Anti-inflammatory and antinociceptive effects, and safety toxicological profile of a new paracetamol analog, LQFM291.

In the scope of a research program with the goal of developing treatments for inflammatory diseases, the pharmacological evaluation of LQFM291, designed by molecular hybridization from butylated hydroxytoluene and paracetamol, was described. The antioxidant profile of LQFM291 was evaluated by electrochemical measurement. Also, acute or repeated treatments with equimolar doses to paracetamol were used to evaluate the antinociceptive and/or anti-inflammatory activities of LQFM291 in animal models. The toxicologic potential of LQFM291 was also evaluated and compared to paracetamol through biochemical and histopathological analysis after the repeated treatment schedule. As a result of the acute treatment, paracetamol showed a similar antinociceptive effect in formalin test compared to LQFM291. Whereas, after the repeated treatment, when carrageenan-induced hyperalgesia and edema tests were performed, paracetamol showed a delayed antinociceptive and anti-inflammatory effect compared to LQFM291. Furthermore, as other advantages the LQFM291 showed a high redox capacity, a gastroprotective activity and a safety pharmacological profile without any liver or kidney damage. These effects can be related to the prevention of oxidative stress by reduction of protein and lipid peroxidation in gastric tissue, maintenance of glutathione levels in hepatic homogenate, and a systemic reduction of pro-inflammatory cytokine levels, which may characterize the LQFM291 as a more viable and effective alternative to relief pain and inflammatory signs in patients with chronic disorders.

Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects.

Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of salvinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective opioid receptor antagonist), naloxonazine (antagonist of specific subtypes mu1 of µ-OR), and nor-binaltorphimine (selective ĸ-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the opioid receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for additional pharmacological characterization.

Overview of the Justicia Genus: Insights into Its Chemical Diversity and Biological Potential.

The genus Justicia has more than 600 species distributed in both hemispheres, in the tropics and temperate regions, and it is used in the treatment of numerous pathologies. This study presents a review of the biological activities of plant extracts and isolated chemical constituents of Justicia (ACANTHACEAE), identified in the period from May 2011 to August 2022. We analyzed over 176 articles with various biological activities and chemical compound descriptions present in the 29 species of Justicia. These have a variety of applications, such as antioxidant and antimicrobial, with alkaloids and flavonoids (e.g., naringenin) the most frequently identified secondary metabolites. The most observed species were Justicia gendarussa Burm., Justicia procumbens L., Justicia adhatoda L., Justicia spicigera Schltdl, and Justicia pectoralis Jacq. The frontier molecular orbitals carried out using density functional theory (M062X and basis set 6-311++G(d,p) indicate reactive sites for naringenin compound and a chemical reaction on phytomedicine activity. The energy gap (206.99 kcal/mol) and dimer solid state packing point to chemical stability. Due to the wide variety of pharmacological uses of these species, this review points toward the development of new phytomedicines.

Pharmacological evaluation of antinociceptive and anti-inflammatory activities of LQFM202: a new piperazine derivative.

Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC50 = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1ß levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202.

Cardiovascular Risk Prediction by the American Diabetes Association Risk-Assessment Tool and Novel and Traditional Cardiovascular Risk Factors in Young Adults With Type 1 Diabetes.

INTRODUCTION: Cardiovascular disease is an important cause of morbidity and mortality in individuals with type 1 diabetes (T1D). The American Diabetes Association (ADA) has the ADA risk-assessment tool for cardiovascular risk (CVR) prediction in individuals with T1D. This study aims to evaluate the prevalence of novel and traditional cardiovascular risk factors (CVRF) and the CVR by the ADA risk-assessment tool: 10-year risk for diabetes complications in young adults with T1D. METHODS: Cross-sectional observational study of T1D individuals aged 18-40 years and T1D duration ≥1 year. The ADA risk-assessment tool was applied to predict CVR. RESULTS: 75 individuals, 61.3% male, with a median age of 30 (26.0-36.0) and 13.0 (6.0-20.0) years of T1D duration. Hypertension was found in 16% of individuals and dyslipidemia in 75.0%. 21.3% were active smokers, 30.7% sedentary, and 42.7% were at least overweight. Most individuals had a 10-year risk <1% for all complications except myocardial infarction (MI). In individuals who were outside the honeymoon period (T1D duration ≥ 5 years), most had a 10-year risk <1% for all complications except MI and amputation. Non-traditional CVRF homocysteine, apolipoprotein B, apolipoprotein B/apolipoprotein A1 ratio, magnesium, and vitamin D correlated with the ADA risk-assessment tool. 10-year risk for MI ≥1% was significantly more frequent in men. CONCLUSION: To our knowledge, this is the first study to apply the ADA risk-assessment tool: 10-year risk for diabetes complications in T1D. Young adults with T1D have a worrying prevalence of CVRF and show suboptimal control. Most individuals with T1D duration ≥1 year have an estimated 10-year risk <1% for all complications, except for MI.

Heterocyclic Compounds: Pharmacology of Pyrazole Analogs From Rational Structural Considerations.

Low quality of life and life-threatening conditions often demand pharmacological screening of lead compounds. A spectrum of pharmacological activities has been attributed to pyrazole analogs. The substitution, replacement, or removal of functional groups on a pyrazole ring appears consistent with diverse molecular interactions, efficacy, and potency of these analogs. This mini-review explores cytotoxic, cytoprotective, antinociceptive, anti-inflammatory, and antidepressant activities of some pyrazole analogs to advance structure-related pharmacological profiles and rational design of new analogs. Numerous interactions of these derivatives at their targets could impact future research considerations and prospects while offering opportunities for optimizing therapeutic activity with fewer adverse effects.

Involvement of the Benzodiazepine Site in the Anticonvulsant Activity of Tapinanthus globiferus against Pentylenetetrazole-induced Seizures in Mice.

Tapinanthus globiferus is often referred to as an all-purpose herb for the treatment of stroke and epilepsy. The present study investigates the anticonvulsant effect of methanolic leaf extract, active fractions, and lupeol (isolate) of Tapinanthus globiferus in mice as well as the underlying mechanisms. Following phytochemical studies of T. globiferus, preliminary assays were performed to evaluate MLE-induced toxic effect and behavioral changes. The pentylenetetrazol (70 mg/kg, i. p.)-induced seizure was evaluated in mice that were pretreated orally with vehicle 10 mL/kg, MLE (4, 20, or 100 mg/kg), fractions (F1 to F6), lupeol 10 mg/kg or diazepam (3 mg/kg). Methanolic leaf extract preserved neuron viability as well as the relative organ weight, and hematological and biochemical parameters. The behavioral endpoints, neuromuscular coordination, and sensory response parameters revealed a dose-dependent effect of methanolic leaf extract. This extract, active fractions, lupeol, and diazepam potentiated the hypno-sedative effect of the barbiturate and attenuated PTZ-induced acute seizure. This antiseizure effect was completely reversed by flumazenil 2 mg/kg (benzodiazepine site antagonist). Altogether, the benzodiazepine site-mediated anticonvulsant effects of methanolic leaf extract, active fractions, and lupeol corroborate traditional application of T. globiferus against epilepsy.

Spontaneous coronary artery dissection: "To stent or not to stent, that is the question". / Disseção coronária espontânea ­ To stent or not to stent that is the question.

Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome that typically occurs in relatively young patients without classical cardiovascular risk factors for coronary artery disease. The etiology appears to be multifactorial and optimal management is not clearly established, so the treatment strategy is often selected based on clinical presentation and coronary anatomy. We present two cases of spontaneous coronary artery dissection with different initial approaches, highlighting the importance of a case-by-case assessment.

Alteplase for Massive Pulmonary Embolism after Complicated Pericardiocentesis.

BACKGROUND: The occurrence of a high-risk pulmonary embolism (PE) within 48 hours of a complicated pericardiocentesis to remove a haemorrhagic pericardial effusion, is an uncommon clinical challenge. CASE SUMMARY: The authors report the case of a 75-year-old woman who presented with signs of imminent cardiac tamponade due to recurring idiopathic pericardial effusion. The patient underwent pericardiocentesis that was complicated by the loss of 1.5 litres of blood. Within 48 hours, the patient had collapsed with clear signs of obstructive shock. This was a life-threating situation so alteplase was administered after cardiac tamponade and hypertensive pneumothorax had been excluded. CT chest angiography later confirmed bilateral PE. The patient achieved haemodynamic stability less than an hour after receiving the alteplase. However, due to the high risk of bleeding, the medical team suspended the thrombolysis protocol and switched to unfractionated heparin within the hour. The cause of the PE was not identified despite extensive study, but after 1 year of follow-up the patient remained asymptomatic. DISCUSSION: Despite the presence of a contraindication, the use of thrombolytic therapy in obstructive shock after exclusion of hypertensive pneumothorax can be life-saving, and low-dose thrombolytic therapy may be a valid option in such cases. LEARNING POINTS: A quick and systematic approach to a collapsed patient with signs of shock is mandatory; understanding the type of shock may help narrow the differential diagnosis and help in therapeutic decisions.After exclusion of cardiac tamponade and hypertensive pneumothorax, life-saving thrombolytic therapy can be administered in obstructive shock due to probable massive pulmonary embolism.Contraindications for thrombolytic therapy originated as exclusion criteria for clinical trials but should not prevent the use of this therapy in life-threatening situations.

Practical band interpolation with a modified tight-binding method.

We present a scheme that interpolates the energy bands of a crystal with a modified tight-binding Hamiltonian. We start from a pseudopotential plane-wave calculation of the eigenvalues in a three-dimensional coarse uniform grid of k-points in the Brillouin zone and from the evaluation of the single particle Hamiltonian and overlap matrix elements for a small localised basis set of atomic orbitals in the same k-point grid. A simple matrix manipulation procedure that replaces the eigenvalues obtained from the atomic orbital method by the eigenvalues of the plane-wave method generates the modified tight-binding Hamiltonian on the coarse grid. A subsequent three-dimensional Fourier interpolation of the modified tight-binding Hamiltonian and overlap matrices leads to a fast, yet accurate, determination of interpolated Hamiltonians and overlap matrices at an arbitrary k-point, or in a denser grid of k-points. We present examples of the application of the scheme to density functional calculations of germanium, graphite, graphene, copper and a SiGe superlattice.

Caryocar brasiliense induces vasorelaxation through endothelial Ca2+/calmodulin and PI3K/Akt/eNOS-dependent signaling pathways in rats

ABSTRACT Caryocar brasiliense Cambess., Caryocaraceae (pequi) is a typical Brazilian Cerrado tree. A previous study showed that the butanolic fraction of pequi leaves promotes endothelium-dependent relaxation mediated by nitric oxide and that it causes reversible hypotension in rats. In the present study, we investigated the cell signaling pathways associated with the butanolic fraction-induced nitric oxide release, and we characterized the chemical composition of its fraction. Vascular reactivity tests, a western blotting analysis, and a chemiluminescence assay were used to investigate the signaling pathways involved in the vasorelaxant effect of the butanolic fraction. Electrospray Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry was used to characterize the butanolic fraction chemical composition. Vasorelaxation was mediated through the activation of the calmodulin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, leading to subsequent endothelial nitric oxide synthase phosphorylation and nitric oxide production, as evidenced by western blotting and chemiluminescence assays, respectively. The chemical characterization of the butanolic fraction revealed the presence of 72 oxygenated compounds, whose molecular formulae are compatible with phenolic compounds, suggesting a potential contribution of these compounds for the butanolic fraction vasorelaxant effect. These findings show that the calmodulin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are involved in the butanolic fraction-induced endothelial nitric oxide synthase activation and are promoted by polyphenol compounds present in the C. brasiliense leaves.

Respuesta al ECG de noviembre de 2018 / Response to ECG, November 2018

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ECG de noviembre de 2018 / ECG, November 2018

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Fractional Flow Reserve-Guided Strategy in Acute Coronary Syndrome. A Systematic Review and Meta-Analysis.

BACKGROUND: There are limited data on the prognosis of deferral of lesion treatment in patients with acute coronary syndrome (ACS) based on fractional flow reserve (FFR). OBJECTIVES: To provide a systematic review of the current evidence on the prognosis of deferred lesions in ACS patients compared with deferred lesions in non-ACS patients, on the basis of FFR. METHODS: We searched Medline, EMBASE, and the Cochrane Library for studies published between January 2000 and September 2017 that compared prognosis of deferred revascularization of lesions on the basis of FFR in ACS patients compared with non-ACS patients. We conducted a pooled relative risk meta-analysis of four primary outcomes: mortality, cardiovascular (CV) mortality, myocardial infarction (MI) and target-vessel revascularization (TVR). RESULTS: We identified 7 studies that included a total of 5,107 patients. A pooled meta-analysis showed no significant difference in mortality (relative risk [RR] = 1.44; 95% CI, 0.9-2.4), CV mortality (RR = 1.29; 95% CI = 0.4-4.3) and TVR (RR = 1.46; 95% CI = 0.9-2.3) after deferral of revascularization based on FFR between ACS and non-ACS patients. Such deferral was associated with significant additional risk of MI (RR = 1.83; 95% CI = 1.4-2.4) in ACS patients. CONCLUSION: The prognostic value of FFR in ACS setting is not as good as in stable patients. The results demonstrate an increased risk of MI but not of mortality, CV mortality, and TVR in ACS patients.

Fractional Flow Reserve-Guided Strategy in Acute Coronary Syndrome. A Systematic Review and Meta-Analysis / Estratégia Guiada por Reserva de Fluxo Fracionada na Síndrome Coronária Aguda: Revisão Sistemática Metanálise

Abstract Background: There are limited data on the prognosis of deferral of lesion treatment in patients with acute coronary syndrome (ACS) based on fractional flow reserve (FFR). Objectives: To provide a systematic review of the current evidence on the prognosis of deferred lesions in ACS patients compared with deferred lesions in non-ACS patients, on the basis of FFR. Methods: We searched Medline, EMBASE, and the Cochrane Library for studies published between January 2000 and September 2017 that compared prognosis of deferred revascularization of lesions on the basis of FFR in ACS patients compared with non-ACS patients. We conducted a pooled relative risk meta-analysis of four primary outcomes: mortality, cardiovascular (CV) mortality, myocardial infarction (MI) and target-vessel revascularization (TVR). Results: We identified 7 studies that included a total of 5,107 patients. A pooled meta-analysis showed no significant difference in mortality (relative risk [RR] = 1.44; 95% CI, 0.9-2.4), CV mortality (RR = 1.29; 95% CI = 0.4-4.3) and TVR (RR = 1.46; 95% CI = 0.9-2.3) after deferral of revascularization based on FFR between ACS and non-ACS patients. Such deferral was associated with significant additional risk of MI (RR = 1.83; 95% CI = 1.4-2.4) in ACS patients. Conclusion: The prognostic value of FFR in ACS setting is not as good as in stable patients. The results demonstrate an increased risk of MI but not of mortality, CV mortality, and TVR in ACS patients.

Resumo Fundamento: Existem dados limitados sobre o prognóstico do adiamento do tratamento das lesões em pacientes com síndrome coronária com base na reserva de fluxo fracionada (FFR). Objetivos: Realizar uma revisão sistemática da evidência atual sobre o prognóstico do adiamento do tratamento de lesões em pacientes com SCA com base na FFR, comparando-o com o prognóstico em pacientes sem SCA. Métodos: Pesquisamos as bases de dados do Medline, EMBASE, e Cochrane Library por estudos publicados entre janeiro de 2000 e setembro de 2017 que compararam o prognóstico do adiamento da revascularização das lesões com base na FFR em pacientes com SCA em comparação a pacientes sem SCA. Conduzimos uma metanálise do risco relativo de quatro desfechos primários: mortalidade, mortalidade cardiovascular, infarto do miocárdio (IM) e revascularização do vaso-alvo (TVR). Resultados: Identificamos sete estudos que incluíram um total de 5107 pacientes. A metanálise mostrou que não houve diferença quanto à mortalidade [risco relativo (RR) = 1,44; IC95%, 0,9-2,4), mortalidade cardiovascular (RR = 1,29; IC95% = 0,4-4,3) e TVR (RR = 1,46; IC95% = 0,9-2,3) após adiamento da revascularização com base na FFR entre pacientes com SCA e pacientes sem SCA. Tal adiamento foi associado com risco adicional de IM (RR = 1,83; IC95% = 1,4-2,4) em pacientes com SCA. Conclusão: O valor prognóstico da FFR na SCA não é tão bom como em pacientes estáveis. Os resultados mostram um risco aumentado de IM, mas não de mortalidade, mortalidade cardiovascular, e TVR em pacientes com SCA.