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Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

Efforts to develop selective agonists for dopamine D 1 -like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric β-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1 -like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1 - and D 2 -like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1 -like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor.

European Journal of Medicinal Chemistry

Comparison of select hematology and serum chemistry analtyes between wild-caught and aquarium-housed lake sturgeon ( Acipenser fulvescens )

Hematology and serum chemistry analytes were compared between wild-caught and aquarium-housed lake sturgeon ( Acipenser fulvescens ) to potentially improve understanding of medical issues in lake sturgeon. Blood samples were taken from 30 lake sturgeon exhibited in 11 institutions in the United States and from 23 experimentally stocked lake sturgeon caught in gill nets in the lower Genesee River in Rochester, New York, USA. For hematology, only segmented neutrophil count was significantly different, with wild-caught fish having a higher number of circulating neutrophils. For clinical chemistry analytes, chloride, uric acid, calcium, phosphate, glucose, aspartate aminotransferase, triglycerides, and creatine kinase were significantly different between the two cohorts. These differences are likely not clinically significant and are attributable to handling stress, variability in environmental parameters, or differences in nutritional status. This is the first report of hematology and serum chemistry values in aquarium-housed lake sturgeon and provides useful reference intervals for clinicians.

New York

Weights, hematology and serum chemistry of free-ranging brown boobies (Sula leucogaster) in Johnston Atoll, Central Pacific

Hematologic and serum chemistry values are reported for 105 brown boobies (Sula leucogaster) from Johnston Atoll, Central Pacific. Hematocrit, estimated total plasma solids, total and differential white cell counts, serum glucose, calcium, phosphorus, uric acid, total protein, albumin, globulin, aspartate aminotransferase, and creatinine phosphokinase were analyzed. Hematologic and serum chemistry values varied with age and sex. Values were compared with those of red-footed boobies and other tropical and temperate marine pelecaniforms.

Johnston Atoll National Wildlife Refuge

Capture myopathy in an endangered sandhill crane (Grus canadensis pulla)

Despite precautions to protect cranes, a 3-year-old endangered Mississippi sandhill crane ( Grus canadensis pulla ) was found caught in a leghold trap in Gautier, Mississippi, on 11 November 1987. The bird could have been in the trap for up to 16 hr and was standing and struggling to escape when it was discovered. Serum chemistries of the crane on 12 November revealed elevated lactic dehydrogenase (2,880 IU/L), alanine aminotransferase (ALT) (152 IU/L), and aspartate aminotransferase (AST) (>1,000 IU/L) values. Following surgical amputation of a fractured toe, the bird never attempted to stand and was unable to stand even when manually supported. Radiographic and physical examination of both legs did not reveal any anatomical abnormalities. Despite medical care, including supportive therapy, no improvement was observed in the bird's ability to stand and to support itself, and the bird died on 19 November. Serum chemistries and the postmortem and histopathologic findings were compatible with capture myopathy described in other species. Because of the possible susceptibility of long-legged birds such as the Mississippi sandhill crane to capture myopathy, special care must be taken when trapping, handling, chemically immobilizing, and transporting these species. In addition, precautions must be taken when conducting a predator-control program to ensure that nontarget wildlife are unlikely to encounter traps. Capture myopathy has only rarely been observed in wild birds, and this case represents the first report in a Mississippi sandhill crane.

Mississippi

Short-term survival and effects of transmitter implantation into western grebes using a modified surgical procedure

Two pilot trials and one study in a closely related grebe species suggest that Western grebes ( Aechmophorus occidentalis ) will not tolerate intracoelomic transmitter implantation with percutaneous antennae and often die within days of surgery. Wild Western grebes (n = 21) were captured to evaluate a modified surgical technique. Seven birds were surgically implanted with intracoelomic transmitters with percutaneous antennae by using the modified technique (transmitter group), 7 received the same surgery without transmitter implantation (celiotomy group), and 7 served as controls (only undergoing anesthesia). Modifications included laterally offsetting the body wall incision from the skin incision, application of absorbable cyanoacrylate tissue glue to the subcutaneous space between the body wall and skin incisions, application of a waterproof sealant to the skin incision after suture closure, and application of a piece of porcine small intestine submucosa to the antenna egress. Survival did not differ among the 3 groups with 7 of 7 control, 6 of 7 celiotomy, and 6 of 7 transmitter birds surviving the 9-day study. Experimental birds were euthanized at the end of the study, and postmortem findings indicated normal healing. Significant differences in plasma chemistry or immune function were not detected among the 3 groups, and only minor differences were detected in red blood cell indices and plasma proteins. After surgery, the birds in the transmitter group spent more time preening tail feathers than those in the control and celiotomy groups. These results demonstrate that, in a captive situation, celiotomy and intracoelomic transmitter implantation caused minimal detectable homeostatic disturbance in this species and that Western grebes can survive implantation of intracoelomic transmitters with percutaneous antennae. It remains to be determined what potential this modified surgical procedure has to improve postoperative survival of Western grebes that are intracelomically implanted with transmitters with percutaneous antennae and released into the wild.

Journal of Zoo and Wildlife Medicine

Effects of season, location, species, and sex on hematologic and plasma biochemical values and body mass in free-ranging Grebes (Aechmophorus species)

The effects of season, location, species, and sex on body weight and a comprehensive array of blood chemistry and hematology analytes were compared for free-ranging western ( Aechmophorus occidentalis ) and Clark's ( Aechmophorus clarkii ) grebes. Birds (n = 56) were collected from Puget Sound, WA, and Monterey Bay and San Francisco Bay, CA, from February 2007 to March 2011. The data supported generalization of observed ranges for most analytes across Aechmophoru s grebe metapopulations wintering on the Pacific coast. Notable seasonal and location effects were observed for packed cell volume (winter 6% greater than fall; winter California [CA] 5% greater than Washington [WA]), total white blood cell count (CA 3.57 × 10 3 cells/µL greater than WA), heterophils (WA 10% greater than CA), lymphocytes (winter 19% greater than fall), heterophil to lymphocyte ratio (fall 5.7 greater than winter), basophils (CA greater than WA), plasma protein (WA about 10 g/L [1.0 g/dL] greater than CA), plasma protein to fibrinogen ratio (winter about 15 greater than fall), potassium (CA 2 mmol/L greater than WA), and liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase: WA greater than CA). Within California, season had a greater effect on body mass than sex (mean winter weights about 200 g greater than fall), whereas within a season, males weighed only about 80 g more than females, on average. These data give biologists and veterinarians quantitative reference values to better assess health at the individual and metapopulation level.

Washington, California

Reference values and comparison of blood chemistry and plasma protein values between gold standard analyzers and four point-of-care devices in free-ranging canvasbacks (Aythya valisineria)

Accurate, timely, and cost-effective blood chemistry analysis is an essential tool for directing emergency treatment, monitoring the health status of captive and free-ranging individuals and flocks, and improving the efficacy of conservation actions. Blood samples were obtained from 52 canvasbacks ( Aythya valisineria ) that were captured on San Francisco Bay, California, during December 2017 as part of a long-term study. Reference values and clinical agreement were determined for blood chemistry and plasma protein parameters among four commonly used point-of-care devices (VetScan ® VS2, i-STAT ® , AlphaTRAK ® 2 glucometer, refractometer) and two gold standard laboratory analyzers (Roche cobas ® c501, Helena SPIFE 3000 system). Canvasback reference values were generally within expected ranges for Anatidae species with the exception of higher upper limits for sodium and chloride. Creatine kinase and aspartate transaminase values exceeded a published threshold for diagnosis of capture myopathy even though study birds were captured using low-stress techniques and successfully released. With the exception of higher alkaline phosphatase in hatch-year canvasbacks, no age or sex differences were observed for any analyte in this population that was captured during a nonbreeding period. Analysis of analyzer agreement found raw VetScan aspartate transaminase, calcium, glucose, and uric acid values; corrected VetScan albumin, potassium, sodium, and total protein values; raw i-STAT glucose and potassium values; and corrected i-STAT sodium and chloride values were clinically interchangeable with Roche cobas values. Raw VetScan and i-STAT glucose values were also interchangeable. However, none of the Roche or point-of-care analyzer plasma protein values were in clinical agreement with gold standard electrophoresis values. The findings of this study highlight the need for analyzer- or technique-specific reference values and provide biologists and veterinarians quantitative reference values using currently available analyzers to better assess and respond to the health of individuals and populations.

California

Environmental presence and persistence of pharmaceuticals: An overview

Emerging contaminants (ECs) in the environment – that is, chemicals with domestic, municipal, industrial, or agricultural sources that are not commonly monitored but may have the potential for adverse environmental effects – is a rapidly growing field of research. The use of “emerging” is not intended to infer that the presence of these compounds in the environment is new. These chemicals have been released into the environment as long as they have been in production or, in the case of hormones and other endogenous compounds, since the rise of animal life. What is emerging is the interest by the scientific and lay communities in the presence of these chemicals in the environment, the analytical capabilities required for detection, and the subtle effects that very small concentrations of these chemicals appear to have on aquatic biota. In December 2006, Environmental Science & Technology devoted an entire special issue (volume 40, number 23) to the topic of ECs, illustrating the increased interest in the subject. Within the EGs, one particular class that has seen a substantial increase in research over the past 10 years is pharmaceuticals and personal-care products (PPCPs). This increased research interest can be demonstrated by several means, including requests for proposals from funding agencies, but the clearest indication of a focused effort to understand the introduction, transformation, and potential health and environmental effects of PPCPs and ECs, in general, is the number of published reports. This increase can be shown by examining six environmental journals that regularly publish PPCP-related papers – Chemosphere , Environmental Science & Technology , Environmental Toxicology and Chemistry , Science of the Total Environment , Water Research , and Water Science and Technology . In 1998 there were 22 papers published on pharmaceuticals, antibiotics, or drugs in these 6 journals; by 2006, this number increased sixfold to 132 papers (Figure 1.1). This growth can be attributed to a number of factors. The presence of pharmaceuticals in surface-water samples from Europe and the United States was documented in several sentinel papers. These ground-breaking works encouraged other scientists to examine the rivers, streams, lakes, and reservoirs in their regions for such chemicals. In addition, the intense public attention paid to news reports on the environmental detections of these chemicals and possible effects of aquatic life has made this issue visible to the wastewater-treatment, drinking-water treatment, and regulatory communities. This has driven the funding bodies associated with these communities to fund studies or request proposals that address the presence, fate, and effects of PPCPs in aquatic systems. The release of the first comprehensive reconnaissance of pharmaceuticals and other wastewater contaminants in the United States provides an example of the intense media interest in this topic. Within 6 days on online publication of this study, 72 newspapers across the United States had published articles describing the results, either locally written or based on international media syndicate reports. There also was substantial concurrent coverage by local and national radio and television outlets, including the Cable News Network, ABC World News Tonight , and National Public Radio. A substantial fraction of these news stories may be attributable to press releases and media briefings prior to publication. However, the interest by television and print journalists in reporting the results of a peer-reviewed journal article to the general public was motivated by the recognition that describing the presence of PPCPs in water supplies would be of interest to the public. To better convey the results of the study published by Koplin et al. to the public, a separate general-interest fact sheet was published to summarize the important points of the study. Because PPCPs are commonly and widely used by individuals, there is likely a preexisting, personal identification with these compounds that does not occur for the wide range of other organic and inorganic contaminants whose presence in the environment has previously been described. This greater public “name recognition” makes itself known through the media to the regulatory and technical community and has prompted interest in sponsoring research that defines the composition and concentrations of PPCPs in potential sources and their fate and effects following relase into the environment. Independent of the drivers that potentially fuel the interest in studies of PPCPs, it is clear that PPCP research has grown beyond surface-water studies to examine issues such as: • Presence in other matrices, such as groundwater, landfill leachates, sediments, and biosolids. • Environmental transport and fate in surface water, groundwater, and soils amended with reclaimed water or biosolids. • PPCP source elucidation, such as wastewater treatment plant (WWTP) effluents, confined animal feeding operations (CAFOs), and aquaculture. • Removal during wastewater and drinking-water treatment. • Effects on aquatic ecosystems, terrestrial ecosystems, and human health. The chapters in this book provide an extensive examination of current environmental pharmaceutical research and are divided into three sections: “Occurrence and Analysis of Pharmaceuticals in the Environment,” “Environment Fate and Transformations of Veterinary Pharmaceuticals,” and “treatment of Pharmaceuticals in Drinking Water and Wastewater.” The purpose of this introductory overview chapter is to outline current (2004-2006) knowledge about the presence and concentration of PPCPs as described in the published literature. Previous reviews should be consulted for discussions on pre-2004 publications. Those reviews will provide the reader with a comprehensive introduction to the topic of PPCPs in the environment. This chapter describes the sources of PPCPs and other organic contaminants often associated with human wastewater into the environment, the range of concentrations present in various environmental compartments, and the potential routes of removal/sequestration. An overview of the sources and fate of veterinary pharmaceuticals will be discussed in Chapter 5, “Fate and Transport of Veterinary Medicines in the Soil Environment.”

Book chapter