Abacavir Increases Purinergic P2X7 Receptor Activation by ATP: Does a Pro-inflammatory Synergism Underlie Its Cardiovascular Toxicity?

The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.

Health Outcomes and Primary Adherence to Secondary Prevention Treatment after St-Elevation Myocardial Infarction: a Spanish Cohort Study.

This retrospective observational study aimed to establish the first prescription and its dispensation (primary adherence) in the first 30 days of the four pharmacotherapeutic classes recommended after a type 1 STEMI episode, determine the potential risk factors for lack of primary adherence, and evaluate the potential impact of primary adherence on cardiovascular outcomes. Of the 613 patients analyzed, 576 were included (64.7 ± 13.8 years, 73.8% men) between January 2008 and December 2013. Primary adherence exceeded 90% in all groups. Complete primary adherence was higher in high-drug coverage patients and was lower in patients with cardiovascular or neuropsychiatric diseases. According to competing risk analysis, 1-year cardiovascular mortality was significantly lower in patients with complete primary adherence than in those without complete prescription or adherence, 1.8% versus 5.6% (HR = 0.286; p = 0.012). Complete primary adherence did not prevent a 1-year cardiovascular event, 5.6% versus 5.5% (p = 0.904).

Impacto pronóstico de la adherencia secundaria a betabloqueantes tras infarto de miocardio con elevación del segmento ST sin disfunción ventricular / Secondary adherence to beta-blockers after ST-elevation myocardial infarction without ventricular dysfunction

INTRODUCCIÓN Y OBJETIVOS: La toma correcta de medicación condiciona la efectividad de un tratamiento. El objetivo del presente trabajo ha sido determinar el impacto de la prescripción y la adherencia secundaria a betabloqueantes en la morbimortalidad cardiovascular a medio y largo plazo, tras un primer episodio de infarto de miocardio con elevación del segmento ST (IAMCEST) tipo 1 sin insuficiencia cardiaca o con fracción de eyección del ventrículo izquierdo ≥ 40%. MÉTODOS: Estudio observacional y retrospectivo en una cohorte de pacientes ingresados entre 2008 y 2013 en el Hospital Clínico Universitario de Valencia. El análisis de incidencia acumulativa estableció la relación entre la mortalidad cardiovascular o la aparición de un nuevo evento vascular con la prescripción de betabloqueantes y la adherencia secundaria, definida como proporción de días cubiertos. RESULTADOS: Durante el primer año tras el alta, la prescripción de betabloqueantes no influyó significativamente sobre los resultados en salud de los 460 pacientes incluidos. Sin embargo, la mortalidad cardiovascular fue menor en los pacientes adherentes respecto a los no adherentes, el 0,6% frente al 6,6% (HR = 0,083; IC del 95%, 0,015-0,448; p = 0,003), y en los pacientes adherentes respecto a los que no recibieron el tratamiento por ausencia de prescripción o por falta de adherencia, el 0,6% frente al 4,8% (HR = 0,115; IC del 95%, 0,022-0,587; p = 0,009). Estos resultados no se objetivaron cuando se analizó todo el periodo de seguimiento (mediana 46,7 meses). CONCLUSIONES: La adherencia secundaria a betabloqueantes mejora el pronóstico durante el primer año tras un IAMCEST con función ventricular izquierda conservada

INTRODUCTION AND OBJECTIVES: Adequate medication intake affects treatment effectiveness. The aim of this study was to establish the impact of prescription and secondary adherence to beta-blockers on medium- and long-term and long-term cardiovascular outcomes, after a first type 1 ST-elevation myocardial infarction (STEMI) episode without heart failure or left ventricular ejection fraction ≥ 40%. METHODS: A retrospective observational study was conducted in a cohort of patients admitted from 2008 to 2013 to the University Clinical Hospital in Valencia. Competing risk analysis assessed the relationship between cardiovascular mortality or new vascular event with beta-blocker prescription and secondary adherence, defined as a proportion of days covered. RESULTS: During after the first year following discharge, beta-blocker prescription was not significantly associated with better health outcomes in the 460 patients included. However, cardiovascular mortality was lower in adherent patients compared to non-adherent patients, at 0.6% vs. 6.6% (HR = 0.083; 95% CI, 0.015-0.448; p = 0.003), and in adherent patients compared to those who did not receive the treatment due to lack of prescription or lack of adherence, with 0.6% vs. 4.8% (HR = 0.115; 95% CI, 0.022-0.587; p = 0.009). These results were not observed when the complete follow-up period was analysed (median 46.7 months). CONCLUSIONS: Secondary adherence to beta-blockers improves 1-year prognosis after STEMI with preserved left ventricular function

Secondary adherence to beta-blockers after ST-elevation myocardial infarction without ventricular dysfunction. / Impacto pronóstico de la adherencia secundaria a betabloqueantes tras infarto de miocardio con elevación del segmento ST sin disfunción ventricular.

INTRODUCTION AND OBJECTIVES: Adequate medication intake affects treatment effectiveness. The aim of this study was to establish the impact of prescription and secondary adherence to beta-blockers on medium- and long-term and long-term cardiovascular outcomes, after a first type 1 ST-elevation myocardial infarction (STEMI) episode without heart failure or left ventricular ejection fraction ≥ 40%. METHODS: A retrospective observational study was conducted in a cohort of patients admitted from 2008 to 2013 to the University Clinical Hospital in Valencia. Competing risk analysis assessed the relationship between cardiovascular mortality or new vascular event with beta-blocker prescription and secondary adherence, defined as a proportion of days covered. RESULTS: During after the first year following discharge, beta-blocker prescription was not significantly associated with better health outcomes in the 460 patients included. However, cardiovascular mortality was lower in adherent patients compared to non-adherent patients, at 0.6% vs. 6.6% (HR = 0.083; 95% CI, 0.015-0.448; p = 0.003), and in adherent patients compared to those who did not receive the treatment due to lack of prescription or lack of adherence, with 0.6% vs. 4.8% (HR = 0.115; 95% CI, 0.022-0.587; p = 0.009). These results were not observed when the complete follow-up period was analysed (median 46.7 months). CONCLUSIONS: Secondary adherence to beta-blockers improves 1-year prognosis after STEMI with preserved left ventricular function.

Tenofovir-induced toxicity in renal proximal tubular epithelial cells: involvement of mitochondria.

OBJECTIVE: In-vivo studies suggest that mitochondria is involved in tenofovir (TFV)-induced renal toxicity, but the underlying mechanisms are still unclear. The aim of the present study was to assess the effects of TFV and its prodrug, TFV disoproxil fumarate, on mitochondrial function and cell survival/viability in a renal proximal tubular cell line. DESIGN AND METHODS: We evaluated parameters of cellular proliferation/survival (cell count, cell cycle, viability) and mitochondrial function (oxygen consumption, mitochondrial membrane potential, reactive oxygen species production) in NRK-52E cells. Intracellular TFV was measured by HPLC and expression of antioxidant genes was analysed by real-time PCR. RESULTS: Similar intracellular levels of TFV were reached with lower concentrations of the prodrug than of the drug, and correlated directly with a decrease in cell number. Both compounds inhibited proliferation and compromised mitochondrial function by decreasing mitochondrial membrane potential and increasing oxygen consumption and mitochondrial superoxide production. Altered oxidative status was confirmed by the overexpression of antioxidant genes. CONCLUSIONS: Intracellular accumulation of TFV induces mitochondrial toxicity in an in-vitro renal model and alters cell proliferation and viability. Our findings call for caution regarding the use of this nucleotide analogue reverse transcriptase inhibitor in patients with other risk factors that compromise mitochondrial function in the kidney.

Inhalable polymer-glycerosomes as safe and effective carriers for rifampicin delivery to the lungs.

Rifampicin loaded glycerosomes, vesicles composed of phospholipids, glycerol and water, were combined with trimethyl chitosan chloride (TMC) to prepare TMC-glycerosomes or, alternatively, with sodium hyaluronate (HY) to obtain HY-glycerosomes. These new hybrid nanovesicles were tested as carriers for pulmonary delivery of rifampicin. Glycerosomes without polymers were also prepared and characterized. All vesicles were similar: they were spherical, multilamellar and able to incorporate good amount of rifampicin (EE%∼55%). The addition of the polymers to the formulations allowed an increase of mean diameter. All the glycerosomes, in particular HY-glycerosomes, were able to deliver the drug to the furthest stages of the Next Generation Impactor and the aptitude of the vesicles to be nebulized was always higher than that of drug dispersion. Rifampicin nanoincorporation in vesicles reduced the in vitro drug toxicity on A549 cells, as well as increased its efficacy against Staphylococcus aureus. Finally, the in vivo biodistribution and accumulation, evaluated after intra-tracheal administration to rats, confirmed the improvement of rifampicin accumulation in lungs.

Faceted phospholipid vesicles tailored for the delivery of Santolina insularis essential oil to the skin.

The aim of this work was to formulate Santolina insularis essential oil-loaded nanocarriers, namely Penetration Enhancer containing Vesicles (PEVs), evaluate the physico-chemical features and stability, and gain insights into their ability to deliver the oil to the skin. S. insularis essential oil was obtained by steam distillation, and was predominantly composed of terpenes, the most abundant being ß-phellandrene (22.6%), myrcene (11.4%) and curcumenes (12.1%). Vesicles were prepared using phosphatidylcholine, and ethylene or propylene glycol were added to the water phase (10% (v/v)) to improve vesicle performances as delivery systems. Vesicles were deeply characterized by light scattering, cryogenic transmission electron microscopy and small/wide-angle X-ray scattering, the results showing polyhedral, faceted, unilamellar vesicles of ∼115 nm in size. The presence of the glycols improved vesicle stability under accelerated ageing conditions, without changes in size or migration phenomena (e.g. sedimentation and creaming). Confocal laser scanning microscopy images of pig skin treated with S. insularis formulations displayed a penetration ability of PEVs greater than that of control liposomes. Moreover, all formulations showed a marked in vitro biocompatibility in human keratinocytes. These findings suggest that the nanoformulation may be of value in enhancing the delivery of S. insularis essential oil to the skin, where it can exert its biological activities.

Rate and extent of oxaliplatin absorption after hyperthermic intraperitoneal administration in peritoneal carcinomatosis patients.

PURPOSE: To determine the rate and extent of hyperthermic intraperitoneal oxaliplatin (HIO) absorption in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and the effect of the isotonic carrier solution on HIO absorption parameters. METHODS: Full pharmacokinetic profiles collected in peritoneum and plasma from 57 subjects treated with CRS followed by 30 min of HIO were pooled with sparse plasma concentrations collected from 50 patients with solid tumors treated with intravenous oxaliplatin. Pharmacokinetic data were jointly analyzed with nonlinear mixed-effect model (NONMEM VII software). The effect of carrier solution (icodextrin 4 % vs. dextrose 5 %) and selected patient covariates on oxaliplatin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and nonparametric bootstrap. RESULTS: An open linear two-compartment disposition model with linear absorption from peritoneum to plasma was used to characterize the oxaliplatin pharmacokinetics in peritoneum and plasma. No patient-related covariates were associated with oxaliplatin pharmacokinetics. The volume of distribution in the peritoneum (V a) exponentially decreased due to the carrier solute absorption. The reduction in V a was 1.76-fold faster when HIO was administered in dextrose 5 %, relative to icodextrin 4 %. For HIO durations of 30 min, the rate of oxaliplatin absorption ranges from 0.84 to 0.96 h(-1) for icodextrin 4 % and from 0.86 to 1.09 h(-1) for dextrose 5 %. The extent of HIO absorption was 38 %, regardless of the carrier solution. CONCLUSIONS: Hyperthermic intraperitoneal oxaliplatin absorption is fast and incomplete. The small difference in oxaliplatin exposure between both carrier solutions evaluated is not clinically relevant for HIO durations of 30 min.

Efavirenz induces interactions between leucocytes and endothelium through the activation of Mac-1 and gp150,95.

OBJECTIVES: The potential cardiovascular (CV) toxicity associated with combined antiretroviral therapy (cART) has been attributed mainly to the nucleoside reverse transcriptase inhibitors abacavir and didanosine. However, the other two components of cART--non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)--may also be implicated, either directly or by influencing the action of the other drugs. This study evaluates the acute direct effects of the NNRTIs efavirenz and nevirapine and one of the most widely employed PIs, lopinavir, on leucocyte-endothelium interactions, a hallmark of CV disease. METHODS: Drugs were analysed in vitro in human cells (interactions of peripheral blood polymorphonuclear or mononuclear cells with human umbilical vein endothelial cells) using a flow chamber system, and in vivo in rat mesenteric vessels by means of intravital microscopy. The expression of adhesion molecules in leucocytes and endothelial cells was studied by flow cytometry, and the role of these molecules in white cell recruitment was evaluated by pre-treating human cells or rats with blocking antibodies. RESULTS: Efavirenz and nevirapine, but not lopinavir, increased the rolling flux and adhesion of leucocytes in vitro and in vivo while inducing emigration in rat venules. Efavirenz, but not nevirapine, augmented the levels of CD11b, CD11c and CD18 in neutrophils and monocytes. The actions of efavirenz, but not of nevirapine, were reversed by antibodies against Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18) or ICAM-1 (CD54). CONCLUSIONS: NNRTIs, but not PIs, interfere with leucocyte-endothelial interactions. However, differences between efavirenz and nevirapine suggest a specific CV profile for each compound.

Profile of leukocyte-endothelial cell interactions induced in venules and arterioles by nucleoside reverse-transcriptase inhibitors in vivo.

BACKGROUND: There is controversy regarding cardiovascular (CV) toxicity of the nucleoside reverse-transcriptase inhibitors used to treat human immunodeficiency virus infection. METHODS: We evaluated the effects of nucleoside reverse-transcriptase inhibitors on leukocyte-endothelium interactions, a hallmark of CV diseases, in rat mesenteric vessels using intravital microscopy and in human arterial cells using a flow chamber system. RESULTS: Abacavir and didanosine increased rolling, adhesion and emigration in rat vessels. These effects were reversed with antibodies against Macrophage-1 antigen (Mac-1) or intercellular adhesion molecule 1 and were reproduced in human cells. Lamivudine, zidovudine, emtricitabine, and tenofovir had no effects. CONCLUSIONS: Our results support the association of abacavir and didanosine with CV diseases.

A single acute dose of pinitol from a naturally-occurring food ingredient decreases hyperglycaemia and circulating insulin levels in healthy subjects.

A limited amount of research suggests that oral ingestion of pinitol (3-O-methyl-d-chiro-inositol) positively influences glucose tolerance in humans. This study assessed the effects of different doses of pinitol supplementation on glucose tolerance, insulin sensitivity and plasma pinitol concentrations. Thirty healthy subjects underwent two one-day trials in which they consumed a nutritive beverage (Fruit Up®) containing 2.5, 4.0 or 6.0g of pinitol and a corresponding placebo equivalent in both energy and carbohydrates. Blood samples were collected frequently over the 240-min test period. The pinitol-enriched beverage reduced serum glucose and insulin at 45 and 60min, but only at a dose of 6.0g. Plasma pinitol concentrations, maximum concentration and AUC increased according to the dose administered. The results show that a single dose of pinitol from a naturally-occurring food ingredient at the highest dose administered acutely influences indices of whole-body glucose tolerance and insulin sensitivity in healthy subjects.

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria / Prescripción potencialmente inapropiada en ancianos institucionalizados en España: los criterios STOPP-START comparados con los criterios de Beers

Objective: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. Methods: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). Results: The mean patients’ age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. Conclusion: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists’ review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes (AU)

Objetivo: Este estudio está orientado a identificar la prescripción potencialmente inapropiada usando los criterios de Beers y STOPP. Las omisiones de prescripciones se detectan en esta población geriátrica aplicando los criterios START. Se compara la utilidad de estos criterios en ancianos institucionalizados. Métodos: Estudio descriptivo de revisión de la medicación y las historias clínicas por farmacéuticos, de 81 pacientes (con 65 o más años) ingresados en una residencia en la provincia de Lleida (España). Resultados: La media de edad de los pacientes fue de 84 años (DE=8), con cinco medicamentos de promedio de tratamiento por residente (prescripciones totales: 416 medicamentos). Los criterios de Beers detectaron el uso de medicación potencialmente inapropiada en el 25% de los pacientes. Los criterios STOPP identificaron una posible medicación inapropiada en el 48% de los pacientes. La mayor frecuencia de uso de medicamentos potencialmente inapropiados para ambos criterios correspondió a las benzodiacepinas de larga duración y los AINE. Los criterios START detectaron 58 prescripciones potencialmente omitidas en el 44% de los pacientes. Entre ellas, la ausencia de suplementos de Calcio-vitamina D en osteoporosis fue la regla más frecuentemente implicada (15% de los pacientes); sin embargo, las omisiones relacionadas con el sistema cardiovascular asociadas a elevado riesgo cardiovascular son las que implicaron hasta un 23% de pacientes. Conclusión: La aplicación de los criterios STOPPSTART ha detectado una elevada proporción de prescripciones potencialmente inapropiadas en pacientes ancianos en una residencia sanitaria en España, con una significativa correlación positiva entre el número de medicamentos prescritos al paciente y el número de prescripciones potencialmente inapropiadas. Los criterios STOPP identificaron más medicación potencialmente inapropiada que los criterios de Beers. Las omisiones detectadas por los criterios START son relevantes y requiere una intervención. La revisión de la medicación por un farmacéutico puede ayudar a identificar potenciales prescripciones inapropiadas y, con un abordaje interdisciplinario, en colaboración con los médicos se podría mejorar la prescripción en pacientes ancianos de residencias geriátricas (AU)

Potentially inappropriate prescribing in institutionalised older patients in Spain: the STOPP-START criteria compared with the Beers criteria.

OBJECTIVE: The aims of this study were to identify potentially inappropriate prescribing using the Beers and STOPP criteria. The START criteria were applied to detect prescription omission in the geriatric population. We compared the utility of these criteria in institutionalised older people. METHODS: Descriptive study reviewing the medication and clinical records of 81 residents (aged 65 years and more) by pharmacists in a nursing home in the Lleida region (Spain). RESULTS: The mean patients''age was 84 (SD=8) years, with an average of 5 drugs per resident (total prescriptions: 416 medicines). The Beers criteria identified potentially inappropriate medication use in 25% of patients and 48% of patients used at least 1 inappropriate medication according to STOPP criteria. The most frequent potentially inappropriate medications for both criteria were long-acting benzodiazepines and NSAIDs. START detected 58 potential prescribing omissions in 44% of patients. Calcium-vitamin D supplementation in osteoporosis was the most frequent rule (15%), but omissions corresponding to the cardiovascular system implied 23% of patients. CONCLUSIONS: The STOPP-START criteria reveal that potentially inappropriate prescribing (PIP) is a highly prevalent problem among Spanish nursing home residents, and a statistically significant positive correlation was found between the number of medicines prescribed and the number of PIP detected in this study. The STOPP criteria detect a larger number of PI medications in this geriatric population than the Beers criteria. The prescribing omissions detected by the START criteria are relevant and require intervention. Pharmacists' review of medications may help identify potentially inappropriate prescribing and, through an interdisciplinary approach, working with physicians may improve prescribing practices among geriatric residents of nursing homes.