Eslicarbacepina en pacientes con hipercolesterolemia asociada a carbamacepina y oxcarbacepina / Eslicarbazepine in patients with hipercholesterolemia associated to carbamazepine and oxcarbacepine

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Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study.

PURPOSE: Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. METHODS: Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50-315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg. RESULTS: A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested. CONCLUSIONS: A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.

Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial.

CONTEXT: Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery. OBJECTIVE: To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days. DESIGN, SETTING, AND PARTICIPANTS: The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010. INTERVENTIONS: Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction. MAIN OUTCOME MEASURE: Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28. RESULTS: Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured. CONCLUSION: In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00872001.

Acadesine: AICA riboside, ARA 100, arasine, GP 1 110.

Acadesine is an adenosine receptor agonist (ARA) in development for the treatment of ischaemia-reperfusion injury and chronic lymphocytic leukaemia. Schering-Plough is developing the compound as a cardioprotective agent in ischaemia-reperfusion injury. Avancell and Protherics are co-developing acadesine for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). Clinical development is underway for both indications. In January 2005, PeriCor Therapeutics obtained a sublicense for the worldwide rights to acadesine and three additional ARA compounds from Dr Mangano who was a founder of the company. Dr Mangano acquired the license of worldwide rights for acadesine from Metabasis in November 2000.Previously, in December 1997, all intellectual property rights and data covering acadesine and related ARAs for cardiovascular and cerebrovascular disorders were transferred from the original developer, Gensia Sicor (SICOR), to Metabasis Therapeutics in an asset-liability transfer agreement.Schering-Plough intends to conduct a randomized, placebo-controlled phase III trial, which is required for regulatory approval. The trial will further evaluate acadesine in patients deemed to be at high risk of ischaemic heart disorders. Patients will have either undergone coronary artery bypass graft surgery, or have a history of cardiovascular events (heart attack or stroke). Protherics presented 2-year mortality results from a study of acadesine, investigating long-term mortality after perioperative myocardial infarction, at the 55th Scientific Session of the American College of Cardiology in 2006.Previously, Gensia Sicor conducted clinical trials of acadesine in Canada, the EU and the US; results of these trials were inconclusive. Acadesine has been shown to selectively cause the death of B-cells, whilst sparing T-cells when administered to blood samples taken from patients with B-CLL. Orphan drug status has been granted for acadesine in the EU for the treatment of B-cell chronic lymphocytic leukaemia.

Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine.

OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the adenosine regulating agent (ARA) acadesine for reducing long-term mortality among patients with post-reperfusion myocardial infarction (MI). BACKGROUND: No prospectively applied therapy exists that improves long-term survival after MI associated with coronary artery bypass graft (CABG) surgery-a robust model of ischemia/reperfusion injury. Pretreatment with the purine nucleoside autocoid adenosine mitigates the extent of post-ischemic reperfusion injury in animal models. Therefore, we questioned whether use of the ARA acadesine-by increasing interstitial adenosine concentrations in ischemic tissue-would improve long-term survival after post-reperfusion MI. METHODS: At 54 institutions, 2,698 patients undergoing CABG surgery were randomized to receive placebo (n = 1,346) or acadesine (n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h) and in cardioplegia solution (placebo or acadesine; 5 microg/ml). Myocardial infarction was prospectively defined as: 1) new Q-wave and MB isoform of creatine kinase (CK-MB) elevation (daily electrocardiography; 16 serial CK-MB measurements); or 2) autopsy evidence. Vital status was assessed over 2 years, and outcomes were adjudicated centrally. RESULTS: Perioperative MI occurred in 100 patients (3.7%), conferring a 4.2-fold increase in 2-year mortality (p < 0.001) compared with those not suffering MI. Acadesine treatment, however, reduced that mortality by 4.3-fold, from 27.8% (15 of 54; placebo) to 6.5% (3 of 46; acadesine) (p = 0.006), with the principal benefit occurring over the first 30 days after MI. The acadesine benefit was similar among diverse subsets, and multivariable analysis confirmed these findings. CONCLUSIONS: Acadesine is the first therapy proven to be effective for reducing the severity of acute post-reperfusion MI, substantially reducing the risk of dying over the 2 years after infarction.

Determination of dichloroanilines in human urine by GC-MS, GC-MS-MS, and GC-ECD as markers of low-level pesticide exposure.

Methods for the determination of 3,4-dichloroaniline (3,4-DCA) and 3,5-dichloroaniline (3,5-DCA) as common markers of eight non-persistent pesticides in human urine are presented. 3,5-DCA is a marker for the exposure to the fungicides vinclozolin, procymidone, iprodione, and chlozolinate. Furthermore the herbicides diuron, linuron, neburon, and propanil are covered using their common marker 3,4-DCA. The urine samples were treated by basic hydrolysis to degrade all pesticides, metabolites, and their conjugates containing the intact moieties completely to the corresponding dichloroanilines. After addition of the internal standard 4-chloro-2-methylaniline, simultaneous steam distillation extraction (SDE) followed by liquid-liquid extraction (LLE) was carried out to produce, concentrate and purify the dichloroaniline moieties. Gas chromatography (GC) with mass spectrometric (MS) and tandem mass spectrometric (MS-MS) detection and also detection with an electron-capture detector (ECD) after derivatisation with heptafluorobutyric anhydride (HFBA) were employed for separation, detection, and identification. Limit of detection of the GC-MS-MS and the GC-ECD methods was 0.03 and 0.05 microg/l, respectively. Absolute recoveries obtained from a urine sample spiked with the internal standard, 3,5-, and 3,4-DCA, ranged from 93 to 103% with 9-18% coefficient of variation. The three detection techniques were compared concerning their performance, expenditure and suitability for their application in human biomonitoring studies. The described procedure has been successfully applied for the determination of 3,4- and 3,5-DCA in the urine of nonoccupationally exposed volunteers. The 3,4-DCA levels in these urine samples ranged between 0.13 and 0.34 microg/g creatinine or 0.11 and 0.56 microg/l, while those for 3,5-DCA were between 0.39 and 3.33 microg/g creatinine or 0.17 and 1.17 microg/l.

Effects of acadesine on myocardial infarction, stroke, and death following surgery. A meta-analysis of the 5 international randomized trials. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

OBJECTIVE: To determine the effects of a purine nucleoside, acadesine, on the incidence of fatal and nonfatal cardiovascular and cerebrovascular complications following coronary artery bypass graft (CABG) surgery. DATA SOURCES: Individual patient data from 5 randomized, placebo-controlled, double-blind clinical trials, including 81 international medical centers of the United States, Canada, and Europe. STUDY SELECTION: All patients from all clinical trials were included: a total of 4043 patients undergoing CABG surgery, evaluable for efficacy, and randomized to receive either placebo (n= 2031) or acadesine (0.1 mg x kg(-1) x min(-1); n=2012) by intravenous infusion for 7 continuous hours and via the cardioplegia solution. DATA EXTRACTION: Individual patient data were collected prospectively using standardized forms and methods and double-data entry. A general parametric approach and analysis-by-patient meta-analysis were used, including both fixed effects and random effects models. Inclusion and exclusion criteria, general methodology, and outcome assessment techniques were similar for all trials. DATA SYNTHESIS: Acadesine decreased the incidence of the primary outcome, perioperative myocardial infarction (MI) by 27% (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.51-0.95; P=.02), decreased the incidence of cardiac death through postoperative day 4 by 50% (OR, 0.52; 95% Cl, 0.27-0.98; P=.04), and decreased the incidence of combined outcome (MI, stroke, or cardiac death) by 26% (OR, 0.73; 95% Cl, 0.57-0.93; P=.01). The random effects models for these outcomes also yielded significant results. The incidence of cerebrovascular accident was not significantly reduced by acadesine (OR, 0.69; 95% Cl, 0.44-1.08; P=.10). A secondary analysis of cardiac death following MI through postoperative day 4 demonstrated that acadesine decreased by 89% the number of deaths from 13.3% (13 deaths/98 MIs) in the placebo group to 1.4% (1 death/71 MIs) in acadesine-treated patients (P=.003). Acadesine also reduced the use of ventricular-assistance devices for severe postoperative heart failure by approximately one third (P=.05). Finally, regarding safety, the incidence of adverse events was similar in the acadesine vs placebo groups, with the exception of a transient increase in serum uric acid in the acadesine group. CONCLUSIONS: The results of this meta-analysis indicate that in patients undergoing CABG surgery, treatment with acadesine before and during surgery can reduce early cardiac death, MI, and combined adverse cardiovascular outcomes.

Effects of acadesine on the incidence of myocardial infarction and adverse cardiac outcomes after coronary artery bypass graft surgery. Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

BACKGROUND: Acadesine (AICA riboside) (5-amino-1-[beta-D-ribofuranosyl]imidazole-4-carboxamide) is a purine nucleoside analog belonging to a new class of agents generally termed adenosine regulating agents (ARAs) that increase the availability of adenosine locally in ischemic tissues. The effects of acadesine on the incidence of fatal and nonfatal myocardial infarction (MI) an on the incidence of all adverse cardiovascular outcomes (cardiac death, MI, congestive heart failure, life-threatening dysrhythmia, or cerebrovascular accident) was investigated in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: In 20 medical centers in the United States participating in the Multicenter Study of Perioperative Ischemia (McSPI), 633 patients undergoing CABG surgery were randomized in a double-blind fashion to receive either placebo (n = 212), low-dose acadesine (0.05 mg.kg-1.min-1, n = 214), or high-dose acadesine (0.1 mg.kg-1.min-1, n = 207) by intravenous infusion starting 15 min before anesthetic induction and continuing for 7 h, as well as added to the cardioplegic solution (final concentration of 5 micrograms/ml for those patients receiving acadesine). Anesthesia was standardized, and perioperative hemodynamics were to be strictly controlled. Twelve-lead electrocardiograms (ECGs), CK-MB isoenzyme concentrations, and autopsy were used to assess the occurrence of MI. RESULTS: There was a similar incidence of adverse events in the acadesine groups and the placebo group, with the exception that serum uric acid transiently increased in the high-dose acadesine group. The incidence of perioperative MI, using the prespecified MI criterion (EGF Q wave, CK-MB elevation, or autopsy evidence), was not different between groups (24% versus 26% versus 21% [P = 0.574]), nor was the incidence of all cardiovascular outcomes (30% versus 30% versus 22% [P = 0.151]). After completion of the study, a post hoc analysis also was performed using the more specific definition of MI (ECG Q wave and CK-MB elevation, or autopsy evidence), and the incidence of MI was lower (P = 0.018, alpha = 0.017, corrected for multiple comparisons), as were adverse cardiovascular outcomes (P = 0.002) and CVA (P = 0.02) for patients treated with 0.1 mg.kg-1.min-1 acadesine. In patients with Q-wave infarction, the high-dose acadesine group had a lower peak median CK-MB (P = 0.042) and area under the CK-MB curve (P = 0.021). No differences were found in the incidence or characteristics of MI (Holter or transesophageal echocardiography). CONCLUSIONS: The results of this trial did not demonstrate a statistically significant difference between acadesine and placebo using the prespecified criterion for MI. Of interest are the results of the post hoc analysis, using the more specific criterion for MI, which indicate that acadesine may reduce the incidence of larger Q-wave infarctions after coronary artery bypass surgery. A second trial is underway to evaluate this contention.

Effect of acadesine, a new metabolic agent, on exercise-induced myocardial ischemia in chronic stable angina.

Acadesine, the first of a class of adenosine-regulating agents, has been shown to possess antiischemic properties in animal models. The aim of the study was to assess the effect of acadesine on exercise-induced myocardial ischemia in patients with chronic stable angina pectoris. Twelve patients with stable angina entered a five-way, randomized double-blind study comparing the effects of four doses of acadesine with placebo on time to 1 mm ST-segment depression and other parameters of exercise tolerance. At each study period patients underwent baseline exercise testing, followed by drug or placebo infusion after a 60 minute rest period. The exercise test was repeated after 30 minutes infusion, which continued throughout recovery. Time to angina, time to 1 mm ST depression, and total exercise time during the placebo infusion were 301.1 +/- 45.3, 314.8 +/- 50.9, and 399.4 +/- 47.6 seconds. The placebo-adjusted percentage change in time to 1-mm ST segment with acadesine 6, 12, 24, and 48 mg/kg was -0.1 +/- 6.2%, 11.1 +/- 13.8%, 12.9 +/- 8.6%, and -3.2 +/- 6.8%, respectively (p = NS vs. baseline). Time to angina, total exercise time, and recovery time of the ST segment were not consistently altered by acadesine. The lack of effect across all acadesine doses is consistent with animal data from ischemia-reperfusion injury studies, where a clear dose dependency was present with a loss of effect at higher doses. Alternatively, the extent of ischemia induced by treadmill exercise may have been insufficient for the antiischemic activity of acadesine to be evident.

Combination of 5-fluorouracil, imidazole carboxamide, BCNU and prednisolone (FIB-P) as a salvage chemotherapy in heavily pretreated breast cancer patients.

The results of treatment with 5-fluorouracil, imidazole carboxamide, BCNU and prednisolone (FIB-P) salvage chemotherapy in 60 patients with heavily pretreated advanced breast cancer are presented. For most of the patients (82%) this was the third line of chemotherapy. Performance status (ECOG) was 1, 2 and 3 in respectively 13, 27, and 20 patients. Predominant metastatic sites were: soft tissue (3/60, 5%), bone (22/60, 37%), and viscera (35/60, 58%). Tumor burden (number of affected organic systems) was 1, 2 and 3 or more in respectively 18, 24 and 16 patients. Average dose intensity received was 0.74 (range, 0.47-0.98); the average number of cycles was 3.8 (range, 2-8). Objective response (CR + PR) was observed in 22 patients (1 CR, 21 PR), with a response rate of 37% (22/60). Median duration of remission was 7 months (range, 3-15). Tumor burden was the only pretreatment patient characteristic that significantly influenced the remission rate (p less than 0.10). Dose intensity significantly affected tumor response (p less than 0.05). Toxic side effects (gastrointestinal disorders, alopecia and myelotoxicity) were generally moderate and tolerable. No treatment-related death occurred. FIB-P proved to be an active salvage chemotherapy in heavily pretreated patients with advanced breast cancer.

AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent.

AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.

Liver cell protection in toxic liver lesion.

Most of the hepatoprotective drugs belong to the group of free radical scavangers. The mechanism of their action involves membrane stabilisation, neutralisation of free radicals and immunomodulation. The authors demonstrate the effect of different-drugs used in therapy of liver diseases (silymarin, silibinin, Aica-P) in human clinico-pharmacological study and in animal experiments. A wide number of methods was used. Both the silymarin preparates and the Aica-P corrected the altered immunreaction and the decreased superoxid-dismutase (SOD) activity of erythrocytes and lymphocytes in patients with alcoholic liver cirrhoses. The scavanger effect of these drugs was demonstrated in the subcellular fractions of liver cells in animal experiments. The data support the therapeutic effect of these drugs in liver diseases.

Comparison of procarbazine, imidazole-carboxamide and cyclophosphamide in relapsing patients with advanced carcinoma of the prostate.

In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed, relapsing clinical stage D prostatic cancer were randomized to receive either imidazole-carboxamide, procarbazine or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on initial therapy were crossed over or randomized to receive an alternate drug. There were 129 patients available for comparison of treatments. The objective response rates (partial regression plus stable disease) were 26% for cyclophosphamide, 27% for imidazole-carboxamide and 14% for procarbazine. Subjective responses were noted in pain relief, improvement in performance status and weight gain. Procarbazine was associated with excessive toxicity, resulting in many patients (28%) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study. The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival. Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease.