Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

The importance of including the C-terminal domain of PTP1B1-400 to identify potential antidiabetic inhibitors.

In the present work, we studied the inhibitory and kinetic implications of classical PTP1B inhibitors (chlorogenic acid, ursolic acid, suramin) using three enzyme constructs (hPTP1B1-285, hPTP1B1-321, and hPTP1B1-400). The results indicate that the unstructured region of PTP1B (300-400 amino acids) is very important both to obtain optimal inhibitory results and propose classical inhibition mechanisms (competitive or non-competitive) through kinetic studies. The IC50 calculated for ursolic acid and suramin using hPTP1B1-400 are around four and three times lower to the short form of the enzyme, the complete form of PTP1B, the one found in the cytosol (in vivo). On the other hand, we highlight the studies of enzymatic kinetics using the hPTP1B1-400 to know the type of enzymatic inhibition and to be able to direct docking studies, where the unstructured region of the enzyme can be one more option for binding compounds with inhibitory activity.

Prescripción de analgésicos y reacciones adversas en pacientes hospitalizados / Analgesic's prescription and drug adverse events in hospitalized patients

RESUMEN Justificación. El dolor tiene alta prevalencia en la población general, siendo mayor en pacientes hospitalizados, con cifras cercanas al 80%. El control del dolor no siempre es adecuado debido a varios factores, siendo uno de los más importantes, el escaso conocimiento en el manejo de los analgésicos. Como una de las primeras medidas de mejoramiento asistencial para reducir el dolor en un hospital, debe conocerse la prevalencia de este síntoma y, asimismo, debe analizarse el abordaje terapéutico realizado. Por este motivo este estudio tuvo como objetivo analizar el uso de analgésicos en pacientes de un hospital de cuarto nivel en Bogotá, Colombia, identificar los analgésicos más utilizados, el rango de dosis, las posibles interacciones y reacciones adversas a medicamentos (RAM) existentes. Resultados. El 78,9% de los pacientes hospitalizados presentaban dolor. Se prescribió analgésicos en 561 pacientes hospitalizados. Los más utilizados fueron: acetaminofén (33,3%) y tramadol (29,7%). El rango de duración de la terapia analgésica más común fue de 1 a 5 días (81,7%). Se identificaron 37 casos de sobredosificación y tres de terapia duplicada. Se presentaron 28 casos de reacciones adversas a medicamento (RAM). Discusión. El adecuado tratamiento del dolor cobra vital importancia al evaluar la satisfacción del paciente. Se encuentran diferentes tendencias de uso de analgésicos en pacientes hospitalizados, siendo los más utilizados el acetaminofén y los antiinflamatorios no esteroidéos (AINE). Se debe seguir investigando en este tema, para tener mayor evidencia que permita generar lineamientos para un adecuado alivio del dolor.

Summary Justification. Pain has a high prevalence in the general population, being higher in inpatient, with figures close to 80%. Pain management is not always suitable due to several factors, one of the most important the lack of knowledge in the management of analgesics. One of the first measures of improving care to reduce pain in a hospital should be determine the prevalence of this symptom and analyze the therapeutic approach performed. That is why the aim of this study was to analyze the use of analgesics in patients of a fourth-level hospital in Bogotá, Colombia, identify the most commonly used analgesics, range of doses, possible interactions and adverse drugs reactions. Results. The 78.9% of the patients were pain. Analgesics were prescribed in 561 hospitalized patients. The most used were acetaminophen (33.3%) and tramadol (29.7%). The most common range of duration of analgesic therapy was 1-5 days (81.7%). 37 cases of overdosing and 3 cases of duplicate therapy were identified. 28 cases of adverse drug reactions (ADRs) were presented. Discussion. Proper treatment of pain plays a vital role in assessing patient satisfaction. There are different trends analgesic use in inpatient, being the most used acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). It should further investigate on this issue to have stronger scientific evidence to dictate a universal application guidelines for proper pain relief.

Analgésicos en el paciente hospitalizado: Revisión de tema / Analgesics in hospitalized patients: Topic review

El dolor como experiencia subjetiva es de alta incidencia en el paciente adulto hospitalizado, por tal motivo el uso de analgésicos en estos pacientes tiene gran impacto en la evolución clínica y en la calidad de la estancia hospitalaria. Entre las opciones terapéuticas para el manejo del dolor se encuentran antiinflamatorios no esteroideos (AINEs), opioides, paracetamol, metamizol; los cuales se pueden administrar en diferentes formas farmacéuticas, que se adaptan a las condiciones de cada uno de los pacientes. Actualmente, el uso de opioides está siendo reevaluado, así como las técnicas de administración, entre las que se destacan la analgesia controlada por el paciente y la analgesia intervencionista (analgesia epidural, bloqueo de nervios periféricos y la infiltración local). El éxito de la terapia analgésica no solo consiste en el adecuado uso de los analgésicos, sino también en las estrategias usadas para objetivar el dolor; esto se consigue por medio de la aplicación de escalas para cuantificar el dolor, de las cuales se destacan la escala visual análoga, la escala verbal numérica y la de valoración verbal.

Pain as a subjective experience is high incidence in the adult hospitalized patient, so the use of analgesics in these patients has a high impact on their medical developments and their comfort during their hospital stay. Among the therapeutic options for pain management there are Non-Steroidal Anti- Inflammatory drugs (NSAIDs), Opioids, Paracetamol and Metamizol. Each has different pharmaceutical dosage forms to adjust to the condition of each patient. Currently the use of Opioids is being re-evaluated as well as the management techniques like patient-controlled analgesia and interventionist analgesia(epidural analgesia, peripheral nerve blocks and local infiltration). The success of analgesic therapy consists of the appropriate use of analgesics and in the strategies used to objectify the pain; this can be achieved with the implementation of scales to quantify the pain like the visual analogous scale, numeric verbal scale and the verbal assessment.

Grammatical aspect is a strength in the language comprehension of young children with autism spectrum disorder.

PURPOSE: The comprehension of tense/aspect morphology by children with autism spectrum disorder (ASD) was assessed via Intermodal Preferential Looking (IPL) to determine whether this population's difficulties with producing these morphemes extended to their comprehension. METHOD: Four-year-old participants were assessed twice, 4 months apart. They viewed a video that presented side-by-side ongoing and completed events paired with familiar verbs with past tense and progressive morphology. Their eye movements were recorded and coded offline; the IPL measures included percentage of looking time at, and latency of first look to, the matching scene. Spontaneous speech samples were also obtained and coded for number of words, past tense, and progressive inflections. RESULTS: Relative to their baseline preferences, these 4-year-old children with ASD looked more quickly to and longer at the matching scene for both morphemes. Children who produced more words, including progressive and past morphemes, and those who performed better on standardized language assessments demonstrated better comprehension of -ing. CONCLUSIONS: Overall, these children with ASD demonstrated consistent comprehension of grammatical aspect morphology; moreover, their degree of comprehension was found to correlate with spontaneous production and standardized test scores.

Portable Intermodal Preferential Looking (IPL): investigating language comprehension in typically developing toddlers and young children with autism.

One of the defining characteristics of autism spectrum disorder (ASD) is difficulty with language and communication.(1) Children with ASD's onset of speaking is usually delayed, and many children with ASD consistently produce language less frequently and of lower lexical and grammatical complexity than their typically developing (TD) peers.(6,8,12,23) However, children with ASD also exhibit a significant social deficit, and researchers and clinicians continue to debate the extent to which the deficits in social interaction account for or contribute to the deficits in language production.(5,14,19,25) Standardized assessments of language in children with ASD usually do include a comprehension component; however, many such comprehension tasks assess just one aspect of language (e.g., vocabulary),(5) or include a significant motor component (e.g., pointing, act-out), and/or require children to deliberately choose between a number of alternatives. These last two behaviors are known to also be challenging to children with ASD.(7,12,13,16) We present a method which can assess the language comprehension of young typically developing children (9-36 months) and children with autism.(2,4,9,11,22) This method, Portable Intermodal Preferential Looking (P-IPL), projects side-by-side video images from a laptop onto a portable screen. The video images are paired first with a 'baseline' (nondirecting) audio, and then presented again paired with a 'test' linguistic audio that matches only one of the video images. Children's eye movements while watching the video are filmed and later coded. Children who understand the linguistic audio will look more quickly to, and longer at, the video that matches the linguistic audio.(2,4,11,18,22,26) This paradigm includes a number of components that have recently been miniaturized (projector, camcorder, digitizer) to enable portability and easy setup in children's homes. This is a crucial point for assessing young children with ASD, who are frequently uncomfortable in new (e.g., laboratory) settings. Videos can be created to assess a wide range of specific components of linguistic knowledge, such as Subject-Verb-Object word order, wh-questions, and tense/aspect suffixes on verbs; videos can also assess principles of word learning such as a noun bias, a shape bias, and syntactic bootstrapping.(10,14,17,21,24) Videos include characters and speech that are visually and acoustically salient and well tolerated by children with ASD.

Comparison of 2D fingerprint methods for multiple-template similarity searching on compound activity classes of increasing structural diversity.

We studied the similarity search performance of differently designed molecular fingerprints using multiple reference structures and different search strategies. For this purpose, nine compound activity classes were assembled that exclusively consisted of molecules with different core structures and that represented different levels of intra-class structural diversity. Thus, there was a strict one-to-one correspondence between test compounds and core structures. Analysis of unique core structures was found to be a better measure of class diversity than distributions of simplified scaffolds. On increasingly diverse classes, a trainable fingerprint using a unique search strategy performed better than others tested herein. Overall, clear preferences were detected for nearest-neighbor search strategies over fingerprint-averaging techniques. Nearest-neighbor searching that relied on selecting database compounds most similar to one of the reference structures often improved compound recovery over other averaging methods, but at the cost of decreasing the ability to detect hits that were structurally distinct from reference molecules.