Fentanyl and other New Psychoactive Synthetic Opioids. Challenges to Prevention and Treatment

ABSTRACT Synthetic opioids have played a significant role in the current opioid crisis in the United States (U.S.) and Canada and are a matter of concern worldwide. New psychoactive opioids (NPOs) are classified in the internationally recognized new psychoactive substances (NPSs) category. This group comprises compounds that may have been synthesized decades ago but appeared only recently in the illicit drug market. Such is the case of fentanyl, fentanyl analogs, and non-fentanyl opioids. Most NPOs have effects similar to morphine, including euphoria and analgesia, and can produce fatal respiratory depression. Here, we present an overview of the systemic and molecular effects of main NPOs, their classification, and their pharmacological properties. We first review the fentanyl group of NPOs, including the four compounds of clinical use (fentanyl, alfentanil, sufentanil, and remifentanil) and the veterinary drug carfentanil. We also provide essential information on non-medical fentanyl analogs and other synthetic opioids such as brorphine, etonitazene, and MT-45, used as adulterants in commonly misused drugs. This paper also summarizes the scarce literature on the use of NPOs in Mexico. It concludes with a brief review of the challenges to prevention and treatment posed by NPOs and some recommendations to face them.

Octreotide and postoperative pancreatic fistula after pancreaticoduodenectomy: What we know so far? A narrative review

Postoperative pancreatic fistula (POPF) is the most feared complication following pancreatic resection. Octreotide, a synthetic somatostatin analog, has been widely used by pancreatic surgeons worldwide after pancreatic resections, often as per surgeon抯 discretion, to prevent POPF especially in cases at high risk of developing POPF. We herein analyze the data available till date of the subject. A PubMed search with keywords 搒omatostatin OR octreotide OR somatostatin analogues AND postoperative pancreatic fistula� was made. Further filters were applied in the search 揅linical Trial, Meta?Analysis, Randomized Controlled Trial, Systematic Review, from 1990 � 2021,� and the 68 results thus obtained were analyzed and included in this narrative review. There is considerable heterogeneity among the studies assessing the role of octreotide in the prevention of POPF making data comparison difficult, and hence results remain inconclusive. Most of the earlier studies used different definitions of POPF and other complications; included patients with varied pancreatic pathologies such as cancer, chronic pancreatitis, and benign lesions; surgical techniques such as pancreaticoduodenectomy, distal pancreatectomy, and other procedures; use of somatostatin and its analogs such as octreotide, lanreotide, pasireotide, and vapreotide; varied surgeon and institutional volume; and so on. Besides, pancreatic surgery is per se a complex surgical procedure and has its own inherent biases related to patient and the pancreas itself affecting the overall outcome. Data indicate favorable role of newer somatostatin analogs, and further studies are urgently needed. The question about the efficacy of prophylactic octreotide to reduce POPF after pancreaticoduodenectomy remains open to debate

ISOLATION AND SEQUENCING OF RESISTANCE GENE ANALOGS FROM THE NBS-LRR REGION OF COFFEA ARABICA GENOME

Coffee is one of the most economically important crops in India and also across the world. Apart from the abiotic stress, a USD 495.5 billion coffee industry suffers from the outbreak of various diseases caused by pathogenic fungus, bacteria and viruses. The presence of Resistance Gene Analogs (RGAs) in coffee plant is the most prominent marker of resistance against the pathogens. The current study aims to isolate resistance gene analogs from the nucleotide binding site – Leucine rich repeats (NBS-LRR) region of the Coffea arabica chromosome.

Chitosan microparticles loaded with essential oils inhibit duo-biofilms of Candida albicans and Streptococcus mutans

Abstract Oral candidiasis is a common fungal infection that affects the oral mucosa, and happens when Candida albicans interacts with bacteria in the oral microbiota, such as Streptococcus mutans, causing severe early childhood caries. C. albicans and S. mutans mixed biofilms are challenging to treat with conventional antimicrobial therapies, thus, new anti-infective drugs are required. Objective This study aimed to test a drug delivery system based on chitosan microparticles loaded with geranium and lemongrass essential oils to inhibit C. albicans and S. mutans mixed biofilms. Methodology Chitosan microparticles loaded with essential oils (CM-EOs) were obtained by spray-drying. Susceptibility of planktonic were performed according CLSI at 4 to 2,048 µg/mL. Mixed biofilms were incubated at 37ºC for 48 h and exposed to CM-EOs at 256 to 4,096 µg/mL. The antimicrobial effect was evaluated using the MTT assay, with biofilm architectural changes analyzed by scanning electron microscopy. RAW 264.7 cell was used to evaluate compound cytotoxicity. Results CM-EOs had better planktonic activity against C. albicans than S. mutans. All samples reduced the metabolic activity of mixed C. albicans and S. mutans biofilms, with encapsulated oils showing better activity than raw chitosan or oils. The microparticles reduced the biofilm on the slides. The essential oils showed cytotoxic effects against RAW 264.7 cells, but encapsulation into chitosan microparticles decreased their toxicity. Conclusion This study demonstrates that chitosan loaded with essential oils may provide an alternative method for treating diseases caused by C. albicans and S. mutans mixed biofilm, such as dental caries.

Pharmacotherapeutic follow-up in patients with type 1 diabetes in context of judicialization: possibility optimize costs

Abstract In Brazil, insulin analogs stand out as one of the most demanded medications by judicial means. However, the guarantee of judicial access does not guarantee rational use. In context, pharmacotherapeutic follow-up (PF) is shown to be clinical effective strategy for patients with diabetes. To evaluate direct medical costs one year after performing PF in patients with type 1 diabetes mellitus using insulin analogs ordered by court in Public Health System (Sistema Único de Saúde - SUS). This is a partial economic analysis, nested within a quasi-experimental study. Patients with T1DM who receive insulin analogs by judicialization in a medium-sized Brazilian city participated. The PF was conducted following the method adapted from the Pharmacotherapy workup (PW). Data were collected considering the period of one year before the start of the intervention and one year after the start of the intervention. Direct medical costs were evaluated and the difference in costs was calculated. 28 patients participated in the intervention. After PF, direct costs were -$3,696.78. Sensitivity analysis showed that there is a 33.4 % chance for PF to present cost savings when compared to baseline. The PF has the potential to reduce direct medical costs from the perspective of the SUS.

Early initiation of antiviral therapy reduces the risk of hepatocellular carcinoma in individuals with chronic hepatitis B virus infection / 临床肝胆病杂志

Chronic hepatitis B virus (HBV) infection is a major cause of viral hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). From chronic HBV infection to HCC, most patients go through the stages of chronic hepatitis, liver cirrhosis, and HCC. During this long process, the ongoing integration of HBV DNA into host DNA increases the risk of HCC, and the death and compensatory proliferation of hepatocytes caused by persistent liver inflammation may promote the accumulation of oncogenic mutations and finally lead to the malignant transformation of hepatocytes. Currently, nucleos(t)ide analogues are widely used anti-HBV drugs, which controls infection by inhibiting HBV replication and can thus effectively slow down disease progression and end-stage liver disease; however, anti-HBV therapy often starts late and has a relatively low treatment rate, and there is still a tendency of increase in the incidence rate of HBV-related HCC. Therefore, how to improve current antiviral strategies to further reduce the risk of HBV-related end-stage liver disease including HCC has become a hotspot in clinical practice. This article summarizes the previous studies supporting the expansion of antiviral therapy and suggests that antiviral therapy should be initiated as early as possible to inhibit viral replication and the sequential events of HBV DNA integration and ultimately reduce the risk of HCC in patients with chronic HBV infection.

Application of strigolactone analogs in storage of Gastrodia elata / 中国中药杂志

This study explored the preservation effect of strigolactone analogs on Gastrodia elata tubers and screened out the suitable preservation measures of G. elata to provide a safer and more effective method for its storage and preservation. Fresh G. elata tubers were treated with 7FGR24, 2,4-D isooctyl ester, and maleic hydrazide, respectively. The growth of flower buds, the activities of CAT, and MDA, and the content of gastrodin and p-hydroxybenzyl alcohol were measured to compare the effects of different compounds on the storage and preservation of G. elata. The effects of different storage temperatures on the preservation of 7FGR24 were compared and analyzed. The gibberellin signal transduction receptor gene GeGID1 was cloned, and the effect of 7FGR24 on the expression level of GeGID1 was analyzed by quantitative polymerase chain reaction(qPCR). The toxicity of the G. elata preservative 7FGR24 was analyzed by intragastric administration in mice to evaluate its safety. The results showed that compared with 2,4-D isooctyl ester and maleic hydrazide, 7FGR24 treatment had a significant inhibitory effect on the growth of G. elata flower buds, and the CAT enzyme activity of G. elata was the highest, indicating that its preservation effect was stronger. Different storage temperatures had different effects on the preservation of G. elata, and the preservation effect was the strongest at 5 ℃. The open reading frame(ORF) of GeGID1 gene was 936 bp in length, and its expression level was significantly down-regulated after 7FGR24 treatment, indicating that 7FGR24 may inhibit the growth of flower buds by inhibiting the gibberellin signal of G. elata, thereby exerting a fresh-keeping effect. Feeding preservative 7FGR24 had no significant effect on the behavior and physiology of mice, indicating that it had no obvious toxicity. This study explored the application of the strigolactone analog 7FGR24 in the storage and preservation of G. elata and preliminarily established a method for the storage and preservation of G. elata, laying a foundation for the molecular mechanism of 7FGR24 in the storage and preservation of G. elata.

Treatment options in hypoparathyroidism

ABSTRACT Hypoparathyroidism remains the single endocrine deficiency disease that is not habitually treated with the missing hormone. In this article, we aim to provide a review of the conventional approach and the novel therapies as well as an overview of the perspectives on the treatment of this rare condition. We conducted a literature review on the conventional therapy using vitamin D analogs and calcium salts, indications for thiazide diuretics and phosphorus binders, PTH analogs history and usage, and the drugs that are currently being tested in clinical trials. Conventional treatment involves calcium salts and vitamin D analogs. Thiazide diuretics can be used to reduce hypercalciuria in some cases. A low-phosphate diet is recommended, and phosphate binders are rarely needed. During pregnancy, a careful approach is necessary. The use of PTH analogs is a new approach despite the limitation of high cost. Studies have included modified PTH molecules, calcilytics, microencapsulation of human parathyroid cells, and allotransplantation.

Tratamiento con análogos de la hormona liberadora de gonadotrofinas (aGnRH) en niñas, niños y adolescentes / Treatment with gonadotropin-releasing hormone analogs (GnRHa) in childhood and adolescence

Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitarygonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.

Biosynthesis and regulatory mechanism of acarbose and its structural analogs: a review / 生物工程学报

Acarbose is widely used as α-glucosidase inhibitor in the treatment of type Ⅱ diabetes. Actinoplanes sp. is used for industrial production of acarbose. As a secondary metabolite, the biosynthesis of acarbose is quite complex. In addition to acarbose, a few acarbose structural analogs are also accumulated in the culture broth of Actinoplanes sp., which are hard to remove. Due to lack of systemic understanding of the biosynthesis and regulation mechanisms of acarbose and its structural analogs, it is difficult to eliminate or reduce the biosynthesis of the structural analogs. Recently, the advances in omics technologies and molecular biology have facilitated the investigations of biosynthesis and regulatory mechanisms of acarbose and its structural analogs in Actinoplanes sp.. The genes involved in the biosynthesis of acarbose and its structural analogs and their regulatory mechanism have been extensively explored by using bioinformatics analysis, genetic manipulation and enzymatic characterization, which is summarized in this review.

Correlation between 99mTc-TRODAT-1 SPECT and 18F-FDOPA PET in patients with Parkinson's disease: a pilot study / Correlação entre 99mTc-TRODAT-1 SPECT e 18F-FDOPA PET em pacientes com doença de Parkinson: um estudo piloto

Abstract Objective: To determine whether technetium-99m-labeled tropane derivative single-photon emission computed tomography (99mTc-TRODAT-1 SPECT) provides results comparable to those of the less widely available, less accessible tool fluorine-18-labeled fluorodopa positron-emission tomography (18F-FDOPA PET) in the setting of a movement disorders clinic. Materials and Methods: In this prospective pilot study, eight subjects with a clinical diagnosis of Parkinson's disease were randomly selected from among patients under treatment at a movement disorders clinic and submitted to 99mTc-TRODAT-1 SPECT and 18F-FDOPA PET. The results were read by two experienced observers, and a semiquantitative analysis was performed. Results: The visual and semiquantitative analyses were concordant for all studies, showing that radiotracer uptake in the contralateral striatum on the most affected side was lower when 99mTc-TRODAT-1 SPECT was employed. The semiquantitative analysis demonstrated a significant correlation between 18F-FDOPA PET and 99mTc-TRODAT-1 SPECT (r = 0.73; p < 0.01). Conclusion: It appears that 99mTc-TRODAT-1 SPECT is a valid option for the study of dopaminergic function in a clinical setting.

Resumo Objetivo: Determinar se a 99mTc-TRODAT-1 SPECT fornece resultados comparáveis aos da 18F-FDOPA PET, ferramenta menos acessível e menos amplamente disponível, no contexto de uma clínica de distúrbios do movimento. Materiais e Métodos: Neste estudo prospectivo, oito indivíduos com diagnóstico clínico de doença de Parkinson foram selecionados aleatoriamente entre pacientes em tratamento em uma clínica de distúrbios do movimento e submetidos a 99mTc-TRODAT-1 SPECT e 18F-FDOPA PET. Os resultados foram lidos por dois observadores experientes e uma análise semiquantitativa foi realizada. Resultados: As análises visual e semiquantitativa foram concordantes para todos os estudos, mostrando que a captação do radiotraçador no estriado contralateral do lado mais afetado foi menor quando a 99mTc-TRODAT-1 SPECT foi empregada. A análise semiquantitativa demonstrou uma correlação significativa entre 18F-FDOPA PET e 99mTc-TRODAT-1 SPECT (r = 0,73; p < 0,01). Conclusão: A 99mTc-TRODAT-1 SPECT parece ser uma opção válida para o estudo da função dopaminérgica em um ambiente clínico.

The effect of nitric oxide, endothelial nitric oxide synthetase, and asymmetric dimethylarginine in hemorrhoidal disease

SUMMARY AIM The aim of this study was to examine the roles of nitric oxide (NOx), endothelial nitric oxide synthetase (eNOS), and asymmetric dimethylarginine (ADMA), which is the major endogenous inhibitor of nitric oxide synthases (NOS), in the pathophysiology of hemorrhoidal disease. METHODS This study included 54 patients with grades 3 and 4 internal hemorrhoidal disease and 54 patients without the disease who attended the General Surgery Clinic. NOx, eNOS, and ADMA levels were measured with the Enzyme-Linked ImmunoSorbent Assay (ELISA) method. RESULTS The patients had higher NO and eNOS levels and lower ADMA levels than the control subjects (p<0.001). A significant highly positive correlation was found between NO and eNOS (p<0.001). Nevertheless, there was a highly negative correlation between ADMA and NO-eNOS(p<0.001, p<0.001). CONCLUSION This preliminary study reveals that higher NOx and eNOS activities and lower ADMA levels in the rectal mucosa are observed in patients with hemorrhoidal disease than in those with normal rectal tissue. The imbalance between endothelium-derived relaxing factors, such as NO and endogenous competitive inhibitor of NOS, ADMA, may cause hemorrhoidal disease. Our study proposes that hemorrhoids display apparent vascular dilatation and present with bleeding or swelling. ADMA is an effective NOS inhibitor and may be a promising therapeutic option for hemorrhoidal disease.

RESUMO OBJETIVO O objetivo deste estudo foi examinar os papéis do óxido nítrico (NOx), do óxido nítrico sintetase endotelial (eNOS) e da dimetilarginina assimétrica (ADMA), que é o principal inibidor endógeno das óxido nítrico sintase (NOS) na fisiopatologia da doença hemorróida. MÉTODOS Este estudo incluiu 54 pacientes com doença hemorróida interna de grau 3 e 4 e 54 pacientes sem a doença que se inscreveram na Clínica Geral de Cirurgia. Os níveis de NOx, eNOS e ADMA foram medidos com o método de Ensaio Imuno absorvente ligado a enzima (ELISA). RESULTADOS Os pacientes têm níveis mais altos de NO e eNOS e níveis mais baixos de ADMA do que os indivíduos controle (p <0,001). Uma correlação altamente positiva significativa foi encontrada entre o NO-eNOS (p <0,001). No entanto, houve uma correlação negativa muito séria entre ADMA e NO-eNOS (p <0,001, p <0,001). CONCLUSÃO Este estudo preliminar revela que os pacientes com doença hemorróida têm atividades mais altas de NOx e eNOS e níveis mais baixos de ADMA na mucosa retal do que os pacientes com tecido retal normal. Desequilíbrio entre o fator relaxante derivado do endotélio, como; O NO e o inibidor competitivo endógeno da NOS, ADMA, podem causar doenças hemorróidas. Nosso estudo propõe que as hemorróidas exibam aparente dilatação vascular e apresentam sangramento ou inchaço, a ADMA é um inibidor eficaz da NOS e pode ser uma opção terapêutica promissora para a doença hemorróida.

In silico and in vitro anti-inflammatory evaluation of 2,6-bis-(3'-ethoxy, 4'-hydroxybenzylidene)-cyclohexanone, 2,6-bis-(3'-Bromo,4'-methoxybenzylidene)-cyclohexanone, and 2,6-bis- (3',4'-dimethoxybenzylidene)-cyclohexanone

The aim of this research is to design the new mono-carbonyl analogs of curcumin, synthesize the molecules, anddetermine its activity in cyclooxygenase inhibition in vitro and in silico. New design MACs were performed bythe Quantitative Structure–Activity Relationship (QSAR) study using the BuildQSAR program. 2,6-bis-(3ʹ-ethoxy,4ʹ-hydroxybenzylidene)-cyclohexanone, 2,6-bis-(3ʹ-Bromo, 4ʹ-methoxybenzylidene)-cyclohexanone, and 2,6-bis-(3ʹ,4ʹ-dimethoxybenzylidene)-cyclohexanone had been synthesized using aldol condensation reaction. The anti-inflammatoryassay was performed to measure the level of malondialdehyde. In silico studies were carried out to evaluate the activityof cyclooxygenase inhibition in cyclooxygenase-1 and cyclooxygenase-2 specific proteins. Molecular operatingenvironment program was used for protocol docking. The results of the QSAR study reveal the good relationshipof anti-inflammatory activities. The in vitro anti-inflammatory activities of 6-bis-(3ʹ-ethoxy, 4ʹ-hydroxybenzylidene)-cyclohexanone, 2,6-bis-(3ʹ-Bromo, 4ʹ-methoxybenzylidene)-cyclohexanone, and 2,6-bis-(3ʹ,4ʹ-dimethoxybenzylidene)-cyclohexanone indicate the promising potential to inhibit cyclooxygenase enzyme with IC50 13.53 μM, 11.56 μM,and 20.52 μM, respectively. The in silico evaluation showing that O atoms (47, from ketones) of 2,6-bis-(3ʹ-Bromo,4ʹ-methoxybenzylidene)-cyclohexanone interact with ARG120 and TYR355 through H acceptor.

Efecto sobre la talla en niñas con pubertad precoz central de diagnóstico tardío tratadas con análogos de GnRH / Effect of GnRH analogs on girls height with late diagnosis central precocious puberty

RESUMEN Objetivo: evaluar el efecto de los análogos de GnRH sobre la predicción de talla final adulta en niñas con pubertad precoz central de diagnóstico tardío. Materiales y métodos: estudio descriptivo, retrospectivo. Se incluyeron niñas atendidas entre 2012 y 2018 en la Unidad de Endocrinología Pediátrica del Hospital Cayetano Heredia con diagnóstico de pubertad precoz central idiopática de diagnóstico tardío. Se realizó evaluación antropométrica, evaluación de estadío Tanner y determinación de edad ósea con el método de Greulich y Pyle, estimando la predicción de talla final adulta mediante el método de Bayley Pinneau antes y después del tratamiento con análogos de GnRH. Se realizó t de student para comparar la predicción de talla antes y después del tratamiento. Se consideró significativo un p< 0,05. Resultados: se incluyeron 23 niñas con edad cronológica media de 8,4 ± 0,4 años y una edad ósea de 10,7 ± 0,8 años al ingreso. El 83,9% de las pacientes tuvieron exceso de peso y el 74,0% estadio Tanner 3 al diagnóstico. El tiempo promedio de tratamiento con análogos de GnRH fue de 20,5 ± 8,4 meses. El efecto del tratamiento calculado con la diferencia de predicción de talla final adulta menos predicción de talla inicial fue de 2,5 ± 4,1 cm (p<0,01). Conclusión: las niñas con diagnóstico de pubertad precoz central de diagnóstico tardío muestran un discreto beneficio sobre la predicción de talla final adulta, por lo que la terapia a esta edad debe ser individualizada.

ABSTRACT Objective: to assess the effect of GnRH analogues on predicted adult final height in girls with a late diagnosis of central precocious puberty. Material and Methods : this is a descriptive and retrospective study. Girls seen between 2012 and 2018 in the Pediatric Endocrinology Unit of Hospital Nacional Cayetano Heredia with a late diagnosis of idiopathic precocious central puberty were included. Anthropometric assessments were performed, Tanner stage assessment and bone age determination using the Greulich and Pyle method were performed, and the final adult height was predicted using the Bailey Pinneau method before and after therapy. A Student-t test was used for comparing the height prediction before and after therapy. A p<0.05 value was considered as significant. Results : twenty-three girls with mean chronological age 8.4 ± 0.4 years were included. Their bone age was 10.7 ± 0.8 on admission. Most of the patients (83.9%) were overweight and 74.3% were Tanner 3 at the time of diagnosis. The average time using GnRH analogues therapy was 20.5 ± 8.4 months. The effect of therapy, which was calculated using the prediction difference for the final adult height minus the initial height prediction was 2.5 ± 4.1 cm (p<0.001). Conclusion : girls with a diagnosis of late diagnosis central precocious puberty show a discrete benefit on the prediction of the final adult height, so therapy at this age should be individualized.

Effect of Using Biomimetic Analogs on Dentin Remineralization with Bioactive Cements

Abstract This study evaluated the impact of using biomimetic analogs (poly-acrylic acid and sodium tri-meta-phosphate) on dentin remineralization using two cement materials, the first is calcium silicate based and the second is calcium hydroxide based materials. Two standardized occlusal cavities (mesial and distal) were prepared within dentin after removal of occlusal enamel. Artificial demineralized dentin was induced through pH cycling (8 h in demineralizing and 16 h in remineralizing solutions). Demineralized cavities were divided into four groups; two groups received cement materials. The other groups were first treated with biomimetic analogs then restored with pulp cement materials. Teeth were sectioned buccolingually into two halves. Treated cavities with analogs were stored in simulated body fluid containing poly-acrylic acid. Untreated cavities were stored in simulated body fluid only. Ground unstained sections of demineralized dentin were examined using light microscope. Specimens were examined after 1, 6 and 12 weeks of storage using energy dispersive X-ray Spectroscopy (EDX) and Vickers microhardness was evaluated. Two-way ANOVA was used to analyze data statistically. Calcium silicate-based cement group with biomimetic analogs showed the highest statistically significant calcium and phosphorous wt% in addition to highest surface hardness values after 12 weeks of storage. Demineralized dentin ground sections showed increase in light zones after total period of storage. Calcium silicate-based cement showed the best ability to enrich the artificial carious dentin with ions for remineralization. Using biomimetic analogs had a significant impact on demineralized dentin surface hardness improvement.

Resumo Este estudo avaliou o impacto do uso de análogos biomiméticos (ácido poli-acrílico e tri-meta-fosfato de sódio) na remineralização da dentina usando dois materiais de cimento, o primeiro à base de silicato de cálcio e o segundo à base de hidróxido de cálcio. Duas cavidades oclusais padronizadas (mesial e distal) foram preparadas na dentina após a remoção do esmalte oclusal. A dentina desmineralizada artificial foi induzida por ciclagem de pH (8 h em soluções desmineralizantes e 16 h em soluções remineralizantes). Cavidades desmineralizadas foram divididas em quatro grupos; dois grupos receberam materiais de cimento. Os outros grupos foram tratados primeiro com análogos biomiméticos e depois restaurados com materiais de cimento de celulose. Os dentes foram seccionados bucolingualmente em duas metades. As cavidades tratadas com análogos foram armazenadas em fluido corporal simulado contendo ácido poli-acrílico. As cavidades não tratadas foram armazenadas apenas em fluido corporal simulado. Secções não coradas de dentina desmineralizada foram examinadas usando microscópio óptico. As amostras foram examinadas após 1, 6 e 12 semanas de armazenamento usando Espectroscopia de Raios-X dispersiva por energia (EDX) e microdureza Vickers. ANOVA a dois fatores foi usada para analisar os dados estatisticamente. O grupo de cimento à base de silicato de cálcio com análogos biomiméticos apresentou os maiores percentagens em peso estatisticamente significantes de cálcio e fósforo, além dos maiores valores de dureza superficial após 12 semanas de armazenamento. Seções desmineralizadas de dentina mostraram aumento nas zonas de luz após o período total de armazenamento. O cimento à base de silicato de cálcio mostrou a melhor capacidade de enriquecer a dentina cariada artificial com íons para remineralização. O uso de análogos biomiméticos teve um impacto significativo na melhoria da dureza superficial da dentina desmineralizada.

Hepatitis B crónica / Chronic B hepatitis

Chronic hepatitis B is a major public health problem, causing 30% of cirrhosis worldwide and up to 50% of hepatocellular carcinoma. In high prevalence regions, virus transmission is mainly vertical, which is associated with a risk of chronic disease in 90% of cases. The development of chronic hepatitis in adults is less than 5%, but it could reach up to 30% in patients with immunosuppression. In the evaluation of subjects with HBV infection is recommended to investigate risk factors for progression to cirrhosis and hepatocellular carcinoma, test for sexually transmitted infections and control liver comorbidities that will affect patient's prognosis, such as chronic alcohol consumption, nonalcoholic fatty liver disease and coinfection with hepatitis C and HIV. Management of patients with chronic hepatitis B includes testing and prevention for contacts, control of comorbidities, and specific treatment with antivirals when indicated. Treatment with nucleotide/nucleoside analogues is considered of choice as they are safe, achieves adequate control of viral replication and reduces the risk of liver complications. The goal of the WHO is to achieve a significant decrease in the prevalence of hepatitis B by 2030 through preventive measures in regions with a high prevalence of the disease.

La infección por el virus de la hepatitis B (VHB) es un importante problema de salud pública, estimándose que causa 30% de los casos de cirrosis a nivel mundial y hasta 50% de los hepatocarcinomas. En las regiones de alta prevalencia, la transmisión del virus es principalmente vertical, la que se asocia a un riesgo de cronificación de hasta 90%. Por el contrario, el desarrollo de hepatitis crónica en adultos es menor de 5% y en inmunosupresión puede alcanzar hasta 30%. En la evaluación de sujetos con infección por VHB es necesaria pesquisar factores de riesgo de progresión a cirrosis y hepatocarcinoma, detectar otras infecciones de transmisión sexual y controlar comorbilidades hepáticas que afectarán el pronóstico del paciente, como el consumo crónico de alcohol, el hígado graso no alcohólico o la coinfección con hepatitis C y VIH. El manejo de los pacientes con hepatitis B crónica requiere preocuparse del testeo y medidas de prevención para los contactos, control de comorbilidades y tratamiento específico con antivirales cuando existe indicación. El tratamiento con análogos de nucleótidos/nucleósidos se considera de elección al ser seguro, lograr un adecuado control de la replicación viral y disminuir riesgo de complicaciones hepáticas. El objetivo de la OMS es lograr una disminución significativa de la prevalencia de la hepatitis B el año 2030 a través de medidas preventivas en regiones de alta prevalencia de la enfermedad.

Metodología para la elaboración de la Guía de práctica clínica / Methodology for the development of the Clinical guideline for the diagnosis and treatment of precocious puberty

Resumen Introducción: La Sociedad Mexicana de Endocrinología Pediátrica presenta recomendaciones para el diagnóstico y el tratamiento de la pubertad precoz (PP), condición definida como el desarrollo de caracteres sexuales por incremento en la secreción hipofisiaria de gonadotropinas antes de los 8 años en las niñas y de los 9 años en los niños. Métodos: Se realizaron tres revisiones sistemáticas de ensayos clínicos controlados sobre intervenciones para el tratamiento de la PP, pruebas diagnósticas y estudios observacionales sobre efectos a largo plazo de la PP. La evaluación de la calidad de los estudios y la extracción de datos se realizó por pares. La evidencia se graduó con el sistema de la Scottish Intercollegiate Guidelines Network (SIGN) y del Oxford Centre for Evidence-Based Medicine (OCEBM) para las recomendaciones sobre la intervención y el diagnóstico, respectivamente. Las recomendaciones generadas se sometieron a un consenso por el método Delphi y fueron validadas por otros 143 endocrinólogos pediatras certificados mediante un cuestionario en línea. Resultados: Mediante consenso se generaron 12 recomendaciones para el diagnóstico de PP, siete sobre diagnóstico de causas secundarias de PP, ocho sobre intervenciones para inhibición de la pubertad, cinco sobre otras intervenciones en PP y 14 para la monitorización del tratamiento y el seguimiento de estos pacientes. Se obtuvo más del 90% de aprobación para cada una de las recomendaciones por el grupo de endocrinólogos certificados que respondieron el cuestionario en línea. Conclusiones: Si bien se logró un alto grado de consenso para las recomendaciones para el diagnóstico, el tratamiento y la monitorización de la PP entre los endocrinólogos pediatras, el nivel de evidencia para la mayoría de estas recomendaciones resultó bajo.

Abstract Background: The Mexican Society of Pediatric Endocrinology presents recommendations for the diagnosis and treatment of precocious puberty (PP), a condition defined as the development of sexual characteristics due to an increase in pituitary gonadotropin secretion before 8 or 9 years of age in girls and boys, respectively. Methods: Three systematic reviews were conducted: controlled clinical trials on interventions for PP treatment, diagnostic tests, and observational studies on the long-term effects of PP. The quality evaluation and data extraction from the studies were conducted by two independent reviewers. The Scottish Intercollegiate Guidelines Network and the Oxford Center for Evidence-Based Medicine systems were used for grading the quality of evidence for recommendations on intervention and diagnosis, respectively. Recommendations were submitted to a consensus by a Delphi method and were validated by another 143 certified pediatric endocrinologists through an online questionnaire. Results: The group generated 12 recommendations on the diagnosis of PP, seven on the diagnosis of secondary causes of PP, eight on interventions for inhibition of puberty, five on other interventions for PP treatment, and 14 for the monitoring and follow-up of these patients. The online questionnaires submitted to certified pediatric endocrinologists showed more than 90% of approval for each one of the recommendations. Conclusions: Although a high degree of consensus for the recommendations for diagnosis, treatment, and monitoring of PP among pediatric endocrinologists was achieved, most of these recommendations showed a low level of evidence.

Inhibición de la pubertad / Puberty blockade: Clinical guideline for the diagnosis and treatment of precocious puberty

Resumen La Sociedad Mexicana de Endocrinología Pediátrica elaboró una guía de práctica clínica para el diagnóstico y el tratamiento de la pubertad precoz. Este documento presenta recomendaciones relacionadas con las intervenciones para inhibir la pubertad precoz central. La descripción detallada de la metodología para el desarrollo de esta guía y del sistema de gradación, así como la síntesis de la evidencia en la que se basa, pueden consultarse en este mismo suplemento.

Abstract The Mexican Society of Pediatric Endocrinology developed a clinical practice guide for the diagnosis and treatment of precocious puberty. This document presents recommendations related to the interventions for the inhibition of central precocious puberty. The detailed description of the methodology for the development of this guide and the grading system, as well as the synthesis of the evidence on which it is based can be consulted in this same supplement.

Effectiveness of insulin analogs compared with human insulins in pregnant women with diabetes mellitus: systematic review and meta-analysis / Efetividade dos análogos da insulina comparados às insulinas humanas em gestantes com diabetes mellitus: Revisão sistemática com metanálise

Abstract Diabetes during pregnancy has been linked to unfavorable maternal-fetal outcomes. Human insulins are the first drug of choice because of the proven safety in their use. However, there are still questions about the use of insulin analogs during pregnancy. The objective of the present study was to determine the effectiveness of insulin analogs compared withhuman insulin in the treatment of pregnant women with diabetes througha systematic review withmeta-analysis. The search comprised the period since the inception of each database until July 2017, and the following databases were used:MEDLINE, CINAHL, EMBASE, ISIWeb of Science, LILACS, Scopus, SIGLE andGoogle Scholar.We have selected 29 original articles: 11 were randomized clinical trials and 18 were observational studies.We have explored data from 6,382 participants. All of the articles were classified as having an intermediate to high risk of bias. The variable that showed favorable results for the use of insulin analogs was gestational age, with a mean difference of - 0.26 (95 % confidence interval [CI]: 0.03-0.49; p = 0.02), but with significant heterogeneity (Higgins test [I2] = 38%; chi-squared test [χ2] = 16.24; degree of freedom [DF] = 10; p = 0.09). This result, in the clinical practice, does not compromise the fetal well-being, since all babies were born at term. There was publication bias in the gestational age and neonatal weight variables. To date, the evidence analyzed has a moderate-to-high risk of bias and does not allow the conclusion that insulin analogs are more effective when compared with human insulin to treat diabetic pregnant women.

Resumo Diabetes durante a gestação tem sido relacionado a desfechos materno-fetais desfavoráveis. As insulinas humanas são a primeira escolha medicamentosa, devido à comprovada segurança no seu uso. Entretanto, ainda há questionamentos sobre o uso dos análogos da insulina na gestação. O objetivo do presente estudo foi determinar a efetividade dos análogos da insulina comparados às insulinas humanas no tratamento de gestantes com diabetes por meio de uma revisão sistemática com metanálise. A busca compreendeu desde o início de cada base de dados até julho de 2017, e foi realizada nos seguintes bancos de dados: MEDLINE, CINAHL, EMBASE, ISI Web of Science, LILACS, Scopus, SIGLE e Google Scholar. Selecionamos 29 artigos originais, sendo 11 ensaios clínicos randomizados e 18 estudos observacionais. Exploramos dados de 6.382 participantes. Todos os artigos foram classificados como sendo de intermediário a alto risco de viés. A variável que demonstrou resultado favorável ao uso dos análogos da insulina foi idade gestacional, com uma diferençamédia de - 0.26 (95% índice de confiança [IC]: 0.03-0.49; p = 0.02), porém com heterogeneidade significativa (teste de Higgins [I2] = 38%; teste do qui quadrado [χ2] =16.24; graus de liberdade [GL] =10; p = 0.09). Esse resultado, na prática clínica, não compromete o bem-estar fetal, uma vez que todos os bebês nasceram a termo. Houve viés de publicação nas variáveis idade gestacional e peso neonatal. Até o momento, as evidências analisadas possuem um risco de viés moderado a elevado e não permitem concluir que os análogos da insulina sejam mais efetivos em comparação às insulinas humanas para tratar gestantes diabéticas.

Qualitative anti-tubercular activity of synthetic ethyl 7-acetyl2-substituted-3-(4-substituted benzoyl) indolizine-1-carboxylate analogues

Both the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB) are currently the majorchallenges in the treatment of TB. Only delamanid and bedaquiline have been recently approved as anti-TB drugs inthe past 40 years. In an attempt to search for active anti-TB compounds against the sensitive strain of Mycobacteriumtuberculosis, H37Rv—a series of synthetic ethyl 7-acetyl-2-substituted-3-(4-substituted benzoyl)indolizine-1-carboxylates (2a–r)—have been screened for in vitro qualitative anti-TB activity using an agar dilution method. Itwas found that compounds 2a, 2b, 2c, 2f, 2g, 2i, 2j, 2l, 2o, 2p, and 2r, which have various functional groups on theindolizine nucleus, were active against the H37Rv strain.