Anorectic interaction and safety of 5-hydroxytryptophan/carbidopa plus phentermine or diethylpropion in rat.

Drug combinations are being studied as potential therapies to increase the efficacy or improve the safety profile of weight loss medications. This study was designed to determine the anorectic interaction and safety profile of 5-hydroxytryptophan (5-HTP)/carbidopa + diethylpropion and 5-HTP/carbidopa + phentermine combinations in rats. The anorectic effect of individual drugs or in combination was evaluated by the sweetened milk test. Isobologram and interaction index were employed to determine the anorectic interaction between 5-HTP/carbidopa and diethylpropion or phentermine. Plasma serotonin (5-HT) was measured by ELISA. Safety of repeated doses of both combinations in rats was evaluated using the tail sphygmomanometer, cardiac ultrasound, hematic biometry and blood chemistry. A single oral 5-HTP, diethylpropion or phentermine dose increased the anorectic effect, in a dose-dependent fashion, in 12 h-fasted rats. A dose of carbidopa at 30 mg/kg reduced the 5-HTP-induced plasmatic serotonin concentration and augmented the 5-HTP-induced anorectic effect. Isobologram and interaction index indicated a potentiation interaction between 5-HTP/30 mg/kg carbidopa + diethylpropion and 5-HTP/30 mg/kg carbidopa + phentermine. Chronic administration of experimental ED40 of 5-HTP/30 mg/kg carbidopa + phentermine, but not 5-HTP/30 mg/kg carbidopa + diethylpropion, increased the mitral valve leaflets area. Moreover, there were no other significant changes in cardiovascular, hematic or blood parameters. Both combinations induced around 20% body weight loss after 3 months of oral administration. Results suggest that 5-HTP/30 mg/kg carbidopa potentiates the anorectic effect of diethylpropion and phentermine with an acceptable safety profile, but further clinical studies are necessary to establish their therapeutic potential in the obesity treatment.

[General characteristics of medical education in Mexico. A look from medical schools]. / Características generales de la educación médica en México. Una mirada desde las escuelas de medicina.

OBJECTIVE: To know the characteristics of medical education and identify its strengths and weaknesses. MATERIALS AND METHODS: A transversal and quantitative study of the characteristics of medical education in 29 medical schools in Mexico was carried out, between April and September 2017. Questionnaire with Likert scale was applied to explore context, regulation, structure, process, results and impact of medical education. Bivariate analysis was performed with a Chi square test and the significance level was equal to or less than 0.05. RESULTS: The political context obtained 64%, economical context 10% and mechanisms of regulation 31%. The educational structure was 61% and the social impact was 93%. CONCLUSIONS: Public policies, regulatory mechanisms and public investment must be strengthened to improve the quality of medical education.

OBJETIVO: Conocer las características de la educación médica e identificar sus fortalezas y debilidades. MATERIAL Y MÉTODOS: Se realizó un estudio transversal y cuantitativo para conocer las características de la educación médica en 29 escuelas de medicina en México, entre abril y septiembre de 2017. Se utilizó un cuestionario con escala tipo Likert para explorar el contexto, la regulación, la estructura, el proceso, los resultados y el impacto de la educación médica. Se realizó un análisis bivariado con ji cuadrada y una significancia estadística de p igual o menor a 0.05. RESULTADOS: El contexto político obtuvo 64%, el contexto económico 10%, los mecanismos de regulación 31%, la estructura educativa 61% y el impacto social 93%. CONCLUSIONES: Se requiere fortalecer las políticas públicas, la regulación y la inversión pública, para mejorar la calidad de la educación médica.

[Educating general practitioners in Latin America: a challenge for universal healthFormação de clínicos gerais na América Latina: um desafio para a saúde universal]. / Formación de médicos generales en América Latina: un reto para la salud universal.

OBJECTIVE: To gather opinions from medical schools regarding the existence of public policies on the health workforce (human resources for health) and whether sufficient public financing and regulatory mechanisms are in place for undergraduate medical education; and to identify areas of opportunity to improve the availability of general practitioners in the Region of the Americas. METHODS: Cross-sectional, descriptive study conducted with 105 medical schools (51 public and 54 private) in 17 countries. A questionnaire with a Likert scale was used to explore three dimensions (political, economic, and regulatory contexts) composed of 4, 2, and 4 variables each, respectively, and validated with the Delphi method. Frequencies of responses to the questions were estimated. A frequency analysis was performed, as well as a bivariate analysis to identify differences between public and private schools, applying the Chi-square test to compare percentages. RESULTS: The political context was considered favorable by 64% of the schools; the economic context, by 37%; and the regulatory context, by 23%. The only significant differences between public and private schools were in the financial resources they administer. CONCLUSIONS: It is necessary to strengthen public policies, public investment, and the regulation of medical education in order to improve the education and availability of general practitioners in the countries of the Region.

OBJETIVO: Conhecer a opinião das faculdades de medicina sobre o volume de políticas públicas e financiamento público e mecanismos reguladores para graduação médica e identificar áreas que possibilitem aumentar o número de clínicos gerais na Região das Américas. MÉTODOS: Estudo transversal descritivo realizado com 105 faculdades de medicina (51 públicas e 54 particulares) em 17 países. Um questionário com uma escala tipo Likert foi usado para explorar três dimensões (contexto político, contexto econômico e regulamentação), contendo 4, 2 e 4 variáveis cada, e foi validado com o método Delphi. As frequências de respostas às perguntas do questionário foram calculadas e analisadas. A fim de identificar diferenças entre as faculdades públicas e particulares, uma análise bivariada com teste qui-quadrado foi realizada para comparar porcentagens. RESULTADOS: O contexto político foi considerado favorável por 64% das faculdades; o contexto econômico por 37%; e a regulamentação por 23%. Apenas foi observada diferença significativa entre as faculdades públicas e particulares na variável recursos financeiros geridos. CONCLUSÕES: É necessário fortalecer as políticas públicas, o investimento público e a regulamentação da educação médica para melhorar a formação e aumentar o número de clínicos gerais nos países da Região.

Anorectic efficacy and safety of the diethylpropion-topiramate combination in rats.

Preclinical Research & Development Current drugs for obesity treatment have limited efficacy and considerable adverse effects. Combination of drugs with complementary mechanisms of action at lower doses may produce a greater efficacy with a better safety profile. This study was designed to assess the anorectic effect and safety of a diethylpropion + topiramate mixture in rats. The anorectic effect of drugs was measured using a sweetened milk consumption model, and the corresponding interaction was determined by isobolographic analysis, interaction index and confidence intervals. Additionally, blood pressure was measured using a sphygmomanometer in the rat tail. Diethylpropion and topiramate alone or in combination increased the anorectic effect in a dose-dependent fashion in either nondeprived or 12 hr food-deprived rats. All theoretical ED30 values of diethylpropion + topiramate combinations at 1:1, 1:3, and 3:1 dose ratios were significantly higher than experimental ED30 values. In addition, interaction indices and confidence intervals confirmed the potentiation between both drugs. Theoretical ED30 of diethylpropion + topiramate combination did not affect the blood pressure. Data suggests that low doses of the diethylpropion + topiramate combination can potentiate the anorectic effect of individual drugs with a better safety profile, which deserves further investigation in clinical trials.

n-3 Fatty acids modulate the mRNA expression of the Nlrp3 inflammasome and Mtor in the liver of rats fed with high-fat or high-fat/fructose diets.

CONTEXT: There is evidence that n-3 polyunsaturated fatty acids (n-3-PUFAs) can inhibit mTORC1, which should potentiate autophagy and eliminate NLRP3 inflammasome activity. OBJECTIVE: Evaluate the effect of a high-fat or high-fat/fructose diet with and without n-3-PUFAs on hepatic gene expression. MATERIALS AND METHODS: We examined the mRNA expression by RT-PCR of Mtor, Nlrp3, and other 22 genes associated with inflammation in rats livers after a 9-week diet. The dietary regimens were low-fat (control, CD), high-fat (HF), high-fat/fructose (HF-Fr), and also each of these supplemented with n-3-PUFAs (CD-n-3-PUFAs, HF-n-3-PUFAs, and HF-Fr-n-3-PUFAs). These data were processed by GeneMania and STRING databases. RESULTS: Compared to the control, the HF group showed a significant increase (between p < 0.05 and p < 0.0001) in 20 of these genes (Il1b, Il18, Rxra, Nlrp3, Casp1, Il33, Tnf, Acaca, Mtor, Eif2s1, Eif2ak4, Nfkb1, Srebf1, Hif1a, Ppara, Ppard, Pparg, Mlxipl, Fasn y Scd1), and a decrease in Sirt1 (p < 0.05). With the HF-Fr diet, a significant increase (between p < 0.05 and p < 0.005) was also found in the expression of 16 evaluated genes (Srebf1, Mlxipl, Rxra, Abca1, Il33, Nfkb1, Hif1a, Pparg, Casp1, Il1b, Il-18, Tnf, Ppard, Acaca, Fasn, Scd1), along with a decrease in the transcription of Mtor and Elovl6 (p < 0.05). Contrarily, many of the genes whose expression increased with the HF and HF-Fr diets did not significantly increase with the HF-n-3-PUFAs or HF-Fr-n-3-PUFAs diet. DISCUSSION AND CONCLUSION: We found the interrelation of the genes for the mTORC1 complex, the NLRP3 inflammasome, and other metabolically important proteins, and that these genes respond to n-3-PUFAs.

Six-month efficacy and safety of amfepramone in obese Mexican patients: a double-blinded, randomized, controlled trial.

Amfepramone, also known as diethylpropion, is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety during periods greater than 3 months has been scarcely studied. To evaluate the 6-month efficacy and safety of amfepramone treatment in obese adult Mexican patients resistant to diet and exercise, a double-blinded, randomized, and placebo-controlled clinical trial study was designed on 156 volunteers with a body mass index (BMI) greater than 30 kg/m2 and less than 45 kg/m2. Patients were randomized to receive a 75 mg tablet of amfepramone or placebo daily for 6 months. Primary outcome was the absolute body weight loss, whereas secondary outcomes were the percentage of patients who achieved at least 5% or 10% weight loss, as well as the improvement of anthropometric and metabolic parameters. Amfepramone treatment produced a superior efficacy to decrease body weight than placebo at 3 months (-4.9±0.25 kg vs. -0.7±0.32 kg) and 6 months (-7.7±0.52 kg vs. -1.1±0.7 kg). In addition, 64 and 34 patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with 8 and 0 patients on placebo. Amfepramone also significantly improved BMI and waist circumference, but it only showed a favorable tendency in the waist-hip index (WHI), glucose, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, heart rate, systolic blood pressure, and diastolic blood pressure at 3 and 6 months. Amfepramone produced only mild adverse events, and they were presented in a greater number than placebo only at 3 months, dry mouth being the the main adverse event. Data suggest that amfepramone is effective and well tolerated in obese Mexican patients during a 6-month regimen.

Oxidant/antioxidant state in tissue of prymary and recurrent pterygium.

BACKGROUND: Pterygium is a disorder of the ocular surface induced by chronic exposure to UV-light. Abundant data is available from patients with primary pterygium, but scarce from those with recurrent pterygium. The present study aimed to explore the oxidant/antioxidant status in tissue of primary and recurrent pterigium in men and women. METHODS: Pathological tissue samples were taken during surgery on patients with primary and recurrent pterygium. Healthy conjunctive tissue samples were taken during cataract surgery. After homogenization of 77 tissue samples, evaluation was made of thiobarbituric reactive substances (TBARS), nitric oxide (NO), total antioxidant status (TAS) and the activity of the three main antioxidant enzymes: glutathione peroxidase, superoxide dismutase and catalase. Gender differences were evaluated. RESULTS: Compared to the control group, in the primary pterygium group there was an increase in NO and TAS, and a tendency to a decrease of all antioxidant enzymes, indicating an increase in non-enzymatic antioxidant activity. Compared to the control group, in the recurrent pterygium group there was a significant decrease in the level of TAS and antioxidant enzymes. A high positive correlation was found between most of measured parameters within the control group and the recurrent pterygium group, but not within the primary pterygium group. Compared to men, a significant difference was observed in the elevated NO level and low TAS level of women in the prymary pterygium group. CONCLUSIONS: The diminished antioxidant defense in the recurrent pterygium group, possibly determined mainly by decreased non-enzymatic activity, supports the idea that oxidative stress plays an important role in the recurrence of this disorder.

[Metformin increases serum concentration of high molecular weight (HMW-adiponectin) in nondiabetic obese subjects]. / La metformina incrementa la concentración sérica de adiponectina de alto peso molecular (adiponectina-HMW) en obesos no diabéticos.

INTRODUCTION: Obesity is associated with low-intensity chronic systemic inflammation. OBJECTIVE: To evaluate the efficacy of two different doses of metformin in comparison with placebo on increased serum levels of high molecular weight (HMW) adiponectin. MATERIAL AND METHODS: An experimental design was developed with a crossover complete treatment and balanced design; 28 female and eight male nondiabetic obese adults participated. All participants received, during a week and in randomized order: placebo or metformin 500 or 850 mg twice daily; there was a week washout period between each treatment. The HMW adiponectin serum concentration (0 and 120 minutes) at the end of each treatment was measured. Analyses of variance (ANOVA), Bonferroni test, and size effect calculations were performed. RESULTS: Differences in concentrations of HMW adiponectin (t0', t120') were measured for each treatment by ANOVA, having values of p = 0.03 and 0.002, respectively. The post hoc analysis reported differences favoring treatment with metformin 850 mg (p = 0.025). The sizes of the effect at times t0 and t120 for metformin 500 mg were 34 and 35%, and for metformin 850 mg, 65 and 84%, respectively.

Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies.

Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. AIM: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. METHOD: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. RESULTS: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. CONCLUSIONS: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.

Estrogens as a Possible Therapeutic Strategy for the Management of Neuroinflammation and Neuroprotection in COVID-19.

The Coronavirus disease 2019 (COVID-19) affects several tissues, including the central and peripheral nervous system. It has also been related to signs and symptoms that suggest neuroinflammation with possible effects in the short, medium, and long term. Estrogens could have a positive impact on the management of the disease, not only due to its already known immunomodulator effect, but also activating other pathways that may be important in the pathophysiology of COVID-19, such as the regulation of the virus receptor and its metabolites. In addition, they can have a positive effect on neuroinflammation secondary to pathologies other than COVID-19. The aim of this study is to analyze the molecular mechanisms that link estrogens with their possible therapeutic effect for neuroinflammation related to COVID-19. Advanced searches were performed in scientific databases as Pub- Med, ProQuest, EBSCO, the Science Citation index, and clinical trials. Estrogens have been shown to participate in the immune modulation of the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to this mechanism, we propose that estrogens can regulate the expression and activity of the Angiotensin-converting enzyme 2 (ACE2), reestablishing its cytoprotective function, which may be limited by its interaction with SARS-CoV-2. In this proposal, estrogens and estrogenic compounds could increase the synthesis of Angiotensin-(1-7) (Ang-(1-7)) that acts through the Mas receptor (MasR) in cells that are being attacked by the virus. Estrogens can be a promising, accessible, and low-cost treatment for neuroprotection and neuroinflammation in patients with COVID-19, due to its direct immunomodulatory capacity in decreasing cytokine storm and increasing cytoprotective capacity of the axis ACE2/Ang (1-7)/MasR.

Low expression of stem cell antigen-1 on mouse haematopoietic precursors is associated with erythroid differentiation.

Sca1 is a surface marker of haematopoietic stem cell but its role in erythropoiesis is still largely unknown. In this work we evaluated the ability of Sca1⁺ cells to differentiate into cells of the erythrocytic lineage. We performed FACS analysis of complete and purified Sca1⁺ bone marrow cells from C3H/HeNHsd mice and measured the expression of CD71 and Terr119 to evaluate the stages in erythroid development. Definitive erythropoiesis was evident within the complete bone marrow, while only proerythroblasts were found in Sca1⁺ cells, suggesting that Sca1 is a negative regulator of erythropoiesis. We also used FDCP-mix cells and their PU.1 and SCL transfectants. The PU.1 transfectant showed significantly increased expression of Sca1 and was not induced to differentiate into red blood cells, while the SCL transfectant showed significantly lower expression of Sca1 and produced red blood cells. The results of this study suggest that increased Sca1 expression on erythropoietic precursors inhibits erythroid differentiation.

Effects on secretory IgA levels in small intestine of mice that underwent moderate exercise training followed by a bout of strenuous swimming exercise.

Intestinal homeostasis effectors, secretory IgA (SIgA) and polymeric immunoglobulin receptor (pIgR), have been evaluated in proximal and distal small intestine with moderate-exercise training but not with strenuous exercise or a combination of these two protocols. Therefore, two groups of mice (n=6-8) were submitted to strenuous exercise, one with and one without previous training. The control group had no exercise protocol. Assessment was made of intestinal SIgA and plasma adrenal hormones (by immunoenzymatic assay), alpha-chain and pIgR proteins in intestinal mucosa (by Western blot), lamina propria IgA plasma-cells (by cytofluorometry), mRNA expression (by real-time PCR) for pIgR, alpha- and J-chains in liver and intestinal mucosa, and pro- and anti-inflammatory cytokines in mucosa samples. Compared to other exercise protocols, training plus strenuous exercise elicited: (1) higher levels of SIgA and pIgR in the proximal intestine (probably by hepatobiliary contribution); (2) higher levels of SIgA in the distal segment; (3) lower mRNA expression of some SIgA- and most pro-inflammatory pIgR-producing cytokines. SIgA and pIgR in both segments were derived from an existing pool of their corresponding producing cells. The apparent decreased translation of mRNA transcripts underlies lower levels of SIgA and pIgR in distal than proximal small intestine. There was no significant difference in the relatively high adrenal hormone levels found in both exercised groups. Further study is required about the effects of training plus strenuous exercise on pool-derived SIgA levels and mRNA expression of pro-inflammatory pIgR-producing cytokines. These results could have important implications for intestinal disorders involving inflammation and infection.

Effects of exercise on oxidative stress in rats induced by ozone.

Oxidative stress (OS) induced by acute exercise is reduced by chronic exercise. Ozone (O(3)) exposure produces OS. The aim of this study was to determine if aerobic exercise (AE) reduced OS produced by O(3). A pilot experiment was performed with male Wistar rats submitted to AE (trained to swim 90 min/day). Adaptation to exercise was demonstrated three weeks after training by means of changes in reduced nitrates (NO(x)) in plasma. Therefore, two-week training was chosen for the following experiments. Six of twelve trained rats were exposed to O(3) (0.5 ppm, 4 h/day, one hour before exercise). Two groups of sedentary animals (n = 6 each) were used as controls, one of which was exposed to O(3). At the end of the experiments NO(x), 8-isoprostane (8-IP), malondialdehyde (MDA), superoxide dismutase (SOD) activity, and carbonyls (CBs) were measured in plasma. CBs did not change in any group. O(3)-induced OS was manifested by reduced NO(x) and SOD activity, as well as increased 8-IP and MDA. Exercise significantly blocked O(3) effects although SOD was also decreased by exercise (a greater drop occurring in the O(3) group). It is concluded that AE protects against OS produced by O(3) and the effect is independent of SOD.

Comparative treatment with hyperbaric oxygen therapy in a model of systemic loxoscelism in rats.

Objectives: Spiders of the Loxosceles genus, known as violin spiders, produce venom with dermonecrotic and systemic effects, as it is a species widely distributed in the world, its study represents a high medical relevance. Systemic loxoscelism, which occurs in 1 in 5 cases and is the most frequent in children, can be fatal, so the study of effective therapy is of great relevance. In the present study, we compared different therapeutic options to mitigate the systemic effects of Loxosceles boneti venom in a model in which prepubertal rats were used. Materials and Methods: A model of systemic intoxication by L. boneti venom was provoked in male Wistar rats. Study groups were formed: healthy control, with venom and untreated control, treatment with N-acetylcysteine, and/or hyperbaric oxygenation therapy. Subsequently, pathological analysis of the kidney and lung was performed. The oxidant-antioxidant response was evaluated, and molecular analysis of the COX-1 and COX-2 enzymes was performed. Results: Regenerative changes were observed at the cellular level in both treatments, being more noticeable in the hyperbaric oxygen therapy (HBO) group. The anti-oxidant response was outstanding in the same group. Conclusion: Both treatments offer considerable benefits, however; further studies are needed to provide adequate therapeutics.

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative.

Obesity remains a global health problem. Chronic low-grade inflammation in this pathology has been related to comorbidities such as cognitive alterations that, in the long term, can lead to neurodegenerative diseases. Neuroinflammation or gliosis in patients with obesity and type 2 diabetes mellitus has been related to the effect of adipokines, high lipid levels and glucose, which increase the production of free radicals. Cerebral gliosis can be a risk factor for developing neurodegenerative diseases, and antioxidants could be an alternative for the prevention and treatment of neural comorbidities in obese patients. AIM: Identify the immunological and oxidative stress mechanisms that produce gliosis in patients with obesity and propose antioxidants as an alternative to reducing neuroinflammation. METHOD: Advanced searches were performed in scientific databases: PubMed, ProQuest, EBSCO, and the Science Citation index for research on the physiopathology of gliosis in obese patients and for the possible role of antioxidants in its management. CONCLUSION: Patients with obesity can develop neuroinflammation, conditioned by various adipokines, excess lipids and glucose, which results in an increase in free radicals that must be neutralized with antioxidants to reduce gliosis and the risk of long-term neurodegeneration.

Effect of moderate exercise on IgA levels and lymphocyte count in mouse intestine.

The aim of the present study was to determine the effect of moderate exercise on the production and secretion of IgA in mouse duodenum, on lymphocyte levels in the lamina propria, and on gene expression encoding for cytokines that regulate the synthesis of α-chain of IgA and the expression of pIgR in the lamina propria. Two groups of young Balb/c mice were fed ad libitum, one sedentary and the other with an exercise program (swimming) for 16 weeks. IgA levels in the duodenum were quantified by ELISA; the number of IgA containing cells as well as B cells, CD4(+) and CD8(+) T cells in the duodenal mucosa was determined by immunohistochemistry; gene expression was analyzed by real-time PCR, and the expression of proteins by Western blotting. Because of physical training, in the duodenum there was a decrease in the number of IgA producing cells, but an increase in the levels of IgA. Additionally, exercise increased the expression of the genes encoding for IL-4, IL-6, IL-10, TNF-α and TGF ß, cytokines that regulate the synthesis of IgA and pIgR, the inflammatory response, and the immune response in the intestine. Thus, the increased IgA found in the duodenal lumen is probably due to the increased production of IgA in the LP and the increased transport of the pIgA-pIgR complex across epithelial cells. Possibly the increased S-IgA levels in the bile also contribute to the change in IgA levels.

Putative mechanism of neurological damage in COVID-19 infection.

The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.The recent pandemic of the coronavirus infectious disease 2019 (COVID-19) has affected around 192 countries, and projections have shown that around 40% to 70% of world population could be infected in the next months. COVID-19 is caused by the virus SARS- CoV-2, it enters the cells through the ACE2 receptor (angiotensin converting enzyme 2). It is well known that SARS-CoV-2 could develop mild, moderate, and severe respiratory symptoms that could lead to death. The virus receptor is expressed in different organs such as the lungs, kidney, intestine, and brain, among others. In the lung could cause pneumonia and severe acute respiratory syndrome (SARS). The brain can be directly affected by cellular damage due to viral invasion, which can lead to an inflammatory response, by the decrease in the enzymatic activity of ACE2 that regulates neuroprotective, neuro-immunomodulatory and neutralizing functions of oxidative stress. Another severe damage is hypoxemia in patients that do not receive adequate respiratory support. The neurological symptoms that the patient presents, will depend on factors that condition the expression of ACE2 in the brain such as age and sex, as well as the mechanism of neuronal invasion, the immune response and the general state of the patient. Clinical and histopathological studies have described neurological alterations in human patients with COVID-19. These conditions could have a possible contribution to the morbidity and mortality caused by this disease and may even represent the onset of neurodegenerative activity in recovered patients.

OX40 agonists for cancer treatment: a patent review.

INTRODUCTION: OX40 is an immune checkpoint in cancer and its presence in cancer is a good prognosis, making it a highly relevant target for the development of new immunotherapies. AREAS COVERED: The patent literature reveals vital information on new trends in cancer therapies. The authors used the patent databases of the six major patent offices in the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Office of Intellectual Property of China and Korean Intellectual Property Office, to generate a panorama of patents related to OX40 agonists. Specific patents have been grouped into innovative patents and adoption patents. EXPERT OPINION: An increasing trend in the development of OX40 agonists in cancer, particularly in the years 2018 and 2019. United States was the leader in generating patents, followed by China and England. Major pharmaceutical companies have at least one anti-OX40 agonist, MEDI6469 and MEDI-0562 (AstraZeneca), PF-04518600 (Pfizer), GSK3174998 (GlaxoSmithKline), BMS-986,178 (Bristol-Myers Squibb) and MOXR0916 (Roche), which represent 68% of clinical trials conducted with OX40 agonists.

The Mechanisms of Action of Botulinum Toxin Type A in Nociceptive and Neuropathic Pathways in Cancer Pain.

BACKGROUND: Botulinum toxin type A (BoNT-A) is widely employed for cosmetic purposes and in the treatment of certain diseases such as strabismus, hemifacial spasm and focal dystonia among others. BoNT-A effect mainly acts at the muscular level by inhibiting the release of acetylcholine at presynaptic levels consequently blocking the action potential in the neuromuscular junction. Despite the great progress in approval and pharmaceutical usage, improvement in displacing BoNT-A to other pathologies has remained very limited. Patients under diagnosis of several types of cancer experience pain in a myriad of ways; it can be experienced as hyperalgesia or allodynia, and the severity of the pain depends, to some degree, on the place where the tumor is located. Pain relief in patients diagnosed with cancer is not always optimal, and as the disease progresses, transition to more aggressive drugs, like opioids is sometimes unavoidable. In recent years BoNT-A employment in cancer has been explored, as well as an antinociceptive drug; experiments in neuropathic, inflammatory and acute pain have been carried out in animal models and humans. Although its mechanism has not been fully known, evidence has shown that BoNT-A inhibits the secretion of pain mediators (substance P, Glutamate, and calcitonin gene related protein) from the nerve endings and dorsal root ganglion, impacting directly on the nociceptive transmission through the anterolateral and trigeminothalamic systems. AIM: The study aimed to collect available literature regarding molecular, physiological and neurobiological evidence of BoNT-A in cancer patients suffering from acute, neuropathic and inflammatory pain in order to identify possible mechanisms of action in which the BoNT-A could impact positively in pain treatment. CONCLUSION: BoNT-A could be an important neo-adjuvant and coadjuvant in the treatment of several types of cancer, to diminish pro-tumor activity and secondary pain.

Catecholamine levels and gene expression of their receptors in tissues of adults with osteosarcoma.

AIM: The purpose of this work was to identify and measure catecholamines, their metabolites, and the gene expression of catecholamine receptors in osteosarcoma tissue. MATERIALS AND METHODS: The levels of 3,4-dihydroxyphenylacetic acid, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid in cancer tissue and in adjacent and non-oncological bone tissue were analysed by high-performance liquid chromatography, and the gene expression of catecholamine receptors and of dopamine ß-hydroxylase, monoaminoxidase, ki67, and Runx2 in the osteosarcoma tissue, tissue adjacent to the tumour, non-oncological bone, and human brain tissue was analysed by RT-PCR. RESULTS: We found significantly higher levels of 3,4-dihydroxyphenylacetic acid and norepinephrine in the cancer sample than in adjacent and non-oncological bone. We found that ß-adrenergic receptors and dopaminergic receptors, dopamine ß-hydroxylase, ki67, Runx2, and serotonergic receptor gene expression were significantly higher in tumour tissue than in adjacent and non-oncological bone. CONCLUSION: Catecholamines and their receptors could be potential molecular markers for osteosarcoma progression.