RESUMO
Detecting the association of genetic variants to the response of biological therapy represents an important advance in developing a personalized therapy. The aim of this work was to study the association of polymorphisms with an optimal response to tildrakizumab in patients with psoriasis in a real-life clinical practice. Ninety patients with plaque psoriasis recruited from-Spanish hospitals receiving tildrakizumab for at least 24 weeks were genotyped for 180 polymorphisms. Optimal response to tildrakizumab was evaluated by absolute PASI ≤1 at 6 and 12 months. Polymorphisms corrected for weight and disease duration with an FDR <0.15 were included in a multiple regression model. Sixty three percent of patients achieved an absolute PASI ≤1 at 6 months, while 71% did so after 12 months. Disease duration (>27 years) and weight (>76 kg) were associated with treatment response; after correcting by these factors, no association (FDR >0.15) was found for any polymorphism and response to tildrakizumab at 6 months. The analysis at 12 months identified the genotype GG for rs610604 (TNFAIP3), CT for rs9373839 (ATG5), and delCTGT/delCTGT for rs72167053 (PDE4D) as risk factors to not achieve an optimal response (PASI ≤1), while CT for rs708567 (IL17RC) was protective, independently of weight and disease duration (FDR <0.15). The final multivariable model at 12 months showed an AUC of 0.90 (95% CI 0.82 to -0.98). We identified a set of polymorphisms that could be helpful to identify psoriatic patients with an optimal response to tildrakizumab at 12 months in real-world practice conditions.
Assuntos
Anticorpos Monoclonais Humanizados , Psoríase , Humanos , Psoríase/tratamento farmacológico , Psoríase/genética , Feminino , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Genótipo , Idoso , Polimorfismo GenéticoRESUMO
BACKGROUND: Prediction of the response to a biological treatment in psoriasis patients would allow efficient treatment allocation. OBJECTIVE: To identify polymorphisms associated with secukinumab response in psoriasis patients in a daily practice setting. METHODS: We studied 180 SNPs in patients with moderate-to-severe plaque psoriasis recruited from 15 Spanish hospitals. Treatment effectiveness was evaluated by absolute PASI ≤3 and ≤1 at 6 and 12 months. Individuals were genotyped using a custom Taqman array. Multiple logistic regression models were generated. Sensitivity, specificity and area under the curve (AUC) were analysed. RESULTS: A total of 173 patients were studied at 6 months, (67% achieved absolute PASI ≤ 3 and 65% PASI ≤ 1) and 162 at 12 months (75% achieved absolute PASI ≤ 3 and 64% PASI ≤ 1). Multivariable analysis showed the association of different sets of SNPs with the response to secukinumab. The model of absolute PASI≤3 at 6 months showed best values of sensitivity and specificity. Four SNPs were associated with the capability of achieving absolute PASI ≤ 3 at 6 months. rs1801274 (FCGR2A), rs2431697 (miR-146a) and rs10484554 (HLCw6) were identified as risk factors for failure to achieve absolute PASI≤3, while rs1051738 (PDE4A) was protective. AUC including these genotypes, weight of patients and history of biological therapy was 0.88 (95% CI 0.83-0.94), with a sensitivity of 48.6% and specificity of 95.7% to discriminate between both phenotypes. CONCLUSION: We have identified a series of polymorphisms associated with the response to secukinumab capable of predicting the potential response/non-response to this drug in patients with plaque psoriasis.
Assuntos
Anticorpos Monoclonais Humanizados , Polimorfismo de Nucleotídeo Único , Psoríase , Humanos , Psoríase/tratamento farmacológico , Psoríase/genética , Feminino , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Adulto , Fármacos Dermatológicos/uso terapêutico , MicroRNAs/genética , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Hepatitis C virus (HCV) infection is the main cause for chronic hepatitis, leading to cirrhosis and hepatic carcinoma. Virally induced immune dysfunction has been called as the cause for viral persistence. Previous results demonstrate that CD4 Jurkat cells stably expressing the HCV core protein show an increased activation of NFAT transcription factor and an impaired IL-2 promoter activity, affecting intracellular signaling pathways in a manner that mimics clonal anergy. We had shown previously that NFAT activates a transcriptional program, ensuing in immunological tolerance. In the present work, we have engineered lentiviral vectors expressing the HCV core to analyze the events, which unfold in the initial phase of HCV core-induced anergy. We show that genes initially described to be up-regulated by ionomycin-induced anergy in mice are also up-regulated in humans, not only by ionomycin but also by HCV core expression. We also show that HCV core is sufficient to cause NFAT nuclear translocation and a slow-down in cell-cycle progression, and using whole genome microarrays, we identify novel genes up-regulated in Jurkat cells expressing HCV core. The relevance of our results is highlighted by the presence of HCV in CD4 T cells from HCV chronically infected patients.
Assuntos
Anergia Clonal , Antígenos da Hepatite C/metabolismo , Fatores de Transcrição NFATC/metabolismo , Linfócitos T/metabolismo , Proteínas do Core Viral/metabolismo , Animais , Ciclo Celular , Proliferação de Células , Doença Crônica , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Hepacivirus/genética , Antígenos da Hepatite C/genética , Humanos , Ionóforos/farmacologia , Células Jurkat , Rim/citologia , Rim/metabolismo , Lentivirus/genética , Camundongos , Fatores de Transcrição NFATC/genética , Análise de Sequência com Séries de Oligonucleotídeos , Transporte Proteico , RNA Viral/genética , RNA Viral/metabolismo , Transdução de Sinais , Linfócitos T/patologia , Linfócitos T/virologia , Proteínas do Core Viral/genéticaRESUMO
1. The novel antimigraineur, dotarizine (30 microM), increased cytosolic Ca2+ concentration, [Ca2+]c, in fura-2-loaded bovine adrenal chromaffin cells. This increase was transient, reached a peak in about 2 - 5 min (0.53+/-0.07 microM; n=19) and then declined to basal levels over a further 5 min period. 2. This transient rise of [Ca2+]c was mimicked by 1 microM thapsigargin and by 30 microM cyclopiazonic acid (CPA), but not by 30 microM flunarizine. Both thapsigargin and CPA occluded the effects of dotarizine and vice versa. 3. All three compounds suppressed the transient [Ca2+]c rises induced by caffeine (10 mM, 10 s); blockade induced by thapsigargin was irreversible and that induced by CPA and dotarizine was reversible. 4. Of the three compounds, only dotarizine blocked reversibly the [Ca2+]c spikes induced by short pulses of high K+ (70 mM, 5 s), suggesting that dotarizine blocks voltage-dependent Ca2+ channels but CPA and thapsigargin do not. 5. Dotarizine caused a gradual and reversible depletion of endoplasmic reticulum (ER) Ca2+ in chromaffin cells transfected with ER-targeted aequorin. CPA had a similar effect. 6. These data show that dotarizine shares with thapsigargin and CPA the ability to deplete Ca2+ in the ER; this novel action of dotarizine could be relevant to its prophylactic effects in migraine. Unlike thapsigargin and CPA, however, dotarizine additionally and reversibly blocks Ca2+ entry through voltage-dependent Ca2+ channels.
Assuntos
Compostos Benzidrílicos/farmacologia , Cafeína/farmacologia , Cálcio/metabolismo , Células Cromafins/efeitos dos fármacos , Piperazinas/farmacologia , Vasodilatadores/farmacologia , Medula Suprarrenal/citologia , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Compostos Benzidrílicos/uso terapêutico , Bovinos , Células Cultivadas , Células Cromafins/metabolismo , Flunarizina/farmacologia , Indóis/farmacologia , Transtornos de Enxaqueca/tratamento farmacológico , Piperazinas/uso terapêutico , Potássio/farmacologia , Tapsigargina/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
Mitochondrial dysfunction has been implicated in a number of neurodegenerative diseases, such as ischemia and Parkinson's disease. We present here a method that allows the rapid quantification of interventions, aimed at inhibiting the effect of mitochondrial membrane potential uncouplers, based on the ratioing properties of the fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1), by using currently available 96-well fluorescent plate readers. A method is presented for evaluation of cross-talk between the two excitation/emission channels. Further characterization of the probe shows that the effect of plasma membrane potential changes on JC-1 fluorescence ratio are negligible, but that the signal is very sensitive to pH. One of the most exciting applications is the possibility to perform end-point measurements, thanks to the ratioing properties of the probe. The system is tested in different culture types with different mitochondrial uncouplers. As an example of a quantitative evaluation, we show that flunarizine is able to inhibit, dose-dependently, FCCP mediated JC-1 signal increase. The procedure is simple and allows for the fast screening of mitochondria-protective compounds.
Assuntos
Benzimidazóis , Carbocianinas , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia , Flunarizina/farmacologia , Potenciais da Membrana/fisiologia , Mitocôndrias/fisiologia , Células PC12 , Ratos , Desacopladores/farmacologiaRESUMO
Dotarizine (a novel piperazine derivative with antimigraine properties) and flunarizine (a Ca2+ channel antagonist) were compared concerning: first, their ability to cause chromaffin cell damage in vitro; second, the possible correlation of their octanol/water partition coefficients and those of another 28 compounds (i.e., Ca2+ channel antagonists, blockers of histamine H1 receptors, antimycotics, beta-adrenoceptor antagonists, neuroleptics), with their ability to cause cell damage; third, their capacity to protect the cells against the damaging effects of veratridine; and fourth, their capabilities to enhance the basal cytosolic Ca2+ concentration in fura-2-loaded single chromaffin cells, or to modify the pattern of [Ca2+]i oscillations elicited by veratridine. After 24-h exposure to 1-30 microM dotarizine, the viability of bovine adrenal chromaffin cells (measured under phase contrast or as lactate dehydrogenase, released into the medium) was similar to that of control, untreated cells; at 100 microM, 80% lactate dehydrogenase release was produced. At 1-3 microM flunarizine caused no cell damage; however 10 microM caused 20% lactate dehydrogenase release and 30 and 100 microM over 90% lactate dehydrogenase release. The time course of cell damage was considerably faster for flunarizine, in comparison to dotarizine. Out of 30 molecules tested (at 10 microM), having different octanol/water partition coefficients (log P), dotarizine was among the molecules causing no cell damage; flunarizine caused 20% cell loss, lidoflazine and verapamil over 50% cell loss, and penfluridol, draflazine, astemizole or nifedipine over 80% cell loss. No correlation was found between log P and cytotoxicity. Both dotarizine (10-30 microM) and flunarizine (3-10 microM) provided protection against veratridine-induced cell death; however, at 30 microM dotarizine afforded a pronounced protection while flunarizine enhanced the cytotoxic effects of veratridine. Dotarizine (30 microM) (but not flunarizine) caused a prompt transient elevation of the basal [Ca2+]i. Both compounds abolished the K+-induced increases of [Ca2+]i as well as the oscillations of [Ca2+]i induced by veratridine. The blocking effects of dotarizine were readily reversed after washout, while those of flunarizine were long-lasting. These differences might be relevant to the clinical use of dotarizine as an antimigraine drug.
Assuntos
Compostos Benzidrílicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Células Cromafins/efeitos dos fármacos , Flunarizina/farmacologia , Piperazinas/farmacologia , Animais , Bovinos , Morte Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cromafins/citologia , Citosol , Flunarizina/metabolismo , Bicamadas Lipídicas/metabolismo , Potássio/farmacologia , Veratridina/farmacologiaRESUMO
PURPOSE: To study the prevalence of altered eating behaviors or eating disorder-related behaviors among adolescents of normal weight that do not fulfill criteria for anorexia nervosa and bulimia nervosa. METHOD: Cross-sectional study by means of a self-completed questionnaire (School of Nutrition of Granada, Spain) and measurement of weight and height in a population of 491 schoolchildren aged 14-18 years. The statistical inferences and estimation of risk are based on comparison of proportions and means test, and the relative inequality of prevalences. RESULTS: Of 491 adolescents of normal weight, 9% (females 2:1) were following diets; 42% presented "recurrent episodes of binging" with the sensation of loss of self-control; and 41%% avoided specific types of food. Overall, 46.2% presented altered eating behavior. Factors significantly associated with this were the occurrence of periods of food abstinence and the use of purgatives [confidence interval 95% (CI 95%) prevalence ratio (PR) 1.41-2.02]. Compensatory behaviors were present in 33% of the adolescents, predominantly in females (CI 95% PR 1.79-3.07). The prevalences of abnormal eating behaviors were 16.3% for those related to anorexia (A-RB) and 17.1% for those related to bulimia (B-RB), with a clear predominance of females (2:1) and public education. There seems to be a greater aesthetic concern among those with B-RB and more worry about weight among those with A-RB. CONCLUSIONS: A high proportion of adolescents with abnormal eating behaviors and an altered perception of body fat may currently be diagnosed as having atypical eating disorder" (Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision) considering that their body mass index was within normal range.
Assuntos
Comportamento do Adolescente , Comportamento Alimentar/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Adolescente , Análise de Variância , Imagem Corporal , Catárticos/administração & dosagem , Estudos Transversais , Feminino , Humanos , Masculino , Valores de Referência , Autoimagem , Espanha/epidemiologia , Estatísticas não Paramétricas , Inquéritos e QuestionáriosRESUMO
The goal of this meta-analysis was to evaluate the effectiveness of clarithromycin versus most commonly used treatments for upper respiratory infections. We performed a systematic review of comparative clinical trials found in the literature. Regarding effectiveness, no significant differences were found in comparisons between clarithromycin and amoxicillin-clavulanic acid for upper respiratory infections, nor for cephalosporins, amoxicillin or amoxicillin-clavulanic acid for otitis media, nor oral penicillin for classic streptococcal tonsillitis. Clarithromycin was more effective than betalactam antibiotics for sinusitis (OR: 1.27, 95% CI: 1.01-1.61 in intent-to-treat analysis). The effectiveness of clarithromycin was better than that for azithromycin, but only reached statistical significance in the per-protocol analysis. The global analysis including all 33 clinical trials showed a small benefit for clarithromycin reaching statistical significance in the fixed-effects model (OR: 1.12, 95% CI: 1.01-1.25). Regarding safety, the incidence of adverse events was significantly lower for clarithromycin compared to amoxicillin and amoxicillin-clavulanic acid. No differences were found when comparing adverse events due to cephalosporins, azithromycin and betalactam antibiotics, but the incidence of adverse events for clarithromycin was higher compared to that of oral penicillin for streptococcal tonsillitis treatment. Overall, all the compared drugs were well tolerated; discontinuations due to adverse events were very low: 2.2% for clarithromycin treatment and 2.5% for the other antibiotics. It was concluded that clarithromycin is an effective and safe treatment for upper respiratory infection, and its new formulation in a single daily dose may improve therapeutic compliance.
Assuntos
Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Ensaios Clínicos como Assunto , HumanosRESUMO
Clarithromycin is a macrolide antibiotic commonly used for the treatment of respiratory infections. The aim of this study was to assess its effectiveness for the treatment of lower respiratory tract infections. A number of meta-analyses of clinical trials comparing clarithromycin to the antibiotics most frequently used in the treatment of lower respiratory tract infections, such as cephalosporins, amoxicillin-clavulanic acid, erythromycin and azithromycin, have been performed. Clarithromycin's effectiveness for the treatment of lower respiratory tract infections was better than that for cephalosporins (OR = 1.43; 95% CI = 1.09-1.86) and, although not to the same extent, that for amoxicillin-clavulanic acid (OR = 1.58; 95% CI = 0.92-2.70); however, the efficacy was only similar to that shown for azithromycin (OR = 0.57; 95% CI = 0.19-1.68). The fourth meta-analysis compared the effectiveness of clarithromycin to that of erythromycin for the treatment of pneumonia and showed a superior odds ratio in favor of clarithromycin (OR = 1.46; 95% CI = 0.97-2.2). Meta-analyses comparing clarithromycin's safety to that of the same drugs in the same conditions used in the assessment of effectiveness showed a similar incidence of adverse events compared to amoxicillin-clavulanic acid, and azithromycin, a slightly lower incidence compared to erythromycin, and a slightly higher incidence compared to cephalosporins. In conclusion, these meta-analyses show that clarithromycin is an effective and safe antibiotic for the treatment of lower respiratory tract infections. Furthermore, a new once-daily dose formulation with a positive impact on therapeutic compliance is currently available, making clarithromycin a first-line treatment for lower respiratory tract infections.
Assuntos
Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Ensaios Clínicos como Assunto , HumanosRESUMO
BACKGROUND: The aim of the present work was to study the nutritional pattern in the school population of a rural town in Cádiz (Spain), with an important industrial development. SUBJECTS AND METHODS: We have studied a representative sample of 344 school-children of both sexes between 8 and 15 year-old. Dietary intake was assessed by "24 hour recall" and the CUVALC program was used to transform it in nutrients. In all the age groups daily caloric and nutrients intake was adjusted to that recommended by Spanish people. RESULTS: The results observed showed that specially protein intake was high in all the age groups. Dietary lipid was high (39%). The saturated fatty acids exceeded the level recommended in 100% school children and the intake of carbohydrates (46%) and crude fiber were low. On the other hand, we observed that vitamin D in girls and calories, calcium and iron in both sexes were lower than recommended allowances in some age groups. In addition, the proportional breakfast calories intake was lower (16.6%) than the 25% recommended. CONCLUSIONS: The population of Ubrique, a rural town in Cádiz (Spain) with an important industrial development had a more occidental than mediterranean nutritional profile.
Assuntos
Fenômenos Fisiológicos da Nutrição do Adolescente , Fenômenos Fisiológicos da Nutrição Infantil , Adolescente , Fatores Etários , Criança , Dieta , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Ingestão de Energia , Feminino , Humanos , Masculino , População Rural , Fatores Sexuais , Espanha , Vitaminas/administração & dosagemRESUMO
INTRODUCTION: Citicoline has a neuroprotector effect since it reduces the lesions of nerve membranes, by increase in the synthesis of phospholipids, and reduces the levels of free fatty acids. In this study we review the existing data on the efficacy of citicoline in the treatment of acute ischemic cerebrovascular disease and its sequelae, both in animals and in clinical trials involving patients. DEVELOPMENT: In various animal models citicoline reduces the volume of cerebral infarction and neurological sequelae and also potentiates the effects of other neuroprotector drugs. On analysis of the literature, we found six randomised clinical trials, double-blind and placebo-controlled in which the effect of citicoline was evaluated in patients who had acute ischemic cerebrovascular accidents. In all of these it was found that citicoline reduced the neurological sequelae. The finding of a broad therapeutic window (24-48 hours) gives this an advantage over the fibrinolytic agents, which have to be given within the first three to six hours. In further controlled trials carried out in patients with sequelae of cerebrovascular disease different degrees of neurological improvement were found, although studies of greater duration are required to see improvement in a longer term. CONCLUSIONS: With the data available, we may affirm that citicoline is a safe, effective drug, although clinical trials are still underway in larger populations of patients. In these trials not only the neurological state but also the area of infarction are assessed to confirm their efficacy.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Citidina Difosfato Colina/uso terapêutico , Nootrópicos/uso terapêutico , Ensaios Clínicos como Assunto , HumanosRESUMO
Anticholinergic agents have proved to be of particular value in the treatment of COPD, as vagal cholinergic tone appears to be the only reversible component of airway narrowing, opposite to what happens in asthma. Anticholinergics block muscarinic receptors on airway smooth muscle an submucosal gland cells. Three subtypes of muscarinic receptors have been demonstrated in human airways. M1 receptors in parasympathetic ganglia facilitate cholinergic neurotransmission. M3 receptors on airway smooth muscle cells and glands mediate bronchoconstriction and mucus secretion. M2 receptors at cholinergic nerve endings inhibit the release of acetylcholine and therefore act as feedback inhibitory receptors (autoreceptors). Ipratropium bromide is a non-selective muscarinic antagonist and therefore blocks M1, M2 and M3 receptors. Tiotropium is a novel, potent, and long-lasting muscarinic antagonist that has a kinetic selectivity for M1 and M3 receptors because it dissociated very quickly from M2 receptors. Once-daily inhaled tiotropium is a safe and effective bronchodilator useful as a first-line maintenance therapy in COPD.
Assuntos
Brônquios/fisiologia , Músculo Liso/fisiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores Muscarínicos/fisiologia , Brônquios/efeitos dos fármacos , Broncodilatadores/uso terapêutico , Humanos , Ipratrópio/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Músculo Liso/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Derivados da Escopolamina/uso terapêutico , Brometo de TiotrópioRESUMO
We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioequivalence study. Significant increases were found in CYP2C9*3 alleles vs. *1 and *2 in AUC(0-infinity) (median (min-max)): 256 (230-516) vs. 150 (100-268) and 169 (124-197) microg h/mL (p<0.01) and half-life time (t1/2) 102 (79-36) vs. 56 (45-94) and 64 (60-80)h (p<0.01). Non-significant differences were observed in C(max) 1.9 (1.8-2.9) vs. 2.4 (1.7-3.4), 2.5 (1.6-2.9) microg/mL or in according to CYP2C8 alleles presence. CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioequivalence studies (AUC(0-infinity), t1/2) may be influenced by the presence of CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Piroxicam/análogos & derivados , Adolescente , Adulto , Alelos , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C9 , Feminino , Genótipo , Humanos , Masculino , Farmacogenética , Piroxicam/farmacocinética , Espanha , Equivalência TerapêuticaRESUMO
Serotonin syndrome, which occurs as a result of enhanced serotonin concentration in the central nervous system, is a well-known adverse effect of serotonin-active medications. The concomitant use of antidepressant drugs associated with lithium as a co-adjuvant seems to increase the risk of this adverse reaction. We report a case of the serotonin syndrome during treatment with lithium and venlafaxine, an antidepressant with a dual selective re-uptake inhibition mechanism, and review the literature for similar cases. A 71-year-old woman developed serotonin syndrome while receiving treatment with moderate doses of lithium and venlafaxine for refractory depression. She had been taking higher doses of venlafaxine during the previous months with no significant secondary effects. Use of the Naranjo adverse drug reaction probability algorithm indicated a probable relationship between serotonin syndrome and treatment with lithium and venlafaxine.
Assuntos
Antidepressivos de Segunda Geração/efeitos adversos , Cicloexanóis/efeitos adversos , Carbonato de Lítio/efeitos adversos , Síndrome da Serotonina/induzido quimicamente , Idoso , Antidepressivos de Segunda Geração/uso terapêutico , Cicloexanóis/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Interações Medicamentosas , Feminino , Humanos , Carbonato de Lítio/uso terapêutico , Cloridrato de VenlafaxinaRESUMO
OBJECTIVES: To identify the individual and occupational factors that are predictors for low back pain among the employees of a university hospital in southern Spain. METHODS: A transverse study was conducted in which the population used was the hospital employees who volunteered to participate. The information was obtained by using a questionnaire, which included demographic and anthropometric variables, habits, characteristics of the work done, and of any pain experienced. The mental health condition of subjects was measured using the GHQ-28, using a score of > or = 6 as the cut-off point. To study the variables associated with pain, crude odds ratios (ORs) were calculated (+/- 95% CI) and adjusted according to a logistic regression model. RESULTS: One thousand one hundred and four subjects participated in the study but only 890 of these completed the questionnaire in full (rate of response, 35.7% of total employees). The population studied was notable for the high proportion of women, for subjects > 41 years of age, and subjects who undertook little or no physical exercise. In addition, according to the GHQ-28 test, 29.9% of the total were 'probable psychiatric cases'. The crude ORs were high in all the occupational categories in comparison with the doctors, with the exception of the maintenance, cleaning, and catering group. They were also higher among women, among subjects with poor mental health, and among women with one or more children. The adjusted ORs showed that having a GHQ-28 score of > or = 6, and belonging to the auxiliary technician category, were independent risk factors for suffering low back pain. Being older than 41 years and in temporary employment were protective variables. CONCLUSIONS: The presence of probable mental illness is the variable most strongly associated with the presence of low back pain in the population studied. Its diagnostic confirmation and appropriate treatment could contribute to reducing the prevalence of vertebral pains in this occupational group.
Assuntos
Dor Lombar/epidemiologia , Doenças Profissionais/epidemiologia , Recursos Humanos em Hospital , Adulto , Feminino , Hospitais Universitários , Humanos , Modelos Logísticos , Dor Lombar/psicologia , Masculino , Doenças Profissionais/psicologia , Razão de Chances , Fatores de Risco , Espanha/epidemiologia , Recursos HumanosRESUMO
BACKGROUND & AIMS: This study has investigated stimulus-secretion coupling of enterochromaffin cells by studying the cellular location and function of voltage-gated Ca(2+) channels within small intestinal crypts. METHODS: Digital fluorescence imaging and electrochemical detection were used to measure intracellular Ca(2+) responses and serotonin (5-hydroxytryptamine [5-HT]) secretion in intact crypts isolated from guinea pig and human duodenum. RESULTS: In fluo-3-loaded crypts, electrical depolarization with high K(+) solution increased cytosolic free [Ca(2+)] only in single cells subsequently identified by immunocytochemistry as enterochromaffin cells. In guinea pig enterochromaffin cells, the L-type Ca(2+) channel agonist FPL 64176 (3 micromol/L) did not change resting intracellular [Ca(2+)] but potentiated the depolarization-evoked increase in [Ca(2+)] (298 +/- 72 nmol/L) by 19 +/- 3-fold. In the majority of human enterochromaffin cells, FPL 64176 alone increased resting [Ca(2+)] by 423 +/- 171 nmol/L. Secretion studies in guinea pig crypts showed that high K(+) and FPL 64176 caused a 12-fold increase in 5-HT release. Noradrenaline caused increases in both enterochromaffin cell [Ca(2+)] and 5-HT release. CONCLUSIONS: Using this approach, we have found that in duodenal crypts, enterochromaffin cells, but not other epithelial cells, contain L-type voltage-gated Ca(2+) channels involved in regulating 5-HT secretion. These data have implications for the pharmacological control of intestinal disorders involving enterochromaffin cell dysfunction.
Assuntos
Canais de Cálcio Tipo L/metabolismo , Duodeno/metabolismo , Células Enterocromafins/metabolismo , Compostos de Anilina/metabolismo , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/análise , Cromatografia Líquida de Alta Pressão , Duodeno/citologia , Duodeno/efeitos dos fármacos , Células Enterocromafins/efeitos dos fármacos , Cobaias , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Serotonina/metabolismo , Xantenos/metabolismoRESUMO
BACKGROUND: The new local anesthetic IQB-9302 is an amide derivative bearing a cyclopropyl group, with remarkable long duration of action and relative low toxicity. In trying to characterize further its safety profile, the current study compared the hemodynamic effects of different concentrations of bupivacaine and IQB-9302 with saline. METHODS: Two groups of eight anesthetized Sprague-Dawley rats were given 0.1, 0.3, 1, 3, and 10 mg/kg of intravenous (i.v.) IQB-9302 or bupivacaine at 20-min intervals; control animals received saline only. Arterial blood pressure and heart rate were monitored during the following 20 min. RESULTS: Both bupivacaine and IQB-9302 reduced heart rate: for bupivacaine, -73.8 beats per min (bpm) (SD: 103.8) and -132.5 bpm (SD: 140.7) at 1 and 3 mg/kg, respectively; for IQB-9302, the reduction amounted to -40.8 bpm (SD: 14.2) and -113.5 bpm (SD: 94.2) at 1 and 3 mg/kg, respectively (baseline range, 318.7-438.2 bpm). The two drugs also produced a comparable increase in the mean arterial blood pressure; bupivacaine increased it by 8.7 mmHg (SD: 6.6) and 12.6 mmHg (SD: 15.4) at 1 and 3 mg/kg, respectively, and IQB-9302, 18.7 mmHg (SD: 21.1) and 20.7 mmHg (SD: 20.5) at 1 and 3 mg/kg, respectively (baseline range, 47.4-134.1 mmHg). All rats treated with 10 mg/kg of either drug died after a drop in heart rate and mean arterial blood pressure. CONCLUSION: IQB-9302 had hemodynamic effects similar to those of bupivacaine in anesthetized rats. The clinical relevance of these effects warrants further investigation.
Assuntos
Anestesia Geral , Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Hemodinâmica/efeitos dos fármacos , Piperidinas/farmacologia , Análise de Variância , Anestésicos Locais/administração & dosagem , Anestésicos Locais/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bupivacaína/administração & dosagem , Bupivacaína/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Infusões Intravenosas , Masculino , Modelos Animais , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Fatores de TempoRESUMO
We established primary cultures of human pheochromocytoma chromaffin cells. We then tried to find what mechanism of their secretory apparatus could be altered to produce the massive release of catecholamines into the circulation and the subsequent hypertensive crisis observed in patients suffering this type of tumor. Their whole-cell Ca2+ channel currents could be pharmacologically separated into components similar to those found in normal human adrenal chromaffin cells: 20% L-type, 30% N-type, and 50% P/Q-type Ca2+ channels. However, modulation of the channels by exogenous or endogenous ATP and opioids, via a G-protein membrane-delimited pathway, was deeply altered; some cells having no modulation or very little modulation alternated with others having normal modulation. This may be the cause of the uncontrolled secretory response, measured amperometrically at the single-cell level. Some cells secreted for long time periods and were insensitive to nifedipine (L-type channel blocker) or to omega-conotoxin MVIIC (N/P/Q-type channel blocker), while others were highly sensitive to nifedipine and partially sensitive to omega-conotoxin MVIIC. Alteration of the autocrine/paracrine modulation of Ca2+ channels may lead to indiscriminate Ca2+ entry and exacerbate catecholamine release responses in human pheochromocytoma cells.
Assuntos
Neoplasias das Glândulas Suprarrenais/fisiopatologia , Canais de Cálcio/metabolismo , Células Cromafins/fisiologia , Exocitose/fisiologia , Feocromocitoma/fisiopatologia , Trifosfato de Adenosina/farmacologia , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Bário/fisiologia , Canais de Cálcio/fisiologia , Células Cromafins/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Condutividade Elétrica , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , D-Penicilina (2,5)-Encefalina/farmacologia , Epinefrina/sangue , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Feniletanolamina N-Metiltransferase/metabolismo , Feocromocitoma/patologia , Células Tumorais CultivadasRESUMO
UNLABELLED: We evaluated the duration of sensory anesthesia after blockade of the ulnar nerve of IQB-9302, a new local amide anesthetic, compared with bupivacaine. A double-blinded, randomized, cross-over study in 12 healthy volunteers aged 18 to 35 yr was performed. Three milliliters of 0.25% IQB-9302 was administered in one wrist and bupivacaine in the other. A week later, the blocks were repeated with a concentration of 0.5%. These concentrations were chosen because they seemed to be equipotent in previous studies. The duration of sensory anesthesia was the main variable measured; secondary outcomes were motor block, time to onset, and time to recovery from block. The duration of sensory block was similar for IQB-9302 and bupivacaine at a concentration of 0.25%; median and range: 409 min (0-800 min) for IQB-9302 and 258 min (0-665 min) for bupivacaine (95% confidence interval for the difference from -47 to 545, P = 0.82, Wilcoxon's test). The results with 0.5% were: 525 min (440-735 min) and 690 min (365-1098 min), respectively (P = 0.026). There were no significant differences in the other variables measured. No important adverse reactions were seen. We conclude that IQB-9302 is an effective new local anesthetic for blockade of ulnar nerve at the concentrations tested. IMPLICATIONS: IQB-9302 is a new local anesthetic that has shown a long duration of action and low cardiovascular toxicity in preclinical studies. We report the results of a phase I clinical trial to compare this new drug with bupivacaine for ulnar nerve block.
Assuntos
Anestésicos Locais , Bupivacaína , Bloqueio Nervoso/métodos , Piperidinas , Nervo Ulnar/efeitos dos fármacos , Adolescente , Adulto , Anestésicos Locais/efeitos adversos , Bupivacaína/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Masculino , Piperidinas/efeitos adversos , Temperatura Cutânea/efeitos dos fármacosRESUMO
Human adrenal medullary chromaffin cells were prepared and cultured from a cystic tumoral adrenal gland whose medullary tissue was unaffected. Adrenaline-containing and noradrenaline-containing cells were identified using a confocal fluorescence microscope and antibodies against dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). Current/voltage (I/V) curves performed with the voltage-clamped cells bathed in 10 mM Ba2+ (holding potential, Vh=-80 mV) revealed the presence of only high-threshold voltage-dependent Ca2+ channels; T-type Ca2+ channels were not seen. By using supramaximal concentrations of selective Ca2+ channel blockers, the whole-cell IBa could be fractionated into various subcomponents. Thus, IBa had a 25% fraction sensitive to 1 microM nifedipine (L-type channels), 21% sensitive to 1 microM omega-conotoxin GVIA (N-type channels), and 60% sensitive to 2 microM omega-agatoxin IVA (P/Q-type channels). The activation of IBa was considerably slowed down, and the peak current was inhibited upon superfusion with 10 microM ATP. The slow activation and peak current blockade were reversed by strong depolarizing pre-pulses to +100 mV (facilitation). A drastic facilitation of IBa was also observed in voltage-clamped human chromaffin cell surrounded by other unclamped cells; in contrast, in voltage-clamped cells not immersed in a cell cluster, facilitation was scarce. So, facilitation of Ca2+ channels in a voltage-clamped cell seems to depend upon the exocytotic activity of neighbouring unclamped cells, which is markedly increased by Ba2+. It is concluded that human adrenal chromaffin cells mostly express P/Q-types of voltage-dependent Ca2+ channels (60%). L-Type channels and N-type channels are also expressed, but to a considerably minor extent (around 20% each). This dominance of P/Q-type channels in human chromaffin cells clearly contrasts with the relative proportion of each channel type expressed by chromaffin cells of five other animal species studied previously, where the P/Q-type channels accounted for 5-50%. The results also provide strong support for the hypothesis that Ca2+ channels of human chromaffin cells are regulated in an autocrine/paracrine fashion by materials co-secreted with the catecholamines, i.e. ATP and opiates.