Intraocular pharmacokinetics of anti-vascular endothelial growth factor agents by intraoperative subretinal versus intravitreal injection in silicone oil-filled eyes of proliferative diabetic retinopathy: a randomized controlled pilot study.

PURPOSE: Intraoperative subretinal anti-vascular endothelial growth factor (VEGF) injections have been used clinically in some case, but the pharmacokinetic characteristics have not yet been determined. In this pilot study, we investigate the pharmacokinetic parameters of anti-VEGF agents by intraoperative subretinal or intravitreal injection in silicone oil (SiO)-filled eyes of patients with proliferative diabetic retinopathy (PDR). METHODS: Randomized controlled trial including 13 patients (16 eyes) with PDR underwent pars plana vitrectomy (PPV) with SiO tamponade and randomly received a subretinal (8 eyes) or intravitreal (8 eyes) conbercept injection (0.5 mg/0.05 ml) intraoperatively. Aqueous humour (AH) was obtained on the 1st, 3rd, 7th, 10th, 14th, 21st and 28th day after the injection. Drug concentrations in the AH were determined by enzyme-linked immunosorbent assay (ELISA). The last best-corrected visual acuity (BCVA) was examined 6 months postoperatively. RESULTS: The clearance rate of anti-VEGF agents by subretinal injection was reduced in vitrectomized eyes with SiO tamponade (p < 0.05). With the same drug dose, subretinal injection (5.49 ± 6.11 µg/ml) resulted in higher drug concentrations in the AH when compared with intravitreal injection (0.42 ± 0.46 µg/ml, p = 0.001) 4 weeks after the treatment. The mean residence time last (MRT0-t ) by subretinal injection (11.57 ± 0.83 days) was significantly longer than the mean MRT0-t by intravitreal injection (7.10 ± 1.00 days, p < 0.001). A self-paired analysis showed that subretinal injection led to the BCVA improvement by +28.59 letters 6 months postoperatively (p = 0.028) while the BCVA did not improve significantly by intravitreal injection (p = 0.715). CONCLUSIONS: The drug maintenance phase was prolonged by intraoperative subretinal injection in SiO-filled eyes of PDR. The results suggest that subretinal injection might be a valuable treatment option for the management of PDR.

Comparative pharmacokinetics of four active components on normal and diabetic rats after oral administration of Gandi capsules.

The Gandi capsule, a famous traditional Chinese medicine (TCM), is a hospital preparation that has been widely used in China for decades for the treatment of diabetes. The aim of this study is to compare the pharmacokinetics of four of the active components of Gandi capsules, which are the primary antidiabetic ingredients, on normal and diabetic Sprague-Dawley rats following oral administration of the capsules. Baicalin, wogonoside, wogonin, loganin and puerarin (internal standard) were prepared using methanol precipitation, and the separation of the five components was achieved through a ZORBAX Eclipse Plus C18 column by gradient elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase. After oral administration of Gandi capsules to the normal and diabetic rats, plasma was harvested and analyzed using liquid chromatography coupled with tandem mass spectrometry, and the primary pharmacokinetic parameters were calculated by DAS 2.0. Compared with the normal group, some pharmacokinetic parameters especially the AUC0-48 h of the four compounds significantly increased in the diabetic groups. The results demonstrated that the four constituents in normal and diabetic rats had obvious differences in some pharmacokinetic characteristics, suggesting that the rate and extent of drug metabolism were altered in diabetic animals. The results could be helpful for demonstrating the compatibility mechanism and providing clinical medication guidance for Gandi capsules.

Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion.

Carnosine is a dipeptide that scavenges free radicals, inhibits inflammation in the central nervous system, and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions. Therefore, we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury. White matter damage was induced by right unilateral common carotid artery occlusion in mice. The animals were treated with 200, 500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury. Then, 37 days later, Klüver-Barrera staining, toluidine blue staining and immunofluorescence staining were performed. Carnosine (200, 500 mg/kg) substantially reduced damage to the white matter in the corpus callosum, internal capsule and optic tract, and it rescued expression of myelin basic protein, and alleviated the loss of oligodendrocytes. However, carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses. These findings show that carnosine, at a particular dose range, protects against white matter damage caused by chronic cerebral ischemia in mice, likely by reducing oligodendroglial cell loss.

Relationships between PON1 Q192R polymorphism and clinical outcome of antiplatelet treatment after percutaneous coronary intervention: a meta-analysis.

This meta-analysis was performed to assess the relationships between the PON1 Q192R (rs662 T>C) polymorphism and the clinical outcome of antiplatelet treatment after percutaneous coronary intervention (PCI). A range of electronic databases were searched: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013) and the Chinese Biomedical Database (CBM) (1982-2013) without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Six clinical cohort studies with a total number of 5,189 patients undergoing PCI for coronary heart disease were included. Our meta-analysis revealed that the PON1 Q192R polymorphism was correlated with an increased risk of major adverse cardiovascular events (MACE) in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.22, 95 % CI 1.04-1.43, P = 0.014; CT+CC vs. TT: OR = 1.38, 95 % CI 1.03-1.86, P = 0.029; CC vs. TT: OR = 1.45, 95 % CI 1.05-1.99, P = 0.024; respectively), especially among Asians. Furthermore, we found significantly positive correlations between the PON1 Q192R polymorphism and the incidence of stent thrombosis in patients receiving antiplatelet treatment after PCI (C allele vs. T allele: OR = 1.42, 95 % CI 1.08-1.87, P = 0.011; CT+CC vs. TT: OR = 1.93, 95 % CI 1.01-3.67, P = 0.046; CC vs. TT: OR = 2.18, 95 % CI 1.09-4.35, P = 0.027; respectively). Our meta-analysis of clinical cohort studies provides evidence that the PON1 Q192R polymorphism may increase the risk of MACE and stent thrombosis in patients receiving antiplatelet treatment after PCI.

Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent.

Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice.

RATIONALE: Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 antagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown. OBJECTIVE: In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice. METHODS: Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests. RESULTS: Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. CONCLUSION: The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.

Spatiotemporal changes of the N-methyl-D-aspartate receptor subunit levels in rats with pentylenetetrazole-induced seizures.

The aim of this study was to examine the expression profiles of N-methyl-D-aspartate (NMDA) receptor subunits in rats during seizure development and kindled process induced by pentylenetetrazole (PTZ). Using quantitative Western blotting, the levels of NR1, NR2A and NR2B subunits were measured in the cortex and hippocampus of rats at different times after PTZ injection. In the early seizure developmental process, both NR1 and NR2A were markedly increased in the cortex, and NR1 was significantly increased in the hippocampus. On the other hand, in the kindled process both NR1 and NR2A decreased in the cortex and hippocampus. However, the NR2B subunit had no appreciable change in both the seizure developmental and kindled process. Therefore, these results showed that expression of NMDA receptors undergoes subunit- and region-related changes in the developmental and kindled seizure of rats induced by PTZ.

Effect of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate, a novel acetylcholinesterase inhibitor, on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats.

It is of interest whether the acetylcholinesterase inhibitor, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), can improve cognitive impairment caused by chronic cerebral ischemia in rats. Two weeks after four-vessel occlusion, apparent impairments of spatial retrieval memory were observed in the Morris water maze. Both TAK-147 at doses of 0.1, 0.3 and 1.0 mg/kg and donepezil at doses of 0.3 and 1.0 mg/kg significantly ameliorated ischemia-induced memory deficits dose-dependently, but tacrine had no appreciable effect. Furthermore, we demonstrate that the intensity of staining by 2,3,5-triphenyltetrazolium in the hippocampal and cortical slices was significantly decreased by ischemia (10 min anoxia/aglycemia), and that it was also significantly restored by treatment with TAK-147 and donepezil.

Reversal of scopolamine-induced spatial memory deficits in rats by TAK-147.

AIM: To evaluate effect of TAK-147 on spatial memory deficit induced by scopolamine. METHODS: Morris water maze was used to measure spatial memory in rats and open field test was used to analyse locomotor activity. RESULTS: In the acquisition memory process, scopolamine (0.4 mg/kg, ip) markedly increased the escape latency to the platform. Ip injection of both TAK-147 and donepezil ameliorated scopolamine-induced deficit, dose-related and significant effect was obtained at doses of 0.1-1.0 mg/kg. In the memory retrieval process, increased latency induced by scopolamine (1.5 mg/kg, ip) was also significantly reversed by treatment with TAK-147 (0.1, 0.3, and 1.0 mg/kg), donepezil (0.3 and 1.0 mg/kg), and tacrine (3 and 5 mg/kg), respectively. TAK-147 has a little potent efficacy to donepezil, and was more potent than tacrine. In the locomotor test, both TAK-147 and donepizil created no appreciable change of locomotor activities, compared with scopolamine or saline. CONCLUSION: TAK-147 plays an important role in spatial cognition, and this result provides additional evidence that TAK-147 is an ideal AChE inhibitor and is useful for the treatment of Alzheimer's disease.

[Effects of TAK-147, a novel acetylcholinesterase inhibitor, on spatial memory deficit as evaluated by Morris water maze of rats]

OBJECTIVE: To evalute the effects of TAK-147, a novel acetylcholinesterase inhibitor on rat spatial memory deficit using the Morris water maze. METHODS: Morris water maze was used to measure spatial memory in rats, and open field test was used to analysis locomotor activity. RESULTS: Scopolamine (0.4mg/kg,IP) significantly increased the latency period in memory acquisition. Intraperitoneal TAK-147 injection ameliorated scopolamine-induced deficit in a dose-related manner. A significant effect was obtained at doses of 0.3 and 1.0 mg/kg. Both TAK-147 (0.3 and 1.0 mg/kg) and tacrine (3 and 5 mg/kg) significantly reversed scopolamine (1.5 mg/kg) increased latency in memory retrieval. However, TAK-147 had a more potent effect than tacrine. In the locomotor test, TAK-147 created no appreciable change, compared with scopolamine or saline. CONCLUSION: A novel acetycholinesterase inhibitor, TAK-147 ameliorates the scopolamine induced impaired spatial memory in rats.