Indoleamine, 2-3 dioxygenase activity could be an early marker of graft rejection in heart transplantation

[Abstract] Background. The indoleamine, 2-3 dioxygenase (IDO) is an inducible intracellular enzyme with immunosuppressive effects mainly on lymphocyte populations. It has been postulated that indirect determination of IDO serum activity may be a marker of renal graft rejection, but its potential usefulness in heart transplantation (HT) is unknown. Methods. This longitudinal study included 98 HT patients (83% males) who survived ≥1 year. Mean age was 54.14 ± 11.57 years. Serum IDO activity was analyzed one month after HT by means of high performance liquid chromatography and correlated with the cumulative incidence of acute rejection (AR) during one-year follow-up. AR was defined as biopsy-proven ≥ ISHLT grade 2R rejection or empirically treated non-biopsy-proven rejection. The study sample was divided into two groups: AR group (n = 51), including patients who experienced at least one AR episode during the first year after HT; No-AR group (N = 47), including the remaining patients. Results. Mean serum IDO activity one month after HT was significantly higher (P = .021) in the AR group (3.32 ± 1.56) than in the no-AR group (2.62 ± 1.35). No significant association between serum IDO activity and gender (male: 3.1 ± 1.56, women: 2.43 ± 0.99, P = .092), recipient age (r = −.07, P = .943) or donor age (r = 0.108, P = 0.293) was observed. By means of binary logistic regression, an odds ratio of 1.4 [CI 95%: 1.033-1.876, P = .03] per unit increase of act-IDO was estimated, with no significant modification upon forced adjustment for age and sex. Mean glomerular filtration rate 1 month after HT was 67.01 ± 28.51 mL/min/m2. No significant correlation between this parameter and serum IDO activity was observed (r = .160, P = .117). Conclusions. Our study suggests that serum IDO activity one month after HT might be associated with a higher risk of AR during one-year follow-up. This association seems to be independent of recipient gender, age or renal function

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: a preliminary report

[Abstract] Background: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8–10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4). Methods: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied. Results: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and > 5 and < 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients. Conclusions: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine.Instituto de Salud Carlos III; RD12/004

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report

Background: Ivabradine, a selective bradycardic drug, inhibits the If. In patients with heart failure (HF), ivabradine reduces the risk of rehospitalization and mortality. The average heart rate (HR) reduction is 8–10 beats, although clinical trials reveal interindividual variability. The aim of the study is to identify variants associated with HR reduction produced by ivabradine in genes involved in the drug metabolism (CYP3A4) or related to the drug target (HCN4). Methods: In an exploratory cohort (n = 11), patients started on ivabradine were genotyped and the HR reduction was studied. Results: The mean HR reduction after the treatment was 18.10 ± 12.26 bpm. The HR reduction was ≥ 15 bpm in 3 patients and &gt; 5 and &lt; 15 bpm in 7 patients. Four synonymous variants, L12L, L520L, P852P, and P1200P, were detected in the HCN4 gene (frequency = 0.045, 0.045, and 0.681, respectively). Moreover, the CYP3A4*1F and CYP3A4*1B were found in one patient each and CYP3A4*1G was presented in 3 patients. Conclusions: This is the first study using an exploratory pharmacogenetic approach that attempts to explain interindividual variability in ivabradine HR reduction. However, more research must be undertaken in order to determine the role of variants in HCN4 and CYP3A4 genes in response to ivabradine

Large-scale application of highly-diluted bacteria for Leptospirosis epidemic control

Background: Leptospirosis is a zoonotic disease of major importance in the tropics where the incidence peaks in rainy seasons. Natural disasters represent a big challenge to Leptospirosis prevention strategies especially in endemic regions. Vaccination is an effective option but of reduced effectiveness in emergency situations. Homeoprophylactic interventions might help to control epidemics by using highly-diluted pathogens to induce protection in a short time scale. We report the results of a very large-scale homeoprophylaxis (HP) intervention against Leptospirosis in a dangerous epidemic situation in three provinces of Cuba in 2007. Methods: Forecast models were used to estimate possible trends of disease incidence. A homeoprophylactic formulation was prepared from dilutions of four circulating strains of Leptospirosis. This formulation was administered orally to 2.3 million persons at high risk in an epidemic in a region affected by natural disasters. The data from surveillance were used to measure the impact of the intervention by comparing with historical trends and non-intervention regions. Results: After the homeoprophylactic intervention a significant decrease of the disease incidence was observed in the intervention regions. No such modifications were observed in non-intervention regions. In the intervention region the incidence of Leptospirosis fell below the historic median. This observation was independent of rainfall. Conclusions: The homeoprophylactic approach was associated with a large reduction of disease incidence and control of the epidemic. The results suggest the use of HP as a feasible tool for epidemic control, further research is warranted. Homeopathy (2010) 99, 156e166