Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFß1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFß1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,-4,-13,-14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and -13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/ß6 integrins. Pirfenidone and nintedanib significantly inhibited TGFß1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

El metilfenidato en el trastorno por despersonalización: a propósito de un caso / Methylphenidate in depersonalization disorder: a case report

El síntoma de despersonalización aparece frecuentemente asociado a otros trastornos mentales, a efectos fisiológicos de substancias o a enfermedades médicas. Raramente, como es el caso presentado, las experiencias de despersonalización forman una entidad aislada, un trastorno de despersonalización primario. Entre los múltiples psicofármacos estudiados, ninguno de ellos ha demostrado ser el tratamiento de elección. Entre los que obtienen mejores resultados destacan: los antagonistas de los receptores de los opioides (naloxona y naltrexona), la combinación de inhibidores selectivos de la recaptación de la serotonina con lamotrigina y la clorimipramina. Y, aunque con prácticamente nula evidencia, se presenta un caso que respondió de forma espectacular al metilfenidato (AU)

The symptom of depersonalization is frequently associated with other mental disorders, physiological effects of substances or medical diseases. However, it is rare that, as in the case presented, the experiences of depersonalization form an isolated entity, a primary depersonalization disorder. Among the many psychoactive drugs studied, none of them has been shown to be the treatment of choice. Among those with which the best results are obtained are opioid receptor antagonists (naloxone and naltrexone), the combination of selective serotonin reuptake inhibitors with lamotrigine and clorimipramine. Although with virtually no evidence, we are presenting a case that responded spectacularly to methylphenidate (AU)

Methylphenidate in depersonalization disorder: a case report.

The symptom of depersonalization is frequently associated with other mental disorders, physiological effects of substances or medical diseases. However, it is rare that, as in the case presented, the experiences of depersonalization form an isolated entity, a primary depersonalization disorder. Among the many psychoactive drugs studied, none of them has been shown to be the treatment of choice. Among those with which the best results are obtained are opioid receptor antagonists (naloxone and naltrexone), the combination of selective serotonin reuptake inhibitors with lamotrigine and clorimipramine. Although with virtually no evidence, we are presenting a case that responded spectacularly to methylphenidate.

Recovery of ventricular function with a left ventricular axial pump in a patient with end-stage toxic cardiomyopathy not a candidate for heart transplantation: first experience in Spain.

BACKGROUND: Toxic cardiomyopathies are rare and the most frequent cause are anthracycline compounds. Early acute toxicity can be reversible, but at present the only effective therapy for late end-stage anthracycline cardiomyopathy seems to be a heart transplantation. Currently, this transplantation is contraindicated in cases of cancer, at least during the first 4 or 5 years. Recently, implantable axial pumps have shown good results and are used with increasing frequency as destination therapy. METHODS: We present a case of end-stage heart failure due to a toxic cardiomyopathy after a bilateral breast cancer treated with resection and chemotherapy (doxorubicin and trastuzumab). Ejection fraction was 23% with dobutamine. A left ventricular axial pump (Incor) was implanted. RESULTS: The immediate postoperative course was uneventful. The left ventricular function improved and on the fourth month the ejection fraction was 55%. On postoperative day 135, the pump was explanted. After 1.5 years, the patient is doing well, with an ejection fraction of 57%. CONCLUSION: This is the first application of an implantable axial pump in Spain. Although toxic cardiomyopathies are rare, in cases of late end-stage left ventricular failure and when the heart transplantation is contraindicated, the implantation of an axial pump can be the solution. The results in previous cases are unknown, although it is possible, as in our case.

Clinical evolution of heart transplantation in patients with previous valvular cardiomyopathy.

OBJECTIVE: Heart transplantation (HT) due to valvular cardiomyopathy is rare, namely, about 3% of cases in the Registry of the International Society for Heart and Lung Transplantation (ISHLT). Usually, these patients present some risk factors such as previous valvular operations and pulmonary hypertension. Since there are few studies in the literature, we retrospectively analyzed our early and long-term results. MATERIALS AND METHODS: We studied our experience in 22 HT cases for valvular cardiomyopathy (9.3% of our total experience), namely, 12 men and 10 women, of overall mean age of 52.6 +/- 10 years. Five patients had mitral; 8, aortic; and 1, tricuspid valve disease; 7 had double valve disease and 1, triple valve disease. Nineteen patients (87%) had been operated previously between 1 and 4 times. The mean ejection fraction was 23% +/- 7.3% and the mean New York Heart Association (NYHA) functional class was 3.7. Fifty-three percent of the patients had pulmonary hypertension. Two patients were operated as an emergency "O." We used the standard HT technique. RESULTS: Four patients (18%) were reoperated due to hemorrhage. The hospital mortality was 2 cases (9%). Another patients (9%) died on follow-up due to cardiac allograft vasculopathy. All surviving patients have been followed to the end of 2006. The mean follow-up has been 72 +/- 53 months. They are functional class I or II. CONCLUSIONS: HT for this indication was more frequent in our experience than in the Registry of the ISHLT. The immediate and long-term results were good, with an 82% mean survival at 6 years. HT can be a good treatment for patients with valvular cardiomyopathy and bad ventricular function and/or multiple valvular reoperations.

Is short-term amiodarone use post cardiac surgery a cause of acute respiratory failure?

AIM: It was believed that amiodarone-related adverse respiratory effects were found only when receiving amiodarone on a long-term basis, but several reports seem to contradict this hypothesis. The aim of this study was to evaluate, in an intensive care unit (ICU), the possibility of acute respiratory toxicity induced by short-term amiodarone administration following cardiac surgery. METHODS: We conducted a prospective clinical trial of 111 consecutive patients admitted to our ICU after cardiac surgery (basically, coronary artery bypass graft and/or valve surgery) and who received short-term prophylactic amiodarone treatment if they were considered at high risk of developing atrial fibrillation. We administered 900 mg/day intravenously for the first 2 days and 600 mg/day on the following days of the ICU stay. The oxygenation index (PaO2/FiO2 ratio) was evaluated at admission, and then 24 and 48 h postsurgery. RESULTS: One-hundred and two patients were included in the study (9 were excluded for bradycardia), and 25 received amiodarone treatment. The Parsonnet and APACHE II scores differed slightly between the treated and nontreated groups. There were no significant differences between the treated and nontreated groups with respect to left atrial pressure, the number of packed red cells transfused or the oxygenation index at admission and 24 and 48 h postsurgery. CONCLUSION: The short-term administration of amiodarone under the conditions of the present study does not seem to affect respiratory function.

Selective prophylaxis of atrial fibrillation with amiodarone after cardiac surgery.

AIM: Atrial fibrillation (AF) is common after cardiac surgery, but prophylaxis for patients especially prone to developing this arrhythmia has not been studied to date. We investigated amiodarone as prophylaxis for AF in selected patients after open-heart surgery. METHODS: In the first stage we studied a group of 204 consecutive cardiac surgery patients and devised a formula from some of the known risk factors of AF for each sex to serve as a predictor model. In this first group we were able to quantify the probability of developing this arrhythmia. In the second stage we applied this formula to a group of 231 consecutive cardiac surgery patients and then selectively treated the high-risk patients for AF: 25 men (16.1%) and 29 women (53.7%). In the first 24 h of treatment with amiodarone, 22 patients (10 men and 12 women) were excluded from the study due to sinus bradycardia. Therapy consisted of amiodarone 900 mg intravenously every 24 h for the first 2 postoperative days, followed by 600 mg intravenously every 24 h until discharge from the Intensive Care Unit. RESULTS: Expected AF in males fell from 34.4% (52/151) in the observation group to 11% (17/155) in the treated group, and in females from 50.9% in the observation group (27/53) to 9.3% (5/54) in the treated group (P<0.001). CONCLUSIONS: Patient-selective prophylaxis of AF with amiodarone can be a highly effective measure.

Impact of highly active antiretroviral therapy on blood pressure in HIV-infected patients. A prospective study in a cohort of naive patients.

OBJECTIVES: To assess the impact of highly active antiretroviral therapy (HAART) on the blood pressure (BP) of naive patients after 1 year of treatment. METHODS: A prospective, observational study of 95 HIV-positive patients in our Unit starting HAART between January 2001 and October 2002 and maintaining the same regimen for 48 weeks of follow-up was carried out. Data on blood pressure (BP) and demographic, epidemiological, clinical, immunovirological and therapeutic characteristics related to HIV infection were collected prior to HAART and at week 48. High blood pressure (HBP) [systolic BP (SBP) > or =140 mm Hg and/or diastolic BP (DBP) > or =90 mm Hg] was defined according to international criteria. RESULTS: Of the 95 patients, 78 were men, 44% had AIDS and 68% were smokers, and their mean age was 40 years. At week 48 the prevalence of HBP was 26% and SBP, DBP and pulse pressure (PP) increased (121.8 versus 116.6 mm Hg, P=0.0001; 76.3 versus 69.7 mm Hg, P=0.004; 46.9 versus 43.8 mm Hg, P=0.001, respectively). Univariate analysis showed that HBP was associated with older age, higher body mass index (BMI), higher baseline lipids, and higher baseline BP. A linear regression model adjusting for age and sex suggested a significant impact of older age, higher baseline SBP, higher baseline hypercholesterolaemia and lower baseline CD4-cell count on SBP increase. CONCLUSIONS: Blood pressure increased after 48 weeks of HAART, leading to an important prevalence of hypertension. The increase in SBP depended on age and baseline lipid profile and immunological status. BP should be periodically measured and treated when necessary in HIV-infected patients on HAART.

Acute myocardial infarction with cardiogenic shock: treatment with mechanical circulatory assistance and heart transplantation.

UNLABELLED: The mortality of cardiogenic shock (CS) after an acute myocardial infarction (AMI) still remains high. Thrombolysis, PTCA or CABG, when possible, can improve the results, but when all the treatments fail death is almost certain. OBJECTIVE: We investigate the use of the mechanical circulatory assistance (MCA) and heart transplantation (HT) to improve the adverse results in this irreversible situation. METHODS: Among 11 patients with irreversible CS after an AMI we used a MCA (Abiomed BVS-5000). After improvement and hemodynamic stabilization, we performed heart transplantation in 7 patients of mean age 52 years (35-60) including two women. The MCA was univentricular in 7 patients and biventricular in 4. Mean duration of the MCA was 5 days (1-12). RESULTS: Three patients died during the MCA: two due to cerebrovascular accidents and one multiorgan failure. Weaning was possible in one patient. Among Seven transplanted patients one died due to sepsis. Seven (64%) patients are long-term survivors. CONCLUSION: When all the treatments have failed for CS after an AMI, MCA may be used as a bridge to heart transplantation in a select group of patients where the procedure is not contraindicated. The long-term results of 64% survivors in our experience is satisfactory.

Sirolimus in heart transplantation: a single center initial experience.

Sirolimus (SRL) is a potent non-nephrotoxic immunosuppressant. In our unit, SRL was administered to 17 heart transplant (HT) recipients at 1770+/-1234 days' posttransplant surgery, for the following reasons: (1) calcineurin inhibitor (CI) withdrawal due to renal insufficiency (RI; n=6); (2) neurotoxicity (n=1) and pancytopenia (n=1); (3) vascular graft disease (VGD) treatment (n=5); (4) immunosuppression optimization due to lung cancer (n=2); (5) CI use was delayed due to postsurgery RI (n=2). The mean follow-up was 190+/-165 days. Mean SRL doses (mg)/concentrations (ng/mL) at 7 (n=17), 30 (n=14), and 180 (n=8) days were: 1.2+/-0.6/5.9+/-6; 1.6+/-0.8/4.8+/-3.1; and 1.7+/-1.0/5.2+/-3.7. Among group 1, CI patients were discontinued without favorable functional impact. Neurotoxicity and pancytopenia improved, but there were no major clinical events in the VGD group. One "bridge" to CI was successfully performed (postsurgery RI). Total leukocyte count fell while hemoglobin, platelet, and cholesterol profiles were not affected. Ten of 15 patients (67%) were discontinued from CI without rejection and with a dose reduction of mycophenolate mofetil. There were 8 episodes (47%) of SRL-related toxicity, leading to 4 discontinuations (23%); 8 patients (47%) have died during follow-up. This retrospective analysis of outcomes in the context of severe complicated patients suggests that more premature introduction SRL is preferable, particularly in a large patient cohort.

Pacemaker endocarditis: approach for lead extraction in endocarditis with large vegetations.

We present the case of a patient with vegetations on a pacing lead from a pacemaker implanted 13 years previously. A new surgical technique for removal of infected leads was developed to avoid the increased risk of septic pulmonary embolism. The electrode with vegetations was removed without cardiopulmonary bypass using the direct surgical approach described.

Predictive factors and long-term evolution of early endothelial dysfunction after cardiac transplantation.

BACKGROUND: Abnormal coronary vasomotion appears to be a common finding after heart transplantation (HTx). However, the pathophysiology and outcome of this functional disturbance remains poorly understood. Aims of the study were to determine the prevalence, predictive factors and long-term evolution of endothelial dysfunction after cardiac transplantation. METHODS: The endothelium-dependent coronary vasomotion of 50 patients, who showed angiographically normal coronary arteries, were studied early (at 3 +/- 1 months) and at follow-up (16 +/- 5 months) after HTx. Endothelial function was studied by selective infusion of serial doses of acetylcholine (ACh) (10(-8), 10(-7)and 10(-6) mol/l) in the left anterior descending coronary artery. Changes in mean luminal diameter after the infusion of each dose were evaluated by quantitative coronary angiography (QCA). RESULTS: At early study, 17 patients (34%) showed a vasoconstriction after maximal dose of ACh (-13.3 +/- 13%) indicative of endothelial dysfunction. Logistic regression analysis identified the following variables as independent predictors of early endothelial dysfunction: donor inotropic support (p = 0.004), female donor (p = 0.04) and rejection at the time of the study (p = 0.01). Forty-one patients were re-studied at follow-up. Nine of them (22%) presented endothelial dysfunction. Early endothelial dysfunction was restored in 6 patients (43%) at follow-up. The number of episodes of rejection was the only variable associated to late endothelial dysfunction. CONCLUSIONS: Endothelial dysfunction is a common finding after cardiac transplantation. The pathogenesis of this functional disturbance appears to be donor-related and immune-mediated. The reversibility of this phenomenon observed at follow-up suggests the episodic nature of the immunologic injury.

[Right ventricular outflow obstruction due to a giant pseudoaneurysm of the anterior descending coronary artery in a patient with Behçet's disease]. / Obstrucción del tracto de salida del ventrículo derecho por un seudoaneurisma gigante de la arteria coronaria descendente anterior en un paciente con enfermedad de Behçet.

Giant pseudoaneurysms of coronary arteries in patients with Behçet's disease is a uncommon finding. It has been described exceptionally in the literature. We present a case of giant pseudoaneurysm of the left anterior descending coronary artery with obstruction of the right ventricular outflow in a patient with Behçet's disease. He improved after surgical resection and steroid treatment.

Liquid chromatographic determination of fenbendazole residues in pig tissues after treatment with medicated feed.

Fenbendazole (FBZ) is an anthelmintic widely used in farm animals to treat parasitic infestations. In pigs, it is administered in the food. The aim of this study was to validate an analytical method for the determination of FBZ and its metabolites in pig tissues. This method is based on oxidation of FBZ and its sulfoxide metabolite to the sulfone metabolite (FBZSO2). The limit of quantitation for this method is 20 ng FBZSO2/g for all tissues. The maximum residue limits (MRLs) established for FBZ and its metabolites in pig tissues are 50 ng/g for muscle, fat, and kidney and 500 ng/g for liver. This method is based on a liquid-liquid extraction followed by an oxidation with peracetic acid and a cleanup procedure based on 2 liquid-liquid extractions. Determination is achieved by high-performance liquid chromatography with ultraviolet detection. The present method is adjusted to the MRL established for FBZ and its metabolite residues. The analysis of the residues shows that after 72 h posttreatment, no FBZSO2 was detected in muscle, fat, and kidney and that liver levels were below the MRL.