Effects of toceranib compared with sorafenib on monocrotaline-induced pulmonary arterial hypertension and cardiopulmonary remodeling in rats

Sorafenib reverses pulmonary arterial hypertension (PAH) and cardiopulmonary remodeling (CPR), but the effects of toceranib are unknown. This study investigated anti-remodeling effects and determined optimal doses of toceranib and sorafenib on monocrotaline (MCT)-induced PAH and CPR in rats. MCT-treated rats were orally treated with a 14-day course of sorafenib (10, 30, or 100 mg/kg), toceranib (1, 3, or 10 mg/kg), or water. Both sorafenib and toceranib significantly reversed the right ventricular (RV) hypertrophy at 10 mg/kg, but only sorafenib significantly improved the RV systolic and mean pressures. Sorafenib significantly normalized the B-type natriuretic peptide mRNA level of the RV and increased the non-muscularized pulmonary artery percentage. However, these effects were only observed at the highest toceranib dose, and neither toceranib dose reduced the fully muscularized pulmonary artery percentage. Further, the inhibition on vascular endothelial growth factor (VEGF) signaling was stronger in sorafenib than in toceranib. Besides the stronger inhibition on mitogen-activated protein kinase signaling, the greater reversal ability of sorafenib may be also due to the simultaneous blockade on the C-X-C chemokine receptor type 4 and autophagy induction. Toceranib insignificantly reversed CPR, and a high-dose therapy did not improve the RV hemodynamic outcomes. Sorafenib significantly reversed CPR, and a low-dose sorafenib therapy may be a suitable therapeutic agent for PAH

Effects of masitinib compared with tadalafil for the treatment of monocrotaline-induced pulmonary arterial hypertension in rats

Targeting vascular remodeling in pulmonary arterial hypertension (PAH) remains a challenge given the lack of potent anti-remodeling abilities of the therapeutic drugs. Although sildenafil has been shown to ameliorate cardiopulmonary remodeling, that of tadalafil is questionable. Masitinib, a tyrosine kinase inhibitor appears safer and more potent than imatinib for treatment of malignancies, but its efficacy on PAH is unknown. Therefore, we investigated the anti-remodeling properties of masitinib (5, 15, 50 mg/kg) and tadalafil (5, 10 mg/kg) using a monocrotaline-induced rat model of PAH. The 14-day treatment with masitinib (15, 50 mg/kg) resulted in significantly decreased right ventricular (RV) systolic pressure (RVSP) and hypertrophy (RVH), and pulmonary vascular remodeling, whereas tadalafil showed weaker anti-remodeling properties. Besides, masitinib significantly blocked the mitogen-associated protein kinase (MAPK) pathway, and reduced phosphodiesterase (PDE)-5 mRNA expression in the lungs. By contrast, tadalafil did not significantly inhibit the MAPK pathway. Further, the 28-day treatment extension revealed that masitinib-treated rats (15 mg/kg) had significantly lower RVSP, and higher heart rate and serum cyclic guanosine monophosphate (cGMP) level, whereas those treated with tadalafil (10 mg/kg) showed insignificantly lower RVSP and higher cGMP level. Moreover, the RVH indices, heart rates, body weight gains, and survival rates of rats in both groups were comparable. Collectively, these results suggest that the treatment with a low-dose masitinib was non-inferior than tadalafil. A lower dose of masitinib may represent a novel approach to target both the cardiopulmonary remodeling and the dysregulated vasoconstriction in PAH

Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats

High-dose imatinib reverses cardiopulmonary remodeling but adverse effects limit its clinical use. Efficacy of the multi-kinase inhibitor sunitinib remains questionable. We compared anti-remodeling effects of imatinib with sunitinib on monocrotaline-induced right ventricular (RV) hypertrophy and pulmonary arterial remodeling in rats, focusing on a lower dose. Fourteen days after monocrotaline injection, oral gavage of imatinib (5, 15, or 50mg/kg), sunitinib (0.3, 1, 3, or 10mg/kg), or water for 14days was started. RV hypertrophy and b-type natriuretic peptide mRNA levels were significantly and dose-dependently reduced, much greater in imatinib- than sunitinib-treated groups. Imatinib normalized muscularization of 20–50μm intra-acinar pulmonary arteries more significantly than sunitinib. At transcript levels, sunitinib significantly upregulated pulmonary nestin, and downregulated platelet-derived growth factor receptor beta (PDGFR-β), fibroblast growth factor receptor 1, vascular endothelial growth factor receptor-2 and vascular endothelial growth factor (VEGF)-A, but not Raf-1 proto-oncogene serine/threonine kinase mRNAs. Sunitinib also suppressed VEGF-A, but not phosphorylated extra-cellular-signal-related kinase (ERK)-1/2 protein expression. The sole PDGFR-β antagonism of imatinib resulted in significant Raf-1 mRNA and phosphorylated ERK-1/2 protein downregulation, suggesting that the equivocal reversal effect of sunitinib may be due to its VEGF signaling inhibition in the lung. Imatinib's greater dose-dependent reversal on cardiopulmonary remodeling may make a low dose suitable for PAH treatment

Effect of a combined Napier grass-oil palm frond feed on the in vivo and in sacco rumen fermentation and digestibility in goats

In Malaysia, the lack of high-quality pasture remains the main factor slowing down the development of the ruminant livestock industry. The oil palm fronds (OPF), abundant and readily available agricultural by-products, appear as a promising solution, though they are unsuitable to be used as a sole feed. Therefore, this study evaluated a combined Napier grass (NP) and OPF (NP+OPF) feed by monitoring the digestibility, in vivo and in sacco, as well as the changes of rumen fermentation parameters (volatile fatty acids, rumen fluid pH and total protozoal counts). Fifteen two-year-old male rumen-fistulated Kacang crossbed goats were used and divided into three groups, where Treatment 1 group was fed 50% NP + 50% concentrate, Treatment 2 group 25% NP + 25% OPF + 50% concentrate, and Treatment 3 group 50% OPF + 50% concentrate. Following dietary adaptation of 10 days, the in vivo and in sacco digestibility and rumen fermentation parameters were determined. Compared to the 50% NP diet, the combined NP-OPF feed showed a significantly lower in sacco digestibility and total volatile fatty acid production (p< 0.05). However, it produced good in vivo digestibility, rumen pH and total protozoal counts which were comparable to the 50% NP diet and significantly better than the 50% oil palm frond feed. Thus, it is concluded that the combined NP-OPF diet is suitable as a ruminant feed

In vitro evaluation of Napier grass-oil palm frond combination as ruminant feed

The effects of different combinations of Napier grass (Pennisetum purpureum) and oil palm (Elaeis guineensis Jacq) fronds on ruminal fermentation patterns in vitro in goats were investigated. Rumen liquor from three 2-year-old Kacang-crossbred goats was mixed with buffer and substrates. Four dietary treatments were compared namely 100% concentrates (CON), 50% OPF with 50% concentrates (OPF 50), 50% Napier grass with 50% concentrates (NP 50), and 25% Napier grass, 25% OPF and 50% concentrates (NP-OPF)). Incubation of the mixture was carried out at 39°C for 24 h. Total gas production (GP) was recorded after 2, 4, 6, 8, 10, 12 and 24 h of incubation. Rumen fluid pH, methane gas, total volatile fatty acids and in vitro dry matter digestibility (IVDMD) were determined at the end of incubation. Long chain fatty acid (LCFA) profiles were obtained in separate runs to determine the apparent biohydrogenation (BH) of linoleic (C18:2n-6) and α-linolenic acids (C18:3n-3). Cumulative gas production was significantly higher for the CON group (P<0.05) but not significantly different in the other groups. The NP 50 diet produced significantly higher methane (P<0.05) while other groups did not differ significantly. For IVDMD, the NP-OPF group had a significantly higher digestibility than the NP 50 and OPF 50 groups. Rumen fluid pH, total VFA and apparent BH values for all treatments were not significantly different. In conclusion, the Napier-OPF combination represents a suitable feed for the small ruminant sector in Malaysia but more studies need to be done on effects of OPF on rumen biohydrogenation

Congenital biliary anomaly with secondary cholangiohepatitis in a Siamese cross kitten

A 5-month-old Siamese cross kitten was presented with jaundice and a palpable abdominal mass at the right cranial quadrant. The extra-hepatic biliary system was markedly distended upon abdominal ultrasonography. Complete bile duct obstruction was ruled out due to the presence of urobilinogen, light brown stool, and consistently normal alkaline phosphatase (ALP) levels. Head tremors developed on the second day of hospitalization. Tentative diagnoses of congenital biliary anomaly and hepatic encephalopathy were derived and exploratory laparotomy revealed a severely distended and tortuous bile duct indistinguishable from the gallbladder with negative duodenal filling. Modified cholechoduodenostomy was performed however the kitten did not recover from general anaesthesia. Secondary cholangiohepatitis and hepatic encephalopathy were confirmed upon histopathologic examination.Primary congenital biliary atresia or choledochal cyst with secondary cholangiohepatitis was suspected. Biliary anomalies are rare in cats with only two cases reported in the literature. These conditions are often challenging to diagnose and due to the limited treatment options, have a poor prognosis