Pharmacokinetics of Jaspine B and Enhancement of Intestinal Absorption of Jaspine B in the Presence of Bile Acid in Rats.

We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile. Further studies demonstrated that the enhanced intestinal permeability with bile salts was due to increased lipophilicity and decreased membrane integrity. Jaspine B was designated as a highly tissue-distributed compound, because it showed large tissue to plasma ratios in the brain, kidney, heart, and spleen. Moreover, the recovery of Jaspine B from the feces and urine after an intravenous administration was about 6.3%, suggesting a substantial metabolism of Jaspine B. Consistent with this observation, 80% of the administered Jaspine B was degraded after 1 h incubation with rat liver microsomes. In conclusion, the facilitated intestinal permeability in the presence of bile salts could significantly increase the bioavailability of Jaspine B and could lead to the development of oral formulations of Jaspine B with bile salts. Moreover, the highly distributed features of Jaspine B in the brain, kidney, heart, and spleen should be carefully considered in the therapeutic effect and toxicity of this compound.

Peritoneal carcinomatosis with desmoplasia and osseous metaplasia mimicking encapsulating peritoneal sclerosis in a cat: case report.

A 13-year-old neutered male Korean short-hair cat presented with anorexia, lethargy, and a severely distended abdomen, suggestive of ascites. Abdominocentesis yielded serosanguineous fluid. A subsequent diagnostic workup, including blood tests, ascitic fluid analysis, imaging studies [radiography, ultrasound, and computed tomography (CT)], and histopathological examination, was performed to identify the underlying cause. Imaging studies revealed characteristics of encapsulating peritoneal sclerosis (EPS) such as peritoneal thickening, fat stranding, and calcification. During laparotomy, fibrous membranes encapsulating the abdominal organs and ascites were observed, and multiple calcified regions were detected on the abdominal wall. Histopathological analysis confirmed the diagnosis of poorly differentiated invasive malignant neoplasms, which were further classified as carcinomatosis based on positive cytokeratin and negative vimentin immunohistochemistry results. To our knowledge, this is the first report of sclerosing peritoneal carcinomatosis with osseous metaplasia in a cat.

Enhanced Bioavailability and Efficacy of Silymarin Solid Dispersion in Rats with Acetaminophen-Induced Hepatotoxicity.

We evaluated the bioavailability, liver distribution, and efficacy of silymarin-D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) solid dispersion (silymarin-SD) in rats with acetaminophen-induced hepatotoxicity (APAP) compared with silymarin alone. The solubility of silybin, the major and active component of silymarin, in the silymarin-SD group increased 23-fold compared with the silymarin group. The absorptive permeability of silybin increased by 4.6-fold and its efflux ratio decreased from 5.5 to 0.6 in the presence of TPGS. The results suggested that TPGS functioned as a solubilizing agent and permeation enhancer by inhibiting efflux pump. Thus, silybin concentrations in plasma and liver were increased in the silymarin-SD group and liver distribution increased 3.4-fold after repeated oral administration of silymarin-SD (20 mg/kg as silybin) for five consecutive days compared with that of silymarin alone (20 mg/kg as silybin). Based on higher liver silybin concentrations in the silymarin-SD group, the therapeutic effects of silymarin-SD in hepatotoxic rats were evaluated and compared with silymarin administration only. Elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels were significantly decreased by silymarin-SD, silymarin, and TPGS treatments, but these decreases were much higher in silymarin-SD animals than in those treated with silymarin or TPGS. In conclusion, silymarin-SD (20 mg/kg as silybin, three times per day for 5 days) exhibited hepatoprotective properties toward hepatotoxic rats and these properties were superior to silymarin alone, which may be attributed to increased solubility, enhanced intestinal permeability, and increased liver distribution of the silymarin-SD formulation.

Unusual case of severe fever with thrombocytopenia syndrome showing clinical manifestations in a companion dog.

Severe fever with thrombocytopenia syndrome (SFTS) virus is an emerging zoonotic virus in East Asia. However, SFTS virus (SFTSV) has not been reported to cause clinical infection in companion dogs to date. We report the case of a 4-year-old companion dog that presented with fever, vomiting, leukocytopenia and thrombocytopenia at a veterinary hospital in the Republic of Korea. It was diagnosed with SFTS, which was confirmed using real-time reverse transcription PCR, sequencing and an indirect immunofluorescence assay, and recovered after supportive care. Further studies are required to investigate SFTSV infection in companion animals, living in close contact with humans, as well as animal-to-human transmission.

Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin.

Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin and ipragliflozin, representative SGLT2 inhibitors. The plasma exposure of DWP16001 was comparable with that of ipragliflozin but higher than that of dapagliflozin. DWP16001 showed the highest kidney distribution among three SGLT2 inhibitors when expressed as an area under curve (AUC) ratio of kidney to plasma (85.0 ± 16.1 for DWP16001, 64.6 ± 31.8 for dapagliflozin and 38.4 ± 5.3 for ipragliflozin). The organic anion transporter-mediated kidney uptake of DWP16001 could be partly attributed to the highest kidney uptake. Additionally, DWP16001 had the lowest half-maximal inhibitory concentration (IC50) to SGLT2, a target transporter (0.8 ± 0.3 nM for DWP16001, 1.6 ± 0.3 nM for dapagliflozin, and 8.9 ± 1.7 nM for ipragliflozin). The inhibition mode of DWP16001 on SGLT2 was reversible and competitive, but the recovery of the SGLT2 inhibition after the removal of SGLT2 inhibitors in CHO cells overexpressing SGLT2 was retained with DWP16001, which is not the case with dapagliflozin and ipragliflozin. In conclusion, selective and competitive SGLT2 inhibition of DWP16001 could potentiate the efficacy of DWP16001 in coordination with the higher kidney distribution and retained SGLT2 inhibition of DWP16001 relative to dapagliflozin and ipragliflozin.

Ultrasonographic evaluation of renal dimension and resistive index in clinically healthy Korean domestic short-hair cats.

Renal length, height, width, resistive index (RI), size of cortex, and medulla were determined by renal ultrasonography in 50 healthy Korean domestic short-hair cats. In the sagittal plane, the renal length was 3.83 +/- 0.51 cm (mean +/- SD) in the left kidney and 3.96 +/- 0.48 cm in the right kidney, whereas the renal height was 2.42 plusmn; 0.27 cm in the left kidney and 2.36 plusmn; 0.28 cm in the right kidney. In the transverse plane, the renal height was 2.42 +/- 0.28 cm in the left kidney and 2.38 +/- 0.27 cm in the right kidney, whereas the renal width was: 2.65 +/- 0.35 cm in the left kidney and 2.63 +/- 0.31 cm in the right kidney. In the dorsal plane, the renal length was 3.84 +/- 0.53 cm in the left kidney and 3.97 +/- 0.54 cm in the right kidney, whereas the renal width was 2.65 +/- 0.34 cm in the left kidney and 2.66 +/- 0.33 cm in the right kidney. There were no significant differences (p > 0.05) among the same structure sizes measured in different planes. In the sagittal plane, the size of the renal cortex was 0.47 +/-; 0.08 cm in the left kidney and 0.47 +/- 0.08 cm in the right kidney, whereas of the size of the renal medulla was 0.55 +/- 0.30 cm in the left kidney and 0.50 +/- 0.07 cm in the right kidney. RI evaluated by pulsed wave Doppler sonography was 0.52 +/- 0.05 in the left kidney and 0.55 +/- 0.05 in the right kidney. The actual renal dimensions determined by gross examination were not statistically different from those determined by ultrasonography. Furthermore the renal dimensions and RI were statistically correlated to the body weight of cats.

Effect of Red Ginseng Extract on the Pharmacokinetics and Efficacy of Metformin in Streptozotocin-Induced Diabetic Rats.

The purpose of this study was to investigate the effect of red ginseng extract on the pharmacokinetics (PK) and efficacy of metformin in streptozotocin-induced diabetic rats. The diabetes mellitus rat model was established by intraperitoneally administering multiple doses of streptozotocin (30 mg/kg, twice on day 1 and 8), and diabetic rats received metformin 50 mg/kg with or without single or multiple administration of Korean red ginseng extract (RGE, 2 g/kg/day, once or for 1 week). RGE administration did not affect the plasma concentration and renal excretion of metformin. Further, diabetic rats were administered metformin (50 mg/kg) and RGE (2 g/kg) alone or concomitantly for 5 weeks, and both regimens decreased the fasting blood glucose and glycated hemoglobin (Hb-A1c) levels. Furthermore, fasting blood glucose levels were reduced by metformin or RGE administered alone but recovered to the control level following co-administration, suggesting that the effect was additive. However, triglyceride and free fatty acid levels were not different with metformin and RGE treatment alone or in combination. Biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels were not different among the three treatment groups. In conclusion, RGE and metformin showed an additive effect in glycemic control. However, the co-administration of RGE and metformin did not cause PK interactions or affect biochemical parameters including the free fatty acid, triglyceride, AST, ALT, or cholesterol levels.

Involvement of intestinal efflux and metabolic instability in the pharmacokinetics of platycodin D in rats.

We aimed to investigate the underlying mechanisms for low bioavailability of Platycodin D (PD) in rats. The bioavailability of PD was 1.89% with different half-lives depending on the administration route (2.14 ± 0.18 h for intravenous injection vs 5.42 ± 1.9 h for oral administration). The mean absorption time was 6.3 h calculated from the mean residence time of both administration routes. Consistent with these parameters, rat intestinal permeability using 3 different intestinal segments showed a low but greatest permeability in lower ileum (0.05 × 10-6 cm/s in jejunum and upper ileum vs 0.13 × 10-6 cm/s in lower ileum). The involvement of efflux system, probably Mrps, in upper ileum, could be explained from the efflux ratio of 6.4 and reduced efflux ratio by an Mrp inhibitor, MK571. The recovery of unchanged PD after the intravenous and oral administration was 50% and 5.2%, respectively, suggesting the contribution of gastrointestinal metabolism. In the gastrointestinal content, 4 metabolites of PD were identified: acetylated PD (m/z 1265.6), deglucose PD (m/z 1061.5), deapiose PD (m/z 1091.5), and deapiose-dexylose-derhamnose PD (m/z 813.4). In conclusion, the intestinal first-pass effect such as the presence of efflux functions in the upper ileum, limited but steady intestinal permeability, and gastrointestinal metabolism could explain the low bioavailability and prolonged absorption time of orally administered PD.

The optimal size and placement of transdermal electrodes are critical for the efficacy of a transcutaneous pacemaker in dogs.

Transcutaneous cardiac pacing (TCP) can be used in dogs with a high risk for bradyarrhythmias prior to anesthesia, either in an emergency room or intensive care unit setting. Furthermore, TCP can also be used on patients diagnosed with bradyarrhythmias that require temporary pacing at the induction of anesthesia for the implantation of a permanent pacemaker. Despite the importance of TCP in emergency medicine, no studies have evaluated the optimal size and placement of the transdermal electrodes crucial for the efficacy of TCP in dogs. This study evaluated four different sizes of electrodes (10.5, 20, 30 and 40 cm2), and four different anatomical sites (anterior-posterior, left-right, apex-base, modified left-right) in order to optimize the efficacy of TCP in dogs. Electrodes with a surface area of 20 cm2 and a modified left-right placement minimized the pacing current and involuntary skeletal muscular contraction (muscular twitching) and so achieved the most optimal effect of TCP in dogs.