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Canine and Feline Differences in the Cytochrome P450 Transcriptome and Drug Metabolism
Get PDFCytochrome P450 (CYP) is an important enzyme superfamily, estimated to metabolize 70-90% of pharmaceuticals. Use of pharmaceuticals with at least 30% metabolism by CYP in humans require phenotyping to determine the CYP isoforms involved and the impact common polymorphisms may have. These same drugs are used off-label in canine and feline patients, yet knowledge regarding the CYP isoforms present in the liver and their enzymatic efficacy is unknown. Using human probes and substrates, differences in feline and canine CYP metabolism have been reported, and reflected in the limited pharmacokinetic (PK) studies of both species. The aim of this dissertation was to characterize canine and feline CYP transcriptome in canine and feline, compare and contrast the predicted hepatic clearance (CLhep) between the two species, and carry out reaction phenotyping of selected pharmaceuticals in canine recombinant CYP (rCYP). The first study determined the physiologic expression of CYP mRNA transcripts in whole blood, kidney, duodenum, liver and lung in healthy, adult male (n=4) and female (n=4) beagles via RNA-sequencing (RNA-seq). A total of 45 canine CYPs were identified, with liver, duodenum and lung expressing a high number of xenobiotic metabolizing CYPs, and expressing prominent endogenous metabolizing CYPs expression present in blood and kidney. In the second study, transcriptomes from the 99 Lives Cat Genome Sequencing Initiative databank combined with experimentally acquired whole transcriptome sequencing of healthy, adult male (n=2) and female (n=2) domestic felines was used to characterize CYP expression across a wide variety of tissues. A total of 20 tissues were analyzed and 47 CYP isoforms identified. Depending on the tissue, 9 to 33 CYP isoform transcripts were expressed. This study was the first to describe feline CYP transcriptome across a wide variety of tissues. Based on the differences in the transcriptome between the two species, the third study compared canine and feline CYP metabolism via in vitro liver microsomes. In canine liver microsomes, 3/30 substrates did not have quantifiable intrinsic clearance (CLint), while midazolam and amitriptyline CLint was too rapid for accurate determination. A predicted hepatic clearance (CLhep) was calculated for 29/30 substrates in feline microsomes. Overall, canine CLhep was faster compared to the feline, with fold differences ranging from 2 to 20 fold. A comparison between the well-stirred (CLhep,ws) and parallel tube model (CLhep,pt) indicates that the CLhep,pt model reports a slightly higher CLhep in both species. With evidence of the variation between the species, reaction phenotyping was applied to identify the CYP isoform pattern for targeted substrates. While the recombinant CYP (rCYP) isoforms are routinely used to screen novel human pharmaceuticals prior to approval, whether the canine isoforms metabolize these drugs in the same pattern is unknown. Utilizing an rCYP metabolic stability assay, 22 drugs used in veterinary medicine were phenotyped using canine rCYP1A1, 1A2, 2B6, 2C21, 2C41, 2D15, 3A12, and 3A26. Four of the 22 substrates required a two or four-fold rCYP dilution in order to achieve the three time points necessary to calculate the CLrCYP. The tricyclic antidepressants, amitriptyline and clomipramine, required a two or four-fold dilution of both rCYP2C41 and rCYP2D15. An isoform reported in only 11% of tested beagles, rCYP2C41, was involved in the metabolism of 9/22 substrates. The contribution of rCYP2B11 in canine drug metabolism altered the rCYP metabolism pattern for 8/22 substrates compared to the CYP metabolism pattern reported for humans. This body of research identified differences in the CYP transcriptome and CYP substrate depletion profile between the two species that suggests the need for species-specific pharmacokinetic studies as a basis for design of dosing regimens. In addition, canine CYP2B11 metabolism does not follow the reported human profile, highlighting the need for canine- and feline-specific reaction phenotyping
Pharmacokinetics of albuterol and butorphanol administered intravenously and via a buccal patch
Get PDFConventional routes of drug administration have several disadvantages. The rate and extent of absorption can vary greatly depending on the drug, its formulation, the presence or absence of food, drug interactions, and the pH of gastrointestinal fluids. Extensive first-pass metabolism can greatly reduce the absorption of many drugs. Better dosage forms or drug delivery mechanisms could minimize some of these problems.
The pharmaceutical industry has recognized the need for, and has developed many new, novel drug delivery systems. Drugs that previously experienced diminished effective concentrations due to the first-pass effect may now be given by a novel route. The dosing frequency of many drugs may be reduced when administered by a novel route or site. Transmucosal drug delivery (TMDD) via the buccal mucosa is one site that is suited to rapid drug absorption and systemic delivery. Drugs selected for TMDD must have physiochemical properties that will allow them to penetrate the mucosa and produce therapeutic blood concentrations. This study utilized a buccal patch less than 1.5 cm in length to deliver albuterol and butorphanol-two drugs with dissimilar physiochemical properties.
The purpose of this study was to establish pharmacokinetic parameters and the bioavailability of albuterol and butorphanol when administered intravenously and buccally. Three dogs weighing at least 20 kg were studied using a randomized crossover design, each receiving albuterol and butorphanol by buccal and intravenous administration. Blood samples were collected and analyzed using ELISA. Values for pharmacokinetic parameters were analyzed using compartmental and non-compartmental models.
For albuterol, extrapolated Cmax and Co after buccal and IV administration were 10.28 �� 2.77 and 57.74 �� 9.04 ng/ml, respectively. Volume of distribution at steady state (Vss) was 2.13 �� 1.30 L/kg and Cl was 4.73 �� 3.91 ml/min/kg. A significant difference existed between the disappearance rate constant of buccal and intravenous albuterol administration. The disappearance half-lives of buccal and IV albuterol were 160.96 �� 24.19 and 364.20 �� 115.20 min, respectively. The bioavailability of buccally administered albuterol was 35%.
Maximal concentration (Cmax) and Co after buccal and IV butorphanol administration were 6.66 �� 1.65 and 8.24 �� 5.55 ng/ml, respectively. Volume of distribution at steady state (Vss) was 27.58 �� 10.14 L/kg and Cl was 137.87 �� 19.55 ml/min/kg. The half-life of buccally administered butorphanol was 259.15 �� 33.12 min and the half-life of IV butorphanol was 172.12 �� 94.95 min. The bioavailability of buccally administered butorphanol was 606%.
The buccal patch used in this study achieved systemic concentrations for both albuterol and butorphanol. Further studies are needed to determine if therapeutic drug concentrations can be achieved with the buccal patch and if the patch can result in clinical efficacy
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Effect of tympanic cavity evacuation and flushing on microbial isolates during total ear canal ablation with lateral bulla osteotomy in dogs.
No full textOBJECTIVE
To evaluate differences in bacterial numbers, identity, and susceptibility in samples obtained from the tympanic cavity on entry (preflush) and after evacuation and lavage (postflush) and assess perioperative and empiric antimicrobial selection in dogs that underwent total ear canal ablation (TECA) with lateral bulla osteotomy (LBO) or reoperation LBO.
DESIGN
Prospective clinical study.
ANIMALS
34 dogs.
PROCEDURE
TECA with LBO or reoperation LBO was performed on 47 ears. Pre- and postflush aerobic and anaerobic samples were obtained from the tympanic cavity. Isolates and antimicrobial susceptibility patterns were compared.
RESULTS
Different isolates (31/44 [70%] ears) and susceptibility patterns of isolate pairs (6/44 [14%] ears) were detected in pre- and postflush samples from 84% of ears. Evacuation and lavage of the tympanic cavity decreased the number of bacterial isolates by 33%. In 26% of ears, bacteria were isolated from post-flush samples but not preflush samples. Only 26% of isolates tested were susceptible to cefazolin. At least 1 isolate from 53% of dogs that received empirically chosen antimicrobials postoperatively was resistant to the selected drugs. Anaerobic bacteria were recovered from 6 ears.
CONCLUSIONS AND CLINICAL RELEVANCE
Accurate microbiologic assessment of the tympanic cavity should be the basis for selection of antimicrobials in dogs undergoing TECA with LBO. Bacteria remain in the tympanic cavity after evacuation and lavage. Cefazolin was a poor choice for dogs that underwent TECA with LBO, as judged on the basis of culture and susceptibility testing results
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