The use of ACE-inhibitors after myocardial infarction

Background: There is good evidence that angiotensin-converting enzyme (ACE) inhibitors are beneficial after myocardial infarction (MI). However, it is not known how widely this evidence is used in practice and whether all eligible patients receive this therapy. Aim: To assess the usage of ACE inhibitors in patients after MI in a large teaching hospital. Method: A one month prospective analysis, combined with a three month retrospective analysis, was conducted at the Royal Brisbane Hospital (RBH) in February-March 2000. Patients admitted with an MI or who had been diagnosed with an MI during admission from November 1999 to March 2000 were identified from the coronary care unit (CCU) records. Inpatient medication charts and outpatient records were then reviewed. Information collected included: ACE inhibitor use, doses, reasons for prescribing/not prescribing ACE inhibitors, and ACE inhibitor prescribers (cardiologists or general physicians). Results: Forty four patients with an MI were included in the study, 28 of whom were prescribed ACE-inhibitors (64%). Twenty four of the 28 patients on ACE inhibitors were prescribed perindopril. The major reason given for prescribing ACE inhibitors was signs of congestive cardiac failure. All ACE inhibitors initiated in patients after MI at RBH were ordered by cardiologists. Conclusion: ACE inhibitors were prescribed appropriately in 88% of patients who met criteria for their use. This high percentage of appropriate prescribing was encouraging. Reevaluation as part of an ongoing quality assurance activity could be used to ensure this is maintained.

Inhibitors of COP-mediated Transport and Cholera Toxin Action Inhibit Simian Virus 40 Infection

Simian virus 40 (SV40) is a nonenveloped virus that has been shown to pass from surface caveolae to the endoplasmic reticulum in an apparently novel infectious entry pathway. We now show that the initial entry step is blocked by brefeldin A and by incubation at 20degreesC. Subsequent to the entry step, the virus reaches a domain of the rough endoplasmic reticulum by an unknown pathway. This intracellular trafficking pathway is also brefeldin A sensitive. Infection is strongly inhibited by expression of GTP-restricted ADP-ribosylation factor 1 (Arf1) and Sar1 mutants and by microinjection of antibodies to betaCOP. In addition, we demonstrate a potent inhibition of SV40 infection by the dipeptide N-benzoyl-oxycarbonyl-Gly-Phe-amide, which also inhibits late events in cholera toxin action. Our results identify novel inhibitors of SV40 infection and show that SV40 requires COPI- and COPII-dependent transport steps for successful infection.

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET.) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ETA) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ETA receptor antagonism may have a role in the treatment of athero-sclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ETA receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the nonselective ET or selective ETA receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors tors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.

Occlusable corneas in toadfishes: light transmission, movement and ultrastruture of pigment during light- and dark-adaptation

The toadfishes Tetractenos hamiltoni and Torquigener pleurogramma (Tetraodontidae) possess occlusable yellow corneas. We examine the light transmission and location of the yellow/orange pigment throughout the cornea, the temporal properties of pigment migration and the ultrastructure of the pigmented processes during light- and dark-adaptation. Each species was dark-adapted during the day and light-adapted during the night and then exposed to either sun illumination or darkness for different lengths of time (0-70 min). Movement of corneal pigment could be induced in both species regardless of time of day or night. The pigment was able to migrate in a dorsal or ventral direction and changed from minimal to maximal pigmentation within 60 min. Three types of transmission curves were found with varying degrees of transmission in the 400-500 nm waveband, indicating that the pigment distribution is not uniform across the cornea; some areas of the cornea transmit near UV light, while others absorb blue light. The gradual change of the transmission characteristics in different areas of the cornea indicates the presence of different concentrations of a single type of pigment. Ultrastructural examination of the corneas showed that the layer containing the pigment is situated within the scleral cornea either surrounding (T. pleurogramma) or abutting (T. hamiltoni) an iridescent layer. Long sheet-like processes or chromatophores extending centrally from dorsal and ventral reservoirs are filled with pigment during the light-adapted state but empty in the dark-adapted state.

Will chymase inhibitors be the next major development for the treatment of cardiovascular disorders?

Chymase is contained in the secretory granules of mast cells. In addition to the synthesis of angiotensin II, chymase is involved in transforming growth factor-beta activation and cleaves Type I procollagen to produce collagen. NK301 and BCEAB are orally-active inhibitors of chymase. NK301 was tested in a dog model of vascular intimal hyperplasia after balloon injury and shown to reduce the increased chymase activity in the injured arteries and prevent intimal thickening. In a hamster model of cardiac fibrosis associated with cardiomyopathy, BCEAB reduced the increased cardiac chymase activity in cardiomyopathy and reduced fibrosis. Chymase inhibitors may be an important development for the treatment of cardiovascular injury associated with mast cell degranulation.

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Back to (non)-Basics: Recent developments in neutral and charge-balanced glycosidase inhibitors

Certain glycosidase inhibitors possess potent antiviral, antitumour and antidiabetic properties. Glyconic acid lactones, the earliest glycosidase inhibitors identified, have planar anomeric carbons that mimic the transition state of glycoside hydrolysis. Other classes include lactams, glycals, epoxides, halides and sulfonium ions, the latter based on the natural product salacinol from an antidiabetic herb.

Action of auxin inhibitors on growth and grain yield of soybean

Soybean genotypes grown in sub-tropical climate may exhibit lodging. The plant lodging is influenced by soil type and fertility level, sowing date, latitude and altitude of the location, plant population and conditions of crop development. Plant regulators and herbicides are able to avoid or reduce plant lodging. This study aimed to verify the effects of the growth regulators TIBA and daminozide on vegetative growth and yield of soybean cultivar CD 214 RR. The experiment was carried out at a field in randomized block design with four replications in a factorial scheme. The A factor was represented by the combination of regulators TIBA and daminozide and its concentrations, and the Factor B was seven times of evaluation of injury and plant height or eight times of evaluation of lodging. In the range of doses used, the application of daminozide resulted in greater injury to soybean plants than TIBA. The smaller plant height was achieved by the application of 6 g ha-1 of TIBA and 1200 g ha-¹ of daminozide. Treatments with daminozide (100 g ha-¹) and TIBA (10 g ha-1) stood out due to the reduced lodging of soybean plants. Grain weight increased linearly when the levels of TIBA increased. There was a negative correlation between lodging and grain yield and a positive correlation between plant height and lodging. There was also a negative correlation between injury caused by the application of plant regulators and lodging.

Role on serine protease inhibitors in the pathogenisis of Steinernema carpocapsae

Tese de Doutoramento, Biologia (Biologia Celular e Molecular), 18 de Novembro de 2013, Universidade dos Açores.

Modulation of translation factor's gene expression by histone deacetylase inhibitors in breast cancer cells

The histone deacetylase inhibitors sodium butyrate (NaBu) and trichostatin A (TSA) exhibit anti-proliferative activity by causing cell cycle arrest and apoptosis. The mechanisms by which NaBu and TSA cause apoptosis and cell cycle arrest are not yet completely clarified, although these agents are known to modulate the expression of several genes including cell-cycle- and apoptosis-related genes. The enzymes involved in the process of translation have important roles in controlling cell growth and apoptosis, and several of these translation factors have been described as having a causal role in the development of cancer. The expression patterns of the translation mechanism, namely of the elongation factors eEF1A1 and eEF1A2, and of the termination factors eRF1 and eRF3, were studied in the breast cancer cell line MCF-7 by real-time quantitative reverse transcription-polymerase chain reaction after a 24-h treatment with NaBu and TSA. NaBu induced inhibition of translation factors' transcription, whereas TSA caused an increase in mRNA levels. Thus, these two agents may modulate the expression of translation factors through different pathways. We propose that the inhibition caused by NaBu may, in part, be responsible for the cell cycle arrest and apoptosis induced by this agent in MCF-7 cells.