Therapy From a Novel Substernal Lead: The ASD2 Study.

OBJECTIVES: The ASD2 (Acute Extravascular Defibrillation, Pacing, and Electrogram) study evaluated the ability to adequately sense, pace, and defibrillate patients with a novel implantable cardioverter-defibrillator (ICD) lead implanted in the substernal space. BACKGROUND: Subcutaneous ICDs are an alternative to a transvenous defibrillator system when transvenous implantation is not possible or desired. An alternative extravascular system placing a lead under the sternum has the potential to reduce defibrillation energy and the ability to deliver pacing therapies. METHODS: An investigational lead was inserted into the substernal space via a minimally invasive subxiphoid access, and a cutaneous defibrillation patch or subcutaneous active can emulator was placed on the left mid-axillary line. Pacing thresholds and extracardiac stimulation were evaluated. Up to 2 episodes of ventricular fibrillation were induced to test defibrillation efficacy. RESULTS: The substernal lead was implanted in 79 patients, with a median implantation time of 12.0 ± 9.0 min. Ventricular pacing was successful in at least 1 vector in 76 of 78 patients (97.4%), and 72 of 78 (92.3%) patients had capture in ≥1 vector with no extracardiac stimulation. A 30-J shock successfully terminated 104 of 128 episodes (81.3%) of ventricular fibrillation in 69 patients. There were 7 adverse events in 6 patients causally (n = 5) or possibly (n = 2) related to the ASD2 procedure. CONCLUSIONS: The ASD2 study demonstrated the ability to pace, sense, and defibrillate using a lead designed specifically for the substernal space.

Synthesis and antiplasmodial activity of novel indoleamide derivatives bearing sulfonamide and triazole pharmacophores.

Due to the recent reports of growing parasite resistance to artemisinins and other antimalarial drugs, development of new antimalarial chemotypes is an urgent priority. Here in, we report a novel series of adamantyl/cycloheptyl indoleamide derivatives bearing sulfonamide and triazole pharmacophores adopting different chemical modifications and evaluated them for antiplasmodial activity in vitro. Among all the indoleamides, compounds 22, 24, 26 and 30 with sulfonamide pharmacophore showed promising activity with IC50 of 1.87, 1.93, 2.00, 2.17 µM against CQ sensitive Pf3D7 strain and 1.69, 2.12, 1.60, 2.19 µM against CQ resistant PfK1 strain, respectively.

Triazole analog 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol induces reactive oxygen species and autophagy-dependent apoptosis in both in vitro and in vivo breast cancer models.

Autophagy is considered as an important cell death mechanism that closely interacts with other common cell death programs like apoptosis. Critical role of autophagy in cell death makes it a promising, yet challenging therapeutic target for cancer. We identified a series of 1,2,3-triazole analogs having significant breast cancer inhibition property. Therefore, we attempted to study whether autophagy and apoptosis were involved in the process of cancer cell inhibition. The lead molecule, 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4-bromophenylamino)-1-(4-chlorophenyl)ethanol (T-12) induced significant cell cycle arrest, mitochondrial membrane depolarization, apoptosis and autophagy in MCF-7 and MDA-MB-231 cells. T-12 increased reactive oxygen species and its inhibition by N-acetyl-L-cysteine protected breast cancer cells from autophagy and apoptosis. Autophagy inhibitor, 3-methyladenine abolished T-12 induced apoptosis, mitochondrial membrane depolarization and reactive oxygen species generation. This suggested that T-12 induced autophagy facilitated cell death rather than cell survival. Pan-caspase inhibition did not abrogate T-12 induced autophagy, suggesting that autophagy precedes apoptosis. In addition, T-12 inhibited cell survival pathway signaling proteins, Akt, mTOR and Erk1/2. T-12 also induced significant regression of tumor with oral dose of as low as 10mg/kg bodyweight in rat mammary tumor model without any apparent toxicity. In presence of reactive oxygen species inhibitor (N-acetyl-L-cysteine) and autophagy inhibitor (chloroquine), T-12 induced tumor regression was significantly decreased. In conclusion, T-12 is a potent inducer of autophagy-dependent apoptosis in breast cancer cells both in vitro and in vivo and can serve as an important lead in development of new anti-tumor therapy.

Synthesis and anticancer activity of γ-(triazolyl ethylidene)butenolides and polyfunctional pyrrolinones.

A series of novel γ-(triazolyl ethylidene)butenolides (4-23) were prepared from commercially available l-ascorbic acid in good yields. These butenolides on reaction with ethanolic ammonia/amines led to formation of respective 5-hydroxy pyrrolinones (24-33). The two of these pyrrolinones on dehydration with p-toluenesulfonic acid, were transformed into γ-(triazolyl ethylidene)pyrrolinones (34, 35). Among all the newly synthesized hybrid molecules tested for anticancer activity in vitro, compounds 24, 25, 26, 27, 28, 30 and 32 showed significant activity against MCF-7, MDA-MB-231, PC-3 or U-937 cells. In particular compound 25 (IC50 = 11.3 µM) exhibited most potent activity against breast cancer cells and preliminary studies revealed that potency of this compound is due to ROS generation, subsequent activation of p38, leading to apoptosis and inhibition of cancer cells.

Accessing a small library of pluripotent 1,4,5-trisubstituted 1H-1,2,3-triazoles via diversity-oriented synthesis.

Diversity-oriented synthesis of structurally different, novel and small drug like molecules based on 1,4,5-trisubstituted 1,2,3-triazoles is developed in a streamlined sequence of different sets of reactions. The method involves the use of simple, readily available and highly economical substrates and reagents. The molecules developed herein have potential to be exploited either as chemotherapeutic agents or as scaffolds for other biologically active compounds.

Late angiographic follow-up in adults with initial angiographic normal or minimally narrowed coronary arteries.

We identified 46 patients with angiographically normal coronary arteries and 16 patients with minor irregularities (luminal narrowing < or =30%) who had repeat coronary angiograms obtained at our institution during the subsequent 15-year period. On follow-up angiograms, 19 of 46 (41%) in the normal coronary group and 13 of 16 (81%) in the minor lesion group showed progression of coronary artery disease (CAD). Five patients (11%) with no angiographic luminal CAD at the time of their baseline angiogram developed an acute myocardial infarction during the follow-up period. Patients in group 1 progressed from no vessels with angiographic lesions to a mean of 0.70 +/- 0.90 vessels diseased and a mean angiographic narrowing of 24 +/- 34% at the time of their follow-up angiograms, yielding a CAD progression rate of 2.6% luminal narrowing per year. Patients in group 2 had a mean progression of 0.69 +/- 0.79% of their vessels and a mean progression in their narrowing of 34 +/- 21%, yielding a CAD progression rate of 6.0% luminal narrowing per year. In conclusion, CAD can manifest late, or more likely, many patients with apparently normal coronary arteries have intimal CAD undetectable by angiography.