Early Diagnosis of Kidney Damage Associated with Tobacco Use: Preventive Application.

Although long-term smoking has been associated with chronic kidney disease, its effect on kidney function in early stages has not been clarified. Therefore, the proposed objectives were: (1) to identify subclinical kidney damage in smokers, through a panel of biomarkers; (2) to evaluate the progression of subclinical kidney damage after two years of consumption in these patients; and (3) study whether quitting smoking reduces kidney damage. A prospective study was carried out (patients recruited from a primary care centre and a clinical smoking unit). Kidney function was assessed using a panel of biomarkers and compared between smokers and non-smokers, taking into account potential risk factors for kidney damage. These results show, for the first time in the literature, the relationship between smoking and early (subclinical) kidney damage and provide a panel of biomarkers capable of detecting this condition (Neutrophil gelatinase-associated lipocalin, Kidney injury molecule-1, N-acetyl-beta-D-glucosaminidase, transferrin, and ganglioside-activating protein GM2). This study also indicates that subclinical damage is maintained when use continues, but can be reversed if patients stop smoking. The use of these biomarkers as diagnostic tools can be a preventive measure in the development of chronic kidney disease associated with smoking and in the prevention of acute events associated with potentially nephrotoxic pharmacological treatment in smokers. Trial registration number: NCT03850756.

Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na(+)/Ca(2+) exchanger.

The mitochondrial Na(+)/Ca(2+) exchanger plays an important role in the control of cytosolic Ca(2+) cycling in excitable cells, essential for the regulation of a plethora of Ca(2+)-dependent physio-pathological events, such as apoptosis in the presence of a Ca(2+) overload. There are very few pharmacological tools available to study both physiological and pathological implications of the mitochondrial Na(+)/Ca(2+) exchanger, where the benzothiazepine CGP37157 is the best-known ligand, used since the 1980s. However, it is not an efficient blocker and lacks of selectivity, as also blocks several other cellular Ca(2+) transporters. Moreover, CGP37157 is a very lipophilic drug, showing very poor water solubility, what has hindered its therapeutic use. Attempting to improve its pharmacokinetic profile as well as its potency and selectivity, we herein describe the synthesis of new CGP37157 analogs, where the benzene-fused ring has been replaced by a pyridine. On top of a better water solubility and lower log P value, some of these new pyridothiazepine derivatives also presented a higher capacity to regulate the mitochondrial Ca(2+) clearance, while keeping the neuroprotective properties presented in the head compound CGP37157.

Benzothiazepine CGP37157 Analogues Exert Cytoprotection in Various in Vitro Models of Neurodegeneration.

Mitochondria regulate cellular Ca(2+) oscillations, taking up Ca(2+) through its uniporter and releasing it through the mitochondrial sodium/calcium exchanger. The role of mitochondria in the regulation of Ca(2+) cycle has received much attention recently, as it is a central stage in neuronal survival and death processes. Over the last decades, the 4,1-benzothiazepine CGP37157 has been the only available blocker of the mitochondrial sodium/calcium exchanger, although it targets several other calcium transporters. We report the synthesis of 4,1-benzothiazepine derivatives with the goal of enhancing mitochondrial sodium/calcium exchanger blockade and selectivity, and the evaluation of their cytoprotective effect. The compound 4c presented an interesting neuroprotective profile in addition to an important blockade of the mitochondrial sodium/calcium exchanger. The use of this benzothiazepine could help to understand the physiological functions of the mitochondrial sodium/calcium exchanger. In addition, we hypothesize that a moderate blockade of the mitochondrial sodium/calcium exchanger would provide enhanced neuroprotection in neurons.

Preoperative smoking cessation counseling activities of anesthesiologists: a cross-sectional study.

BACKGROUND: Smokers undergoing surgery are at a higher risk of complications than non-smokers. Preoperative evaluation by an anesthesiologist could provide an excellent opportunity to promote smoking cessation. Previous surveys of anesthesiologists have found that self-reported smoking cessation counseling rates have room for improvement, but no study has surveyed patients to obtain more accurate estimates. METHODS: A single-center study was conducted from January 2010 to June 2010 in a tertiary teaching hospital. A telephone survey was conducted, which included all adult cigarette smokers who visited the preoperative anesthesia clinic. The survey recorded anesthesiologist-delivered interventions to help patients quit smoking before surgery. At the end of the study period, the self-reported smoking cessation counseling of the anesthesiologist was evaluated by questionnaire. RESULTS: One thousand one hundred and sixty-five patients were evaluated, of which 217 were current smokers with a median pack-year of 15 (interquartile range 5.25-30.00) and 34% were scheduled to undergo major surgery. With regard to preoperative interventions, most anesthesiologists (85%) asked about smoking status, although only 31% advised patients about the health risks of smoking and 23% advised patients to quit before surgery. Provision of assistance to help patients quit was provided in 3% of cases. By contrast, 75% of anesthesiologists stated that they frequently or almost always advised patients about the health risks of smoking. CONCLUSIONS: This study shows significant discrepancies between direct patient surveys of preoperative smoking cessation counseling activities by anesthesiologists and the self-reported perceptions of the anesthesiologists. Future studies are urgently needed to evaluate the provision of educational materials and other interventions to improve smoking cessation counseling rates among anesthesiologists and to narrow these discrepancies.

Benzothiazepine CGP37157 and its 2'-isopropyl analogue modulate Ca²âº entry through CALHM1.

CALHM1 is a Ca(2+) channel discovered in 2008, which plays a key role in the neuronal electrical activity, among other functions. However, there are no known efficient blockers able to modulate its Ca(2+) handling ability. We herein describe that benzothiazepine CGP37157 and its newly synthesized analogue ITH12575 reduced Ca(2+) influx through CALHM1 at low micromolar concentrations. These results could serve as a starting point for the development of more selective CALHM1 ligands using CGP37157 as a hit compound, which would help to study the physiological role of CALHM1 in the control of [Ca(2+)]cyt in excitable cells, as well as its implication in CNS diseases.

PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice.

ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca(2+) overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.

Benzothiazepine CGP37157 and its isosteric 2'-methyl analogue provide neuroprotection and block cell calcium entry.

Benzothiazepine CGP37157 is widely used as tool to explore the role of mitochondria in cell Ca(2+) handling, by its blocking effect of the mitochondria Na(+)/Ca(2+) exchanger. Recently, CGP37157 has shown to exhibit neuroprotective properties. In the trend to improve its neuroprotection profile, we have synthesized ITH12505, an isosteric analogue having a methyl instead of chlorine at C2' of the phenyl ring. ITH12505 has exerted neuroprotective properties similar to CGP37157 in chromaffin cells and hippocampal slices stressed with veratridine. Also, both compounds afforded neuroprotection in hippocampal slices stressed with glutamate. However, while ITH12505 elicited protection in SH-SY5Y cells stressed with oligomycin A/rotenone, CGP37157 was ineffective. In hippocampal slices subjected to oxygen/glucose deprivation plus reoxygenation, ITH12505 offered protection at 3-30 µM, while CGP37157 only protected at 30 µM. Both compounds caused blockade of Ca(2+) channels in high K(+)-depolarized SH-SY5Y cells. An in vitro experiment for assaying central nervous system penetration (PAMPA-BBB; parallel artificial membrane permeability assay for blood-brain barrier) revealed that both compounds could cross the blood-brain barrier, thus reaching their biological targets in the central nervous system. In conclusion, by causing a mild isosteric replacement in the benzothiazepine CGP37157, we have obtained ITH12505, with improved neuroprotective properties. These findings may inspire the design and synthesis of new benzothiazepines targeting mitochondrial Na(+)/Ca(2+) exchanger and L-type voltage-dependent Ca(2+) channels, having antioxidant properties.

Prevalencia de enfermedades crónicas diagnosticadas en población inmigrante y autóctona / Prevalence of diagnosed chronic disorders in the inmigrant and native population

ObjetivoEstimar la prevalencia de problemas de salud crónicos en inmigrantes y compararla con la de la población autóctona, utilizando la historia clínica electrónica (HCE) de atención primaria (AP).MétodosEstudio descriptivo transversal con pacientes de 16 y más años incluidos en el sistema sanitario público de la Comunidad de Madrid. Se estimaron prevalencias ajustadas por edad para cada sexo y nacionalidad (agrupada en regiones) a partir de los episodios de atención registrados en la HCE de AP con alguna anotación en 2005 o 2006.ResultadosEl 36,8% de la población inmigrante presentaba alguna enfermedad crónica (55,3% de autóctonos) tras ajustar por edad, con más frecuencia en mujeres y en población de origen africano y latinoamericano. Las enfermedades más prevalentes en los extranjeros fueron las alergias (tasa cruda: 10,2%), las lumbalgias (9,1%), problemas crónicos de piel (6,8%) y trastornos mentales (6,4%).ConclusionesLa prevalencia de enfermedades crónicas es menor en la población extranjera y varía según el sexo y la procedencia(AU)

ObjectiveTo estimate the prevalence rates of chronic disorders in immigrants and to compare them with those in the native population, based on electronic clinical records in primary care (ECRPC).MethodsWe performed a descriptive cross-sectional study in patients aged 16 and over included in the Madrid Regional Public Health System. Age-adjusted prevalence rates for each sex and region were estimated on the basis of medically examined cases registered in the ECRPC with any new data entry made in 2005 or 2006.ResultsAfter age-adjustment, a total of 36.8% immigrants had some chronic health problem (vs. 55.3% natives). These disorders were more frequent among women and among the population from Africa and Latin America. The highest overall prevalence rates in the foreign population were allergy (10.2% crude rate), low-back pain (9.1%), chronic skin problems (6.8%) and mental disorders (6.4%).ConclusionsThe prevalence rate of chronic disease is lower in the foreign population and differs according to sex and country of origin(AU)

[Prevalence of diagnosed chronic disorders in the immigrant and native population]. / Prevalencia de enfermedades crónicas diagnosticadas en población inmigrante y autóctona.

OBJECTIVE: To estimate the prevalence rates of chronic disorders in immigrants and to compare them with those in the native population, based on electronic clinical records in primary care (ECRPC). METHODS: We performed a descriptive cross-sectional study in patients aged 16 and over included in the Madrid Regional Public Health System. Age-adjusted prevalence rates for each sex and region were estimated on the basis of medically examined cases registered in the ECRPC with any new data entry made in 2005 or 2006. RESULTS: After age-adjustment, a total of 36.8% immigrants had some chronic health problem (vs. 55.3% natives). These disorders were more frequent among women and among the population from Africa and Latin America. The highest overall prevalence rates in the foreign population were allergy (10.2% crude rate), low-back pain (9.1%), chronic skin problems (6.8%) and mental disorders (6.4%). CONCLUSIONS: The prevalence rate of chronic disease is lower in the foreign population and differs according to sex and country of origin.