period. CERHR evaluations involve the critical review of reproductive, developmental, and other relevant toxicity data by independent panels of scientists. The products of these evaluations are expert panel reports. The public has opportunities to provide oral comments at the panel meeting and written comments on draft and final expert panel reports. The NTP evaluates these comments, the conclusions of the expert panel, and any new data not available at the time of the panel meeting, and prepares an NTP brief that describes in plain language the NTP's conclusions on the reproductive and developmental hazard from specified chemical exposures. The NTP brief, expert panel report, and public comments comprise the NTP monograph on the chemical. Monographs are sent to federal regulatory agencies, the NTP Executive Committee, and the NTP Board of Scientific Counselors, and are publicly available. Over the last five years, CERHR conducted expert panel evaluations on 14 chemicals. At this time, 13 panel reports have been published and 12 NTP-CERHR monographs have been issued. Additionally, CERHR conducted a 2-day workshop on the role of thyroid hormones in reproductive and developmental health.     

Development and validation of the Vitiligo Extent Score for a Target Area (VESTA) to assess the treatment response of a target lesion

Since localized treatment for vitiligo is as essential as systemic treatment, a reliable instrument for target evaluation is needed besides those for whole body evaluation. We developed the Vitiligo Extent Score for a Target Area (VESTA) using reference images of both marginal and perifollicular repigmentation to measure the repigmentation rate (%) in a target lesion. In the validation study, a total of 65 dermatologists in 10 institutes evaluated 17 pairs of vitiligo images (pre‐ and post‐treatment) using both a rough estimate and the VESTA. The VESTA (concordance correlation coefficient: 0.949, 95% confidence interval [CI] 0.942–0.955) was significantly more accurate than the rough estimate (0.896, 95% CI: 0.883–0.908). It was also associated with better inter‐rater reliability over the rough estimate, albeit not significant. The VESTA can afford intuitive, convenient, and reliable assessment of the treatment response in a target area, and would be useful in clinical practice as well as retrospective studies.     

HPLC fluorescence method for the determination of nizatidine in human plasma and its application to pharmacokinetic study

A sensitive high‐performance liquid chromatographic (HPLC) method was developed for the determination of nizatidine in human plasma. Nizatidine was derivatized by 4‐fluoro‐7‐nitrobenzofurazan (NBD‐F). Chromatographic separation was performed on a Inertsil C₁₈ column (150 mm × 4.6 mm, 5 µm) using isocratic elution by a mobile phase consisting of methanol/water (55:45) at a flow rate of 1.2 mL/min. Amlodipine was used as the internal standard (IS). Fluorescence detector was used operated at 461 nm (excitation) and 517 nm (emission), respectively. The calibration curve was linear over the range of 50–2000 ng/mL. This method was successfully applied to a pharmacokinetic study after oral administration of a dose (150 mg) of nizatidine. Copyright © 2013 John Wiley & Sons, Ltd.