Northward migration past the nearctic biogeographical divide; neotropical Gyrodactylus spp. infecting Astyanax have crossed the Trans-Mexican Volcanic Belt.

The neotropical fish genus Astyanax (Characidae) and its associated helminths migrated northward from South America following the Great American Biotic Interchange (GABI): ca. 150 Astyanax spp. are found throughout South and Central America, up to the Mexico-USA border. Most characids are distributed south of the Trans-Mexican Volcanic Belt (TMVB), which bisects the country and represents a major transition zone between the neotropical and nearctic realms. Here, we characterize parasites of the monogenean genus Gyrodactylus infecting Astyanax spp. in Mexico: Astyanax aeneus south of the TMBV, Astyanax mexicanus north of it. Based on morphological, phylogenetic (internal transcribed spacer (ITS) and cytochrome oxidase subunit II (cox 2)) and statistical analyses of morphometric data, we confirmed the validity of Gyrodactylus pakan and Gyrodactylus teken, and erected two new species, Gyrodactylus aphaa n. sp. and Gyrodactylus ricardoi n. sp. These four gyrodactylids are part of a complex of morphologically cryptic species, which are phylogenetically closely related to each other, and sister species to Gyrodactylus carolinae and Gyrodactylus heteracanthus, parasites of characins in Brazil. Four gyrodactylid lineages (G. pakan, G. ricardoi n. sp., G. teken, Gyrodactylus sp. A) are distributed north of the TMVB; G. pakan is also widely distributed south of the TMVB, together with G. aphaa n. sp. Based on the ITS phylogeny, Brazilian parasites form a sister clade to all Mexican gyrodactylids, whose derived clades are distributed in progressively more northerly latitudes in Mexico - the three most-derived species north of the TMVB. This would suggest that gyrodactylid species diverged gradually, presumably as their characid fish hosts colonized and adapted to new environments north of the TMVB.

Association of COX-inhibitors with cancer patients' survival under chemotherapy and radiotherapy regimens: a real-world data retrospective cohort analysis.

Introduction: We conducted an extensive, sex-oriented real-world data analysis to explore the impact and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs) on cancer treatment outcomes. This is particularly relevant given the role of the COX-2/PGE2 pathway in tumor cell resistance to chemotherapy and radiotherapy. Methods: The study applied a retrospective cohort design utilizing the TriNetX research database consisting of patients receiving cancer treatment in 2008-2022. The treated cohorts included patients who were prescribed with coxibs, aspirin or ibuprofen, while individuals in the control cohort did not receive these medicines during their cancer treatment. A 1:1 propensity score matching technique was used to balance the baseline characteristics in the treated and control cohorts. Then, Cox proportional hazards regression and logistic regression were applied to assess the mortality and morbidity risks among patient cohorts in a 5-year follow-up period. Results: Use of coxibs (HR, 0.825; 95% CI 0.792-0.859 in females and HR, 0.884; 95% CI 0.848-0.921 in males) and ibuprofen (HR, 0.924; 95% CI 0.903-0.945 in females and HR, 0.940; 95% CI 0.917-0.963 in males) were associated with improved survival. Female cancer patients receiving aspirin presented increased mortality (HR, 1.078; 95% CI 1.060-1.097), while male cancer patients also had improved survival when receiving aspirin (HR, 0.966; 95% CI 0.951-0.980). Cancer subtype specific analysis suggests coxibs and ibuprofen correlated with survival, though ibuprofen and aspirin increased emergency department visits' risk. Secondary analyses, despite limited by small cohort sizes, suggest that COX inhibition post-cancer diagnosis may benefit patients with specific cancer subtypes. Discussion: Selective COX-2 inhibition significantly reduced mortality and emergency department visit rates. Further clinical trials are needed to determine the optimal conditions for indication of coxibs as anti-inflammatory adjuvants in cancer treatment.

Exploration of the Binding Site of Arachidonic Acid in gp63 of Leishmania mexicana and in Orthologous Proteins in Clinically Important Parasites.

Recently, we published that the monoclonal antibody (D12 mAb) recognizes gp63 of L. mexicana, and it is responsible for COX activity. This D12 mAb exhibited cross-reactivity with Trypanosoma cruzi, Entamoeba histolytica, Acanthamoeba castellanii, and Naegleria fowleri. COX activity assays performed in these parasites suggested the potential presence of such enzymatic activity. In our investigation, we confirmed that wild-type recombinant gp63 exhibits COX-like activity, in contrast to a mutated recombinant gp63 variant. Consequently, our objective was to identify sequences orthologous to gp63 and subsequently analyze the binding of arachidonic acid (AA) to the putative active sites of these proteins. Given the absence of a crystallized structure for this protein in the Protein Data Bank (PDB), it was imperative to first obtain a three-dimensional structure by homology modeling, using leishmanolysin from Leishmania major (PDB ID: LML1) as a template in the Swiss model database. The results obtained through molecular docking simulations revealed the primary interactions of AA close to the Zinc atom present in the catalytic site of gp63-like molecules of several parasites, predominantly mediated by hydrogen bonds with HIS264, HIS268 and HIS334. Furthermore, COX activity was evaluated in commensal species such as E. dispar and during the encystment process of E. invadens.

Advances, limitations and perspectives in the use of celecoxib-loaded nanocarriers in therapeutics of cancer.

Cancer is highlighted as a major global health challenge in the XXI century. The cyclooxygenase-2 (COX-2) enzyme rises as a widespread tumor progression marker. Celecoxib (CXB) is a selective COX-2 inhibitor used in adjuvant cancer therapy, but high concentrations are required in humans. In this sense, the development of nanocarriers has been proposed once they can improve the biopharmaceutical, pharmacokinetic and pharmacological properties of drugs. In this context, this article reviews the progress in the development of CXB-loaded nanocarriers over the past decade and their prospects. Recent advances in the field of CXB-loaded nanocarriers demonstrate the use of complex formulations and the increasing importance of in vivo studies. The types of CXB-loaded nanocarriers that have been developed are heterogeneous and based on polymers and lipids together or separately. It was found that the work on CXB-loaded nanocarriers is carried out using established techniques and raw materials, such as poly (lactic-co-glicolic acid), cholesterol, phospholipids and poly(ethyleneglycol). The main improvements that have been achieved are the use of cell surface ligands, the simultaneous delivery of different synergistic agents, and the presence of materials that can provide imaging properties and other advanced features. The combination of CXB with other anti-inflammatory drugs and/or apoptosis inducers appears to hold effective pharmacological promise. The greatest advance to date from a clinical perspective is the ability of CXB to enhance the cytotoxic effects of established chemotherapeutic agents.

Bayesian Modeling for Nonstationary Spatial Point Process via Spatial Deformations.

Many techniques have been proposed to model space-varying observation processes with a nonstationary spatial covariance structure and/or anisotropy, usually on a geostatistical framework. Nevertheless, there is an increasing interest in point process applications, and methodologies that take nonstationarity into account are welcomed. In this sense, this work proposes an extension of a class of spatial Cox process using spatial deformation. The proposed method enables the deformation behavior to be data-driven, through a multivariate latent Gaussian process. Inference leads to intractable posterior distributions that are approximated via MCMC. The convergence of algorithms based on the Metropolis-Hastings steps proved to be slow, and the computational efficiency of the Bayesian updating scheme was improved by adopting Hamiltonian Monte Carlo (HMC) methods. Our proposal was also compared against an alternative anisotropic formulation. Studies based on synthetic data provided empirical evidence of the benefit brought by the adoption of nonstationarity through our anisotropic structure. A real data application was conducted on the spatial spread of the Spodoptera frugiperda pest in a corn-producing agricultural area in southern Brazil. Once again, the proposed method demonstrated its benefit over alternatives.

Molecular identification of Sarcocystis aucheniae in the wild South American camelid Vicugna vicugna.

Vicuñas (Vicugna vicugna) are wild South American camelids (SACs) protected by law in Argentina, and information on pathogens that infect them is scarce. In this study, an adult vicuña found dead in the province of Salta was examined, and evidence of infection by Sarcocystis sp. protozoans was sought. Infection of skeletal muscles by S. aucheniae, with the production of macroscopic sarcocysts, a disease known as SAC sarcocystosis, has been described in the other three SACs - llamas, alpacas, and guanacos - but its occurrence in vicuñas has so far remained unknown. In the analyzed individual, many macroscopic cysts compatible with S. aucheniae were found upon necropsy in the muscular tissue of the neck and diaphragm. Analysis of 18 S rRNA and cytochrome c oxidase subunit 1 (cox-1) gene sequences by BLAST searches and construction of phylogenetic trees demonstrated that the etiological agent was S. aucheniae. Our results show for the first time that vicuñas act as intermediate hosts in the life cycle of this parasite. In addition, this study provides the first cox-1 sequences for S. aucheniae isolates from the four SAC species acting as intermediate hosts and suggests that this marker could be useful for genotypification of this parasite species. The impact of SAC sarcocystosis on the health, well-being, and fitness of vicuñas, and the relevance of vicuña infections in the epidemiology of S. auchaniae, remain to be elucidated.

In silico studies on leishmanicide activity of limonoids and fatty acids from Carapa guianensis Aubl.

The oil of Carapa guianensis showed leishmanicidal activity, with its activity being related to limonoids, but fatty acids are the major constituents of this oil. The present study evaluated the physicochemical, pharmacokinetic, and toxicity profiles of limonoids and fatty acids already identified in the species. Based on these results, 2 limonoids (methyl angosinlate, 6-OH-methyl angosinlate) and 2 fatty acids (arachidic acid; myristic acid) were selected for the prediction of possible targets and molecular docking. Included in this study were: Gedunin, 6α-acetoxygedunin, Methyl angosenlato, 7-deacetoxy-7-oxogedunin, Andirobin, 6-hydroxy-angolensate methyl, 17ß-hydroxyazadiradione, 1,2-dihydro-3ß-hydroxy-7-deacetoxy-7-oxogedunin, xyllocensin k, 11beta-Hydroxygedunin, 6α,11-11ß-diacetoxygedunin, Oleic Acid, Palmitic Acid, Stearic Acid, Arachidic Acid, Myristic Acid, Palmitoleic Acid, Linoleic Acid, Linolenic Acid, and Beenic Acid. Regarding physicochemical aspects, fatty acids violated LogP, and only limonoid 11 violated Lipinski's rule. A common pharmacokinetic aspect was that all molecules were well absorbed in the intestine and inhibited CYP. All compounds showed toxicity in some model, with fatty acids being mutagenic and carcinogenic, and limonoids not being mutagenic and carcinogenic at least for rats. In in vivo models, fatty acids were less toxic. Molecular dockings were performed on COX-2 steroids (15 and 16) and hypoxia-inducible factor 1 alpha for limonoids (3,6), with this target being essential for the intracellular development of leishmania. Limonoids 3 and 6 appear to be promising as leishmanicidal agents, and fatty acids are promising as wound healers.

Antinociceptive and Anti-Inflammatory Activities of Acetonic Extract from Bougainvillea x buttiana (var. Rose).

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory properties and its potential action mechanisms. Methods: Analgesic and anti-inflammatory activities were evaluated using three murine pain models and two acute inflammation models. In vitro, the ability of the extract to inhibit proteolytic activity and the activities of the enzymes phospholipase A2 (PLA2) and cyclooxygenase (COX) were evaluated. In silico analysis was performed to predict the physicochemical and Absorption, distribution, metabolism, and excretion (ADME) profiles of the compounds previously identified in BxbRAE-100%. Results: In vivo BxbRAE-100% decreased the nociceptive behaviors in the writhing model, the tail immersion, and the formalin test, suggesting that the extract has the potential to relieve pain at peripheral and central levels. Additionally, topical or oral BxbRAE-100% treatment reduced dose-dependent 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation and carrageenan-induced paw edema, respectively. In vitro, BxbRAE-100% significantly inhibited proteolytic activity and PLA2, COX-1 and COX-2 activities. In silico, the compounds previously identified in BxbRAE-100% met Lipinski's rule of five and showed adequate ADME properties. Conclusions: These results support the use of B. x buttiana in Traditional Mexican Medicine and highlight its potential for the development of new treatments for pain and inflammation.

First Molecular Diagnosis of Oestrus ovis (Linnaeus, 1758) Larvae Causing Conjunctival Ophthalmomyiasis in Mexico City, Mexico.

PURPOSE: Human ophthalmomyiasis is a rare ocular parasitosis that results from the accidental infestation of dipteran larvae of several species, including Oestrus ovis (Linnaeus, 1758). This study aims to present the fourth documented human case of ophthalmomyiasis in Mexico, identifying the etiological agent through morphological and molecular analyses. Additionally, we investigated the phylogenetic position and genetic distances among different specimens globally characterized based on mitochondrial Cox1 sequences. METHODS: A total of five larval specimens were extracted from the patient's eye, with two specimens allocated for identification based on morphological features using a stereomicroscope, and the remaining three preserved in absolute ethanol, one of them used for subsequent analysis using molecular methods. The mitochondrial Cox1 region was amplified and sequenced using automated Sanger sequencing. The resulting sequence was deposited in GenBank under accession number OR440699 and subjected to BlastN analysis against 35 other Cox1 sequences of O. ovis from GenBank. The identity and phylogenetic position of the strains were further explored using parsimony and maximum likelihood phylogenetic methods. RESULTS: Morphological examination of the larval specimens extracted from the patient's eye unequivocally identified them as O. ovis species. BlastN analysis and comprehensive phylogenetic investigations involving a total of 36 Cox1 sequences confirmed the taxonomic identity of the larvae. Notably, our sequence was positioned within the cluster formed by the Brazilian and two Iranian samples. This finding underscores a shared genetic ancestry among these distinct geographical isolates and provides valuable insights into the evolutionary relationships within O. ovis populations. CONCLUSION: The presence of O. ovis infestation in Mexico City suggests potential shifts in environmental conditions favoring fly proliferation, highlighting the need for vigilance in urban healthcare settings.

Visual EMDR stimulation mitigates acute varied stress effects on morphology of hippocampal neurons in male Wistar rats.

Introduction: Stress is a pervasive health concern known to induce physiological changes, particularly impacting the vulnerable hippocampus and the morphological integrity of its main residing cells, the hippocampal neurons. Eye Movement Desensitization and Reprocessing (EMDR), initially developed to alleviate emotional distress, has emerged as a potential therapeutic/preventive intervention for other stress-related disorders. This study aimed to investigate the impact of Acute Variable Stress (AVS) on hippocampal neurons and the potential protective effects of EMDR. Methods: Rats were exposed to diverse stressors for 7 days, followed by dendritic morphology assessment of hippocampal neurons using Golgi-Cox staining. Results: AVS resulted in significant dendritic atrophy, evidenced by reduced dendritic branches and length. In contrast, rats receiving EMDR treatment alongside stress exposure exhibited preserved dendritic morphology comparable to controls, suggesting EMDR's protective role against stressinduced dendritic remodeling. Conclusions: These findings highlight the potential of EMDR as a neuroprotective intervention in mitigating stress-related hippocampal alterations.

Collagen modifications predictive of lymph node metastasis in dogs with carcinoma in mixed tumours.

Introduction: Mixed tumours in the canine mammary gland are the most common histological type in routine diagnosis. In general, these neoplasms have a favourable prognosis that does not evolve into metastatic disease. However, some cases develop into lymph node metastases and are associated with worse patient survival rates. Methods: Here is a retrospective study of 46 samples of primary mixed tumours of the canine mammary gland: 15 cases of benign mixed tumours (BMT), 16 cases of carcinoma in mixed tumours without lymph node metastasis (CMT), and 15 cases of carcinomas in mixed tumours with lymph node metastasis (CMTM). In addition, we selected 23 cases of normal mammary glands (NMT) for comparison. The samples were collected from biopsies performed during nodulectomy, simple mastectomy, regional mastectomy, or unilateral/bilateral radical mastectomy. We used multiphoton microscopy, second harmonic generation, and two-photon excited fluorescence, to evaluate the characteristics of collagen fibres and cellular components in biopsies stained with haematoxylin and eosin. We performed Ki67, ER, PR, and HER-2 immunostaining to define the immunophenotype and COX-2. We showed that carcinomas that evolved into metastatic disease (CMTM) present shorter and wavier collagen fibres as compared to CMT. Results and discussion: When compared to NMT and BMT the carcinomas present a smaller area of fibre coverage, a larger area of cellular coverage, and a larger number of individual fibres. Furthermore, we observed a correlation between the strong expression of COX-2 and a high rate of cell proliferation in carcinomas with a smaller area covered by cell fibres and a larger number of individual fibres. These findings highlight the fundamental role of collagen during tumour progression, especially in invasion and metastatic dissemination.

The Impact of Mutational Hotspots on Cancer Survival.

BACKGROUND: Cofactors, biomarkers, and the mutational status of genes such as TP53, EGFR, IDH1/2, or PIK3CA have been used for patient stratification. However, many genes exhibit recurrent mutational positions known as hotspots, specifically linked to varying degrees of survival outcomes. Nevertheless, few hotspots have been analyzed (e.g., TP53 and EGFR). Thus, many other genes and hotspots remain unexplored. METHODS: We systematically screened over 1400 hotspots across 33 TCGA cancer types. We compared the patients carrying a hotspot against (i) all cases, (ii) gene-mutated cases, (iii) other mutated hotspots, or (iv) specific hotspots. Due to the limited number of samples in hotspots and the inherent group imbalance, besides Cox models and the log-rank test, we employed VALORATE to estimate their association with survival precisely. RESULTS: We screened 1469 hotspots in 6451 comparisons, where 314 were associated with survival. Many are discussed and linked to the current literature. Our findings demonstrate associations between known hotspots and survival while also revealing more potential hotspots. To enhance accessibility and promote further investigation, all the Kaplan-Meier curves, the log-rank tests, Cox statistics, and VALORATE-estimated null distributions are accessible on our website. CONCLUSIONS: Our analysis revealed both known and putatively novel hotspots associated with survival, which can be used as biomarkers. Our web resource is a valuable tool for cancer research.

Loss of CDX2 and high COX2 (PTGS2) expression in metastatic colorectal cancer.

Lack of expression of the tumour suppressor gene caudal-type homeobox 2 (CDX2) associates with poor outcomes in early stage colorectal cancer (CRC). Yet its prognostic value in the context of other prognostic biomarkers in metastatic CRC (mCRC) is unknown. Overexpressed cyclooxygenase-2 (COX2) has been reported in advanced CRC. However, CDX2 and COX2 relationship in mCRC remains undetermined. We aimed to assess their expression in mCRC tumours from a clinically characterised cohort and their influence on overall survival (OS) and progression-free survival (PFS) in first line. Among 720 consecutive mCRC patients, 346 had tumour samples appropriate for tissue microarray assembly and immunohistochemistry analyses. Clinical and survival data were retrospectively assessed. Loss of CDX2 expression was detected in 27 (7.8%) samples, enriched in poorly differentiated tumours (20%; p < 0.01) and in those with the BRAF p.V600E variant (40%; p < 0.01). Most tumours (93.4%) expressed COX2. COX2-negative samples were enriched in poorly differentiated mCRC. In unadjusted analyses, median OS (p < 0.001) and median PFS (p < 0.05) were inferior for patients with CDX2-negative versus CDX2-positive tumours. In conclusion, loss of CDX2 was significantly associated with poorly differentiated mCRC and BRAF p.V600E allele and a prognostic marker of worse OS.

Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects.

In this research work, a series of 16 quinazoline derivatives bearing ibuprofen and an amino acid were designed as inhibitors of epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) and cyclooxygenase-2 (COX-2) with the intention of presenting dual action in their biological behavior. The designed compounds were synthesized and assessed for cytotoxicity on epithelial cancer cells lines (AGS, A-431, MCF-7, MDA-MB-231) and epithelial non-tumorigenic cell line (HaCaT). From this evaluation, derivative 6 was observed to exhibit higher cytotoxic potency (IC50) than gefitinib (reference drug) on three cancer cell lines (0.034 µM in A-431, 2.67 µM in MCF-7, and 3.64 µM in AGS) without showing activity on the non-tumorigenic cell line (>100 µM). Furthermore, assessment of EGFR-TKD inhibition by 6 showed a discreet difference compared to gefitinib. Additionally, 6 was used to conduct an in vivo anti-inflammatory assay using the 12-O-tetradecanoylphorbol-3-acetate (TPA) method, and it was shown to be 5 times more potent than ibuprofen. Molecular dynamics studies of EGFR-TKD revealed interactions between compound 6 and M793. On the other hand, one significant interaction was observed for COX-2, involving S531. The RMSD graph indicated that the ligand remained stable in 50 ns.

Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Nomogram for predicting overall survival after curative gastrectomy using inflammatory, nutritional and pathological factors.

PURPOSE: To establish a nomogram for predicting the overall survival (OS) in patients with gastric cancer (GC) based on inflammatory, nutritional and pathological factors. METHODS: GC patients underwent curative gastrectomy from January 2012 to June 2017 in our hospital were included, and were classified into training set and validation set with a ratio of 7:3. Then variables associated with OS were analyzed using univariate and multivariate Cox regression analysis. Nomograms predicting OS were built using variables from multivariable Cox models. Finally, Kaplan-Meier curve and Log-rank test were also conducted to analyze the 1-yr, 3-yr and 5-yr OS to validate the efficiency of risk stratification of the nomogram. RESULTS: A total of 366 GC patients were included. After univariate and multivariate Cox regression analysis, age (HR = 1.52, 95% CI = 1.01-2.30, P = 0.044), CA50 (HR = 1.90, 95% CI = 1.12-3.21, P = 0.017), PNI (HR = 1.65, 95% CI = 1.13-2.39, P = 0.009), SII (HR = 1.46, 95% CI = 1.03-2.08, P = 0.036), T stage (HR = 2.26, 95% CI = 1.01-5.05, P = 0.048; HR = 7.24, 95% CI = 3.64-14.40, P < 0.001) were independent influencing factors on the survival time of GC patients. Five factors including CEA, prognostic nutritional index (PNI), systemic immune-inflammation index (SII), ln (tumor size), T stage, and N stage were identified and entered the nomogram, which showed good discrimination and calibration in both sets. On internal validation, 1-yr, 3-yr and 5-yr nomogram demonstrated a good discrimination with an area under the ROC curve (AUC) of 0.77, 0.84 and 0.86, respectively. The AUC for 1-yr, 3-yr and 5-yr nomogram in validation set was 0.77, 0.79 and 0.81, respectively. The OS in low risk group of training cohort and validation cohort was significantly higher than that of intermediate risk group and high risk group, respectively. CONCLUSIONS: We established a nomogram based on PNI, SII and pathological factors for predicting OS in GC patients. In addition, its efficiency was validated by validation set and stratified analysis.

Comparison between 200 mg generic celecoxib hard capsules and Celebra®: bioequivalence study in healthy male and female subjects under fasting conditions after a single dose / Comparação entre celecoxibe genérico de 200 mg em cápsulas duras e Celebra®: estudo de bioequivalência em indivíduos saudáveis do sexo masculino e feminino, em jejum, após uma dose única

ABSTRACT BACKGROUND AND OBJECTIVES: The objective of this study was to assess the bioequivalence between two 200 mg celecoxib hard capsule formulations administered to healthy male and female participants under fasting conditions with the aim of providing an alternative pharmaceutical product to the reference drug, Celebra®. METHODS: A randomized, open label, single dose, 2x2 crossover trial was conducted with 60 adult healthy subjects under fasting conditions comparing single doses of two celecoxib hard capsules formulation. Pharmacokinetic parameters were calculated following the determination of drugs concentrations in human plasma using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). RESULTS: Statistical analysis provided geometric mean of test/reference ratio, confidence intervals, intra-subject variation coefficient and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Confidence intervals for the geometric mean (90% CI) of the test/reference drugs for celecoxib were 98.26 to 122.75% for Cmax, 100.27% to 110.78% for AUC0-t, and 96.87% to 110.29% for AUC0-∞. The power of the test found was 95.09% for Cmax, 100.00% for AUC0-t, and 99.99% for AUC0-∞. CONCLUSION: The formulations met the Brazilian standards for interchangeability, as the confidence intervals for Cmax and AUC0-t ratios are within the range of 80% to 125%, thus meeting the requirements of the legislation during market registration. The researched product was approved by the regulatory authorities and became a commercially competitive option to the reference product for the Brazilian population.

RESUMO JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar a bioequivalência entre duas formulações de cápsulas duras de celecoxibe de 200 mg administradas a participantes saudáveis do sexo masculino e feminino em condições de jejum com o objetivo de fornecer um produto farmacêutico alternativo ao fármaco de referência, Celebra®. MÉTODOS: Estudo randomizado, aberto, de dose única e cruzado 2x2. Foi conduzido com 60 indivíduos adultos saudáveis em condições de jejum, comparando doses únicas de duas formulações de cápsulas duras de celecoxibe. Os parâmetros farmacocinéticos foram calculados após a determinação das concentrações dos fármacos no plasma humano usando uma cromatografia líquida validada com um método detector de espectrômetro de massa em tandem (LC-MS/MS). RESULTADOS: A análise estatística forneceu a média geométrica da razão teste/referência, os intervalos de confiança, o coeficiente de variação intra-sujeito e o poder do teste para os parâmetros farmacocinéticos Cmáx, AUC0-t e AUC0-∞. Os intervalos de confiança para a média geométrica (IC 90%) dos fármacos teste/referência para o celecoxibe foram 98,26 a 122,75% para Cmáx, 100,27% a 110,78% para AUC0-t e 96,87% a 110,29% para AUC0-∞. O poder do teste encontrado foi de 95,09% para Cmáx, 100,00% para AUC0-t e 99,99% para AUC0-∞. CONCLUSÃO: As formulações atenderam aos padrões brasileiros de intercambialidade, pois os intervalos de confiança para as razões Cmáx e AUC0-t estão dentro da faixa de 80% a 125%, atendendo, assim, às exigências da legislação para o registro no mercado. O produto pesquisado foi aprovado pelas autoridades regulatórias e tornou-se uma opção comercialmente competitiva ao produto de referência para a população brasileira.

Phylogenetic relationship between Contracaecum spp. (Nematoda, Anisakidae) parasitizing cormorants (Aves, Phalacrocoracidae) in Argentina.

Species of the genus Contracaecum (Family Anisakidae) exhibit a broad host and geographical distribution, parasitizing aquatic organisms such as piscivorous birds and mammals as their definitive hosts. Several Contracaecum species have been reported parasitizing cormorants (Family: Phalacrocoracidae) in South America. The objective of this study was to highlight phylogenetic relationships between Contracaecum species parasitizing cormorants based on both molecular analyses and the papillae arrangement on the male tail. Some Contracaecum species parasitizing Red-legged cormorants from the Ría Deseado (RD), and other nematodes parasitizing eight Neotropic cormorants from San Miguel del Monte lagoon (SMML), Argentina, were collected and analyzed. Both morphological and phylogenetic analyses allowed us to recognize two species: Contracaecum chubutensis parasitizing Phalacrocorax gaimardi, and Contracaecum australe parasitic in Phalacrocorax brasilianus. According to the obtained sequences (mtDNA cox2, ITS1, ITS2, and SSrRNA), Contracaecum sp. parasitizing P. gaimardi exhibited concordance with the previously reported C. chubutensis parasitizing P. atriceps from Bahía Bustamante, Chubut province. Likewise, Contracaecum sp. isolates parasitizing P. brasilianus showed concordance with C. australe from Chile. Besides, the papillae arrangement on the male tail allowed us to understand the interspecific and genetic relationships between the Contracaecum species. The analyses confirm that C. chubutensis specimens parasitizing P. gaimardi from RD present a new host record for the species, whereas, those C. australe specimens parasitizing P. brasilianus from SMML provide a new geographical record for the species and the extension of its distribution range. Present results also confirm the inland and marine distribution of C. australe and C. chubutensis, respectively.

Dichotomous outcomes vs. survival regression models for identification of predictors of mortality among patients with severe acute respiratory illness during COVID-19 pandemics.

Introduction: As the studies predicting mortality in severe acute respiratory illness (SARI) have inferred associations either from dichotomous outcomes or from time-event models, we identified some clinical-epidemiological characteristics and predictors of mortality by comparing and discussing two multivariate models. Methods: To identify factors associated with death among all SARI hospitalizations occurred in Botucatu (Brazil)/regardless of the infectious agent, and among the COVID-19 subgroup, from March 2020 to 2022, we used a multivariate Poisson regression model with binomial outcomes and Cox proportional hazards (time-event). The performance metrics of both models were also analyzed. Results: A total of 3,995 hospitalized subjects were included, of whom 1338 (33%) tested positive for SARS-CoV-2. We identified 866 deaths, of which 371 (43%) were due to the COVID-19. In the total number of SARI cases, using both Poisson and Cox models, the predictors of mortality were the presence of neurological diseases, immunosuppression, obesity, older age, and need for invasive ventilation support. However, the Poisson test also revealed that admission to an intensive care unit and the COVID-19 diagnosis were predictors of mortality, with the female gender having a protective effect against death. Likewise, Poisson proved to be more sensitive and specific, and indeed the most suitable model for analyzing risk factors for death in patients with SARI/COVID-19. Conclusion: Given these results and the acute course of SARI and COVID-19, to compare the associations and their different meanings is essential and, therefore, models with dichotomous outcomes are more appropriate than time-to-event/survival approaches.

Fatal neural angiostrongyliasis in the Bolivian squirrel monkey (Saimiri boliviensis boliviensis) leading to defining Angiostrongylus cantonensis risk map at a zoo in Australia.

Neural angiostrongyliasis (NA) is a parasitic disease caused by Angiostrongylus cantonensis (rat lungworm). This study presents a case of NA in a captive Bolivian squirrel monkey from a zoo in western Sydney, Australia. The objective was to identify the A. cantonensis cox1 haplotype responsible for the infection and compare its mitochondrial DNA (mtDNA) to known Australian mtDNA. An epidemiological investigation was conducted to assess the risk of infection, focusing on the resident rat population in the zoo. Methods involved trapping rats and collecting rat faeces for Angiostrongylus detection, speciation, and cox1 haplotype confirmation. Various techniques were employed, including necropsy, morphological examination, and molecular methods such as ITS-2 qPCR, cox1 sequencing, and ITS-2 metabarcoding. Cluster analysis of rat faeces distribution and Angiostrongylus detection utilised an equal sampling effort (ESE) approach. Gastropods were collected throughout the study for Angiostrongylus surveillance using a hypersensitive qPCR assay. Results revealed significant clustering of rat faeces near exhibits with fresh food provision and absence of predators. Angiostrongylus-positive faeces were uniformly distributed across the zoo property. Mitochondrial DNA analysis confirmed the presence of the Ac13 haplotype of A. cantonensis in the monkey. Morphology, ITS-2 metabarcoding and partial cox1 sequencing detected only A. cantonensis, with the Ac13 cox1 haplotype predominating. A high prevalence of infection (64%, 9/14) was found in brown rats, with quantification of larvae indicating high shedding rates. Co-infections with both Ac13 and local SYD.1 A. cantonensis cox1 haplotypes were observed. Only three gastropods (all of which were Angiostrongylus-negative) were found in the survey. To minimise the risk of exposure for susceptible species, targeted rodent control was implemented in areas with higher exposure risk. A potential strategy (which requires further exploration) to consider for future zoo design was suggested. This study provides insights into the epidemiology and genetic diversity of A. cantonensis in Australia, emphasising the importance of control measures to prevent future outbreaks.