Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

OBJECTIVE: To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. SAMPLE POPULATION: Skin samples from 5 Greyhounds. PROCEDURE: Skin samples from the dogs' thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32 degrees C). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. RESULTS: Mean+/-SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01+/-0.05 microg/cm2 of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.     

Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

OBJECTIVE: To determine the effects of various vehicles on the penetration and retention of hydrocortisone applied to canine skin. SAMPLE POPULATION: 20 canine skin samples obtained from the thorax, neck, and groin regions of 5 Greyhounds. PROCEDURE: Skin was harvested from dogs after euthanasia and stored at -20 degrees C until required.The skin was then defrosted and placed into diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of hydrocortisone that contained trace amounts of radiolabelled [14C]-hydrocortisone in each vehicle (ie, PBS solution [PBSS] alone, 50% ethanol [EtOH] in PBSS [wt/wt], and 50% propylene glycol in PBSS [wt/wt]) were applied to the outer (stratum corneum) surface of each skin sample, and aliquots of receptor fluid were collected for 24 hours and analyzed for hydrocortisone. RESULTS: The maximum flux of hydrocortisone was significantly higher for all sites when dissolved in a vehicle containing 50% EtOH, compared with PBSS alone or 50% propylene glycol, with differences more prominent in skin from the neck region. In contrast, higher residues of hydrocortisone were found remaining within the skin when PBSS alone was used as a vehicle, particularly in skin from the thorax and neck. CONCLUSIONS AND CLINICAL RELEVANCE: Penetration of topically applied hydrocortisone is enhanced when EtOH is used in vehicle formulation. Significant regional differences (ie, among the thorax, neck, and groin areas) are also found in the transdermal penetration and skin retention of hydrocortisone. Variability in clinical response to hydrocortisone can be expected in relation to formulation design and site of application.     

Modification of the effective mesh size for measuring landscape fragmentation to solve the boundary problem

Patch-based landscape metrics can be biased by the boundaries and the extent of a reporting unit if the boundaries fragment patches. We call this the “boundary problem”. The effective mesh size m _eff is a convenient method to quantify landscape fragmentation, that is based on the probability that two points chosen randomly in a region will be connected, e.g., not be separated by roads, railroads, or urban development. The cutting-out (CUT) procedure, used in the original computation of m _eff, suffers from the boundary problem because the boundaries of the reporting units are considered to be additional barriers. Therefore, m _eff will be underestimated, particularly if reporting units are embedded within the broader landscape. In this paper, we present a solution to overcome this limitation by a new method called “cross-boundary connections” (CBC) procedure. It attributes the connections between two points that are located in different reporting units to both reporting units. We systematically compare the CBC procedure to the CUT procedure and show that the boundary problem is intrinsic to the CUT procedure, while the CBC procedure is independent of the size and administrative boundaries of reporting units. In addition, we elucidate the superior performance of the new procedure in the case study of South Tyrol where m _eff is being used for sustainability reporting on the level of municipalities. The new CBC procedure eliminates the bias due to the boundaries and the size of reporting units in measuring landscape fragmentation through m _eff.     

An Open‐label Phase 1 Dose‐escalation Clinical Trial of a Single Intravenous Administration of Gemcitabine in Dogs with Advanced Solid Tumors

Background

A broad range of gemcitabine dosages have been used in dogs.

Hypothesis/Objectives

To determine maximally tolerated dose (MTD), dose‐limiting toxicity (DLT), and preliminary antitumor activity of intravenous administration of gemcitabine in dogs with advanced solid tumors.

Animals

Twenty‐two client‐owned dogs.

Methods

Dogs with advanced cancer were prospectively enrolled in an open‐label Phase 1 study of gemcitabine. Gemcitabine was administered as a 30‐minute intravenous bolus starting at 800 mg/m², using escalation of 50 mg/m² increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Treatment continued until disease progression or unacceptable toxicosis. Additional dogs were enrolled at MTD to better characterize tolerability, and to assess the extent and duration of gemcitabine excretion.

Results

Twenty‐two dogs were treated at 4 dose levels, ranging from 800 to 950 mg/m². Neutropenia was identified as DLT. MTD was 900 mg/m². DLT consisting of grade 4 febrile neutropenia was observed at 950 mg/m² in 2 dogs. There were no nonhematologic DLTs. Twenty dogs received multiple doses, and none had evidence of severe toxicosis from any of their subsequent treatments. At 900 mg/m², 2 complete and 5 partial responses were observed in dogs with measurable tumors. The amount of gemcitabine excreted in urine decreased over time, and was undetectable after the first 24 hours.

Conclusions and Clinical Importance

The recommended dose of gemcitabine for future Phase 2 studies is weekly 900 mg/m². In chemotherapy‐naïve dogs with advanced solid tumor this dose level merits further evaluation.     

Masked,diluted and drowned out: how global seafood trade weakens signals from marine ecosystems

Nearly 40% of seafood is traded internationally and an even bigger proportion is affected by international trade, yet scholarship on marine fisheries has focused on global trends in stocks and catches, or on dynamics of individual fisheries, with limited attention to the link between individual fisheries, global trade and distant consumers. This paper examines the usefulness of fish price as a feedback signal to consumers about the state of fisheries and marine ecosystems. We suggest that the current nature of fisheries systems and global markets prevent transmission of such price signals from source fisheries to consumers. We propose several mechanisms that combine to weaken price signals, and present one example – the North Sea cod – to show how these mechanisms can be tested. The lack of a reliable price feedback to consumers represents a challenge for sustainable fisheries governance. We therefore propose three complimentary approaches to address the missing feedback: (i) strengthening information flow through improved traceability and visibility of individual fishers to consumers, (ii) capitalizing on the changing seafood trade structures and (iii) bypassing and complementing market mechanisms by directly targeting citizens and political actors regarding marine environmental issues through publicity and information campaigns. These strategies each have limitations and thus need to be pursued together to address the challenge of sustainability in global marine fisheries.     

Phenotypic characterization and validation of provitamin A functional genes in early maturing provitamin A-quality protein maize (Zea mays) inbred lines

The number of drought and low-N tolerant hybrids with elevated levels of provitamin A (PVA) in sub-Saharan Africa could increase when PVA genes are optimized and validated for developed drought and low-N tolerant inbred lines. This study aimed to (a) determine the levels of drought and low-N tolerance, and PVA concentrations in early maturing PVA-quality protein maize (QPM) inbred lines, and (b) identify lines harbouring the crtRB1 and LcyE genes as sources of favourable alleles of PVA. Seventy early maturing PVA-QPM inbreds were evaluated under drought, low-N and optimal environments in Nigeria for two years. The inbreds were assayed for PVA levels and the presence of PVA genes using allele-specific PCR markers. Moderate range of PVA contents was observed for the inbreds. Nonetheless, TZEIORQ 55 combined high PVA concentration with drought and low-N tolerance. The crtRB1-3′TE primer and the KASP SNP (snpZM0015) consistently identified nine inbreds including TZEIORQ 55 harbouring the favourable alleles of the crtRB1 gene. These inbreds could serve as donor parents of the favourable crtRB1-3′TE allele for PVA breeding in maize.     

Chimpanzee reservoirs of pandemic and nonpandemic HIV-1

Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome (AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus (SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P. t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.     

Both wheat (Triticum aestivum) bran arabinoxylans and gut flora-mediated fermentation products protect human colon cells from genotoxic activities of 4-hydroxynonenal and hydrogen peroxide

Dietary fibers are fermented by the gut flora to yield short chain fatty acids (SCFAs), which inhibit the growth of tumor cells, induce glutathione S-transferases (GSTs), and protect cells from the genotoxic activity of 4-hydroxynonenal (HNE). Here, we investigated effects of wheat bran-derived arabinoxylans and fermentation products on these parameters of chemoprevention. Newly isolated water extractable (WeAx) and alkali extractable arabinoxylans (AeAx) were fermented under anaerobic conditions with human feces. Resulting fermentation supernatants (FSs) were analyzed for SCFAs and used to treat HT29 colon cancer cells. Cell growth, cytotoxicity, antigenotoxicity against hydrogen peroxide (H2O2) or HNE, and GST activity were determined. Nonfermented WeAx decreased H2O2-induced DNA damage by 64%, thus demonstrating chemoprotective properties by this nonfermented wheat bran fiber. The fermentation of WeAx and AeAx resulted in 3-fold increases of SCFA, but all FSs (including the control without arabinoxylans) inhibited the growth of the HT29 cells, reduced the genotoxicity of HNE, and enhanced the activity of GSTs (FS WeAx, 2-fold; FS AeAx, 1.7-fold; and control FS, 1.4-fold), which detoxify HNE. Thus, increases in SCFAs were not reflected by enhanced functional effects. The conclusion is that fermentation mixtures contain modulatory compounds that arise from the feces and might add to the effectiveness of SCFAs.