ACE inhibitors and angiotensin II receptor antagonists in acute coronary syndrome

Angiotensin II (AT II) is a final product of the renin-anglotensin-aldosterone system (RAS) and presents one of the most influential factors in the pathogenesis of atherosclerosis, acute coronary syndrome, myocardial dysfunction and heart failure. ACE-inhibitors (ACEI), beside beta adrenergic blockers, are a cornerstone of the current chronic heart failure (CHF) treatment. Evidence based medicine has not yet proved any significant beneficial effects of ACEI in patients with unstable angina pectoris (UAP), although according to the SoLVD study testing the possible effects of ACEI in patients with significant left ventricular dysfunction and/or CHF, there was a significant hospitalization rate reduction as well as less transformation of UAP to myocardial infarction in patients treated with ACEI. In the GISSI 3, ISIS 4 and CCS studies, ACEI was given within the first 24 hours and continued for 4-6 weeks. According to pooled results, ACE inhibitor could save 11/1000 patients with ST-elevation myocardial infarction (STEMI) and only 1/1000 patients with non ST-elevation myocardial infarction (NSTEMI). In the SAVE, AIRE and TRACE studies, ACEI was started later, i.e. 3-16 days after acute myocardial infarction and continued for several years. ACEI therapy resulted in a significantly lower mortality during the first year, and an even 20% relative reduction in the total mortality during the 4-year follow up. The effects of ACEI were even more prominent in more severe myocardial dysfunction, as it was well known that they could slow or stop unfavorable myocardial remodeling. Conclusively, ACEI should be given as early as possible to all patients with acute myocardial infarction, if no contraindications. The HOPE study showed efficacy of ACEI in the primary prevention of ischemic heart disease in high risk individuals, and the EUROPA study showed a favorable effect of ACEI in the secondary prevention of ischemic heart disease in low risk patients. According to these findings, ACEI should be given permenantly following myocardial infarction. These findings suggest the need of a permanent treatment with ACEI in patients having sustaned myocardial infarction. Angiotensin-1 receptor antagonists (AT-1 antagonists) are a newer generation of neurohormonal antagonists, which block the effects of AT II produced not only through a classic, ACE-dependent pathway but also via alternative pathways (non ACE-dependent) and selectively bind to AT-1 receptors for AT II. Therefore, they have some theoretical advances in comparison with ACEI. There are 2 relevant studies elucidating their possible role in treating patients with or post-myocardial infarction. The OPTIMAAL study did not prove losartan to be better than an ACEI (captopril), while the VALIANT study showed that the effects of valsartan vs. captopril were statistically nonsignificantly different. Furthermore, there is no sense to combine AT-1 antagonist and ACEI, while a combination of AT-1 antagonist and a beta blocker is justified. In other words, AT-1 antagonist (the class effect is disputable) should be given to patients with acute myocardial infarction or to post-myocardial infarction patients who cannot take ACEI.     

Exercise and allergic diseases

The aim of this study was to compare exercise-induced bronchial reaction between healthy control subjects and subjects with allergic rhinitis (AR) and allergic asthma (AA). It included 16 controls, 16 subjects with AR and 19 subjects with AA. A skin prick test, pulmonary function test, histamine challenge test and exercise challenge test (ECT) were performed in all subjects. Bronchial reaction to exercise was expressed as the fall index FEV1 (%), AUC(0-30) (min x %), and fall index FEF(25-75) (%). After ECT, subjects with AA had a significantly greater bronchial reaction to exercise than subjects with AR and controls (respective fall index FEV1 8.4, 2.9, and 2.4%, P=0.0083; AUC(0-30) 127.7, 29.6, and 33.1 min x %, P=0.025; and fall index FEF(25-75) 14.6, 0.06, and 1.9%, P<0.001). No difference was found between subjects with AR and controls. In conclusion, ECT induced a significantly greater bronchial reaction in patients with AA and bronchial hyperreactivity to histamine than in patients with AR and bronchial normoreactivity to histamine and controls. This difference was not found between subjects with AR and controls.     

In vitro and in vivo characterization of a novel naphthylamide ATP-sensitive K+ channel opener, A-151892

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels. 2. A-151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide-sensitive whole-cell current and fluorescence-based membrane potential responses (-log EC(50)=7.63) in guinea-pig bladder smooth muscle cells. 3. Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4-dihydropyridine opener [(125)I]A-312110. A-151892 displaced [(125)I]A-312110 binding to bladder membranes with a -log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites. 4. In pig bladder strips, A-151892 suppressed phasic, carbachol-evoked and electrical field stimulus-evoked contractility in a glibenclamide-reversible manner with -log IC(50) values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (-log IC(50)=7.81) and portal vein (-log IC(50)=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle. 5. In vivo, A-151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED(35%) values of 8.05 and 7.43, respectively. 6. These results demonstrate that naphthylamide analogs exemplified by A-151892 are novel K(ATP) channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms.     

Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.     

Interfraction interval in patients with stage III non-small-cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy: final results in 536 patients

We investigated the influence of interfraction interval (IFI) on treatment outcome in patients with stage III non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy (Hfx RT) with or without concurrent chemotherapy (CHT). During 3 randomized phase III and 1 phase II study, a total of 536 patients were treated with Hfx RT alone or with concurrent carboplatin/etoposide. Two hundred eighty-five patients were treated with IFI of 4.5-5.0 hours, while 251 patients were treated with IFI of 5.5-6.0 hours. "Shorter" (4.5-5.0 hours) IFI led to better overall survival (OS) (P = 0.0000) and local recurrence-free survival (LRFS) (P = 0.0000). Multivariate analyses showed IFI to be an independent prognosticator of both OS and LRFS. These results were confirmed when we separated all patients (n = 536) into those treated with Hfx RT only (n = 127) and those treated with concurrent RT/CHT (n = 409). Various RT-related high-grade acute toxicity was not different between the 2 IFI, but patients treated with shorter IFI had a significantly higher incidence of hematological toxicity (P = 0.002). None of the late high-grade toxicities were different between the 2 interfraction intervals. Using regression analysis, it was shown that IFI was not a significant predictor of any of acute or late high-grade (> or =3) toxicity. IFI is an important prognosticator of OS and LRFS in patients with stage III NSCLC treated with Hfx RT with or without concurrent carboplatin/etoposide. IFI led to higher incidence only of hematological toxicity, but was not predictive of any acute or late high-grade (> or =3) toxicity. A carefully designed randomized trial seems necessary to give better insight into the issue of optimal IFI in this disease.     

Neuromusculoskeletal chest pain

To determine frequency of neuromusculoskeletal etiology of chest pain is performed. By means of a retrospective analysis and on the basis of the history of the patients' disease, data were collected after chest pain had been medically worked out. The causes to chest pain were in 82% of cardial etiology, in 9% of neuromusculoskeletal etiology, in 6% of gastrointestinal etiology and 3% others. All the patients suffering from neuromusculoskeletal causes to chest pain were, besides anti-rheumatic therapy, also treated by certain form of cardiac therapy. The task of a doctor is to accurately recognize serious disorders as possible causes to chest pain. However, the doctor must not make wrong diagnosis of potentially dangerous conditions thus causing unwanted psychological and economical consequences. In order to realize this, adequate diagnostic possibilities are necessary besides the knowledge about all possible causes to chest pain.     

Antibody response and virus tissue distribution in chickens inoculated with wild-type and recombinant fowl adenoviruses

We demonstrated that the long tandemly repeated region (TR-2) is dispensable for in vitro replication of fowl adenovirus 9 (FAdV-9). The TR-2-deleted recombinant FAdV-9 expressing the enhanced green fluorescence protein was further characterized for in vivo effects. Groups of chickens were exposed to recombinant or wild-type FAdV-9 by intramuscular injection, through the feed or drinking water and one group served as a negative control. The antibody (Ab) response, evaluated by ELISA and a plaque reduction test depended on the virus, dosage and the route of inoculation. Although the highest levels of anti-viral Ab were detected in chickens inoculated intramuscularly (i.m.) with wild-type FAdV-9, the deletion of TR-2 did not have a significant effect on the immune response. The tissue distribution of the virus was examined by the polymerase chain reaction (PCR) and was similar for both wild-type and recombinant viruses. Based on these results the TR-2 was dispensable for viral replication in vivo and did not influence virus distribution, and the recombinant FAdV-9 induced the same immune response as the wild-type virus.     

Public stem cell banks: considerations of justice in stem cell research and therapy

If stem cells fulfill their therapeutic promise, moving them from the laboratory into the clinic will raise several concerns about justice. One concern is that, for biological reasons alone, stem cell‐based therapies might not be available for every patient who needs one. Worse, depending on how we address the problem of biological access, they might benefit primarily white Americans. We can avoid this outcome—although at a cost—by carefully selecting the stem cells we make available.     

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

Purpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200mg/m², and VP 16, 200mg/m², both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.