Explore the vast range of titles available.

The pharmacokinetic profile of firocoxib administered orally at 5 mg/kg as a single dose to three mature koalas of each sex is described. After single dose administration, the harmonic means for maximal plasma concentration (C max ), time to reach C max (T max ) and elimination half-life (t 1/2 ) were 79.2 ng/mL, 3.69 h, and 5.01 h, respectively. Males exhibited a higher C max than females (217.4 vs 48.4 ng/mL), suggesting greater oral absorption, while females had a slower elimination (t 1/2 : 5.87 h vs 4.38 h in males), however these sex differences were not significant. After a wash-out period, the same dose was administered every 12 h, on six occasions to the same koalas. With repeat dosing, females had higher trough concentrations at 24 and 48 h, and 12 h after the last dose, compared to the males. No observable adverse effects were evident in any of the koalas following repeat dosing. The target plasma concentration was approximately 100 ng/mL based on in vitro studies in other species to inhibit 80% of cyclooxygenase-2 activity (inhibitory concentration 80 [IC80]). During single firocoxib administration, this plasma concentration was attained only in the males and not in the females. Two unidentified metabolites were also observed in the chromatograms. Acknowledging the lipophilic nature of firocoxib and that it is therefore likely to persist in animals’ tissues longer than in plasma, firocoxib appears a useful nonsteroidal anti-inflammatory drug for the koala. The oral dose of 5 mg/kg twice a day for a maximum of six doses appears safe for mature male koalas. The data presented here suggests that mature females may require a higher dose (perhaps double the dose i.e., i.e., 10 mg/kg). Until further studies confirm the sex differences in pharmacokinetic profile of firocoxib and safety of higher doses in female koalas, a once daily administration of a higher dose is suggested.

Abstract Background Many horses receive firocoxib over multiple years, and studies evaluating hematologic and biochemical values in these animals are lacking. Objective To describe the hematologic and biochemical values of horses receiving long-term firocoxib. Animals A total of 79 horses receiving long-term firocoxib and 153 horses not receiving long-term firocoxib and not presenting for a specific medical problem. Methods Retrospective study comparing horses receiving firocoxib (F group) and no firocoxib (NF group). Signalment, hematologic, and biochemical values were compared between the two groups. Simple linear regression was used to evaluate the relationship between the duration of firocoxib administration and specific laboratory variables. Results Horses receiving long-term firocoxib (F) were 19 (5–33) years as compared to 15 (1–33) years for the NF group (p < 0.0001). The most common reason for receiving firocoxib was osteoarthritis in 44/79 (56%) of the animals in the F group. Horses in the F group had a total protein concentration of 6.6 (5.8–8.0) g/dL as compared to 6.5 (5.1–8) g/dL in the NF group (p = 0.03). The sodium concentration for F horses was 139 (133–143) mmol/L as compared to 138 (129–145) mmol/L for NF horses (p = 0.01). Total white blood cell count was 6.11 (2.82–14.36) 103 cells/uL in the F group as compared to 6.46 (3.04–14.71) 103 cells/uL in the NF group (p = 0.03). None of the laboratory variables were associated with the duration of firocoxib administration. Conclusions and Clinical Importance Many horses receive firocoxib for multiple years, and equine practitioners should be aware that expected changes in laboratory values are minimal.

To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg ) improved the antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against . Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI.

Prostate cancer is a major cause of cancer-related mortality in men in developed countries. The compound, 4-acetylantroquinonol B (4AAQB), is isolated from Antrodia cinnamomea (commonly known as Niu-Chang-Chih), which has been shown to inhibit cancer growth. However, the anticancer activity of 4AAQB has not previously been examined in prostate cancer. This study aimed to investigate the effect of 4AAQB on cancer and angiogenesis, as well as to explore its mechanism of action. Human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) were used in cell viability, cell migration, and cell cycle functional assays to evaluate the anticancer and antiangiogenic efficacy of 4AAQB in vitro. The effects of 4AAQB in vivo were determined using xenograft and angiogenesis models. The signaling events downstream of 4AAQB were also examined. The 4AAQB compound inhibited PC3 cell growth and migration, and reduced in vivo cancer growth, as shown in a subcutaneous xenograft model. Furthermore, 4AAQB inhibited HUVEC migration, tube formation, and aortic ring sprouting; it also reduced neovascularization in a Matrigel implant angiogenesis assay in vivo. The 4AAQB compound also decreased metastasis in the PC3 prostate cancer model in vivo. Serum or vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (Akt), and extracellular signal-regulated kinase ½ (ERK ½) phosphorylation were attenuated by 4AAQB in both PC3 and HUVEC. In conclusion, 4AAQB is a potential candidate for prostate cancer therapy.

Butyrolactone I (BTL-I) is a butanolide isolated from the deep-sea-derived fungus, Aspergillus sp. It provides a potential new target for the prevention and treatment of food allergies. This study aimed to investigate the metabolic and pharmacokinetic profile of BTL-I in rats. The metabolic profiles were obtained by UHPLC–Q-TOF-MS. As a result, eleven metabolites were structurally identified, and the proposed metabolic pathways of BTL-I were characterized. The main metabolites were the oxidative and glucuronidative metabolites. In addition, a sensitive UHPLC–MS/MS method was established for the quantitation of BTL-I in rat plasma (LOQ = 2 ng/mL). The method was fully validated and successfully applied to the pharmacokinetic study of BTL-I in rats after oral administration or intravenous administration. The oral bioavailability was calculated as 6.29%, and the maximum plasma concentrations were 9.85 ± 1.54 ng/mL and 17.97 ± 1.36 ng/mL for intravenous and intragastric dosing groups, respectively.

Oxidized low-density lipoprotein (oxLDL) inhibits mammalian target of rapamycin (mTOR) and induces autophagy and apoptosis in vascular endothelial cells (VECs) that play very critical roles for the cardiovascular homostasis. We recently defined 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) as a new activator of mTOR. Therefore, we hypothesized that 3BDO had a protective role in VECs and thus stabilized atherosclerotic lesions in apolipoprotein E -/- (apoE -/- ) mice. Our results showed that oxLDL inhibited the activity of mTOR and increased the protein level of autophagy-related 13 (ATG13) and its dephosphorylation, thus inducing autophagy in human umbilical vein endothelial cells (HUVECs). All of these effects were strongly inhibited by 3BDO. In vivo experiments confirmed that 3BDO activated mTOR and decreased the protein level of ATG13 in the plaque endothelium of apoE -/- mice. Importantly, 3BDO did not affect the activity of mTOR and autophagy in macrophage cell line RAW246.7 and vascular smooth muscle cells of apoE -/- mice, but suppressed plaque endothelial cell death and restricted atherosclerosis development in the mice. 3BDO protected VECs by activating mTOR and thus stabilized atherosclerotic lesions in apoE -/- mice.

Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in both veterinary and human medicine. Gastrointestinal injury is a frequent adverse event associated with NSAID use and evidence suggests that NSAIDs induce gastrointestinal microbial imbalance (i.e., dysbiosis) in both animals and people. It is unknown, however, whether cyclooxygenase (COX)-2-selective NSAIDs induce dysbiosis, or if this phenomenon occurs in horses administered any class of NSAIDs. Therefore, our objectives were to determine whether the composition and diversity of the fecal microbiota of adult horses were altered by NSAID use, and whether these effects differed between non-selective and COX-2-selective NSAIDs. Twenty-five adult horses were randomly assigned to 1 of 3 groups: control (n = 5); phenylbutazone (n = 10); or, firocoxib (n = 10). Treatments were administered for 10 days. Fecal samples were collected every 5 days for 25 days. DNA was extracted from feces and the 16S rRNA gene amplified and sequenced to determine the composition of the microbiota and the inferred metagenome. While the fecal microbiota profile of the control group remained stable over time, the phenylbutazone and firocoxib groups had decreased diversity, and alteration of their microbiota profiles was most pronounced at day 10. Similarly, there were clear alterations of the inferred metagenome at day 10 compared to all other days, indicating that use of both non-selective and selective COX inhibitors resulted in temporary alterations of the fecal microbiota and inferred metagenome. Dysbiosis associated with NSAID administration is clinically relevant because dysbiosis has been associated with several important diseases of horses including abdominal pain (colic), colitis, enteric infections, and laminitis.

Consumption of flaxseed lignans is associated with various health benefits; however, little is known about the bioavailability of purified lignans in flaxseed. Data on their bioavailability and hence pharmacokinetics (PK) are necessary to better understand their role in putative health benefits. In the present study, we conducted a comparative PK analysis of the principal lignan of flaxseed, secoisolariciresinol diglucoside (SDG), and its primary metabolites, secoisolariciresinol (SECO), enterodiol (ED) and enterolactone (EL) in rats. Purified lignans were intravenously or orally administered to each male Wistar rat. SDG and its primary metabolites SECO, ED and EL were administered orally at doses of 40, 40, 10 and 10 mg/kg, respectively, and intravenously at doses of 20, 20, 5 and 1 mg/kg, respectively. Blood samples were collected at 0 (pre-dose), 5, 10, 15, 20, 30 and 45 min, and at 1, 2, 4, 6, 8, 12 and 24 h post-dosing, and serum samples were analysed. PK parameters and oral bioavailability of purified lignans were determined by non-compartmental methods. In general, administration of the flaxseed lignans SDG, SECO and ED demonstrated a high systemic clearance, a large volume of distribution and short half-lives, whereas administration of EL at the doses of 1 mg/kg (intravenously) and 10 mg/kg (orally administered) killed the rats within a few hours of dosing, precluding a PK analysis of this lignan. PK parameters of flaxseed lignans exhibited the following order: systemic clearance, SDG < SECO < ED; volume of distribution, SDG < SECO < ED; half-life, SDG < ED < SECO. The percentage of oral bioavailability was 0, 25 and < 1 % for SDG, SECO and ED, respectively.

Background Cisplatin combined with a nonselective cyclooxygenase (cox) inhibitor has potent antitumor activity against transitional cell carcinoma (TCC) in dogs, but this treatment is limited by renal toxicosis. Cox‐2 is expressed in TCC, but only in limited sites within the kidney. A cox‐2 inhibitor could enhance the antitumor activity of cisplatin with potentially fewer adverse effects on the kidney. Hypothesis Cisplatin/cox‐2 inhibitor treatment will have greater antitumor activity but no more renal toxicosis than cisplatin alone in dogs with TCC. Animals Forty‐four dogs with naturally occurring urinary bladder TCC. Methods Dogs were randomized to receive cisplatin (60 mg/m2 IV q21d), firocoxib (5 mg/kg PO q24h), or the combination. Tumor measurements were determined before and at 6‐week intervals during treatment. Renal function was monitored by serum creatinine concentration, iohexol clearance, and urine specific gravity. Toxicoses were graded according to Veterinary Co‐Operative Oncology Group (VCOG) criteria. Results The remission rate with cisplatin/firocoxib (57%) was significantly (P = .021) higher than that with cisplatin alone (13%). Renal and gastrointestinal toxicoses were common in dogs receiving cisplatin, but there were no significant differences between dogs receiving cisplatin or cisplatin/firocoxib. Firocoxib alone induced partial remission or stable disease in 20 and 33% of dogs, respectively. Conclusions Firocoxib significantly enhanced the antitumor activity of cisplatin resulting in partial remission in more than half of the cases. The toxicoses inherent to cisplatin, however, were noted in dogs receiving this combination. Firocoxib had antitumor effects as a single agent and can be considered a palliative treatment for dogs with TCC.

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.