RESUMO
LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.
Assuntos
Anticonvulsivantes/uso terapêutico , Compostos Organoplatínicos/efeitos adversos , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pregabalina/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Pregabalina/administração & dosagem , Pregabalina/farmacologiaRESUMO
CONTEXT: Reducing dietary advanced glycation end-products (AGEs) may favor diabetes control. OBJECTIVE: Critically analyze studies about the effect of dietary AGEs restriction on inflammation, oxidative stress, and glycemic control in patients with type 2 diabetes mellitus (DM2). DATA SOURCE: This systematic review was conducted according to PRISMA methodology. The PubMed, Web of Science, LILACS, and Cochrane Library databases were searched, using the terms "type 2 diabetes," "advanced glycation end products" and "diet." DATA EXTRACTION: Seven original studies were included in this review. The duration of the studies ranged from 1 day to 16 weeks. All extracted data were compiled, compared, and critically analyzed. DATA ANALYSIS: Glycemic variables were considered the primary outcomes. The secondary outcomes were glycation, inflammatory, and oxidative stress markers. CONCLUSION: Although serum insulin, homeostasis model assessment of insulin resistance, and glycated hemoglobin values were lower after the consumption of AGEs restricted diets in most studies, there was a lack of unanimity regarding dietary AGEs' positive effect on inflammation, oxidative stress, and blood glucose. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020152640.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Glicemia , Hemoglobinas Glicadas , Produtos Finais de Glicação Avançada , HumanosRESUMO
PROBLEM: Endometriosis has been suggested to be an autoimmune disease and recently, an allelic variation of the PTPN22 (C1858T) gene was revealed to be associated with the development of autoimmunity. The aim of the study was to determine the frequency of the PTPN22 (C1858T) polymorphism in Brazilian women with endometriosis as compared with controls. METHOD OF STUDY: Case-control study included 140 women with endometriosis and a control group consisting of 180 healthy fertile women without a history of endometriosis and/or autoimmune diseases from the ABC School of Medicine. The PTPN22 (C1858T) polymorphism was studied by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). RESULTS: Genotypes CC, CT and TT of PTPN22 polymorphism presented frequencies of 67.9, 30.0 and 2.1% in the women with endometriosis (P = 0.008); 76.2, 19.0 and 4.8% in women with minimal/mild endometriosis (P = 0.173); 61.0, 39.0 and 0.0% in women with moderate/severe endometriosis (P < or = 0.001) and 82.8, 16.1 and 1.1% in control group. Allele C and T were present in 82.9 and 17.1%; 85.7 and 14.3%; 80.5 and 19.5%; and 90.8 and 9.2% respectively, in women with endometriosis (P = 0.004), women with minimal/mild endometriosis (P = 0.148), women with moderate/severe endometriosis (P = 0.002) and control group. CONCLUSION: The data suggest that in Brazilian women polymorphism PTPN22 (C1858T) may be an important genetic predisposing factor for endometriosis, especially, in advanced disease.
Assuntos
Endometriose/genética , Predisposição Genética para Doença , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Brasil/epidemiologia , Endometriose/epidemiologia , Feminino , Frequência do Gene , Humanos , Polimorfismo GenéticoRESUMO
BACKGROUND: Carbon dioxide pneumoperitoneum induces peritoneal oxidative stress. The aim of this study was to verify the effect of intra-abdominal pressure on oxidative stress in the peritoneum and on post-operative adhesion formation. METHODS: Forty-one rabbits underwent laparoscopic surgery: either gasless, or with CO(2)-pneumoperitoneum at pressures of 5, 10 or 15 mmHg. Serial parietal peritoneal biopsies were taken at various time-points: immediately after reaching the abdominal cavity, 30, 60, 90 and 120 min afterwards, and 15 min after abdominal desufflation. 8-iso prostaglandin F(2alpha) (8-iso PGF(2alpha)), a marker of oxidative stresss, was assayed by enzyme immunoassay and adhesion formation was scored by second-look laparoscopy on day 14. RESULTS: The gasless group showed no significant changes in 8-iso PGF(2alpha). Conversely, significant changes occurred in CO(2)-pneumoperitoneum in a time- and pressure-dependent manner. Adhesions developed only in the CO(2)-pneumoperitoneum groups, and total adhesion score was correlated with the amount of CO(2) insufflated and intra-abdominal pressure, but not with 8-iso PGF(2alpha), which was correlated with intra-abdominal pressure. CONCLUSION: Intra-abdominal pressure increased 8-iso PGF(2alpha) in the parietal peritoneum in a graded fashion, whilst gasless laparoscopy had no impact. It also influenced the frequency and severity of adhesion formation, but no causal link was found between 8-iso PGF(2alpha) and post-operative adhesion formation.
Assuntos
Cavidade Abdominal/fisiologia , Dinoprosta/biossíntese , Laparoscopia , Animais , Dióxido de Carbono/efeitos adversos , Dinoprosta/análogos & derivados , Feminino , Doenças Peritoneais/etiologia , Pneumoperitônio Artificial/efeitos adversos , Período Pós-Operatório , Pressão , Coelhos , Fatores de Tempo , Aderências Teciduais/etiologiaRESUMO
STUDY OBJECTIVE: To identify oxidative stress in peritoneum during laparoscopic and open surgery by measuring products of lipid peroxidation, and to determine whether surgical approach influences the type of oxidative metabolite synthesized. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: University-affiliated hospital. PATIENTS: Twenty-eight consecutive women with uterine myomas or ovarian cysts. INTERVENTION: Laparoscopic or open surgery (14 patients each). MEASUREMENTS AND MAIN RESULTS: We obtained 1 x 1-cm squares of peritoneum at the beginning and end of surgical procedures away from sites of surgery. 8-Isoprostaglandin F(2alpha), hydroxyeicosatetranoic acids (HETEs), and malondyaldehyde (MDA) were measured by enzyme-immunoassay, high-performance liquid chromatography, and thiobarbituric acid adduction method, respectively. Comparisons showed significant increases in 5-HETE and 8-prostane in the laparoscopy group, which were correlated with duration of pneumoperitoneum and volume of carbon dioxide (CO(2)) insufflated, respectively. In the laparotomy group only MDA rose significantly related to duration of surgery. CONCLUSIONS: Lipid peroxidation was observed in peripheral peritoneum during laparoscopic surgery, mediated through noncyclooxygenase and lipoxygenase pathways, and appears to be due to effects of CO(2) pneumoperitoneum. Biochemical reactions were also observed in the laparotomy group, but are thought to be related to mechanisms other than lipid peroxidation.
Assuntos
Laparoscopia/métodos , Laparotomia/métodos , Estresse Oxidativo , Adulto , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Dinoprosta/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/análise , Laparoscopia/efeitos adversos , Laparotomia/efeitos adversos , Leiomioma/patologia , Leiomioma/cirurgia , Peroxidação de Lipídeos , Malondialdeído/análise , Pessoa de Meia-Idade , Cistos Ovarianos/patologia , Cistos Ovarianos/cirurgia , Peritônio/química , Pneumoperitônio Artificial , Probabilidade , Estudos Retrospectivos , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgiaRESUMO
BACKGROUND: The objective of this study was to verify whether in vitro exposure of human peritoneal mesothelial cells to carbon dioxide (CO(2)) influences the levels of 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), a marker of oxidative stress. METHODS: Mesothelial cells were exposed to either: (i). 100% CO(2) for 4 h; (ii). 100% helium (an alternative gas with which to create hypoxic conditions) for 4 h; (iii). 100% CO(2) for 24 h; or (iv). standard conditions (control). After gas exposure, mesothelial cells were returned to standard conditions and harvested immediately (T(0)), and at 1-(T(1)) and 3 (T(3)) h afterwards. Cell viability and culture medium pH were monitored throughout the experiments. 8-iso-PGF(2alpha) was assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Exposure to CO(2) decreased the culture medium pH whereas helium increased the pH. 8-iso-PGF(2alpha) levels in all treated groups were significantly higher than in the control group: in the 4 h CO(2) group at T(1); in the 24 h CO(2) group at T(0) and T(1); and in the 4 h helium group at T(0), T(1) and T(3). 8-iso-PGF(2alpha) levels following 4 h CO(2) exposure were significantly lower than after 24 h CO(2) exposure at T(1), and lower than following 4 h helium exposure at all time points. CONCLUSIONS: Exposure to both CO(2) and helium induces oxidative stress in mesothelial cells. Hypoxia-reoxygenation may play a role in this process.