ABSTRACT
El Consejo Federal de Medicina de Brasil (CFM) -órgano normativo y fiscalizador del ejercicio ético de la medicina- prohibió, en 2008, la participación de médicos brasileños en investigaciones que utilizaran placebo para enfermedades con tratamiento eficaz y efectivo, en contraposición a la Declaración de Helsinki, que permite su uso en condiciones metodológicamente justificadas. Con el objetivo de verificar si la normativa ética del CFM modificó el uso de placebo en ensayos clínicos de fase III en Brasil, se analizaron varias características de sus registros en el ClinicalTrials.gov, en los períodos de 2003 a 2007 y de 2009 a 2013. Se concluye que: a) la normativa promulgada por el CFM en 2008 fue ineficaz y prevaleció la posición adoptada por la Declaración de Helsinki; b) el patrocinio de ensayos con placebo por parte de la industria farmacéutica multinacional fue significativo; c) predominaron las investigaciones de fármacos para enfermedades crónicas, y fueron poco significativas para las enfermedades postergadas, de importancia para Brasil.
In 2008, Brazil's Federal Council of Medicine [Conselho Federal de Medicina] (CFM) - regulatory and supervisory agency on the ethical practice of medicine - banned the participation of Brazilian doctors in studies using placebos for diseases with efficient and effective treatment. This position differs with the Helsinki Declaration, which allows the use of placebos in methodologically justified conditions. To ascertain whether the CMF's ethical regulation modified the use of placebos in phase III clinical trials in Brazil, characteristics of the records in ClinicalTrials.gov were researched in the periods from 2003 to 2007 and from 2009 to 2013. The conclusions reached were: a) the regulations issued by the CFM in 2008 were ineffective and the position adopted by the Helsinki Declaration prevails; b) there was significant sponsorship by the multinational pharmaceutical industry of trials with placebos; c) the research was predominantly on new drugs for chronic diseases, with little study done of the neglected diseases which are of great importance to Brazil.
Subject(s)
Animals , Rats , Apoptosis/genetics , Gene Expression Regulation, Enzymologic/genetics , Heme/deficiency , Nerve Degeneration/genetics , Neurons/metabolism , Porphyrias/complications , Apoptosis/drug effects , Caspases/drug effects , Caspases/metabolism , Cell Survival/drug effects , Cell Survival/genetics , Collagen Type XI/drug effects , Collagen Type XI/metabolism , Cyclic AMP Response Element-Binding Protein/drug effects , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Down-Regulation/drug effects , Down-Regulation/physiology , Enzyme Inhibitors , Gene Expression Regulation, Enzymologic/drug effects , Heme/biosynthesis , Heptanoates , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Membrane Proteins/drug effects , Membrane Proteins/genetics , Membrane Proteins/metabolism , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecules/drug effects , Neural Cell Adhesion Molecules/genetics , Neural Cell Adhesion Molecules/metabolism , Neurons/drug effects , Neurons/pathology , Poly(ADP-ribose) Polymerases , Porphyrias/metabolism , Porphyrias/physiopathology , RNA, Messenger/drug effects , RNA, Messenger/metabolism , RNA-Binding Proteins/drug effects , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , SMN Complex Proteins , Up-Regulation/drug effects , Up-Regulation/physiology , Vesicular Transport Proteins/drug effects , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolismABSTRACT
Chronic stress is associated with the development of cardiovascular diseases. The sympathoneural system plays an important role in the regulation of cardiac function both in health and disease. In the present study, the changes in gene expression of the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine-â-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) and protein levels in the right and left heart auricles of naive control and long-term (12 weeks) socially isolated rats were investigated by Taqman RT-PCR and Western blot analysis. The response of these animals to additional immobilization stress (2 h) was also examined. Long-term social isolation produced a decrease in TH mRNA level in left auricles (about 70 percent) compared to the corresponding control. Expression of the DBH gene was markedly decreased both in the right (about 62 percent) and left (about 81 percent) auricles compared to the corresponding control, group-maintained rats, whereas PNMT mRNA levels remained unchanged. Exposure of group-housed rats to acute immobilization for 2 h led to a significant increase of mRNA levels of TH (about 267 percent), DBH (about 37 percent) and PNMT (about 60 percent) only in the right auricles. Additional 2-h immobilization of individually housed rats did not affect gene expression of these enzymes in either the right or left auricle. Protein levels of TH, DBH and PNMT in left and right heart auricles were unchanged either in both individually housed and immobilized rats. The unchanged mRNA levels of the enzymes examined after short-term immobilization suggest that the catecholaminergic system of the heart auricles of animals previously exposed to chronic psychosocial stress was adapted to maintain appropriate cardiovascular homeostasis.
Subject(s)
Animals , Male , Rats , Catecholamines/metabolism , Dopamine beta-Hydroxylase/metabolism , Gene Expression Regulation, Enzymologic/genetics , Heart Atria/enzymology , Phenylethanolamine N-Methyltransferase/metabolism , /metabolism , Blotting, Western , Catecholamines/genetics , Dopamine beta-Hydroxylase/genetics , Phenylethanolamine N-Methyltransferase/genetics , Rats, Wistar , Restraint, Physical , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger , Social Isolation , Stress, Physiological , Time Factors , /geneticsABSTRACT
OBJECTIVE: We tested the hypothesis that inducible nitric oxide synthase (iNOS) modulates angiogenesis in human models and this information could be extrapolated in elucidating the pathophysiology of oral submucous fibrosis (OSF). A hypothesis which looks inadequate, but is deep rooted in literature is the epithelial alteration ("atrophy") seen in OSF and the events that lead to its causation. This aspect was tried to be addressed and an alternative pathogenetic pathway for the disease is proposed. MATERIALS AND METHODS: This immunohistochemical study sought to investigate the expression of iNOS in OSF samples (n=30) a using monospecific antibody (SC- 2050, Santa Cruz Biotechnology, Inc) to the protein and also to correlate it with different grades of epithelial dysplasia associated with the disease. Twenty (20) healthy adults acted as controls. RESULTS: iNOS staining was not demonstrated in normal oral epithelium. In oral epithelial dysplasia, staining was seen in all cases (100%) in the basal layers of the epithelium and in 30% of cases it extended into the parabasal compartments as well. iNOS staining was uniformly positive in moderate dysplasia with an increase in intensity and distribution noted as the severity of dysplasia progressed. There were highly significant differences in overall positivity for iNOS in epithelium between cases and controls (Mann-Whitney U=11.000, Wilcoxon W=221.00, P=0.000). Significant comparisons were made of mild Vs moderate dysplasia (Mann-Whitney U=48.000, P=0.014) CONCLUSIONS: This study supports our earlier morphological assessment (image analysis) of the nature of vascularity in OSF mucosa. The significant vasodilation noticed in these cases argues against the concept of ischemic atrophy of the epithelium. This observation of vascularity and iNOS expression helped to explain the vasodilation noticed (sinusoids) in this disease; NO being a net vasodilator. The mechanism of activation of iNOS in dysplasia is difficult to explain. The role of contingent paracrine-activating factors on keratinocytes and macrophages is discussed.