Ototoxicidad en pacientes oncológicos: experiencia y propuesta de un protocolo de vigilancia / Ototoxicity in cancer survivors: experience and proposal of a surveillance protocol

Introducción: La ototoxicidad se presenta en diversos porcentajes según estudios tras el tratamiento con quimioterapia basada en platino y/o radioterapia craneal. El objetivo es mostrar nuestra experiencia en la monitorización de la ototoxicidad. Material y métodos: Se realizó una revisión del 1999 al 2019 en el registro de pacientes oncológicos pediátricos de nuestro hospital y remitidos a la Unidad de Hipoacusia Infantil. Resultados: 46 pacientes fueron remitidos a nuestra unidad. 41 pacientes recibieron platinos como parte de su tratamiento, 17 pacientes fueron sometidos a una intervención neuroquirúrgica y 18 pacientes recibieron radioterapia craneal. A todos se les realizó una anamnesis y otoscopia, y la monitorización se llevó a cabo con una audiometría tono-verbal y/o productos de distorsión. Se objetivó una hipoacusia como secuela del tratamiento en ocho pacientes (21,05% de los pacientes remitidos para seguimiento audiológico). Fue imposible determinar la situación audiológica al finalizar el tratamiento en ocho pacientes. La adaptación audioprotésica fue necesaria en dos pacientes. En la coordinación con Oncología Pediátrica, se consideró oportuno el cambio de cisplatino por carboplatino por ototoxicidad importante durante el tratamiento en un único paciente. Conclusión: Es imprescindible una adecuada coordinación con Oncología Pediátrica para realizar una vigilancia activa de la ototoxicidad y modificar, si es posible, la dosificación o el tipo de quimioterápico en caso de verse afectada la audición. En nuestra experiencia, y siguiendo las recomendaciones actuales, realizamos una valoración pretratamiento, una monitorización durante el tratamiento, al finalizarlo y después de forma anual por el riesgo de desarrollo diferido de una hipoacusia. (AU)

Introduction: Ototoxicity occurs in different percentages in patients after treatment with platinum-based chemotherapy or cranial radiation therapy. The aim of this study was to present experience in ototoxicity monitoring. Material and methods: A review was made of the registry of paediatric cancer patients referred to the Children's Hearing Loss Unit from 1999 to 2019. Results: Of the 46 patients referred to this unit, 41 had received platinum as part of their treatment, 17 patients underwent neurosurgery, and 18 patients received cranial radiation therapy. An anamnesis and otoscopy were performed on all of them, and the monitoring was carried out with tone-verbal audiometry and/or distortion products. Hearing loss was observed in eight patients (21.05% of patients referred for audiological follow-up) as a consequence of the treatment. It was impossible to determine the audiological situation in eight patients at the end of treatment. Hearing aid adaption was necessary in two patients. In coordination with Paediatric Oncology, a change from cisplatin to carboplatin due to bilateral grade two ototoxicity was considered appropriate during treatment in one patient. Conclusion: Adequate coordination with Paediatric Oncology is essential to carry out active surveillance for ototoxicity and to modify, if possible, the dosage or type of chemotherapy in case hearing is affected. In our experience, and following current recommendations, a pre-treatment assessment is usually performed, as well as monitoring during treatment, at the end of treatment, and annually thereafter due to the risk of a later development of hearing loss. (AU)

Marine Pharmacology in 2016-2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The review of the 2016-2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016-2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016-2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.

SCLC-CellMiner: A Resource for Small Cell Lung Cancer Cell Line Genomics and Pharmacology Based on Genomic Signatures.

CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.

Lung-on-a-chip: the future of respiratory disease models and pharmacological studies.

Recently, organ-on-a-chip models, which are microfluidic devices that mimic the cellular architecture and physiological environment of an organ, have been developed and extensively investigated. The chips can be tailored to accommodate the disease conditions pertaining to many organs; and in the case of this review, the lung. Lung-on-a-chip models result in a more accurate reflection compared to conventional in vitro models. Pharmaceutical drug testing methods traditionally use animal models in order to evaluate pharmacological and toxicological responses to a new agent. However, these responses do not directly reflect human physiological responses. In this review, current and future applications of the lung-on-a-chip in the respiratory system will be discussed. Furthermore, the limitations of current conventional in vitro models used for respiratory disease modeling and drug development will be addressed. Highlights of additional translational aspects of the lung-on-a-chip will be discussed in order to demonstrate the importance of this subject for medical research.

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development.

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic-pharmacodynamic (PK-PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK-PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK-PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

Network Pharmacology-Based Pharmacological Mechanism of the Chinese Medicine Rhizoma drynariae Against Osteoporosis.

d_abstr_R Rhizoma drynariae is the main traditional Chinese medicine used for the treatment of osteoporosis, but its anti-osteoporotic targeting mechanism has not been fully elucidated due to the complexity of its active ingredients. In this study, the pharmacological mechanism of action of Rhizoma drynariae against osteoporosis was studied by integrating pharmacological concepts. The pharmacokinetic characteristics of selected major active constituents of Rhizoma drynariae and the SMILES structural similarity were used to predict related targets. A literature search was conducted to identify known osteoporosis treatment targets, which were then combined with the predicted targets to construct the direct or indirect target interaction network map of Rhizoma drynariae against osteoporosis. Finally, data on the key targets of the interactions, ranked according to relevant node parameters obtained through pathway enrichment analysis and screening of key targets and active ingredients of Rhizoma drynariae, were used to perform molecular docking simulation. We screened 16 active ingredients of Rhizoma drynariae, and 7 key targets with direct or indirect effects with a high frequency were obtained. These main pathways were found to play important roles in the PI3k-akt signaling pathway, osteoclast differentiation, Wnt signaling pathway, and estrogen signaling pathway. Molecular docking showed that most active ingredients of Rhizoma drynariae had strong binding efficiency with key targets. Based on network pharmacology, we conclude that Rhizoma drynariae plays an anti-osteoporotic role by directly or indirectly targeting multiple major signaling pathways and influencing the proliferation and differentiation of multiple types of cells.

Network Pharmacology Identifies the Mechanisms of Action of Shaoyao Gancao Decoction in the Treatment of Osteoarthritis.

BACKGROUND Osteoarthritis (OA) affects the health and wellbeing of the elderly. Shaoyao Gancao decoction (SGD) is used in traditional Chinese medicine (TCM) for the treatment of OA and has two active components, shaoyao (SY) and gancao (GC). This study aimed to undertake a network pharmacology analysis of the mechanism of the effects of SGD in OA. MATERIAL AND METHODS The active compounds and candidates of SGD were obtained from the Traditional Chinese Medicine (TCM) Databases@Taiwan, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the STITCH database, the ChEMBL database, and PubChem. The network pharmacology approach involved network construction, target prediction, and module analysis. Significant signaling pathways of the cluster networks for SGD and OA were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS Twenty-three bioactive compounds were identified, corresponding to 226 targets for SGD. Also, 187 genes were closely associated with OA, of which 161 overlapped with the targets of SGD and were considered to be therapeutically relevant. Functional enrichment analysis suggested that SGD exerted its pharmacological effects in OA by modulating multiple pathways, including cell cycle, cell apoptosis, drug metabolism, inflammation, and immune modulation. CONCLUSIONS A novel approach was developed to systematically identify the mechanisms of the TCM, SGD in OA using network pharmacology analysis.

ADME: Assessing Pharmacokinetic-Pharmacodynamic Parameters of Oligonucleotides.

We describe tactics to assess pharmacokinetic (PK) and pharmacodynamic (PD) parameters of oligonucleotides. The chapter includes recommendations on the design of single-dose preclinical PK studies, preclinical PKPD studies, and toxicological studies, and on best practice for scaling PK and PD parameters from animal to human. We focus on single-stranded oligonucleotides, but relevant differences to double-stranded RNAs are also addressed.

Discovery of the Anti-Tumor Mechanism of Calycosin Against Colorectal Cancer by Using System Pharmacology Approach.

BACKGROUND The aim of our study was to elucidate the biological targets and pharmacological mechanisms for calycosin (CC) against colorectal cancer (CRC) through an approach of system pharmacology. MATERIAL AND METHODS Using a web-based platform, all CRC-causing genes were identified using a database of gene-disease associations (DisGeNET), and all well-known genes of CC identified using the databases of prediction of protein targets of small molecules (Swiss Target Prediction), drug classification, and target prediction (SuperPred). The carefully selected genes of CRC and CC were concurrently constructed by using a database of functional protein association networks (STRING), and use of software for visualizing complex networks (Cytoscape), characterized with production of protein-protein interaction (PPI) network of CC against CRC. The important biological targets of CC against CRC were identified through topological analysis, then the biological processes and molecular pathways of CC against CRC were further revealed for testing these important biotargets by enrichment assays. RESULTS We found that the key predictive targets of CC against CRC were estrogen receptor 2 (ESR2), ATP-binding cassette sub-family G member 2 (ABCG2), breast cancer type 1 susceptibility protein (BRCA1), estrogen receptor 1 (ESR1), cytochrome p450 19A1 (CYP19A1), and epidermal growth factor receptor (EGFR). Visual analysis revealed that the biological processes of CC against CRC were positively linked to hormonal metabolism, regulation of genes, transport, cell communication, and signal transduction. Further, the interrelated molecular pathways were chiefly related to endogenous nuclear estrogen receptor alpha network, forkhead box protein A1 (FOXA1) transcription factor network, activating transcription factor 2 (ATF2) transcription factor network, regulation of telomerase, plasma membrane estrogen receptor signaling, estrogen biosynthesis, androgen receptor, FOXA transcription factor networks, estrogen biosynthesis, and phosphorylation of repair proteins. CONCLUSIONS Use of system pharmacology revealed the biotargets, biological processes, and pharmacological pathways of CC against CRC. Intriguingly, the identifiable predictive biomolecules are likely potential targets for effectively treating CRC.

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

Prediction of the Formation of Reactive Metabolites by A Novel Classifier Approach Based on Enrichment Factor Optimization (EFO) as Implemented in the VEGA Program.

The study is aimed at developing linear classifiers to predict the capacity of a given substrate to yield reactive metabolites. While most of the hitherto reported predictive models are based on the occurrence of known structural alerts (e.g., the presence of toxophoric groups), the present study is focused on the generation of predictive models involving linear combinations of physicochemical and stereo-electronic descriptors. The development of these models is carried out by using a novel classification approach based on enrichment factor optimization (EFO) as implemented in the VEGA suite of programs. The study took advantage of metabolic data as collected by manually curated analysis of the primary literature and published in the years 2004⁻2009. The learning set included 977 substrates among which 138 compounds yielded reactive first-generation metabolites, plus 212 substrates generating reactive metabolites in all generations (i.e., metabolic steps). The results emphasized the possibility of developing satisfactory predictive models especially when focusing on the first-generation reactive metabolites. The extensive comparison of the classifier approach presented here using a set of well-known algorithms implemented in Weka 3.8 revealed that the proposed EFO method compares with the best available approaches and offers two relevant benefits since it involves a limited number of descriptors and provides a score-based probability thus allowing a critical evaluation of the obtained results. The last analyses on non-cheminformatics UCI datasets emphasize the general applicability of the EFO approach, which conveniently performs using both balanced and unbalanced datasets.

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations.

Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the "connectivity" framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.

Physiological assesment of vestibular function and toxicity in humans and animals.

Physiological methods that can be similarly recorded in humans and animals have a major role in sensory toxicology, as they provide a bridge between human sensory perception data and the molecular and cellular data obtained in animal studies. Vestibular toxicity research lags well behind other sensory systems in many aspects, including the availability of methods for functional assessment in animals that could be robustly translated to human significance. Here we review the methods available for the assessment of vestibular function in both humans and laboratory animals, with an emphasis on their similarity or divergence, to highlight their potential utility for the predictive assessment of vestibular toxicity.

Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.

Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16ß-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

The impact of in silico screening in the discovery of novel and safer drug candidates.

Drug discovery is a multidisciplinary and multivariate optimization endeavor. As such, in silico screening tools have gained considerable importance to archive, analyze and exploit the vast and ever-increasing amount of experimental data generated throughout the process. The current review will focus on the computer-aided prediction of the numerous properties that need to be controlled during the discovery of a preliminary hit and its promotion to a viable clinical candidate. It does not pretend to the almost impossible task of an exhaustive report but will highlight a few key points that need to be collectively addressed both by chemists and biologists to fuel the drug discovery pipeline with innovative and safe drug candidates.

Reações adversas na cavidade oral em decorrência do uso de medicamentos / Side effects in oral cavity in consequent of medication use

Introdução: as reações adversas a medicamentos constituem um problema importante na prática do profissional da área da saúde, já que essas reações são causas de hospitalização, aumento no tempo de permanência hospitalar e da morbimortalidade. Muitas das reações adversas aos fármacos apresentam-se na cavidade oral. Objetivo: descrever os principais medicamentos com potencial de efeitos colaterais na cavidade oral, agrupando os que causam efeitos adversos semelhantes. Método: trata-se de estudo bibliográfico e descritivo por meio de utilização de estudos originais e atualizados a partir dos bancos de dados oficiais SciELO, PUBMED e LILACS. Priorizaram-se artigos em língua portuguesa, inglesa e espanhola, que incluíam revisões bibliográficas, meta-análises e relatos de casos publicados entre 2000 e 2015. Foram utilizados como descritores os termos: manifestações orais e medicamentos, lesões orais e medicamentos, mucosa oral e medicamentos e reação medicamentosa na cavidade oral. Resultados e Discussão: dezenove artigos foram analisados detalhadamente e mostram predominância de relatos de caso. Vários medicamentos foram associados com alterações patológicas nos tecidos orais, sobretudo os medicamentos utilizados em oncologia e medicamentos com ação no sistema nervoso central. As reações adversas às drogas dependem do fármaco e são bastante variáveis, e dentre as encontradas destacam-se ulceração de mucosa, hiperplasia gengival, xerostomia e diminuição do fluxo salivar. Conclusão: algumas lesões são comuns a diferentes medicamentos e, dessa forma, é fundamental a observação correta da possibilidade de sequela associada à terapia medicamentosa. Uma anamnese adequada com um levantamento do histórico médico completo do paciente é essencial para o profissional de saúde estar apto a fazer o diagnóstico das alterações e concluir o tratamento adequado para a solução do problema. (AU)

Introduction: adverse drug reactions are an important problem in the practice of health professionals, since these reactions may cause hospitalization, increase in length of hospital stay and morbidity and mortality. Many adverse drug reactions occur in the oral cavity. Objective: to describe the main drugs with potential side effects in the oral cavity, grouping those that cause similar adverse effects. Methods: bibliographic and descriptive study through use of original studies from three databases: SciELO, PubMed and LILACS. Selected papers were in Portuguese, English and Spanish, which included literature reviews, meta-analysis and case reports published between 2000 and 2015. The terms used were: oral medications and manifestations, oral lesions and medicines, oral mucosa and drugs and adverse drug reaction in the oral cavity. Results and Discussion: nineteen articles were analyzed in detail and case reports were predominant. Several drugs have been associated with pathological changes in oral tissue, in particular drugs used in oncology and those acting on the central nervous system. Adverse drug reactions depend on the medication and are quite variable. Among the found reaction are: ulcerative mucosa, gingival hyperplasia, xerostomia and decreased salivary flow. Conclusion: some lesions are common to different drugs, making critical the proper observation of possible sequelae associated with drug therapy. Detailed anamnesis with a complete medical history of the patient is essential for the proper diagnosis and a better therapeutic decision. (AU)

Cerebral open flow microperfusion (cOFM) an innovative interface to brain tissue.

Cerebral open flow microperfusion (cOFM) is a new in-vivo technique for continuous sampling of the interstitial fluid in brain tissue. cOFM can be used to monitor substance transport across the blood-brain barrier (pharmacokinetics) and to investigate metabolic changes in brain tissue after drug application (pharmacodynamics). The possibility of long-term implantation into the brain makes cOFM an outstanding tool in the development of brain relevant pharmaceutics.

DisSim: an online system for exploring significant similar diseases and exhibiting potential therapeutic drugs.

The similarity of pair-wise diseases reveals the molecular relationships between them. For example, similar diseases have the potential to be treated by common therapeutic chemicals (TCs). In this paper, we introduced DisSim, an online system for exploring similar diseases, and comparing corresponding TCs. Currently, DisSim implemented five state-of-the-art methods to measure the similarity between Disease Ontology (DO) terms and provide the significance of the similarity score. Furthermore, DisSim integrated TCs of diseases from the Comparative Toxicogenomics Database (CTD), which can help to identify potential relationships between TCs and similar diseases. The system can be accessed from http://123.59.132.21:8080/DisSim.

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

BackgroundTarantulas (Theraphosidae) represent an important source of novel biologically active compounds that target a variety of ion channels and cell receptors in both insects and mammals. In this study, we evaluate and compare the pharmacological activity of venoms from three taxonomically different theraphosid spiders bred in captivity: Poecilotheria regalis, an aggressive arboreal tarantula from southeastern India; Ceratogyrus darlingi, an aggressive tarantula from southern Africa; and Brachypelma epicureanum, a docile tarantula from the Yucatan dry forest of Mexico. Prior to this study, no research had been conducted with regard to the composition and pharmacological activity of these venoms.MethodsThe pharmacological characterization of the venoms was described for the first time by the assessment of their toxicity in crickets (LD50) along with their nociceptive (by using the formalin test), hyaluronidase, phospholipase A2, edematogenic and caseinolytic activity.ResultsP. regalis and B. epicureanum venoms induced a similar lethal effect on crickets (LD50 = 5.23 ± 3.1 and 14.4 ± 5.0 μg protein/g 48 h post-injection, respectively), whereas C. darlingi venom (119.4 ± 29.5 μg protein/g 48 h post-injection) was significantly less lethal than the other two venoms. All three venoms induced similar edematogenic activity on rats but did not induce nociceptive behavior. The assessment of enzymatic activity indicated that P. regalis venom induces significantly higher hyaluronidase activity (27.6 ± 0.9 TRU/mg) than both C. darlingi (99.7 ± 1.9 TRU/mg) and B. epicureanum (99.6 ± 1.6 TRU/mg); these latter venoms did not display phospholipase A2or caseinolytic activity.ConclusionsThis study demonstrates that these theraphosid spiders of different habitats produce venoms with different activities. P. regalis venom displays a high level of hyaluronidase activity, which may be associated with its potentially medically significant bite.(AU)

Transferência de conhecimento no contexto da cooperação internacional: o caso da sociedade moçambicana de medicamentos / Knowledge transfer in the context of international cooperation: the case of the Mozambican medicines society

A despeito do crescimento da cooperação técnica internacional, sobretudo horizontal (também chamada sul-sul), a literatura sobre o processo de transferência de conhecimento nesse contexto ainda é escassa. A fim de analisar como mecanismos de transferência de conhecimento e capacidade absortiva se inter-relacionam nesse processo, realizou-se um estudo de caso sobre a implementação da Sociedade Moçambicana de Medicamentos (SMM). A partir de uma revisão teórica entendeu-se capacidade absortiva como um conjunto de rotinas e processos organizacionais mediante os quais as firmas adquirem, assimilam, transformam e exploram o conhecimento para produzir capacidade organizacional dinâmica, podendo essa ser dividida em duas dimensões: capacidade absortiva potencial (CAP) e realizada (CAR). A CAP é a habilidade da organização de reconhecer e assimilar conhecimento externo. Já a CAR corresponde à capacidade da organização de transformar e explorar o conhecimento. Quanto maiores os níveis de capacidade absortiva potencial e capacidade absortiva realizada, maior é a efetividade da transferência de conhecimento. A distância entre a CAP e a CAR, por sua vez, pode ser reduzida com o auxílio dos mecanismos de transferência de conhecimento. No contexto da cooperação internacional, essa diminuição do espaço entre as duas dimensões vai ao encontro do conceito de desenvolvimento de capacidades apresentado pelo modelo de cooperação Sul-Sul estruturante em saúde. Esse modelo envolve ações de capacitação de servidores públicos dos países recipiendários, que culminariam no fortalecimento das organizações de saúde e no desenvolvimento institucional daqueles países. Para operacionalizar a pesquisa foram definidas duas variáveis: mecanismos (composto pelas categorias: 1- treinamentos, 2 - movimento de pessoas, 3 - expatriação e 4 - manuais) e capacidade absortiva (dividida pelas categorias capacidade absortiva potencial ­ aquisição e assimilação ­ e realizada - transformação e exploitação). A coleta de dados foi feita por meio de documentos oficiais e entrevistas. Foram realizadas 29 entrevistas com 21 profissionais tanto do nível gerencial quanto do operacional, sendo que alguns foram entrevistados mais de uma vez. A análise dos dados foi feita por meio da análise de conteúdo, com o auxílio do software NVivo. Os resultados evidenciam que o mecanismo movimento de pessoas impacta na capacidade absortiva potencial (CAP), enquanto que a expatriação e a criação de manuais são fundamentais para a capacidade absortiva realizada (CAR). Ainda, verificou-se a potencialidade da utilização dos mecanismos de transferência de conhecimento em bases não comerciais, com o intuito de promover desenvolvimento humano. Entretanto, a falta de convergência entre os objetivos dos atores da cooperação impossibilitou, mais uma vez, que se ultrapassasse o patamar de capacitação de servidores públicos para a estruturação e aprimoramento das instituições ligadas à política de saúde. A contribuição teórica deste trabalho é demonstrar como os diferentes mecanismos de transferência de conhecimento afetam a CAP e a CAR no contexto da cooperação Sul-Sul.

Despite the growth of International Technical Cooperation (ITC), especially horizontal (South-South), the literature concerning the process of Knowledge Transfer (KT) in the ITC context is still scarce. In order to analyze how the mechanisms of Knowledge Transfer and the absorptive capacity are interrelated in that process, this case study was conducted about the implementation of the Mozambican Medicines Society (SMM). From a literature review, Absorptive Capacity is considered a set of routines and organizational processes by which firms acquire, assimilate, transform and exploit knowledge to produce dynamic organizational capability. This can be divided in two dimensions: Potential Absorptive Capacity (PAC) and Realized (RAC). The PAC is the organization's ability to recognize and assimilate external knowledge. On the other hand, RAC corresponds to the capacity of the organization to transform and exploit knowledge. The higher levels of PAC and RAC in an organization, the greater the effectiveness of knowledge transfer is. The distance between the PAC and RAC can be reduced with the assistance of the mechanisms of KT. In international cooperation, the gap reduction between PAC and RAC is in line with the concept of Capacity Development presented by the model of South-South cooperation structuring in health. This model involves training for government workers at the beneficiary countries, resulting in strengthening the health organizations and institutional development in those countries. To perform the study, two variables were defined. The first variable, Mechanisms, is composed by training, movement of people, expatriation and manuals. The second variable, Absorptive Capacity, is composed of PAC (acquisition and assimilation), and RAC (transformation and exploitation). The data collection was done through studying official documents and a total of 29 interviews with 21 professionals from both managerial and operational positions, some of them were interviewed multiple times. The data analysis was done using the method of content analysis, with the assistance of the software NVivo. The results show that the mechanism movement of people influences the Potential Absorptive Capacity (PAC) while expatriation and creating manuals impact Realized Absorptive Capacity (RAC). Also, it was observed that the mechanisms of knowledge transfer in non-commercial basis can promote human development. However, the absence of governance structure, made it impossible to go beyond the level of training of public employees for structuring and improvement of institutions related to health policy. The theoretical contribution of this work is to demonstrate how the different mechanisms of knowledge transfer affect the PAC and RAC in the context of South-South cooperation.