Intravenous dopexamine in the treatment of acute congestive heart failure: Results of a multicenter,double-blind,placebo-controlled withdrawal study

Summary Acute hemodynamic effects of intravenous infusion of dopexamine were evaluated by a placebo-controlled withdrawal study in patients with acute congestive heart failure. Twenty patients were enrolled at 10 centers in Japan. All patients had a pulmonary capillary or diastolic pressure of 15 mmHg or greater and a cardiac index of 2.5 l/min/m² or less.Phase I: Intravenous dopexamine was introduced in a single-blind, uncontrolled fashion at the rate of 0.5 µg/kg/min and was titrated up to achieve a 30% or more increase in the cardiac index. Two patients withdrew from the study due to sinus tachycardia and ventricular ectopy or exacerbation of heart failure.Phase II: The remaining 18 responders who were free of limiting side effects were randomized in double-blind fashion to continue dopexamine or to switch to placebo for an additional 60 minutes. At the end of phase II, the hemodynamic improvement obtained in phase I of the study disappeared completely after substitution of placebo but was maintained in dopexamine-treated patients. Our findings suggest that dopexamine, when given in appropriate doses to selected patients, shows balanced vasodilator action suitable for the treatment of acute congestive heart failure.See Appendix 1 for complete list of participating centers and principal investigators     

A double-blind comparative study of intracoronary administration of GE-0943 and urokinase: multicenter study

Coronary thrombolysis with plasminogen proactivator, GE-0943, was undertaken in patients with acute myocardial infarction and compared with urokinase. Fifty patients were given 6000 units of GE-0943 intracoronary and the totally occluded infarct-related arteries were recanalized in 92.0%. Fifty-four patients who were given 3000 units of GE-0943 intracoronary demonstrated a recanalization rate of 68.2%, while intracoronary administration of urokinase in 54 patients showed a recanalization rate of 70.4%. There was only one patient with hemorrhagic complication among GE-0943 3000-units group, none among GE-0943 6000-units group, and 5 among urokinase group. Thus, intracoronary administration of GE-0943 is very effective and safe with a dose up to 6000 units.     

Cotransfection of plasmids with ras and myc oncogenes to diploid cells derived from rodent fetuses: alteration of neoplastic transformation frequency depending on the gestation period

To analyze the mechanism of neoplastic transformation of rodent diploid cells by ras and myc oncogenes, human EJ c-Ha-ras and mouse c-myc second and third exons promoted by SV40 promoter were connected to pSV2neo and pSV2gpt, respectively. Mouse and rat primary fetal cells cotransfected with both genes formed transformed and nontransformed colonies in a medium containing G418 and mycophenolic acid (MPA). The proportion of transformed colonies in the total G418/MPA-resistant colonies decreased dependent on the stage of the gestation period of rat fetuses from which primary cells had been obtained. Analysis of randomly isolated colonies showed that the transformed colonies had a high copy number and high amount of expression of the introduced genes, were anchorage independent, and were tumorigenic in nude mice. On the other hand, the nontransformed colonies had a low copy number, low amount of expression, and no tumorigenicity. This contrast indicated not only that the activated Ha-ras and myc oncogenes had been integrated, but also that the amplification or overexpression (or both) of these genes was required for the rodent diploid cells to be transformed. We conclude that early-stage rat fetal cells might have endogenous factors that promote cell transformation. Alternatively, late-stage cells might have factors that suppress cell transformation by activated Ha-ras and myc oncogenes.     

Limited value of anaerobic threshold for assessing functional capacity in patients with heart failure

Exercise tolerance was assessed in 146 patients with cardiac dysfunction in terms of anaerobic threshold (ATge). Patients were divided into four classes according to the peak oxygen uptake: Class A (72 patients) exceeding 1000 ml/min; Class B (27 patients) 800-999 ml/min; Class C (37 patients) 500-799 ml/min; and Class D (10 patients) below 500 ml/min. An incidence of the ATge breakpoint was lower in patients of Class C (38%) than in those of either Class B (70%, p < 0.05) or Class A (87%, p < 0.05). The ATge could not be determined in any patients in Class D. The V-slope method improved the ability to determine ATge by 20%. In Classes C and D, ATge detection was precluded considerably by the fact that the initial workloads of exercise test involved oxygen uptake levels already close to or above the ATge. An oscillatory hyperventilation pattern was also significantly related to failure in defining ATge in Class C patients. Of the 51 patients whose ATge was undetermined, 9 had an atrial septal defect In two of these, exercise-induced right-to-left shunting led to progressive arterial hypoxemia, and the consequent hyperventilation masked the appearance of ATge. Thus, ATge is virtually undetectable in patients with severe heart failure largely because of the early onset of anaerobic metabolism or abnormal ventilatory responses to exercise. Accordingly, the clinical application of ATge in the assessment of functional capacity would be limited to patients with mild to moderate heart failure.     

Helicobacter pylori eradication to prevent gastric cancer： underlying molecular and cellular mechanisms

Numerous cellular and molecular events have been described in development of gastric cancer. In this article, we overviewed roles of Helicobacter pylori (H pylori) infection on some of the important events in gastric car-cinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carci-nogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phe-notype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H py/ori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However, some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population, and warrant further investigation.     

Home oxygen therapy (HOT) for patients with heart failure associated with sleep disturbed breathing

Recently, there is increasing evidence that sleep apnea may adversely affect pathophysiology and outcomes of congestive heart failure (CHF). Repetitive nocturnal apneas may worsen CHF through a number of mechanisms including the repetitive arterial oxygen desaturation, increased left ventricular afterload, or an activation of sympathetic nervous system. Although central sleep apnea (CSA) is relatively rare, prospective studies revealed that 33 to 82 % of patients with CHF have evidence of CSA and characteristic Cheyne-Stokes respiration (CSR). We assessed an efficacy of nasal O2 therapy at night using a conventional O2 concentrator in ambulatory patients with stable CHF and CSR. O2 resulted in a significant improvement of sleep together with an increase in left ventricular function and quality of life. Therefore, home oxygen therapy(HOT) can be a valuable nonpharmacological option for the treatment of patients with CHF and CSR-CSA.     

Evaluation of a New Formulation of Epoprostenol Sodium in Japanese Patients with Pulmonary Arterial Hypertension (EPITOME4)

Introduction

Pulmonary arterial hypertension (PAH) is associated with poor prognosis despite significant recent advances in its treatment. An intravenous formulation of epoprostenol sodium containing glycine and mannitol (epoprostenol GM; GlaxoSmithKline, London, UK) is widely used to treat PAH. A new formulation of epoprostenol sodium containing arginine and sucrose excipients (epoprostenol AS; Actelion Pharmaceuticals Japan Ltd., Tokyo, Japan) shows better stability at room temperature after preparing diluted solutions. The primary objective of this study was to evaluate the safety and tolerability of switching from epoprostenol GM to epoprostenol AS in Japanese patients with PAH. The authors also evaluated the efficacy and treatment satisfaction after switching formulations.

Methods

This was a two-site, open-label, single-arm, Phase 3b study. Eight adult Japanese PAH patients (seven females) treated with a stable dose of epoprostenol GM for ≥30 days were switched to epoprostenol AS and followed for 12 weeks. Outcomes included safety, changes from baseline to 12 weeks in pulmonary hemodynamic factors (pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output), and treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM-9).

Results

The mean (range) age and time since diagnosis of PAH were 48 (25–69) years and 6.2 (0.6–13.9) years, respectively. There were no unexpected safety or tolerability concerns after switching formulations. The epoprostenol dose was maintained after switching formulations. There were no significant changes in pulmonary hemodynamic factors from baseline to week 12. Regarding treatment satisfaction, there was a significant improvement in convenience, which is demonstrated in the score of the domain increased from 51.40 ± 10.19 at baseline to 58.33 ± 12.96 at week 12 (P < 0.05).

Conclusions

Switching from epoprostenol GM to the same dose of epoprostenol AS was well tolerated over 12 weeks of treatment, and pulmonary hemodynamics were maintained. Switching to epoprostenol AS was also associated with improvements in treatment satisfaction (convenience). Clinical Trials: JapicCTI-122017.