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.

Exploring COX-2 inhibitors in tuberculosis: A whole-blood model approach for immune response and adjunt therapy evaluation.

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.

Lobe-specific responses of TRAMP mice dorsolateral prostate following celecoxib and nintedanib therapy.

Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-ß, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-ß signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-ß signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.

Celecoxib in the treatment of orofacial pain and discomfort in rats subjected to a dental occlusal interference model.

PURPOSE: To evaluate the effect of a selective cyclooxygenase 2 (COX-2) inhibitor on trigeminal ganglion changes and orofacial discomfort/nociception in rats submitted to an experimental model of dental occlusal interference (DOI). METHODS: Female Wistar rats (180-200 g) were divided into five groups: a sham group (without DOI) (n=15); and four experimental groups with DOI treated daily with 0.1 mL/kg saline (DOI+SAL), 8, 16, or 32 mg/kg celecoxib (DOI+cel -8, -16, -32) (n=30/group). The animals were euthanized after one, three, and seven days. The bilateral trigeminal ganglia were analyzed histomorphometrically (neuron cell body area) and immunohistochemically (COX-2, nuclear factor-kappa B [NFkB], and peroxisome proliferator-activated receptor-y [PPARy]). A bilateral nociception assay of the masseter muscle was performed. The number of bites/scratches, weight, and grimace scale scores were determined daily. One-way/two-way analysis of variance (ANOVA)/Bonferroni post hoc tests were used (P < .05, GraphPad Prism 5.0). RESULTS: DOI+SAL showed a reduction in neuron cell body area bilaterally, whereas DOI+cel-32 exhibited a significative increase in neuron cell body area compared with DOI+SAL group (P < 0.05). The ipsilateral (P=0.007 and P=0.039) and contralateral (P < 0.001 and P=0.005) overexpression of COX-2 and NFkB and downregulation of PPARy (P=0.016 and P < 0.001) occurred in DOI+SAL, but DOI+cel-32 reverted this alteration. DOI+SAL showed increase in isplateral (P < 0.001) and contralateral (P < 0.001) nociception, an increased number of bites (P=0.010), scratches (P < 0.001), and grimace scores (P=0.032). In the group of DOI+cel-32, these parameters were reduced. CONCLUSIONS: Celecoxib attenuated DOI-induced transitory nociception/orofacial discomfort resulting from trigeminal COX-2 overexpression.

C-reactive protein as an effector molecule in Covid-19 pathogenesis.

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.

Therapeutic evaluation of galangin on cartilage protection and analgesic activity in a rat model of osteoarthritis

BACKGROUND Osteoarthritis (OA) is a form of arthritis due to degradation of articular cartilage. OA is asso ciated with stiffness, joint pain, and dysfunction, affecting adults worldwide. Galangin is a bioactive fla vonoid that exerts several therapeutic and biological activities. Anti-hyperglycemic, anti-inflammatory, anti-cancer, and anti-apoptotic activities of galangin have been reported in several studies. In the present study, rats were divided into normal control, OA (control), galangin 10 mg/kg (low-dose), galangin 100 mg/kg (high-dose), and celecoxib 30 mg/kg (positive control) groups. All doses were administered orally for 14 consecutive days. The urinary type II collagen (mCTX-II) level as well as reactive oxygen spe cies, tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, superoxide dismutase, catalase, lipid peroxidation, reduced glutathione, and glutathione peroxidase levels were measured. In addition, the CTX-II mRNA and protein expression levels were measured. RESULTS Galangin supplementation significantly reduced the mCTX-II level compared with controls. Galangin treatment significantly reduced reactive oxygen species, lipid peroxidation, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha levels, but increased catalase, superoxide dismutase, glu tathione peroxidase, and reduced glutathione levels. Galangin treatment significantly reduced the CTX-II mRNA and protein expression levels. The low CTX-II level in tissue indicated the inhibition of cartilage degradation. CONCLUSIONS In summary, supplementation with galangin was effective against OA. The identification of potential therapeutic agents that inhibit inflammation may be useful for the management and prevention of OA

Role of Tissue Factor in the Pathogenesis of COVID-19 and the Possible Ways to Inhibit It.

COVID-19 (Coronavirus Disease 2019) is a highly contagious infection and associated with high mortality rates, primarily in elderly; patients with heart failure; high blood pressure; diabetes mellitus; and those who are smokers. These conditions are associated to increase in the level of the pulmonary epithelium expression of angiotensin-converting enzyme 2 (ACE-2), which is a recognized receptor of the S protein of the causative agent SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Severe cases are manifested by parenchymal lung involvement with a significant inflammatory response and the development of microvascular thrombosis. Several factors have been involved in developing this prothrombotic state, including the inflammatory reaction itself with the participation of proinflammatory cytokines, endothelial dysfunction/endotheliitis, the presence of antiphospholipid antibodies, and possibly the tissue factor (TF) overexpression. ARS-Cov-19 ACE-2 down-regulation has been associated with an increase in angiotensin 2 (AT2). The action of proinflammatory cytokines, the increase in AT2 and the presence of antiphospholipid antibodies are known factors for TF activation and overexpression. It is very likely that the overexpression of TF in COVID-19 may be related to the pathogenesis of the disease, hence the importance of knowing the aspects related to this protein and the therapeutic strategies that can be derived. Different therapeutic strategies are being built to curb the expression of TF as a therapeutic target for various prothrombotic events; therefore, analyzing this treatment strategy for COVID-19-associated coagulopathy is rational. Medications such as celecoxib, cyclosporine or colchicine can impact on COVID-19, in addition to its anti-inflammatory effect, through inhibition of TF.

Celecoxib treatment dampens LPS-induced periapical bone resorption in a mouse model.

AIM: To evaluate the efficacy of selective and nonselective inhibitors of cyclooxygenase-2 enzymes in the treatment of experimental apical periodontitis induced by bacterial lipopolysaccharide (LPS) in vivo in a mouse model. METHODOLOGY: Thirty-six C57BL/6 mice were used. After access cavity preparation, a solution containing E. coli LPS (1.0 µg µL-1 ) was inoculated into the root canals of the mandibular and maxillary right first molars (n = 72) After 30 days, apical periodontitis was established and the animals were systemically treated with celecoxib, a selective COX-2 inhibitor (15 mg kg-1 ), or indomethacin, a nonselective COX-2 inhibitor (5 mg kg-1 ), for 7 and 14 days. Blocks containing teeth and bone were removed for histopathological and histometric analyses (haematoxylin and eosin), evaluation of osteoclasts numbers (tartrate-resistant acid phosphatase enzyme - TRAP) and immunohistochemistry for RANK, RANKL and OPG. Gene expression was performed using reverse transcription and real-time polymerase chain reaction (qRT-PCR) for RANK, RANKL, OPG, TRAP, MMP-9, cathepsin K and calcitonin receptor. Histopathological, histometric, TRAP, immunohistochemistry and qRT-PCR data were evaluated using Kruskal-Wallis followed by Dunn's test (α = 0.05). RESULTS: Systemic administration of celecoxib for 7 and 14 days prevented periapical bone resorption (P < 0.0001), differently from indomethacin that exacerbated bone resorption at 7 days (P < 0.0001) or exerted no effect at 14 days (P = 0.8488). Celecoxib treatment reduced osteoclast formation in apical periodontitis, regardless of the period of treatment (P < 0.0001 for 7 days and P = 0.026 for 14 days). Administration of celecoxib or indomethacin differentially modulated the expression of genes involved in bone resorption. At 7 days, celecoxib and indomethacin treatment significantly inhibited expression of mRNA for cathepsin K (P = 0.0005 and P = 0.016, respectively) without changing TRAP, MMP-9 and calcitonin receptor gene expression. At 14 days, celecoxib significantly inhibited expression of mRNA for MMP-9 (P < 0.0001) and calcitonin receptor (P = 0.004), whilst indomethacin exerted no effect on MMP-9 (P = 0.216) and calcitonin receptor (P = 0.971) but significantly augmented cathepsin K gene expression (P = 0.001). CONCLUSIONS: The selective COX-2 inhibitor celecoxib reduced osteoclastogenic signalling and activity that dampened bone resorption in LPS-induced apical periodontitis in mice, with greater efficacy than the nonselective inhibitor indomethacin.

Clinical comparison of platelet-rich plasma injection and daily celecoxib administration in the treatment of early knee osteoarthritis: A randomized clinical trial.

BACKGROUND: Oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and intra-articular corticosteroid injections are the recommended first line of treatment for knee osteoarthritis (OA); however, they have serious side effects. Platelet-rich plasma (PRP) has been posited as an effective and safer alternative treatment for knee OA. Hitherto, there is only one study comparing the effectiveness of PRP against an NSAID. AIM OF THE STUDY: The aim of this study was to determine the effectiveness of PRP against celecoxib in the treatment of early knee OA. METHODS: 60 patients with knee OA grade II and III were randomly alocated in two groups. Group 1 received one injection of autologous PRP in each affected knee, with a reinjection after 15 days; Group 2 received 200 mg of oral celecoxib each 24 h for a year. Visual Analogue Scale (VAS), total Western Ontario and McMaster Universities Arthritis Index (WOMAC) and WOMAC subscales for pain, stiffness and function were measured at baseline and at 1, 3, 6 and 12 months after the start of the treatment. RESULTS: At the end of the study PRP was significantly better than celecoxib (p < 0.05) in improving VAS (40.40%), total WOMAC (58.95%) and WOMAC subscales of pain (50.60%), stiffness (34.13%) and function (51.90%). Significant differences remained after adjusting for age, sex or knee OA grade II or III. CONCLUSIONS: Intra-articular PRP is significantly better than celecoxib in improving pain, function and stiffness in early knee OA. This significant difference is independent of age, sex or knee OA grade II or III.

Monitoramento do horizonte tecnológico: Medicamentos em desenvolvimento para o tratamento da atrofia muscular espinhal (AME) / Monitoring the technological horizon: Drugs under development for the treatment of spinal muscular atrophy (SMA)

A DOENÇA: As Atrofias Musculares Espinhais (AME) são um conjunto de doenças neuromusculares de etiologia genética relacionadas à hereditariedade de genes autossômicos recessivos. Os sinais e sintomas da AME são provenientes da degeneração e perda dos neurônios motores na medula espinhal e tronco encefálico, resultando em fraqueza muscular progressiva. Essas atrofias apresentam grande variabilidade clínica ocasionada pela perda ou deficiência da proteína de sobrevivência do neurônio motor (SMN - do inglês: Survival Motor Neuron). A maioria dos casos (95-98%) ocorre pela deleção homozigótica do gene SMN1, porém também pode ser decorrente de mutação heterozigótica pontual em um dos alelos desse gene. A mutação do gene SMN1 no cromossomo não sexual de número cinco, específica no loci denominado 5q11-13, dá origem à AME proximal ou denominada 5q. Essa mutação leva a uma troca de uma base nitrogenada citosina para timina, ocasionando a deleção do éxon 7. Dessa forma, essa mutação resulta em um RNA mensageiro (RNAm) encurtado, que codifica proteínas SMN truncadas, em menor quantidade e mais instáveis, sendo rapidamente degradadas. Um outro gene, o SMN2, também produz proteínas SMN, similares às transcritas pelo gene SMN1, contudo em uma quantidade menor. Assim, a presença do gene SMN2 em pacientes com AME mimetizam as manifestações clínicas da doença, ou seja, funciona como uma reserva de segurança para a perda do gene SMN. TRATAMENTO: Atualmente, o tratamento farmacológico da AME é limitado. Três medicamentos possuem registros de comercialização no mundo com indicação em bula para a doença. São eles: nusinersena, onasemnogeno abeparvoveque e ridisplam, este último registrado pelo Food and Drug Administration (FDA) em agosto de 2020. Os dois primeiros já estão registrados também no Brasil. O nusinersena é um medicamento administrado por via intratecal que atua como um oligonucleotídeo. antissenso (ou antissentido). Por meio de uma ligação à região intrônica 7, o nusinersena impede que os fatores de silenciamento/remoção intrônicos processem e removam o éxon 7 do RNAm do gene SMN2. A retenção do éxon 7 no RNAm de SMN2, permite a leitura e tradução correta destes genes, potencializando a produção de proteína funcional relacionada com a sobrevivência do neurônio motor, a proteína SMN (13). O medicamento foi registrado pelo FDA em 2016 e pela Anvisa em 2017. ESTRATÉGIA DE BUSCA: Para localizar os medicamentos em fase de pesquisa clínica para AME, foram consultados os sítios eletrônicos ClinicalTrials. gov, Embase, Medline (via PubMed) e no Google Acadêmico utilizando os termos "Spinal Muscular Atrophy". As buscas foram realizadas em 17 de julho de 2019. Consideraram-se as tecnologias a partir da fase II de pesquisa clínica, com a AME como alvo e sem registro para essa indicação terapêutica no Brasil. Posteriormente, utilizando-se os códigos de registro do ClinicalTrials.gov referentes aos estudos clínicos com os medicamentos identificados na etapa descrita no parágrafo anterior e aos nomes de cada uma dessas tecnologias, realizou-se busca nas bases de dados MEDLINE (via PubMed) e EMBASE, para a pesquisa de resultados publicados dos estudos clínicos. Além disso, uma busca complementar por resultados desses estudos publicados em anais de congressos científicos também foi realizada. MEDICAMENTOS EM FASE DE PESQUISA CLÍNICA: Modificador do padrão de splicing. Firefish. Sunfish. Jewelfish. Firefish + Sunfish + Jewelfish. Branaplan. Terapia Gênica: Onasemnogeno Abeparvoveque. Modificadores da Contração Muscular: Piridostigmina. CK-212707/ CK-107. SRK-015. Amifampridina. Anti-Inflamatório não Esteroidal que Altera os Níveis de Proteína SMN: Celecoxibe. LIMITAÇÕES: A maioria dos estudos localizados ainda está em andamento, estando disponíveis apenas resultados de análises interinas ou parciais apresentados em eventos científicos. Deste modo, as informações estão disponíveis apenas por meio de resumos ou pôsteres e alguns dados relevantes não estão disponíveis. No estudo FIREFISH, foi relatado que mais pacientes em uso de risdiplam não tiveram complicações decorrentes da doença, mas não informa quantos ou qual a proporção de indivíduos que apresentaram este resultado (19­22). Já a respeito do estudo SUNFISH, os autores reportaram a ocorrência de eventos adversos leves, mas não informaram a natureza e tipo destes eventos. INFORMAÇÕES ADICIONAIS: O Institute for Clinical and Economical Review (ICER) publicou relatório comparando o onasemnogeno abeparvoque ao nusinersena em termos clínicos e econômicos. No caso do nusinersena, os benefícios são mais evidentes entre pacientes pré-sintomáticos. Ambas as terapias possuem custo elevado e as análises de custo-efetividade do nusinersena mostram valores de custo-efetividade incremental superiores aos comumente aceitos nos Estados Unidos, tanto para anos de vida ajustados à qualidade (AVAQ) quanto para anos de vida ganhos (AVG). Quanto ao onasemnogeno abeparvoveque, no momento da avaliação ainda não havia sido definido um preço para o medicamento, embora os autores acreditem que ele também apresentará custo elevado e razão de custo efetividade incremental, seja por anos de vida ajustados à saúde, ou por anos de vida ganho superior aos limiares de custo-efetividade comumente utilizados. A conclusão dos autores do relatório foi de que ambas as terapias poderiam trazer benefícios clínicos importantes ao paciente, em termos de mortalidade, necessidade de ventilação mecânica e marcos de desenvolvimento motor para pacientes com AME tipo I. Ao obter aprovação do FDA, o onasemnogeno abeparvoveque teve seu preço estipulado em 2,1 milhões de dólares. A empresa fabricante do medicamento informou que irá trabalhar com os pagadores para implementar acordos de 5 anos baseados em desfechos e em opções de pagamentos ao longo do tempo. Estas informações, embora sejam provenientes de um cenário diferente do brasileiro, podem trazer questões relevantes para tomadas de decisão acerca de incorporações. Embora os Estados Unidos e o Brasil apresentem diferenças quanto ao cenário econômico e o tipo de sistema de saúde, problemas relacionados a restrições orçamentárias ocorrem em ambas as nações. Em termos de custo-efetividade, embora não tenham sido realizadas análises econômicas, é provável que ambos os medicamentos apresentem razões de custo-efetividade incremental elevadas. CONCLUSÕES: A AME é uma doença altamente incapacitante e é a causa mais comum de mortalidade infantil dentre as condições hereditárias. Sua heterogeneidade clínica resulta em dificuldades para o desenvolvimento de terapias efetivas e de estudos clínicos adequados. O objetivo do tratamento é promover melhoras na função motora e retardar a progressão de doença. Nos últimos dois anos, a perspectiva de tratamento medicamentoso da AME apresentou um avanço. O medicamento nusinersena possui registro no Brasil e foi incorporado ao SUS no primeiro semestre de 2019 para o tratamento de AME 5q tipo I. O onasemnogeno abeparvoveque foi registrado em agosto de 2020 para uso no Brasil, indicado para pacientes com AME com menos de dois anos de idade, e ainda carece de avaliação para incorporação no SUS (Informação atualizada em 24/09/ 2020). Por sua vez, o risdiplam foi registrado no FDA em agosto de 2020. A principal vantagem do risdiplam se deve ao fato da sua administração ser por via oral, porém o medicamento apresenta uso contínuo. A comparação publicada em 2019 pelo ICER quanto aos as pectos clínicos e econômicos do nusinersena e do onasemnogeno abeparvoveque conclui que ambas terapias trazem benefícios clínicos importantes para pacientes com AME 5q tipo I, sendo os efeitos do nusinersena mais evidentes em pacientes com AME pré-sintomática. As análises econômicas mostraram que as razões de custo-efetividade do nusinersena superam os limiares comumente aceitos nos Estados Unidos para AVAQ e AVG. Embora o onasemnogeno abeparvoveque não tivesse preço definido no momento da análise, é esperado que a mesma tendência seja observada. Foram localizadas ainda seis tecnologias em investigação (branaplan, piridostigmina, reldesemtiv, SRK-15, amifampridina, celecoxibe), entretanto, ainda em fases iniciais de estudo, com pouca ou nenhuma informação sobre seus resultados. Além disso, o perfil de segurança e eficácia dessas tecnologias precisa ser confirmado por meio de mais estudos clínicos comparativos. Desta forma, verifica-se que há no horizonte tecnológico potenciais tecnologias em desenvolvimento e que futuramente poderão ser utilizadas no tratamento da AME.

Coadministration of lithium and celecoxib reverses manic-like behavior and decreases oxidative stress in a dopaminergic model of mania induced in rats.

The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel), Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats, which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All these impairments were reversed by treatment with Li and/or Cel, in a way dependent on cerebral area and biochemical analysis. Li and Cel coadministration reversed the d-AMPH-induced decrease in catalase activity in cerebral structures. The activity of glutathione peroxidase was decreased in the frontal cortex of animals receiving d-AMPH, and treatment with Li, Cel, or a combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy.

Cutaneous Application of Celecoxib for Inflammatory and Cancer Diseases.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and particularly selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Cxb) are considered promising cancer chemopreventive for colon, breast, prostate, lung, and skin cancers. However, the clinical application to the prevention is limited by concerns about safety, potential to serious toxicity (mainly for healthy individuals), efficacy and optimal treatment regimen. Cxb exhibits advantages as potent antiinflammatory and gastrointestinal tolerance compared with conventional NSAID's. Recent researches suggest that dermatological formulations of Cxb are more suitable than oral administration in the treatment of cutaneous disease, including skin cancer. To date, optimism has been growing regarding the exploration of the topical application of Cxb (in the prevention of skin cancers and treatment of cutaneous inflammation) or transdermal route reducing risks of systemic side effects. OBJECTIVE: This paper briefly summarizes our current knowledge of the development of the cutaneous formulations or delivery systems for Cxb as anti-inflammatory drug (for topical or transdermal application) as well its chemopreventive properties focused on skin cancer. CONCLUSION: New perspectives emerge from the growing knowledge, bringing innovative techniques combining the action of Cxb with other substances or agents which act in a different way, but complementary, increasing the efficacy and minimizing toxicity.

Efficacy of Celecoxib Adjunct Treatment on Bipolar Disorder: Systematic Review and Meta-Analysis.

BACKGROUND: Bipolar Disorder (BD) is a psychiatric disorder characterized by mood disturbances. The pathophysiology of BD is still poorly understood. In the last years, research studies focused on the role of inflammation in BD. OBJECTIVE: Performed a systematic review and meta-analysis to evaluate the potential effect of the cyclo- oxygenases (Cox)-2 inhibitor Celecoxib adjunct treatment in BD through randomized controlled trials (RCT). METHODS: A search on the electronic databases was proceeded, on MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), Biomed Central, Web of Science, IBECS, LILACS, PsycINFO, Congress Abstracts, and Grey literature (Google Scholar and the British Library) for studies published from January 1990 to February 2018. A search strategy was developed using the terms: "Bipolar disorder" or "Bipolar mania" or "Bipolar depression" or "Bipolar mixed" or "Bipolar euthymic" and "Celecoxib" or "Cyclooxygenase-2 inhibitors" or "Cox-2 inhibitors" as text words and Medical Subject Headings (i.e., MeSH and EMTREE) and searched. The therapeutic effects of adjunctive treatment with Celecoxib were analyzed. The meta-analysis was performed including the results of the Young Mania Rating Scale (YMRS) at the end of RCT. RESULTS: Three primary studies were included in the systematic review, with a total of 121 patients. The meta-analysis showed a significant effect on the YMRS scores from patients with BD who used Celecoxib adjuvant treatment in comparison to placebo. CONCLUSION: The systematic review suggests that adjuvant treatment with Celecoxib improves the response of major treatments in patients with BD when compared with adjuvant placebo treatment. Systematic Review Registration Number: The review protocol was registered at PROSPERO (registration number: CRD42017067635); in June 06 2017.

Treatment of hepatocarcinoma with celecoxib and pentoxifylline: a case report / Manejo del hepatocarcinoma con celecoxib y pentoxifilina: reporte de un caso

Background: Hepatocellular carcinoma (HCC) is the sixth most frequent tumor worldwide and it is responsible for approximately 750 000 deaths each year. It is the third leading cause of cancer death in Mexico. Despite the existing therapeutic regimens, HCC has a poor prognosis with a life expectancy of approximately one month in advanced cases. The use of celecoxib and pentoxifylline has recently been reported in tumor patients with promising results due to its anti-inflammatory, antiangiogenic, antifibrotic and proapoptotic effects. Nonetheless, the combination of both drugs for the treatment of HCC has never been employed. Clinical case: 58-year-old male patient, who arrived to the examination room for presenting nausea, jaundice, asthenia, adynamia and encephalopathy grade I-II. The patient had a history of alcoholism for 47 years and diagnosis of cirrhosis in Child C stage. An image with focal lesion in the right lobe of 8 x 8 cm, which was highly vascularized, suggested HCC by means of imaging studies (ultrasound, computed axial tomography [CAT] and magnetic resonance imaging). Management began in January, 2015, and continues until today with 400 mg of pentoxifylline every 12 hours, 200 mg of celecoxib every 12 hours and vitamin supplements. Conclusion: After one month, patient showed a surprising response, reduction in tumor size almost in its entirety, improvement of clinical condition, and turned into Child A stage. Eight months after treatment it was observed by CAT that the tumor had practically disappeared. Patient has survived for more than two years. These results are encouraging; however, it is necessary to conduct multicenter studies that prove the efficacy of the treatment.

Introducción: El hepatocarcinoma (HPC) es el sexto tumor más frecuente a nivel mundial y provoca aproximadamente 750 000 muertes al año. Representa la tercera causa de muerte por cáncer en México. A pesar de los esquemas terapéuticos existentes, el pronóstico en el HPC es malo, con un promedio aproximado de vida de un mes en casos avanzados. Recientemente se ha reportado el uso de celecoxib y pentoxifilina en pacientes tumorales con resultados prometedores debido a sus efectos antiinflamatorios, antiangiogénicos, antifibróticos y proapoptóticos. Sin embargo, nunca han sido usados en combinación para el tratamiento de HPC. Caso clínico: Paciente masculino de 58 años que acudió a consulta por presentar náuseas, ictericia, astenia, adinamia y encefalopatía grado I-II; tenía antecedente de alcoholismo durante 47 años y diagnóstico de cirrosis en estadio Child C. Mediante ultrasonido, tomografía axial computarizada (TAC) y resonancia magnética se evidenció una imagen con lesión focal en lóbulo derecho de 8 x 8 cm, altamente vascularizada, sugestiva de HPC. Se inició manejo en enero de 2015 y el paciente continúa hasta la fecha con pentoxifilina (400 mg/12 h), celecoxib (200 mg/12 h) y suplementos vitamínicos. Conclusión: Después de un mes el paciente mostró una respuesta sorprendente, reducción del tamaño de la lesión casi en su totalidad, mejoría del estadio clínico y cambió a un estadio Child A. Ocho meses después de implementar el tratamiento se observó por medio de TAC que el tumor casi había desaparecido. El paciente ha sobrevivido por más de dos años. Los resultados son alentadores; sin embargo, es necesario realizar estudios multicéntricos que demuestren su real eficacia.

Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice.

Prostate cancer is the second most diagnosed cancer in the world, and alternative methods to prevent and treat different lesion grades need to be evaluated. The objective was to evaluate the morphological, hormonal, and inflammatory responses in the prostate anterior lobe in transgenic adenocarcinoma of the mouse prostate (TRAMP), following Celecoxib and Goniothalamin (GTN) treatments. All animals were treated for 4 weeks, from 8 weeks of age and euthanized either immediately after treatment (12-week-old mice: immediate response) or later (22-week-old mice: late response). The results showed a significant increase of high-grade prostatic intraepithelial neoplasia (HGPIN) and well-differentiated adenocarcinoma (WDA), according to the age in the control groups. Celecoxib treatment decreased the WDA incidence in the late response group. GTN led to a significant healthy tissue increase, and an LGPIN and HGPIN decrease in the immediate response group. In the late response group, GTN led to healthy area increase and there was no occurrence of WDA. AR and ERα immunoexpressions were reduced by both treatments in the immediate response groups. However, only GTN was able to decrease the ERα level in the late response group. Regarding COX-2 immunoreactivity, both treatments reduced the frequency of this enzyme. We can conclude that the prostate anterior lobe is a good model to study prostate cancer, considering its slow progression. Both treatments led to cancer delay in the prostate anterior lobe. However, GTN pointed towards a better treatment spectrum in the signaling pathways in the prostate microenvironment, particularly in ERα.

Iodine prevents the increase of testosterone-induced oxidative stress in a model of rat prostatic hyperplasia.

Oxidative stress and inflammation are involved in the development and/or progression of benign prostatic hyperplasia (BPH). Molecular iodine (I2) induces antiproliferative and apoptotic effects in prostate cancer cells, but it is unknown if I2 regulates oxidative stress in the normal and/or tumoral prostate. The purpose of this study was to analyze the effects of I2 and celecoxib (Cxb) on oxidative stress and inflammation in a model of prostatic hyperplasia. Cxb was used as positive control of cyclooxygenase-2 (COX-2) inhibition. Prostatic hyperplasia was induced in male Wistar rats (170g) with testosterone (5mg/kg/week, for three weeks). One week before hyperplasia induction, I2 (25mg/day/rat) or Cxb (1.25mg/day/rat) was supplied for four weeks in the drinking water. Prostatic hyperplasia was evaluated by histological analysis, DNA content, and/or proliferating cell nuclear antigen (PCNA) expression. Lipoperoxidation (malondialdehyde) and nitrite (NO2-) levels were analyzed by colorimetric methods, while nitric oxide synthase (NOS), COX, and myeloperoxidase (MPO) enzymes were analyzed using RT-PCR, immunoblotting, and/or enzymatic assays. Levels of 15-F2t-isoprostanes, prostaglandins (PGE2), leukotrienes (LTB4), and tumor necrosis factor alpha (TNFα) were measured by ELISA. Control testosterone-treated animals exhibited hyperplasia in the dorsolateral prostate, as well as increments in almost all oxidative parameters except for COX-1, TNFα, or MPO. I2 and Cxb prevented epithelial hyperplasia (DNA content) and oxidative stress induction generated by testosterone in almost the same intensity, and the minimum I2 dose required was 2.5mg/rat. The antioxidant capacity of I2 was also analyzed in a cell-free system, showing that this element inhibited the conversion of nitrate (NO3-) to NO2-. I2 did not modify the prostatic oxidative state in testosterone untreated rats. In summary, our data showed that antiproliferative and antioxidant effects of I2 involve the inhibition of NOS and the COX-2 pathway. Further studies are necessary to analyze the therapeutic and/or adjuvant effects of I2 with first-line medications used to treat BPH.

In Vitro and In Vivo Evaluation of DMSO and Azone as Penetration Enhancers for Cutaneous Application of Celecoxib.

BACKGROUND: Celecoxib (CXB) has been explored as an anti-inflammatory or chemopreventive drug for topical treatment of skin diseases and cancer. OBJECTIVE: The main aim of this work was to investigate the potential of dimethylsufoxide (DMSO) and Azone (AZ) as penetration enhancers (P.Es) for topical delivery of CXB. METHOD: The in vitro studies, drug release, skin permeability and potential cytotoxicity/genotoxicity were carried out with formulations containing or not DMSO or AZ (5% and 10%). Skin irritation in rabbits and topical anti-inflammatory activity in mice were assayed in vivo. RESULTS: Skin permeation was minimal while higher retention in stratum corneum (SC) and epidermis plus dermis was found (28.0 and 3-fold respectively) from 10.0% AZ compared to the control indicating a localized CXB effect. CXB associated to 5% or 10% DMSO has shown high drug permeation through skin with low retention. Associations of CXB with both enhancers were not cytotoxic or genotoxic, suggesting safety for cutaneous application. In vivo skin irritation assays of all formulations indicated mild irritation effects and, thus, possible use for longer periods. In vivo anti-inflammatory tests showed that ear edema could be inhibited by CXB associated with 5.0% DMSO (53.0%) or 10.0% AZ (40.0%). These inhibition values were almost 2-fold higher when compared to a commercial formula. CONCLUSION: Although DMSO- associated CXB is an efficient edema inhibitor its high skin permeation suggests risks of systemic effects, whereas association to 10% AZ may improve topical delivery of the drug with good anti-inflammatory activity and no cytotoxic/genotoxic or significant skin irritation effects.

Anti-inflammatory therapies in TRAMP mice: delay in PCa progression.

The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late-response groups at 22 weeks. The ventral prostate was collected for light microscopy, immunohistochemistry, western blotting, TUNEL, and ELISA. Morphological analyses indicated that GTN treatment delayed the progression of prostatic adenocarcinoma, leading to a significant decrease of prostatic lesion frequency in both experimental period responses to this treatment, mainly high-grade prostatic intraepithelial neoplasia and well-differentiated adenocarcinoma. Also, the celecoxib treatment showed a particular decrease in the proliferative processes (PCNA) in both the experimental periods. Despite celecoxib diminishing the COX2 and IGFR1 levels, GTN presented higher action spectrum considering the decrease of a greater molecular number involved in the proliferative and inflammatory processes in prostatic cancer. Goniothalamin attenuated the pro-inflammatory response in TRAMP prostatic microenvironment, delaying prostate cancer (PCa) progression. Celecoxib treatment was efficient in the regulation of COX2 in the TRAMP mice, mainly in the advanced disease grade. Finally, we concluded that inflammatory process control in early grades of PCa was crucial for the downregulation of the signaling pathways involved in the proliferative processes in advanced cancer grades.

Experimental evidence of pharmacological management of anchorage in Orthodontics: A systematic review.

INTRODUCTION: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed. OBJECTIVES: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage. METHODS: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed. RESULTS: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs). CONCLUSIONS: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.