RESUMO
The use of phosphodiesterase inhibitors in the treatment of Parkinson's disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra.
Assuntos
Corpo Estriado , Levodopa , Oxidopamina , Inibidores da Fosfodiesterase 5 , Citrato de Sildenafila , Substância Negra , Animais , Citrato de Sildenafila/farmacologia , Levodopa/farmacologia , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Ratos , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Dopamina/metabolismo , Comportamento Animal/efeitos dos fármacos , Quimioterapia Combinada , Serotonina/metabolismo , Modelos Animais de Doenças , Monoaminas Biogênicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismoRESUMO
PURPOSE: Bladder dysfunction associated with type 2 diabetes mellitus (T2DM) includes urine storage and voiding disorders. We examined pathological conditions of the bladder wall in a rat T2DM model and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. MATERIALS AND METHODS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats were used as the T2DM and control groups, respectively. Tadalafil was orally administered for 12 weeks. Micturition behavior was monitored using metabolic cages, and bladder function was evaluated by cystometry. Bladder blood flow was evaluated by laser speckle imaging, and an organ bath bladder distention test was used to measure adenosine triphosphate (ATP) release from the bladder urothelium. The expression levels of vesicular nucleotide transporter (VNUT), hypoxia markers, pro-inflammatory cytokines and growth factors in the bladder wall were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Bladder wall contractions in response to KCl and carbachol were monitored using bladder-strip tests. RESULTS: With aging, OLETF rats had higher micturition frequency and greater urine volume than LETO rats. Although bladder capacity was not significantly different, non-voiding bladder contraction occurred more frequently in OLETF rats than in LETO rats. Bladder blood flow was decreased and ATP release was increased with higher VNUT expression in OLETF rats than in LETO rats. These effects were suppressed by tadalafil administration, with accompanying decreased HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF expression. The impaired contractile responses of bladder strips to KCl and carbachol in OLETF rats with aging were restored by tadalafil administration. CONCLUSIONS: The T2DM rats had polyuria, increased ATP release induced by decreased bladder blood flow and impaired contractile function. PDE5 inhibition improved these changes and may prevent T2DM-associated urinary frequency and bladder storage and voiding dysfunctions.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Fosfodiesterase 5 , Poliúria , Tadalafila , Bexiga Urinária , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Ratos , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Poliúria/tratamento farmacológico , Ratos Endogâmicos OLETF , Micção/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Contração Muscular/efeitos dos fármacos , Trifosfato de Adenosina/metabolismoRESUMO
INTRODUCTION: There is a rising concern about developing innovative, efficacious PDE5I molecules that provide better safety, efficacy, and tolerability with less adverse effects. Innovative PDE5I with dual targets have also been defined in the literature. Additionally, some of PDE5I are able to selectively inhibit other enzymes such as histone deacetylase, acetylcholine esterase, and cyclooxygenase or act as nitric oxide donors. This review presents knowledge concerning the advanced trends and perspectives in using PDE5I in treatment of ED and other conditions. AREAS COVERED: Pre-clinical and early clinical trials that investigated the safety, efficacy, and tolerability of novel PDE5I such as Udenafil, Mirodenafil, Lodenafil, Youkenafil, Celecoxib, and TPN729 in treatment of ED and other conditions. EXPERT OPINION: Preclinical and limited early clinical studies of the new molecules of PDE5I have demonstrated encouraging results; however, safety, efficacy, and tolerability are still issues that necessitate further long-term multicenter clinical studies to ensure justification of their uses in treatment of ED and other conditions. Progress in molecular delivery techniques and tailored patient-specific management and additional therapeutic technology will dramatically improve care for ED and other conditions. The dream of ED and many other conditions becoming more effectively managed may be feasible in the near future.
Assuntos
Desenvolvimento de Medicamentos , Disfunção Erétil , Inibidores da Fosfodiesterase 5 , Humanos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Masculino , Animais , Drogas em Investigação/farmacologia , Drogas em Investigação/efeitos adversosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and inducible NOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors, including head and neck cancers. We show for the first time to our knowledge that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-programmed cell death protein 1, and anti-cytotoxic T lymphocyte-associated protein 4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA-sequencing analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid/T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid/T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.
Assuntos
Vacinas Anticâncer , Carcinoma Ductal Pancreático , Imunoterapia , Células Mieloides , Neoplasias Pancreáticas , Inibidores da Fosfodiesterase 5 , Tadalafila , Microambiente Tumoral , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Células Mieloides/imunologia , Células Mieloides/efeitos dos fármacos , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/farmacologia , Humanos , Camundongos , Imunoterapia/métodos , Animais , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , MesotelinaRESUMO
Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFß1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFß1 suppression. Overall, TGFß1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.
Assuntos
Fator 9 de Crescimento de Fibroblastos , Fibrose , MicroRNAs , Inibidores da Fosfodiesterase 5 , Hiperplasia Prostática , Tadalafila , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Tadalafila/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Humanos , Fator 9 de Crescimento de Fibroblastos/metabolismo , Fator 9 de Crescimento de Fibroblastos/genética , Próstata/efeitos dos fármacos , Próstata/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proliferação de Células/efeitos dos fármacosRESUMO
INTRODUÇÃO: Hipertensão pulmonar (HP) é definida pela presença de uma pressão arterial pulmonar média (PAPm) em repouso ≥25 mmHg. O Grupo 1 da HP é o mais bem caracterizado dos cinco grupos, engloba uma variedade de distúrbios, incluindo pacientes com HP idiopática, HP hereditária, HP induzida por medicamentos ou associada a distúrbios sistêmicos de colágeno, doenças cardíacas congênitas, doença hepática, esquistossomose ou vírus da imunodeficiência humana (HIV). Doença rara, estima-se mundialmente uma prevalência de aproximadamente 15 casos/1.000.000 indivíduos, com uma incidência anual de 2 a 5 casos/1.000.000 adultos (1,2). Doença grave, com sobrevida mediana de 2,8 anos, possui tratamento no SUS estabelecido em PCDT, que inclui além de bloqueadores do canal de cálcio, inibidores da fosfodiesterase 5 (PDE5i) sildenafila; antagonistas de receptor da endotelina 1 (ERA) ambrisentana e bosentana; prostanoides iloprosta e selexipague. Pacientes que mantém um risco intermediário ou alto apesar de terapia dupla com ERA e PDE5i devem associar ao tratamento preferencialmente selexipague, tendo o iloprosta como alternativa. Riociguate é um estimulador de guanilato ciclase solúvel (sGC) administrado por via oral que não está incorporado no PCDT para o tratamento da HP grupo 1, apesar de aprovado em bula para esta indicação. PERGUNTA: A terapia dupla (riociguate + ERA) é eficaz e segura no tratamento de pacientes com HAP do grupo 1 que não alcançaram resposta satisfatória com terapia dupla com PDE5i + ERA em comparação à terapia tripla (PDE5i + ERA + selexipague)? EVIDÊNCIAS CLÍNICAS: O demandante localizou apenas evidências que suportam a eficácia e segurança da substituição do PDE5i pelo riociguate, em monoterapia ou em combinação com ERA. Não há evidência para a proposta terapia dupla (riociguate + ERA) versus tripla (ERA + PDE5i + selexipague). AVALIAÇÃO ECONÔMICA: O demandante conduziu uma avaliação de custo-minimização com base na ausência de comprovação de superioridade entre as opções de tratamento. A economia de recursos seria entre R$ 113,15 (cenário considerando menor preço BPS) a R$ 11.092,35 (cenário preços SIGTAP) a favor da terapia dupla (riociguate + ERA) por paciente-ano. Porém, ao considerar o uso de iloprosta ao invés de selexipague na composição da terapia tripla, haveria um incremento de R$ 26.685,15 por paciente-ano. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Para a estimativa do impacto orçamentário foram combinados dados epidemiológicos com demanda aferida (pacientes tratados com bosentena, ambrisentana, sildenafila e iloprosta no SUS), valores projetados (tendência linear) para 2025, onde haveria 5.958 pacientes, sendo então considerados um percentual (75%) (3) de falha à terapia dupla e um percentual (24,8%) de elegíveis à terapia combinada tripla (4). Para o cenário alternativo, com a incorporação do riociguate, o market share da terapia dupla foi estimado entre 15% até 42% ao longo de cinco anos. Estimou-se, com base no cenário de preços SIGTAP e com 100% dos pacientes em terapia tripla fazendo uso do selexipague, uma economia de cerca de 18 milhões de reais em cinco anos. EXPERIÊNCIAS INTERNACIONAIS: Foram pesquisadas diversas agências de avaliação de tecnologias em saúde e outros institutos, mas não foi encontrado nenhum posicionamento em relação à incorporação do riociguate versus selexipague. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 07 tecnologias para compor o esquema terapêutico de pessoas adultas com hipertensão arterial pulmonar HAP I, que atenda às características desta demanda. Uma em fase 3 e em pré-registro na EMA e FDA: sotatercepte. Duas em fase 3 de desenvolvimento seralutinibe e ralinepag. Todas estas 3 envolveram centros de pesquisa no Brasil. E quatro em fase 2 de desenvolvimento: imatinibe, KER-012, LTP001 e MK-5475. CONSIDERAÇÕES FINAIS: Os estudos RESPITE e REPLACE apresentam evidências de que pacientes com HAP em uso de PDE5i com resposta insuficiente podem se beneficiar da substituição do tratamento pelo riociguate. Não há evidências sobre a comparação entre a terapia dupla (riociguate + ERA) versus tripla (selexipague + PDE5i + ERA). O demandante apresentou comparações indiretas que consideraram populações diferentes e análises de subgrupos sem poder estatístico, concluindo que, por não haver diferença estatística, as opções dupla e tripla teriam igual eficácia. Tal conclusão é inadequada, pois não há dados que corroborem para superioridade ou equivalência de eficácia entre as opções. Não foram localizadas evidências de comparação de riociguate versus selexipague com qualquer combinação de medicamentos. O parecerista considera relevante o risco de que se incorporado o riociguate, que este seja utilizado em monoterapia, em substituição ao PDE5i, e que o demandante não apresentou análises econômicas para esta comparação. Pela falta de evidência atual, um modelo que compare a terapia dupla versus a tripla terá limitações importantes, pois faltam dados de eficácia. Em uma análise de custo-minimização, observa-se economia de recursos a favor da terapia dupla, exceto se a terapia tripla for composta de iloprosta, ao invés de selexipague. PERSPECTIVA DO PACIENTE: A Chamada Pública nº 50/2023 esteve aberta entre 29/12/2023 e 21/01/2024, recebendo 16 inscrições. A participante relatou que, em 2021, apresentou sintomas como cansaço, falta de ar, desmaios e edemas, os quais foram se agravando. Consultou diferentes especialistas e teve repetidos episódios de internamento até que recebeu o diagnóstico de HAP primária idiopática veno-oclusiva. Iniciou o tratamento com sildenafila e ambrisentana. Posteriormente, foi acrescentado iloprosta ao esquema, retirado após poucos meses de uso em virtude dos eventos adversos. Em janeiro de 2023, iniciou o uso do riociguate, em substituição à sildenafila, pois a terapia estava dando pouco resultado. Considerou que, com a utilização do riociguate, houve melhora do seu estado de saúde e da qualidade de vida, conseguindo respirar sem suporte de oxigênio, assim como realizar atividades cotidianas. Atualmente, utiliza um esquema composto por ambrisentana, riociguate e selexipague. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, os membros do Comitê de Medicamentos da Conitec, em sua 128ª Reunião ordinária, realizada em 10 de abril de 2024, deliberaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação do riociguate associado a ERA para tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague. Para essa recomendação, a Conitec considerou principalmente a escassez de dados sobre a eficácia e segurança comparativa dos tratamentos, cujas evidências restringem-se ao uso dos tratamentos em monoterapia ou em terapia dupla para cerca de 70% da amostra. Ainda, a Comissão ponderou que as análises apresentadas estavam baseadas em desfechos secundários e análises de subgrupos, o que gerou um intervalo de credibilidade amplo, inadequadamente utilizado para afirmar igualdade de eficácia. Considerou ainda questionável o modelo de custo-minimização e a economia de recursos apresentada, pois apesar de o selexipague ser a opção de preferência quando necessária a terapia tripla, o uso de iloprosta em terapia tripla associado ao ERA e PDE5i também é indicado no PCDT e seria uma opção de menor custo que a terapia dupla de riociguate com ERA. CONSULTA PÚBLICA: A Consulta Pública nº 26 foi realizada entre os dias 24/05/2024 e 12/06/2024, recebendo o total de 334 contribuições. Dentre estas, 331 discordaram da recomendação preliminar da Conitec, uma concordou e duas expressaram não ter opinião formada. Entretanto, examinando essas contribuições, notase que esses participantes, na verdade, também discordam da recomendação inicial, uma vez que enviaram comentários defendendo e justificando a importância da incorporação do riociguate. Os principais argumentos em prol da incorporação abordaram a importância do acesso público ao medicamento e da ampliação das opções de tratamento, a possibilidade de manter a terapia dupla e o incremento à qualidade de vida trazido pela utilização do medicamento em avaliação. Sobre os resultados positivos e facilidades referentes ao uso tecnologia em avaliação, os participantes com experiência com o riociguate indicaram os benefícios para a saúde e o aumento da qualidade de vida. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Comitê de Medicamentos da Conitec, em sua 131ª Reunião Ordinária, no dia 04 de julho de 2024, deliberaram, por maioria simples, recomendar a não incorporação do riociguate associado a ERA para tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague. Para essa recomendação, os membros do Comitê de Medicamentos consideraram que as incertezas na síntese de evidências e na avaliação econômica da recomendação inicial foram mantidas. Assim, foi assinado o Registro de Deliberação nº 910/2024. DECISÃO: não incorporar, no âmbito do Sistema Único de Saúde - SUS, o riociguate associado a ERA para o tratamento de pacientes adultos com hipertensão arterial pulmonar (HAP - Grupo I) que não alcançaram resposta satisfatória com terapia dupla com PDE5i e ERA, como alternativa à terapia tripla com selexipague, publicada no Diário Oficial da União número 163, seção 1, página 140, em 23 de agosto de 2024.
Assuntos
Humanos , Receptores de Epoprostenol/agonistas , Inibidores da Fosfodiesterase 5/farmacologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Guanilato Ciclase/uso terapêutico , Sistema Único de Saúde , Brasil , Eficácia , Análise Custo-Benefício/economiaRESUMO
INTRODUCTION: Benign prostatic hyperplasia (BPH) is a condition that affects over 50% of men as they enter their fifth decade of life, often leading to lower urinary tract symptoms (LUTS). Primary treatment options include alpha blockers, 5-alpha reductase inhibitors, and phosphodiesterase-5 inhibitors. However, these medications can have some side effects, and there is a noticeable dearth of information addressing the long-term use of these medications. Thus, the exploration of all treatment modalities helps ensure patients receive personalized and effective care. Consequently, the primary objective of this review is to identify potential emerging medications for the treatment of BPH. AREAS COVERED: We conducted an extensive review of articles discussing pharmacotherapy for BPH spanning the last 15 years. Our information gathering process involved Scopus, PubMed-MEDLINE, Cochrane, Wiley Online Library Google Scholar, ClinicalTrials.gov, and the PharmaProjects database. This approach ensures that readers gain an in-depth knowledge of the existing therapeutic agents as well as promising avenues for managing BPH. EXPERT OPINION: BPH treatment targets a patient's specific constellation of symptoms. Therefore, a broad knowledge base encompassing various treatment options is paramount in ensuring optimal treatment. Looking forward, the emphasis on personalization promises to reshape the landscape of BPH treatment and improve patient outcomes.
Assuntos
Inibidores de 5-alfa Redutase , Desenvolvimento de Medicamentos , Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/fisiopatologia , Humanos , Masculino , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/fisiopatologia , Inibidores de 5-alfa Redutase/uso terapêutico , Inibidores de 5-alfa Redutase/farmacologia , Inibidores de 5-alfa Redutase/administração & dosagem , Animais , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos alfa/farmacologia , Desenho de Fármacos , Pessoa de Meia-IdadeRESUMO
Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6-K8 mouse clonal ß cells. Sildenafil amplified insulin secretion by enhancing Ca2+ influx. These effects required other depolarizing stimuli in MIN6-K8 cells but not in KATP channel-deficient ß cells, which were already depolarized, indicating that sildenafil-amplified insulin secretion is depolarization-dependent and KATP channel-independent. Interestingly, sildenafil-amplified insulin secretion was inhibited by pharmacological inhibition of R-type channels, but not of other types of voltage-dependent Ca2+ channels (VDCCs). Furthermore, sildenafil-amplified insulin secretion was barely affected when its effect on cyclic GMP was inhibited by PDE5 knockdown. Thus, sildenafil stimulates insulin secretion and Ca2+ influx through R-type VDCCs independently of the PDE5/cGMP pathway, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential antidiabetic medicine and a tool to elucidate the novel mechanism of insulin secretion.
Assuntos
Cálcio , Secreção de Insulina , Células Secretoras de Insulina , Insulina , Inibidores da Fosfodiesterase 5 , Citrato de Sildenafila , Citrato de Sildenafila/farmacologia , Animais , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Secreção de Insulina/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Cálcio/metabolismo , Insulina/metabolismo , Linhagem CelularRESUMO
BACKGROUND: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140â mg erenumab on day 1. They were then randomized to receive sildenafil 100â mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. RESULTS: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12â h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p < 0.001) during the first hour after administration compared to placebo. CONCLUSION: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT05889455.
Assuntos
Estudos Cross-Over , GMP Cíclico , Transtornos de Enxaqueca , Receptores de Peptídeo Relacionado com o Gene de Calcitonina , Citrato de Sildenafila , Humanos , Adulto , Masculino , Método Duplo-Cego , Feminino , Citrato de Sildenafila/farmacologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/induzido quimicamente , Pessoa de Meia-Idade , GMP Cíclico/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Inibidores da Fosfodiesterase 5/farmacologia , Adulto JovemRESUMO
OBJECTIVE: This study aimed to assess the erectogenic properties of isoliquiritigenin taking sildenafil (SDF) as the standard. METHODS: The binding affinity of isoliquiritigenin (ISL) with the erectile marker proteins (endothelial nitric oxide synthase [eNOS] and enzyme phosphodiesterase type 5 [PDE5]) was investigated using Autodock Vina, which was validated using molecular dynamics simulation. Furthermore, the effect of ISL on the eNOS and PDE5 messenger ribonucleic acid (mRNA) expression and the sexual behavior of mice was investigated, along with the assessment of the pharmacokinetics of ISL. KEY FINDINGS: The results revealed that the binding affinity of ISL-eNOS/PDE5 and SDF-eNOS/PDE5 was in the range of -7.5 to -8.6 kcal/mol. The ISL-eNOS/PDE5 complexes remained stable throughout the 100 ns simulation period. Root mean square deviation, Rg, SASA, hydrogen, and hydrophobic interactions were similar between ISL-eNOS/PDE5 and SDF-eNOS/PDE5. Analysis of mRNA expressions in paroxetine (PRX)-induced ED mice showed that the co-administration of PRX with ISL reduced PDE5 and increased eNOS mRNA expression, similar to the co-administered group (PRX+SDF). The sexual behavior study revealed that the results of PRX+ISL were better than those of the PRX+SDF group. Pharmacokinetic evaluation further demonstrated that ISL possesses drug-like properties. CONCLUSIONS: The results showed that ISL is equally potent as SDF in terms of binding affinity, specific pharmacological properties, and modulating sexual behavior.
Assuntos
Chalconas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Disfunção Erétil , Óxido Nítrico Sintase Tipo III , Animais , Masculino , Chalconas/farmacologia , Chalconas/farmacocinética , Disfunção Erétil/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Camundongos , Citrato de Sildenafila/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Simulação de Acoplamento Molecular , RNA Mensageiro/metabolismo , Simulação de Dinâmica Molecular , Paroxetina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mmâ Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Circulação Cerebrovascular , Estudos Cross-Over , Citrato de Sildenafila , Humanos , Citrato de Sildenafila/uso terapêutico , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/efeitos adversos , Masculino , Feminino , Idoso , Método Duplo-Cego , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Circulação Cerebrovascular/efeitos dos fármacos , Pessoa de Meia-Idade , Cilostazol/uso terapêutico , Cilostazol/farmacologia , Cilostazol/efeitos adversos , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/farmacologia , Resultado do Tratamento , Fluxo Pulsátil/efeitos dos fármacos , Imageamento por Ressonância Magnética , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiopatologiaRESUMO
ABSTRACT: Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and sudden cardiac death in a few case reports. Therefore, we investigated the in vitro and in vivo effect of sildenafil treatment and dosage on platelet activation and mitogen-activated protein kinase (MAPK) phosphorylation. BALB/C mice were segregated into four groups, each having four mice each (control, low [3.25 mg/kg], medium [6.5 mg/kg], and high [13 mg/kg] sildenafil), and after the treatment, blood was drawn from each mouse and washed platelets prepared. Washed platelets were incubated with CD41 PE-Cy7 and Phospho-p38 MAPK PE antibodies and analyzed using a flow cytometer for platelet activation and adenosine 5'- diphosphate (ADP)/collagen-induced MAPK phosphorylation. Washed platelets obtained from the venous blood of 18 human volunteers, were incubated with PAC-1 FITC and Phospho-p38 MAPK PE antibodies, and platelet activation (ADP and collagen), followed by flow cytometry analysis. There was a significant increase in both platelet activation as well as MAPK phosphorylation in the presence of collagen in the high-dose (13 mg/kg) sildenafil group (P = 0.000774). Further, increased platelet activation was observed in samples that were treated with high-dose sildenafil as compared to the untreated samples (P < 0.00001). These studies show the risk of prothrombotic episodes in patients on high-dose sildenafil (100 mg), in those with even mild endothelial dysfunction due to ADP, and collagen-induced platelet activation through MAPK phosphorylation, which was not seen in the low-and intermediate-dose cohorts.
Assuntos
Difosfato de Adenosina , Colágeno , Ativação Plaquetária , Citrato de Sildenafila , Adulto , Animais , Humanos , Masculino , Camundongos , Difosfato de Adenosina/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Relação Dose-Resposta a Droga , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Inibidores da Fosfodiesterase 5/farmacologia , Fosforilação , Ativação Plaquetária/efeitos dos fármacos , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/efeitos adversos , Citrato de Sildenafila/farmacologiaRESUMO
PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.
Assuntos
Autofagia , Progressão da Doença , Regulação para Baixo , Fibroblastos , Sistema de Sinalização das MAP Quinases , Inibidores da Fosfodiesterase 5 , Hiperplasia Prostática , Masculino , Humanos , Autofagia/fisiologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Fibroblastos/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Pessoa de Meia-Idade , GMP Cíclico/metabolismo , Idoso , Transdução de SinaisRESUMO
PDE5 inhibitors was reported to play a protective role in both regulating lipid metabolism and reducing heart failure (HF). This study aimed to clarify the effectiveness of PDE5 inhibitors against hyperlipidemia-related HF by combining evidence from population-based study and animal models. The nationwide cohort study found that post-diagnostic use of PDE5 inhibitors was associated with a significantly lower risk of HF compared with patients who used alprostadil, especially among individuals with hyperlipidemia (adjusted HR = 0.56, 95% CI = 0.40-0.78). In animal models, sildenafil significantly recovered the cardiac structure and function induced by AAB surgery, as well as reversed liver dysfunction and ameliorated hyperlipidemia induced by HFD via reducing the level of ALT, AST and serum lipids. Lipidomic analysis identified four lipid metabolites involved in sildenafil administration, including FA 16:3, LPC O-18:1, DG24:0_18:0 and SE28:1/20:4. This study revealed the protective effect of PDE5 inhibitors against HF in hyperlipidemia, indicating the potential of being repurposed as an adjuvant for HF prevention in patients with hyperlipidemia if these findings can be further confirmed in clinical trials.
Assuntos
Insuficiência Cardíaca , Hiperlipidemias , Inibidores da Fosfodiesterase 5 , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/sangue , Hiperlipidemias/complicações , Animais , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Humanos , Pessoa de Meia-Idade , Feminino , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Idoso , Modelos Animais de Doenças , Metabolismo dos Lipídeos/efeitos dos fármacos , Estudos de CoortesRESUMO
Hydroxycarbodenafil, an analogue of carbodenafil, was detected in a dietary supplement in China in 2020. However, previous reports have not identified some carbon signals from the piperazine ring in nuclear magnetic resonance (NMR) experiments. Because the compound contains an amide bond, the reaction was suggested to be characteristic of compounds with rotational isomers. Variable-temperature NMR is used to determine the rotational barrier between different conformations by changing the measurement temperature. Using this technique, we succeeded in obtaining the first distinct data, including the carbon signals of the piperazine ring in the NMR spectrum of hydroxycarbodenafil. We also confirmed that this technique could be applied to other carbodenafil analogues. Multi-stage mass spectrometry (MSn) measurements with a high-resolution mass spectrometer specific to the substructures were performed to develop a protocol for the structural determination of the carbodenafil analogues. In addition, hydroxycarbodenafil was analysed using X-ray crystallography, and its inhibitory activity against phosphodiesterase type 5 (PDE5) was measured. The IC50 value of the inhibitory activity of hydroxycarbodenafil for PDE5A1, a PDE5 isoform, of 2.9â¯nM was lower than the 4.5â¯nM for sildenafil, a positive control.
Assuntos
Espectroscopia de Ressonância Magnética , Inibidores da Fosfodiesterase 5 , Temperatura , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/análise , Inibidores da Fosfodiesterase 5/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Cristalografia por Raios X/métodos , Espectrometria de Massas em Tandem/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/análiseRESUMO
The vomeronasal organ (VNO) is a specialized chemoreceptive structure in many vertebrates that detects chemical stimuli, mostly pheromones, which often elicit innate behaviors such as mating and aggression. Previous studies in rodents have demonstrated that chemical stimuli are actively transported to the VNO via a blood vessel-based pumping mechanism, and this pumping mechanism is necessary for vomeronasal stimulation in behaving animals. However, the molecular mechanisms that regulate the vomeronasal pump remain mostly unknown. In this study, we observed a high level of expression of phosphodiesterase 5A (PDE5A) in the vomeronasal blood vessel of mice. We provided evidence to support the potential role of PDE5A in vomeronasal pump regulation. Local application of PDE5A inhibitors-sildenafil or tadalafil-to the vomeronasal organ (VNO) reduced stimulus delivery into the VNO, decreased the pheromone-induced activity of vomeronasal sensory neurons, and attenuated male-male aggressive behaviors. PDE5A is well known to play a role in regulating blood vessel tone in several organs. Our study advances our understanding of the molecular regulation of the vomeronasal pump.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Órgão Vomeronasal , Animais , Órgão Vomeronasal/metabolismo , Camundongos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Citrato de Sildenafila/farmacologia , Feromônios/metabolismo , Agressão/fisiologia , Feminino , Camundongos Endogâmicos C57BLRESUMO
Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then â¼15-75 min (TAD 1) and â¼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal D O 2 ${D_{{{\mathrm{O}}_2}}}$ and V Ì O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA D O 2 ${D_{{{\mathrm{O}}_2}}}$ .
Assuntos
Oxigênio , Placenta , Circulação Placentária , Tadalafila , Artéria Uterina , Animais , Feminino , Tadalafila/farmacologia , Tadalafila/administração & dosagem , Gravidez , Ovinos , Artéria Uterina/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/irrigação sanguínea , Circulação Placentária/efeitos dos fármacos , Oxigênio/sangue , Fluxo Sanguíneo Regional/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/administração & dosagem , Imageamento por Ressonância Magnética , Feto/irrigação sanguínea , Feto/efeitos dos fármacosRESUMO
OBJECTIVE: The aim of study was to investigate the effect of avanafil, a second-generation phosphodiesterase-5 (PDE5) inhibitor, on cerebral ischemia reperfusion (CI/R) model. METHODS: 32 male albino Wistar rats were used. Four groups were constituted, as I: the healthy (sham), II: the CI/R group, III: the CI/R +I 10 mg/kg avanafil group, and IV: the CI/R + 20 mg/kg avanafil group. Avanafil was administered twice via oral gavage, first shortly after ischemia reperfusion and once more after 12 h. The rats were euthanized after 24 h. Histopathological and Real Time PCR analyzes were performed on cerebral tissues. RESULTS: IL-1ß, NLRP3 and TNF-α mRNA expressions were statistically higher in the CI/R group when compared to healthy (sham) group. Conversely, the IL-1ß, NLRP3, and TNF-α mRNA expressions were significantly decreased in both of the avanafil-treated groups when compared to CI/R group. Histopathological results showed that both doses of avanafil also decreased cellular damage in cerebral tissue that occurred after CI/R. CONCLUSION: Avanafil, was found to have ameliorated inflammatory response and cellular injury caused by CI/R. The mRNA expression of IL-1ß, NLRP3, and TNF-α decreased in the I/R groups and approached the control group levels with a high dose of avanafil.
Assuntos
Isquemia Encefálica , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Pirimidinas , Ratos Wistar , Traumatismo por Reperfusão , Animais , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Inflamassomos/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêuticoRESUMO
Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.
Assuntos
Diabetes Mellitus Experimental , Inibidores da Fosfodiesterase 5 , Ratos Zucker , Dicloridrato de Vardenafila , Dicloridrato de Vardenafila/farmacologia , Dicloridrato de Vardenafila/toxicidade , Animais , Ratos , Inibidores da Fosfodiesterase 5/farmacologia , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Retina/efeitos dos fármacos , Retina/patologia , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Células Ependimogliais/metabolismoRESUMO
Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed inâ vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.