Pharmacokinetics and bioavailability of solid dispersion formulation of tilmicosin in pigs.

Tilmicosin (TMS) is a semisynthetic macrolide antibiotic restricted to veterinary use but is only partially soluble in aqueous solutions, which limits its administration in treatments. We developed a strategy to enhance the supersaturated solubility of TMS using amorphous solid dispersion (SD). The dissolution profile shown that the dissolution rate of TMS-SD was obviously faster than TMS. The pharmacokinetics of tilmicosin (TMS) and tilmicosin solid dispersion (TMS-SD) in pigs after oral administration at a single dose of 50 mg/kg b.w were investigated. The tmax of TMS-SD (2.50 hr) was 1.80 times faster than TMS (4.50 hr) (p < .05). There were no significant differences in the other PK parameters (Cmax , t1/2ß , V/F, CL/F, MRT, and AUC0-inf ) (p > .05). The mean relative bioavailability of TMS-SD compared with TMS was 140.39%, according to the AUC0-inf values. These results demonstrated that the solid dispersion technique enhanced the bioavailability of TMS and the new formulation administered to animals via drinking water may be used as a therapeutic alternative for clinical treatments.

Central Blockade of E-Prostanoid 3 Receptor Ameliorated Hypertension Partially by Attenuating Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats.

Hypertension, as one of the major risk factors for cardiovascular disease, significantly affects human health. Prostaglandin E2 (PGE2) and the E3-class prostanoid (EP3) receptor have previously been demonstrated to modulate blood pressure and hemodynamics in various animal models of hypertension. The PGE2-evoked pressor and biochemical responses can be blocked with the EP3 receptor antagonist, L-798106 (N-[(5-bromo-2methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide). In the hypothalamic paraventricular nucleus (PVN), sympathetic excitation can be introduced by PGE2, which can activate EP3 receptors located in the PVN. In such a case, the central knockdown of EP3 receptor can be considered as a potential therapeutic modality for hypertension management. The present study examined the efficacy of the PVN infusion of L-798106, by performing experiments on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The rats were administered with chronic bilateral PVN infusion of L-798106 (10 µg/day) or the vehicle for 28 days. The results indicated that the SHRs had a higher mean arterial pressure (MAP), an increased Fra-like (Fra-LI) activity in the PVN, as well as a higher expression of gp91phox, mitogen-activated protein kinase (MAPK), and proinflammatory cytokines in the PVN compared with the WKYs. Additionally, the expression of Cu/Zn-SOD in the PVN of the SHRs was reduced compared with the WKYs. The bilateral PVN infusion of L-798106 significantly reduced MAP, as well as plasma norepinephrine (NE) levels in the SHRs. It also inhibited Fra-LI activity and reduced the expression of gp91phox, proinflammatory cytokines, and MAPK, whereas it increased the expression of Cu/Zn-SOD in the PVN of SHRs. In addition, L-798106 restored the balance of the neurotransmitters in the PVN. On the whole, the findings of the present study demonstrate that the PVN blockade of EP3 receptor can ameliorate hypertension and cardiac hypertrophy partially by attenuating ROS and proinflammatory cytokines, and modulating neurotransmitters in the PVN.