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Hiroyuki Enomoto,1 Shinji Fujikoshi,2 Jumpei Funai,3 Nao Sasaki,4 Michael H Ossipov,5 Toshinaga Tsuji,6 Levent Alev,7 Takahiro Ushida8 1Medical Science, Eli Lilly Japan K.K., Tokyo, 2Statistical Science, 3Science Communications, 4Medical Science, Eli Lilly Japan K.K., Kobe, Japan; 5Clinical Division, inVentiv Health, LLC, Blue Bell, PA, USA; 6Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 7Medical Department, Lilly Turkey, Istanbul, Turkey; 8Multidisciplinary Pain Center, Aichi Medical University, Nagakute, Aichi, Japan Background: Comorbid depression and depressive symptoms are common in patients with chronic low back pain (CLBP). Duloxetine is clinically effective in major depressive disorder and several chronic pain states, including CLBP. The objective of this post hoc meta-analysis was to assess direct and indirect analgesic efficacy of duloxetine for patients with CLBP in previous clinical trials. Methods: Post hoc path analyses were conducted of 3 randomized, double-blind, clinical studies of patients receiving duloxetine or placebo for CLBP. The primary outcome measure for pain was the Brief Pain Inventory, average pain score. A secondary outcome measure, the Beck Depression Inventory-II, was used for depressive symptoms. The changes in score from baseline to endpoint were determined for each index. Path analyses were employed to calculate the proportion of analgesia that may be attributed to a direct effect of duloxetine on pain.Results: A total of 851 patients (400 duloxetine and 451 placebo) were included in this analysis. Duloxetine significantly improved pain scores compared with placebo (p

The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope ® , a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.

In treating Major Depressive Disorder with associated painful physical symptoms (PPS), the effect of duloxetine on PPS has been shown to decompose into a direct effect on PPS and an indirect effect on PPS via depressive symptoms (DS) improvement. To evaluate the changes in relative contributions of the direct and indirect effects over time, we analyzed pooled data from 3 randomized double-blind studies comparing duloxetine 60 mg/d with placebo in patients with major depressive disorder and PPS. Changes from baseline in Montgomery-Åsberg Depression Rating Scale total and Brief Pain Inventory-Short Form average pain score were assessed over 8 weeks. Path analysis examined the (1) direct effect of treatment on PPS and/or indirect effect on PPS via DS improvement and (2) direct effect of treatment on DS and/or indirect effect on DS via PPS improvement. At week 1, the direct effect of duloxetine on PPS (75.3%) was greater than the indirect effect through DS improvement (24.7%) but became less (22.6%) than the indirect effect (77.4%) by week 8. Initially, the direct effect of duloxetine on PPS was markedly greater than its indirect effect, whereas later the indirect effect predominated. Conversely, at week 1, the direct effect of treatment on DS (46.4%) was less than the indirect effect (53.6%), and by week 8 it superseded (62.6%) the indirect effect (37.4%). Thus, duloxetine would relieve PPS directly in the initial phase and indirectly via improving DS in the later phase.

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.

Purpose: This phase I study was designed to determine the maximum tolerated dose (MTD) and the dose to be recommended for a future phase II study of tasisulam sodium in Japanese patients with advanced, refractory solid tumors. Safety, pharmacokinetics and preliminary anti-tumor activities were assessed. Due to high-affinity albumin binding, an albumin-tailored dose to reduce the variability in tasisulam exposure was also studied., Methods: A dose escalation scheme of tasisulam was used over 4 dose levels. Dose levels 1-3 targeted the maximum plasma concentration (C max) of 300, 340, and 360 μg/mL. Dose level 4 used an albumin-tailored range of C max-targeted doses to achieve an albumin-corrected exposure (AUCalb) of 1,200-6,400 μg h/mL, the range chosen for global tasisulam studies. Tasisulam was administered intravenously on day 1 of each 21-day (dose levels 1 and 2) or 28-day (dose levels 3 and 4) cycle., Results: The major adverse events were related to bone marrow suppression, particularly neutropenia and thrombocytopenia. Dose-limiting toxicities (DLTs) were not observed until dose level 4, where 3 out of 6 patients experienced DLT, despite a tendency toward lower AUCalb variability (CV %) in the albumin-tailored dose group (38 %) compared with the targeted C max groups (50-236 %)., Conclusions: Tasisulam in doses up to dose level 3 (target C max 360 μg/mL) was well tolerated. Although albumin-tailored dosing provided less AUCalb variability, a MTD that aligns with other global tasisulam studies was not identified. A lower AUCalb range may be required for the Japan population.

This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P<0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onset-type groups for several subscale domains (P<0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.

Background: Recently gemcitabine has been approved for treatment of metastatic or recurrent breast cancer in Japan; however, no systematically investigated safety study of long-term gemcitabine monotherapy has been reported despite its wide use globally for multiple indications., Patients and Methods: In a previously reported phase II study, 62 Japanese metastatic breast cancer patients with progressive disease after treatment with anthracyclines and taxanes were treated with gemcitabine 1250 mg/m(2) on days 1 and 8 of a 21-day cycle. For this report we re-analyzed the safety profiles for the 13 patients who received 10 or more cycles of the therapy., Results: Most grade 3/4 adverse events seen after 10 cycles were hematological toxicities. These were similar to those seen before the 10th cycle; however, 2 patients showed grade 3 nonhematological severe adverse events including acute cardiac failure and loss of consciousness. All adverse events were reversible and manageable. One patient received gemcitabine treatment for up to 54 cycles without unmanageable toxicities., Conclusion: Toxicities seen in long-term gemcitabine treatment were reversible and manageable in this setting of heavily pretreated Japanese metastatic breast cancer patients.

Purpose: Gemcitabine (GEM)-paclitaxel combination therapy has been confirmed as a standard therapy for metastatic/recurrent breast cancer (MBC) in Western countries. This study was conducted to assess the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients., Methods: Patients were administered paclitaxel 175 mg/m(2) on day 1, and GEM 1,000 or 1,250 mg/m(2) on days 1 and 8 of 21-day cycle. The primary endpoint of this study was overall response rate; secondary endpoints were duration of response, time to progression, survival time and rate., Results: Paclitaxel 175 mg/m(2) plus GEM 1,250 mg/m(2) was determined as the recommended dose. A total of 56 patients received 506 cycles of treatment (median: 7.5 cycles) with a relative dose intensity of 79.6% for GEM and 85.8% for paclitaxel. The response rate was 44.6% (25/56 patients), median time to progression 8.6 months and median survival time 27.1 months. In triple-negative patients, the response rate was 35.7% (5/14 patients), and the median time to progression was 6.0 months. The most frequent grade ≥ 3 toxicities were neutropenia (82.1%), leukopenia (62.5%) and ALT increase (14.3%)., Conclusions: This study confirmed the efficacy and safety of GEM-paclitaxel combination therapy in Japanese MBC patients.

Objectives: The objective of this study was to determine the relative value of dobutamine stress echocardiography (DSE) and dipyridamole thallium imaging (DT) in the preoperative assessment of cardiovascular risk before noncardiac surgery., Design: Prospectively DSE was performed in patients who had undergone DT as a part of their preoperative evaluation., Setting: A large urban veterans' affairs medical center., Participants: Thirty-seven patients undergoing major noncardiac surgery were assessed for complications during a 1-month follow-up period., Interventions: Both DSE and DT were performed before surgery. The medium interval between the two tests were 15.5 days., Measurements: Left ventricular wall motion was assessed at baseline and peak dobutamine dose in a standard fashion. Wall motion was scored and indexed using a 16-segment model. A positive DSE was defined as failure of augmentation, new or worsening of baseline wall motion abnormalities in two or more contiguous segments. Myocardial perfusion studies after DT were performed according to conventional method. A positive DT was defined as a reversible perfusion defect, increased lung uptake, and/or transient left ventricular dilatation. Complications were defined as myocardial infarction or cardiac death occurring as a result of the operation, or need for revascularization before surgery., Results: DSE was positive in 19 patients, whereas DT was positive in 25 patients. Fourteen patients had both an abnormal DSE and DT. Five patients had major postoperative cardiac complications: fetal myocardial infarction (1); fatal cardiac arrest (1); and severe coronary artery disease necessitating coronary artery bypass surgery (2) or percutaneous transluminal coronary angioplasty (1). DSE was positive in all 5 (100%), whereas DT was positive in 4 of 5 (80%) patients with complications. The sensitivity for each test was comparable: for DSE it was 100% (95% C.I. 56% to 100%) and for DT 80% (37% to 96%). Specificity for DSE (60%, 43%-74%) was somewhat higher than DT (38%, 24% to 54%), although this did not reach statistical significance (p = 0.06)., Conclusions: The ability of DSE to predict major cardiac complications related to noncardiac surgery appears to be similar to DT and may be used as an alternative to DT imaging in the preoperative risk assessment of patients undergoing noncardiac surgery.

Background: A high incidence of embolic phenomena is associated with atrial fibrillation (AF) and the left atrial appendage (LAA) is frequently the source of the emboli. Thrombus formation may be due to stasis within the fibrillating and inadequately emptying LAA. Because LAA emptying in AF may be the result of mechanical compression by the adjacent left ventricle, it is possible that left ventricular diastolic filling duration will importantly influence passive emptying of the LAA. We hypothesized that the magnitude of emptying of the LAA in AF is related to the duration of left ventricular diastolic filling which is determined by the ventricular response rate in AF., Objective: The objective of our study was to determine the relationship of ventricular response rate in AF to LAA emptying and to assess the influence of sinus rhythm and heart rate on LAA emptying immediately after direct current cardioversion to sinus rhythm., Methods: To study this, we used transesophageal echocardiography to measure LAA ejection fraction ([LAAmax-LAAmin]/LAAmax x 100%) and evaluated its relationship to left ventricular response rate (VRR) in 26 patients with AF (mean age, 65 +/- 7 [1 SD] years)., Results: There was a strong inverse relationship between LAA ejection fraction and VRR in AF (r = -0.73; p < 0.001). LAA ejection fraction during AF was 26 +/- 10%, and immediately after successful cardioversion, it increased to 46 +/- 12% (p < 0.001). However, during sinus rhythm there was no relationship between LAA ejection fraction and VRR (r = 0.06; p = NS) in the subgroup of patients who were successfully converted to sinus rhythm. There were poor relationships between LAA ejection fraction and peak transmitral flow velocity (r = -0.41; p = NS) or pulmonary venous flow velocity (r = -0.03; p = NS) in AF., Conclusion: These results indicate that the magnitude of LAA emptying in AF is strongly and inversely influenced by ventricular rate. Direct current cardioversion to sinus rhythm is associated with an increase in the magnitude of LAA emptying that is not influenced by heart rate. The magnitude of LAA emptying may be an important factor in the formation of thromboemboli in AF. The extent to which controlling the VRR in chronic AF will prevent stasis and LAA thrombus formation remains to be determined.

Coronary artery disease has emerged as the leading cause of late morbidity and mortality in heart transplant recipients. The incidence of allograft coronary artery disease has been reported to be as high as 40% to 50% by 5 years. Coronary angiography remains the standard approach for surveillance of coronary artery disease in this patient population. However, the detection and surveillance of allograft coronary disease by noninvasive methods remains a challenge. The purpose of this study was to determine the value of dobutamine stress echocardiography as a noninvasive screening test to rule out the presence of anatomically significant allograft coronary artery disease and to assess its prognostic power. Dobutamine stress echocardiography was carried out according to a standard protocol in which dobutamine was infused at 5, 10, 20, 30, and 40 micrograms/kg/min intravenously at 5-minute stages with 12-lead electrocardiogram and blood pressure monitoring. Left ventricular wall motion was analyzed at baseline and at peak dobutamine dose. Mean age (+/- standard error of the mean) of the study population was 50.5 +/- 1.5 years, and mean duration (+/- standard error of the mean) since transplantation was 57 +/- 5 months. The sensitivity, specificity, and positive and negative predictive accuracy of dobutamine stress echocardiography were 95%, 55%, 69%, and 92%, respectively. In the 12-month follow-up study 12 patients with abnormal dobutamine stress echocardiographic findings had 15 major cardiac events whereas no event occurred in patients with normal dobutamine stress echocardiograms.(ABSTRACT TRUNCATED AT 250 WORDS)

The central hypothesis of this investigation is that a shortening myocyte generates a time-varying transmural pressure, or intracellular pressure. A mathematical model was formulated for a single myocyte, consisting of a fluid-filled cylindrical shell with axially arranged contractile filaments, to quantitate the fiber-fluid interaction. In this model, the intracellular pressure mediates the interaction between myofilament force, cell shortening, and the mechanical properties of the sarcolemma. Shortening of myofibrils, which are embedded in the fluid-filled myocytes, deforms the myocyte, thereby altering its transmural fluid pressure. This increase in transmural pressure counteracts fiber shortening, hence constituting an internal load to shortening. The shortening of the myocyte is accompanied by thickening, due to the incompressible nature of its contents. Consequently, the overall contractile performance of the cell is integrally linked to the generation of intracellular pressure. The model manifests a positive transmural pressure during shortening, but not without shortening. The pressure in the myocyte, therefore, is not a direct function of the force generated, but rather of shortening. Intracellular pressure was measured through a fluid-filled glass micropipette (5 mu ID) employing a servo-nulling pressure transducer in a standard micropuncture technique. Measured intracellular pressure in a contracting isolated skeletal myocyte of the giant barnacle is observed to be dynamically related to shortening, but not to tension without shortening. The relation between the force of contraction, cell shortening, and intracellular pressure was assessed during both isotonic and isometric contractions. The results support the prediction that isometric, or nondeforming, contractions will not develop intracellular pressure and identify a reason for relengthening of the myocytes during relaxation.

Objectives: The purpose of this study was to examine whether dobutamine stress echocardiography can detect reversal of ischemia-induced left ventricular regional wall motion abnormality immediately after percutaneous transluminal coronary angioplasty., Background: Although angioplasty is routinely performed as a means of coronary revascularization, at present there is a question whether this results in an immediate improvement in ischemia-induced left ventricular regional function., Methods: Thirty-five patients underwent dobutamine stress echocardiography 24 h before and 24 to 48 h after angiographically successful coronary angioplasty. Only patients with normal wall motion at rest were included. Dobutamine infusion was begun at 5 micrograms/kg per min and increased at 5-min intervals (10, 20, 30, 40 micrograms/kg per min). Echocardiographic images were stored into cine loops and analyzed off line with simultaneous comparison of images acquired at baseline, 5 micrograms/kg per min, peak infusion and recovery. Echocardiographic images were interpreted independently, without knowledge of other data, by two experienced cardiologists using the 16-myocardial segment model., Results: Before angioplasty, dobutamine stress echocardiography induced wall motion abnormalities in 31 patients (88%). Wall motion score at peak dobutamine infusion improved in 28 (90%) of the 31 patients after angioplasty. Wall motion score at peak dobutamine infusion for the group improved from 20 +/- 3 before angioplasty to 17 +/- 2 after angioplasty (p < 0.001). There was no change in the rate-pressure product achieved for the group before and after angioplasty (20,038 +/- 6,415 beats/min x mm Hg before versus 20,775 +/- 5,435 after angioplasty, p = NS). Before angioplasty, dobutamine stress echocardiography induced angina in 13 patients (37%), whereas angina occurred only once after angioplasty. Electrocardiographic changes diagnostic of ischemia occurred seven times, all before angioplasty., Conclusions: We conclude that dobutamine stress echocardiography is an excellent method to demonstrate an immediate improvement in stress-induced regional left ventricular dysfunction in the distribution of the vessel undergoing successful angioplasty.

This investigation was designed to assess the potential use of laser coronary angioplasty as an intraoperative adjunct in the surgical treatment of ischemic heart disease. Among 17 postmortem hearts, simulated laser coronary angioplasty was performed at 53 sites with a No. 4F guiding catheter and 240 micron (200 micron core) quartz optical fiber. Perforation complicated laser coronary angioplasty in 33 (62%) of the 53 attempts. Most (n = 29) perforations were thermal; four were purely mechanical. Perforation sites were characterized by extensive calcific deposits (21 of 33 cases [64%] ) and the origin of a side branch (13 of 33 [39%] ). Excessive tortuosity of the extramural coronary artery contributed to arterial perforation in four cases, and precluded attempts to perform laser coronary angioplasty in two other cases. In 19 of the 53 attempts to perform laser coronary angioplasty, a high-frequency two-dimensional echocardiographic probe was used to image the coronary artery during antegrade manipulation of the optical fiber/guiding catheter and laser irradiation of the target arterial stenosis. Although perforation nevertheless occurred in 11 (58%) of 19 sites, only one mechanical perforation resulted; the remaining 10 were thermal. Characteristics of the perforation sites in this group were similar to those noted for the group as a whole. Experience with this model of laser coronary angioplasty indicates that even when access problems associated with percutaneous laser coronary angioplasty are obviated by a simulated intraoperative approach, perforation of the underlying coronary arterial wall continues to represent the "rate-limiting" complication of laser coronary angioplasty. Most perforations occurred in relation to calcific deposits, branch points, and tortuous coronary segments.(ABSTRACT TRUNCATED AT 250 WORDS)