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Muhammad Irfan Kamaruddin,1,2 Momoko Nakamura-Shibasaki,1 Yu Mizuno,1 Yoshiaki Kiuchi1 1Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Ophthalmology, Hasanuddin University, Makassar, South Sulawesi, Indonesia Purpose: Ripasudil is a novel Rho-associated protein kinase inhibitor that is used to treat ocular hypertension. However, the comparison of the intraocular pressure (IOP)-lowering effects between ripasudil alone and other ocular hypotensive drugs has not been studied thoroughly. The purpose of this study is to examine the ocular hypotensive effects of 0.4% ripasudil, 2% pilocarpine, 0.5% timolol and 0.1% dorzolamide in rabbits. We also studied the IOP changes when 0.4% ripasudil was combined with 2% pilocarpine, 0.5% timolol or 0.1% dorzolamide. Methods: One drop of saline solution, 0.4% ripasudil, 0.5% timolol, 2% pilocarpine or 1% dorzolamide or a combination of these agents was applied topically to the left eyes of eight healthy albino rabbits. Posttreatment changes in the IOP of albino rabbits were monitored using a rebound tonometer over a 5-h time course. Changes in IOP after application of saline served as the control. One-way analysis of variance and Dunnett’s post hoc tests were used for statistical analyses. Results: After topical instillation, 0.4% ripasudil resulted in significant decreases in IOP at 0.5 and 1 h compared with the control group. Treatment with timolol, pilocarpine or dorzolamide had no significant effect on IOP. Treatment with timolol, pilocarpine or dorzolamide in combination with ripasudil resulted in significant reductions in IOP at 1 h. However, none of these agents enhanced the IOP-lowering effects of ripasudil. Conclusion: Ripasudil has stronger IOP-lowering effects than timolol, pilocarpine or dorzolamide hypotensive agents in our rabbit model. Addition of timolol, pilocarpine or dorzolamide did not enhance the IOP-lowering effects of ripasudil alone. Keywords: ripasudil, timolol, pilocarpine, dorzolamide, intraocular pressure, rabbit

Tomohiro Mizuno,1,* Fumihiro Mizokami,2,* Kazuhiro Fukami,2 Kazuhiro Ito,2 Masataka Shibasaki,3 Tadashi Nagamatsu,1 Katsunori Furuta,4 1Department of Analytical Pharmacology, Meijo University Graduate School of Pharmacy, Nagoya, Japan; 2Department of Pharmacy, National Center for Geriatrics and Gerontology, 3Department of Respiratory Medicine, National Center for Geriatrics and Gerontology, 4Department of Clinical Research and Development, National Center for Geriatrics and Gerontology, Obu, Japan *These authors contributed equally to this work Background: Vancomycin (VCM) treatment outcomes depend on the characteristics of the patient, and it is well known that hypoalbuminemia is a risk factor for poor treatment outcomes, as reported in a previous study. However, the reason that severe hypoalbuminemia has an influence on the treatment outcome of VCM remains unknown. Objective: To elucidate the association between severe hypoalbuminemia and VCM treatment outcomes, we examined pharmacokinetic/pharmacodynamic (PK/PD) parameters in elderly patients with severe hypoalbuminemia. Methods: We conducted a retrospective observational study of 94 patients with methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia who had been treated with VCM between January 2006 and December 2012. The 94 patients were divided into severe hypoalbuminemia and non-severe hypoalbuminemia groups. The PK/PD parameters and treatment outcomes of VCM were compared between the two groups. Results: The half-life of VCM in the severe hypoalbuminemia group was significantly longer than in the non-severe hypoalbuminemia group (33.2 ± 5.4 vs 24.9 ± 1.6; P = 0.049). Area under the concentration curve (AUC)/minimum inhibitory concentration (MIC) values of 250–450 and >450 µg × h/mL were significantly associated with 28-day mortality in the severe hypoalbuminemia group (P < 0.001), whereas AUC/MIC values of

Fumihiro Mizokami,1 Masataka Shibasaki,2 Yasunori Yoshizue,1 Takeshi Noro,1 Tomohiro Mizuno,3 Katsunori Furuta41Department of Pharmacy, 2Department of Respiratory Medicine, National Center for Geriatrics and Gerontology, Obu, 3Department of Analytical Pharmacology, Meijo University Graduate School of Pharmacy, Nagoya, 4Department of Clinical Research and Development, National Center for Geriatrics and Gerontology, Obu, JapanBackground: Methicillin-resistant Staphylococcus aureus (MRSA) infections are associated with significant mortality and health care costs. To improve treatment outcomes for MRSA, a better understanding of the pharmacokinetic/pharmacodynamic parameters of vancomycin is required to develop optimal dosing strategies, particularly in elderly patients (≥75 years of age) with limited renal function. The purpose of this study was to determine whether pharmacokinetic indices for vancomycin are associated with mortality from MRSA hospital-acquired pneumonia in elderly patients.Methods: We conducted a retrospective observational study with 28-day mortality as the primary outcome for 94 patients with MRSA hospital-acquired pneumonia who had been treated with vancomycin from January 2006 through December 2012. Our most recent sampling of MRSA isolates had a minimum inhibitory concentration (MIC) for vancomycin of 1 µg/mL (86%), indicating that the area under the curve (AUC) was equal to the AUC/MIC in these isolates. The primary data from 28-day survivors and nonsurvivors were compared.Results: Among 94 elderly patients, the mean age was 82 (75–99) years. Multivariate analyses revealed that, among the factors examined, only the nonoptimal AUC (450 µg*h/mL) was an independent predictor of 28-day mortality in elderly patients (odds ratio 23.156, 95% confidence interval 6.814–78.687, P < 0.001). We detected a significant difference for increasing nephrotoxicity in nonsurvivors (nine of 32 patients [28%]) compared with survivors (three of 62 patients [4.8%], P = 0.003).Conclusion: This finding indicates that patients with potentially poor renal function are likely to have increased AUC values and a poor prognosis. Consideration of the pharmacokinetics/pharmacodynamics of vancomycin and targeting an AUC/MIC value of 250–450 µg*h/mL may result in improved treatment outcomes for elderly patients with MRSA hospital-acquired pneumonia.Keywords: methicillin-resistant Staphylococcus aureus, elderly patients, vancomycin, pharmacokinetics, pharmacodynamics

As much as 50% of cardiac output can be distributed to the skin in the hyperthermic human, and therefore the control of cutaneous vascular conductance (CVC) becomes critical for the maintenance of blood pressure. Little is known regarding the magnitude of cutaneous vasoconstriction in profoundly hypotensive individuals while heat stressed. This project investigated the hypothesis that leading up to and during syncopal symptoms associated with combined heat and orthostatic stress, reductions in CVC are inadequate to prevent syncope. Using a retrospective study design, we evaluated data from subjects who experienced syncopal symptoms during lower body negative pressure (N = 41) and head-up tilt (N = 5). Subjects were instrumented for measures of internal temperature, forearm skin blood flow, arterial pressure, and heart rate. CVC was calculated as skin blood flow/mean arterial pressure x 100. Data were obtained while subjects were normothermic, immediately before an orthostatic challenge while heat stressed, and at 5-s averages for the 2 min preceding the cessation of the orthostatic challenge due to syncopal symptoms. Whole body heat stress increased internal temperature (1.25 [+ or -] 0.3[degrees]C; P < 0.001) and CVC (29 [+ or -] 20 to 160 [+ or -] 58 CVC units; P < 0.001) without altering mean arterial pressure (83 [+ or -] 7 to 82 [+ or -] 6 mmHg). Mean arterial pressure was reduced to 57 [+ or -] 9 mmHg (P < 0.001) immediately before the termination of the orthostatic challenge. At test termination, CVC decreased to 138 [+ or -] 61 CVC units (P < 0.001) relative to before the orthostatic challenge but remained approximately fourfold greater than when subjects were normothermic. This negligible reduction in CVC during pronounced hypotension likely contributes to reduced orthostatic tolerance in heat-stressed humans. Given that lower body negative pressure and head-up tilt are models of acute hemorrhage, these findings have important implications with respect to mechanisms of compromised blood pressure control in the hemorrhagic individual who is also hyperthermic (e.g., military personnel, firefighters, etc.). skin blood flow; baroreceptors; hyperthermia; orthostasis doi: 10.1152/ajpheart.00290.2010.

Chemical research is presented describing the asymmetric structural determination study of epoxidated enones employing the complex oxide and BINOL triphenylarsine compound.