Impacts of Surgically Performed Renal Denervation on the Cardiovascular and Electrophysiological Variables in the Chronic Atrioventricular Block Dogs　- Comparison With Those of Amiodarone Treatment.

BACKGROUND: In order to begin to precisely clarify the impact of renal denervation on the blood pressure, atrial fibrillation and ventricular tachyarrhythmias, in addition to proarrhythmic potential, its cardiovascular effects were assessed by using the chronic complete atrioventricular block dogs. METHODS AND RESULTS: Cardiohemodynamic and electrophysiological effects, together with neurohumoral factors and/or electrolytes, were assessed before and 4 weeks after either renal denervation (n=5) or amiodarone treatment (n=6). Amiodarone hydrochloride was given orally to the animals every day in a dose of 200 mg/day for the first 7 days followed by 100 mg/day for the following 21 days. The renal denervation decreased the systolic pressure, idioventricular rate, prolonged ventricular effective refractory period, and slightly suppressed the adrenergic tone and the renin-angiotensin-aldosterone system, but hardly affected the atrial effective refractory period and terminal repolarization period. Amiodarone prolonged the atrial effective refractory period, whereas no significant change was detected in the other variables. CONCLUSIONS: Surgically performed renal denervation may possess the anti-ventricular tachyarrhythmic rather than anti-atrial fibrillatory potentials, and it also modestly decreased the blood pressure. Thus, currently obtained information may be used as guidance for better understanding the utility and limitation of renal denervation against various types of cardiovascular diseases. (Circ J 2016; 80: 1556-1563).

An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation.

In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®-NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX-albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).

Pharmacological characterization of microminipig as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies.

We tried to establish the halothane-anesthetized microminipigs as an alternative animal model for non-clinical toxicity and/or safety pharmacology studies. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia on their cardiovascular system (n = 5). Then, we examined the cardiovascular effects of dl-sotalol in doses of 0.1, 0.3 and 1 mg/kg, i.v. on the halothane-anesthetized microminipigs (n = 6). Induction of the halothane anesthesia by itself prolonged the QT interval as well as QTcF, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs. dl-Sotalol showed more potent negative chronotropic, dromotropic and hypotensive effects together with repolarization delay in microminipigs than in dogs, although each cardiovascular response to dl-sotalol was directionally similar between them, suggesting greater basal sympathetic tone and/or smaller volume of distribution of the drug in microminipigs than in dogs. Analyses of proarrhythmic surrogate markers indicate that Tpeak-Tend and short-term variability of QT interval may be more sensitive to detect the dl-sotalol-induced direct electrophysiological changes in microminipigs than in dogs, but its reverse will be true for J-Tpeakc. Thus, these results may help better understand the drug-induced cardiovascular responses in microminipigs.

Lysocellin, a metabolite of the novel drug 'alopestatin', induces G1 arrest and prevents cytotoxicity induced by etoposide.

We report here that lysocellin, a polyether antibiotic from a streptomycete, induces G1 phase arrest in human osteosarcoma MG63 cells. Lysocellin up-regulates p21WAF1/Cip1 and down-regulates cyclin D1 at the mRNA level. In addition, cyclin D1 is down-regulated by the proteasome-dependent signal pathway in MG63 cells. In drug combination studies, we found that lysocellin treatment weakened the cytotoxic activity of etoposide in MG63 cells using a colony-formation assay. To study the in vivo efficacy of lysocellin, we isolated a novel compound related to lysocellin from the same streptomycete, and found that the novel drug is converted to lysocellin in vivo and decreases etoposide-induced alopecia in a neonatal rat model. We raise the possibility that this novel drug, named 'alopestatin', may be a promising agent against alopecia.

Effects of acute intravenous administration of pentamidine, a typical hERG-trafficking inhibitor, on the cardiac repolarization process of halothane-anesthetized dogs.

Although acute treatment of pentamidine does not directly modify any ionic channel function in the heart at clinically relevant concentrations, its continuous exposure can prolong QT interval. Recent in vitro studies have indicated that hERG trafficking inhibition may play an important role in the onset of pentamidine-induced long QT syndrome. In this study, we examined acute in vivo electropharmacological effects of pentamidine using the halothane-anesthetized canine model (n = 5). The clinically relevant total dose of 4 mg/kg of pentamidine (namely, 1 mg/kg, i.v. over 10 min followed by 3 mg/kg, i.v. over 10 min with a pause of 20 min) decreased the mean blood pressure, ventricular contraction, preload to the left ventricle, and peripheral vascular resistance. Pentamidine also enhanced the atrioventricular conduction in parallel with its cardiohemodynamic actions, but it gradually prolonged both the ventricular repolarization period and effective refractory period, whereas no significant change was detected in the intraventricular conduction. Thus, acute administration of a clinically relevant dose of pentamidine can suppress cardiac function and vascular tone with reflex-mediated increase of sympathetic activity, whereas it may delay the repolarization process, suggesting that inhibition of potassium-channel trafficking might be induced more acutely in vivo than those previously expected in vitro.

Solvolysis of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoate derivatives.

The solvolysis reaction of (4,5)-anti-4-aryl-5-tosyloxy-2(E)-hexenoates 4a-k gave (4,5)-anti-4-aryl-5-hydroxy-2(E)-hexenoates 2a-k and (4,5)-anti-5-aryl-4-hydroxy-2(E)-hexenoates 5a-k along with the complete inversion. This 1,2-aryl migration was induced by treatment with heating in water-saturated nitromethane. On the basis of the substituent effect on the aromatic ring, this 1,2-aryl migration is thought to proceed via the sigma-bridged phenonium ion. The product selectivity between 2a-k and 5a-k was found to be subtly governed by the substituent and substitution pattern in the aromatic ring of the substrates 4a-k.