A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid

The vanilloid receptor transient receptor potential type V1 (TRPV1) integrates responses to multiple stimuli, such as capsaicin, acid, heat, and endovanilloids and plays an important role in the transmission of inflammatory pain. Here, we report the identification and in vitro characterization of A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel, potent, and selective TRPV1 antagonist. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). When compared with other known TRPV1 antagonists, A-425619 exhibited superior potency in blocking both naive and phorbol ester-sensitized TRPV1 receptors. Like capsazepine, A-425619 demonstrated competitive antagonism (pA2 = 2.5 nM) of capsaicin-evoked calcium flux. Moreover, A-425619 was 25- to 50-fold more potent than capsazepine in blocking TRPV1 activation. A-425619 showed no significant interaction with a wide range of receptors, enzymes, and ion channels, indicating a high degree of selectivity for TRPV1 receptors. These data show that A-425619 is a structurally novel, potent, and selective TRPV1 antagonist.     

Epidemiology and outcomes of peritonitis in children on peritoneal dialysis in Australasia

Peritonitis is a common complication and major cause of morbidity in children on peritoneal dialysis. In this retrospective longitudinal study, we analysed data retrieved from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) on 167 patients aged less than 18 years of age who were treated with peritoneal dialysis during the period from October 2003 to December 2007. During this period there were 100 episodes of peritonitis in 57 patients (0.71 episodes/patient-year), with Gram-positive organisms most commonly isolated (44%). Peritonitis occurred frequently in the first 6 months after starting dialysis, with survival analysis showing peritonitis-free survival rates of 72%, 56% and 36% at 6 months, 1 year and 2 years respectively. Age was a weak predictor of peritonitis on univariate analysis, but previous peritonitis was the only significant predictor in a multivariate Cox proportional hazards model (adjusted hazard ratio 2.02; 95% CI: 1.20 to 3.40, p = 0.008). Peritonitis episodes infrequently resulted in relapse (5%), recurrence (7%) or the need for either temporary or permanent haemodialysis (5% and 7% respectively) and there were no patient deaths directly attributable to peritonitis. Compared with single organism peritonitis, polymicrobial peritonitis was not associated with any statistically significant differences in outcome. Further prospective studies are required to determine the most appropriate prophylactic measures and antibiotic regimens for use in pediatric patients.     

Sirolimus is Associated With Impaired Hematopoiesis in Heart Transplant Patients? A Retrospective Analysis

Background

Proliferation signal inhibitors may adversely impact bone marrow function. We sought to describe the impact of sirolimus on hemoglobin and erythropoiesis in heart transplant recipients.

Methods

We have conducted a single-center, retrospective analysis of all heart transplant patients treated with sirolimus. We measured serum hemoglobin (Hb) at baseline and at 3 months to determine the prevalence of anemia and change in Hb after sirolimus initiation. We also characterized hematologic profile of patients to gain insights into the effects of sirolimus on erythropoiesis.

Results

There were 84 patients included in the study. The prevalence of anemia increased from 71% to 75% after sirolimus initiation. Anemic patients were more likely to be male (P = .026) and have worse renal function (glomerular filtration rate 49 ± 27 vs 70 ± 42 mL/min; P = .012). A ≥20 g/L drop in Hb was observed in 25% of the overall cohort. Patients investigated for anemia (n = 67) had a low Hb (111 ± 24 g/L), normal mean corpuscular volume (87 ± 47 FL), and low serum iron levels (10 ± 5 μmol/L) and transferrin saturation (0.22 ± 0.12). Serum ferritin was variable (263 ± 370 μg/L). Bone marrow evaluation in 19 patients revealed adequate marrow iron stores in all cases.

Conclusion

Anemia is prevalent in heart transplant patients treated with sirolimus and increases over time. Patients have a characteristic hematologic profile suggestive of anemia of chronic disease and functional iron deficiency.     

The mystery of the lost and found right coronary artery

Most coronary artery anomalies are discovered only incidentally during coronary angiography. Recognition and identification of these anomalies especially during coronary intervention procedures are of importance because of their occasional association with symptoms due to atherosclerotic coronary disease. Anomalous origin of the right coronary artery (RCA) from the left anterior descending coronary artery (LAD) is one of the most uncommon coronary anomalies. We report an extremely interesting case of anomalous RCA from the LAD presenting as acute inferior ST elevation MI, with ostial total block of the RCA, precluding its visualization during coronary angiography. Interventional Cardiologists need to be aware of such anatomical variations, as occasionally, this can lead to a diagnostic dilemma, as in our case. © 2010 Wiley‐Liss, Inc.     

Trifurcation stenting using two guide catheters

Trifurcating coronary artery disease is a complex atherosclerotic process involving the origin of one or more of three side branches arising from a main trunk. The approach to treat trifurcation lesions has not been standardized. We describe a technique to percutaneously treat this lesion using routine day‐to‐day hardware and a unique two guide catheter technique. © 2009 Wiley‐Liss, Inc.     

Transradial simultaneous kissing stenting (SKS) with SheathLess access

Transradial coronary intervention is usually performed via a 5 or 6 Fr sheath due to the small calibre of radial arteries. Simultaneous kissing stenting (SKS) technique requires a guiding catheter 7 Fr or larger and is therefore difficult to perform via transradial approach. Conversion to femoral approach or additional arterial access is usually required to achieve this goal. To overcome this limitation, a hydrophilic 7.5 Fr SheathLess guiding catheter can be exploited. This catheter possesses approximately the same size outer diameter as a 6 Fr sheath and an internal diameter of a 7.5 Fr catheter. A smooth and successful performance of SKS through transradial approach is described using this catheter. © 2009 Wiley‐Liss, Inc.     

Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs

Aerosolized propylene glycol (PG) was generated as log-normally distributed particulate clouds in different concentrations using a novel capillary aerosol generator (CAG) and evaluated in a battery of non-clinical studies intended to assess its potential inhalation and systemic toxicity in 2 species before ICH-compliant "first-time-in-man" studies. Exposures were nose-only in rats, and via face mask with oropharyngeal tube in dogs. The CAG-generated PG aerosol had a mass median aerodynamic diameter (MMAD) of 2.29μm, with a 1.56 geometric standard deviation (GSD) in the rat studies, and a MMAD of 1.34μm (1.45 GSD) in the dog studies, consistent with expected particle size exposures in man. International Congress on Harmonization (ICH) Guidelines were followed, which recommend preliminary non-clinical safety studies using the vehicle and device (CAG-PG) prior to the first human exposure including safety pharmacology, pharmacokinetic (PK) studies, single dose toxicity studies, and repeated dose toxicity studies in two species. In the rat, the only biologically relevant findings included clinical signs of ocular and nasal irritation indicated by minor bleeding around the eyes and nose, and minimal laryngeal squamous metaplasia. This finding is commonly observed in inhalation studies in the rat, and likely related to the unique sensitivity of the tissue, as well as the circuitous airflow pathway through the larynx which increases particle deposition. In the female Beagle dog, treatment-related decreases in hemoglobin, red blood cells and hematocrit were observed in the two highest exposure groups, equivalent to approximately 18 and 60mg/kg/day. In male dogs from the high dose group, similar small decreases, albeit, non-statistically significant decreases were observed in these hematological markers as well. PK studies in rats and dogs showed that the absorption of PG following pulmonary inhalation exposure occurs rapidly, and equilibrium between lung tissue and plasma is achieved quickly. With daily inhalations of PG aerosols, there is evidence of minor tissue accumulation of PG in each species. Inhalation exposure to CAG-generated PG aerosols achieved PG concentrations in the systemic circulation that were similar to those attained via the oral route. Systemic elimination of PG appears to be saturable, presumably via hepatic metabolism. PG elimination in the high dose groups for both species showed terminal plasma and lung concentration-time profiles suggesting a zero-order elimination process. There was no apparent tissue toxicity of the lung, liver and kidney in these studies. Under the conditions of these studies, the NOEL for the rat was determined to be 20mg/kg/day for the 28-day study. In the Beagle dog, the NOEL was approximately 6.05mg/kg/day for the 28-day study. Overall, these studies allowed us to conclude that PG aerosol generated with the capillary aerosol generator could be administered safely in man, with an adequate margin of safety needed to conduct "first-time-in-man" human exposure studies.     

Identification of chemical components of combustion emissions that affect pro-atherosclerotic vascular responses in mice

Combustion emissions cause pro-atherosclerotic responses in apolipoprotein E-deficient (ApoE/?) mice, but the causal components of these complex mixtures are unresolved. In studies previously reported, ApoE?/? mice were exposed by inhalation 6?h/day for 50 consecutive days to multiple dilutions of diesel or gasoline exhaust, wood smoke, or simulated "downwind" coal emissions. In this study, the analysis of the combined four-study database using the Multiple Additive Regression Trees (MART) data mining approach to determine putative causal exposure components regardless of combustion source is reported. Over 700 physical-chemical components were grouped into 45 predictor variables. Response variables measured in aorta included endothelin-1, vascular endothelin growth factor, three matrix metalloproteinases (3, 7, 9), metalloproteinase inhibitor 2, heme-oxygenase-1, and thiobarbituric acid reactive substances. Two or three predictors typically explained most of the variation in response among the experimental groups. Overall, sulfur dioxide, ammonia, nitrogen oxides, and carbon monoxide were most highly predictive of responses, although their rankings differed among the responses. Consistent with the earlier finding that filtration of particles had little effect on responses, particulate components ranked third to seventh in predictive importance for the eight response variables. MART proved useful for identifying putative causal components, although the small number of pollution mixtures (4) can provide only suggestive evidence of causality. The potential independent causal contributions of these gases to the vascular responses, as well as possible interactions among them and other components of complex pollutant mixtures, warrant further evaluation.     

Cardiopulmonary response to inhalation of secondary organic aerosol derived from gas-phase oxidation of toluene

The biological response to inhalation of secondary organic aerosol (SOA) was determined in rodents exposed to SOA derived from the oxidation of toluene, a precursor emitted from anthropogenic sources. SOA atmospheres were produced to yield 300 μg·m(-3) of particulate matter (PM) plus accompanying gases. Whole-body exposures were conducted in mice to assess both pulmonary and cardiovascular effects. ApoE(-/-) mice were exposed for 7 days and measurements of TBARS and gene expression of heme-oxygenase-1 (HO-1), endothelin-1 (ET-1), and matrix metalloproteinase-9 (MMP-9) were made in aorta. Pulmonary inflammatory responses in both species were measured by bronchoalveolar lavage fluid (BALF) cell counts. No pulmonary inflammation was observed. A mild response was observed in mouse aorta for the upregulation of ET-1 and HO-1, with a trend for increased MMP-9 and TBARS, and. Overall, toluene-derived SOA revealed limited biological response compared with previous studies using this exposure protocol with other environmental pollutants.