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1.
Artigo em Inglês | MEDLINE | ID: mdl-36141480

RESUMO

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Pré-Eclâmpsia , Feminino , Retardo do Crescimento Fetal , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/tratamento farmacológico , Humanos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico
2.
Ulus Travma Acil Cerrahi Derg ; 28(10): 1373-1381, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36169464

RESUMO

BACKGROUND: This study aimed to evaluate the healing effects of adipose tissue-derived mesenchymal stem cells (AT-MSC) and sildenafil citrate alone or in combination of colon anastomosis experimental model. METHODS: A total of 40 female Wistar rats were randomly distributed to four groups: Control (without any intervention post-anas-tomosis), stem cell (AT-MSC injection on the anastomosis site), SIL (oral gavage of 10 mg/kg sildenafil citrate), and stem cell + SIL (AT-MSC injection and oral administration of sildenafil citrate) groups. Rats were euthanized 5 days post-anastomosis. Intra-abdominal adhesion status and anastomotic burst pressure were measured to assess anastomotic healing. Hydroxyproline and TNF-α level, neu-trophil leukocyte infiltration, epithelial regeneration, and necrosis in the anastomosis tissue were examined. RESULTS: Anastomosis leakage and anastomosis burst pressure were not different among the groups. Treatment with sildenafil, stem cell, and stem cell + SIL reduced the degree of perianastomotic adhesions compared to control (p<0.05). A significant increase was noted in hydroxyproline in the stem cell and stem cell + SIL groups (p=0.001). AT-MSC injection alone or in combination with sildenafil citrate reduced the TNF-α concentration at the anastomosis site (p=0.001). Histopathological examination revealed that all treatments enhanced the clearance of the necrotic debris, reduced leukocytes infiltration, and accelerated the retraction of anastomo-sed ends except control (p=0.001). Epithelial regeneration was more pronounced in the stem cell group than other groups (p=0.001). Macrophage density was lower in groups treated with the SIL or stem cell groups than the control and stem cell + SIL groups (p=0.001). CONCLUSION: Sildenafil citrate and/or AT-MSC in the anastomosed rats promoted the anastomosis healing that was more pro-nounced in groups receiving stem cell injections.


Assuntos
Células-Tronco Mesenquimais , Fator de Necrose Tumoral alfa , Anastomose Cirúrgica , Animais , Colo/cirurgia , Feminino , Hidroxiprolina , Células-Tronco Mesenquimais/metabolismo , Modelos Teóricos , Ratos , Ratos Wistar , Citrato de Sildenafila/farmacologia
3.
Pak J Biol Sci ; 25(8): 705-714, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36098196

RESUMO

<b>Background and Objective:</b> <i>Chrysomya albiceps</i> are the insects most commonly associated with corpses, they are of medical and forensic value and thus their immature stages are used to estimate the post mortem interval (PMI) and may provide medicolegal experts essential information regardless of the time, place and cause of death. The current study's goal was to determine the impacts of these pharmaceuticals compounds in some of the biochemical parameters enzymes of the <i>C. albiceps</i> third instar larvae. <b>Materials and Methods:</b> The experiment was performed from April to June, 2018. <i>C. albiceps</i> was fed rabbit tissues during its development for three generations tramadol is administered an overdose of (30.8 mg kg<sup></sup><sup>1</sup>), sildenafil citrate an overdose of (10.26 mg kg<sup></sup><sup>1</sup>) and diazepam an overdose of dissolved in distilled water (4.06 mg kg<sup></sup><sup>1</sup>), by intra-injection into the abdominal cavity twice daily for one week and rabbits injected with distilled water were also used to raise the control group. <i>Chrysomya albiceps</i> larvae in their third instars measured enzymes by using a spectrophotometer. <b>Results:</b> The results indicated to significantly increase of antioxidant enzymes activity of control group of TP, TAC, SOD, GST and CAT and decrease of MDA and significantly decreased of TP, TAC, SOD, GST and CAT and increase of MDA for the tramadol, sildenafil and diazepam groups for the three generations of larvae, respectively. <b>Conclusion:</b> In conclusion, the evidence suggested that decreased antioxidant enzyme activity and increase of MDA might be involved in the production of free radicals in <i>C. albiceps</i> oxidative stress is caused by these pharmaceuticals compounds.


Assuntos
Dípteros , Tramadol , Animais , Antioxidantes , Diazepam , Larva , Preparações Farmacêuticas , Coelhos , Citrato de Sildenafila , Superóxido Dismutase , Água
4.
Arch Ital Urol Androl ; 94(3): 319-322, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36165478

RESUMO

OBJECTIVES: The aim of this study was to investigate the impact of the addition of 50 mg daily sildenafil to pentoxifylline-colchicine combination ther-apy on the Peyronie's plaque features in patients with the acute phase of Peyronie's disease (PD). METHODS: In this retrospective and non-randomized clinical study, patients were divided into 2 groups as group 1; (n = 107) who received colchicine and pentoxyfillin plus 50 mg daily oral sildenafil, and as group 2; (n = 79) who received only colchicine and pentoxyfillin. Patients were compared in terms of degree of curvature, pain in erection and erectile function at the baseline and at 6-month follow up. Pain in erection and erectile func-tion were evaluated by visual Analogue Scale (EF-VAS), and the shortened version of the International Index of Erectile Function (IIEF-5). Improvement in the degree of curvature and change in EF-VAS scores were primary endpoints of the study. Change in IIEF-5 score was the secondary endpoint of the study. RESULTS: The two groups were statistically similar in terms of demographics and baseline features of PD. A statistically signifi-cant reduction in degree of curvature and EF-VAS scores was shown in group 1 compared to group 2.There was also a signifi-cantly higher IIEF-5 score in group 1 compared to group 2. No significant side effects were detected in both groups during treatment period. CONCLUSIONS: Adding sildenafil to pentoxifylline-colchicine com-bination treatment seems to improve PD related symptoms in the acute phase PD. PDE5i may contribute to relieve the Peyronie's symptoms in ED patients through their antifibrotic effects.


Assuntos
Disfunção Erétil , Induração Peniana , Pentoxifilina , Colchicina/farmacologia , Colchicina/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Dor , Induração Peniana/tratamento farmacológico , Pênis , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Estudos Retrospectivos , Citrato de Sildenafila/uso terapêutico , Resultado do Tratamento
5.
J Chromatogr A ; 1678: 463366, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35914410

RESUMO

Sexual enhancement dietary supplements have often been adulterated with phosphodiesterase type 5 (PDE-5) inhibitors used for treatment of erectile dysfunction, and widely distributed through online markets. As the illegal adulterants, the original PDE-5 inhibitor drugs and a numerous number of synthetized analogues, more than 80, have already been found. Therefore, analytical methods that detect various PDE-5 inhibitors and uncover newly synthesized analogues are needed. In this study, we have developed a rapid and reliable screening method for PDE-5 inhibitors and their structural analogues by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by hierarchical clustering based on similarity of MS/MS spectra. Forty reference standards of PDE-5 inhibitors/analogues were measured using a quadrupole-orbitrap mass spectrometer in data-dependent mode. The 60 most intense fragment ions were extracted from each MS/MS spectra, and the ions observed within 1.5 mDa mass tolerance were considered to be the same ion. Based on fragment ion tables representing detected ions for each compound, hierarchical clustering was performed. The resulting dendrogram showed that the reference standards were separated into seven clusters according to their characteristic structures. Subsequently, two additional standards spiked into a herbal sample were analyzed. While herbal components were clearly separated from the clusters of the reference standards, the spiked standards were clustered closely with the structurally similar standards. Furthermore, application of our method to dietary supplements allowed for detection of sildenafil and tadalafil as adulterants. These results suggest that our screening method facilitates discovery of adulterant PDE-5 inhibitors/analogues by illustrating their structural similarity.


Assuntos
Inibidores da Fosfodiesterase 5 , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Análise por Conglomerados , Suplementos Nutricionais/análise , Contaminação de Medicamentos , Íons , Inibidores da Fosfodiesterase 5/análise , Citrato de Sildenafila , Espectrometria de Massas em Tandem/métodos
6.
AAPS PharmSciTech ; 23(6): 224, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962205

RESUMO

In the context of increasing application of modelling methods in the field of pharmaceutics, this study aims to reduce the weight of sildenafil orally disintegrating tablets (ODTs) and optimize their formulation through modelling methods. To achieve the goal, the back-propagation neural network (BPNN)-based non-dominated sorting genetic algorithm II (NSGA-II) was introduced to establish the models and to optimize the percentage of magnesium stearate (MgSt), crospovidone (PVPP), and croscarmellose sodium (CCNa) to obtain satisfactory candidate ODTs. Ultimately, the bioequivalence trial was conducted to verify the effectiveness of the formulation. With the support of the neural network, the model showed satisfactory results in the prediction of hardness and disintegration time of ODTs, and the pareto front obtained by the NSGA-II suggested that there was a strong "competition" between disintegration time and hardness. Since disintegration time should be given the priority, the optimal formulation was determined as 1% MgSt, 6% CCNa, and 2.6% PVPP. The bioequivalence trial results indicated a bioequivalence between the test and the reference formulations of sildenafil, and better medication experience for the test formulation. A bioequivalent formulation with better medication experience is successfully prepared using the NSGA-II. It proves that the NSGA-II is applicable to multi-objective optimization of the drug formulation.


Assuntos
Algoritmos , Administração Oral , Composição de Medicamentos/métodos , Dureza , Citrato de Sildenafila , Solubilidade , Comprimidos
7.
Front Immunol ; 13: 883886, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935981

RESUMO

Successful TB treatment is hampered by increasing resistance to the two most effective first-line anti-TB drugs, namely isoniazid and rifampicin, thus innovative therapies focused on host processes, termed host-directed therapies (HDTs), are promising novel approaches for increasing treatment efficacy without inducing drug resistance. We assessed the ability of Sildenafil, a type-5 phosphodiesterase inhibitor, as a repurposed compound, to serve as HDT target, by counteracting the suppressive effects of myeloid-derived suppressor cells (MDSC) obtained from active TB cases on T-cell responsiveness. We confirm that MDSC suppress non-specific T-cell activation. We also show that Sildenafil treatment fails to reverse the MDSC-mediated suppression of T-cell functions measured here, namely activation and proliferation. The impact of Sildenafil treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.


Assuntos
Mycobacterium tuberculosis , Células Supressoras Mieloides , Tuberculose , Humanos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Linfócitos T
8.
Multimedia | Recursos Multimídia | ID: multimedia-9852
9.
Int J Mol Sci ; 23(13)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35806018

RESUMO

Reduced renal medullary oxygen supply is a key factor in the pathogenesis of acute kidney injury (AKI). As the medulla exclusively receives blood through descending vasa recta (DVR), dilating these microvessels after AKI may help in renoprotection by restoring renal medullary blood flow. We stimulated the NO-sGC-cGMP signalling pathway in DVR at three different levels before and after hypoxia/re-oxygenation (H/R). Rat DVR were isolated and perfused under isobaric conditions. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (10-6 mol/L) impaired cGMP degradation and dilated DVR pre-constricted with angiotensin II (Ang II, 10-6 mol/L). Dilations by the soluble guanylyl cyclase (sGC) activator BAY 60-2770 as well as the nitric oxide donor sodium nitroprusside (SNP, 10-3 mol/L) were equally effective. Hypoxia (0.1% O2) augmented DVR constriction by Ang II, thus potentially aggravating tissue hypoxia. H/R left DVR unresponsive to sildenafil, yet sGC activation by BAY 60-2770 effectively dilated DVR. Dilation to SNP under H/R is delayed. In conclusion, H/R renders PDE5 inhibition ineffective in dilating the crucial vessels supplying the area at risk for hypoxic damage. Stimulating sGC appears to be the most effective in restoring renal medullary blood flow after H/R and may prove to be the best target for maintaining oxygenation to this vulnerable area of the kidney.


Assuntos
Injúria Renal Aguda , Óxido Nítrico , Animais , Hipóxia , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/farmacologia , Vasoconstrição
10.
Am J Vet Res ; 83(8)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35895800

RESUMO

OBJECTIVE: To develop a topical sildenafil hydrogel and evaluate its effect on wound healing in dogs. ANIMALS: 6 purpose-bred, sexually intact, adult Beagles. PROCEDURES: Hydrogels containing sildenafil citrate, N-methyl-2-pyrrolidone, propylene glycol, and poloxamer 407 were developed. Four excision wounds were created along the dorsum of the dogs. Each wound was treated for 21 days with a nonadherent bandage (C) or with a hydrogel containing 0% (G), 5% (5S), or 10% (10S) sildenafil. Daily bandage changes with wound imaging were performed. Biopsy specimens were collected 5 times. RESULTS: Hydrogels were homogenous at room temperature and released > 90% of the sildenafil within 8 hours in vitro. Time to first granulation tissue was significantly shorter for the sildenafil groups (mean ± SD, 2.8 ± 0.8 days [5S and 10S]), compared with the control groups (5.2 ± 0.4 days [C] and 6.3 ± 1.4 days [G]). The G wounds had a 10% to 14% lower contraction rate, compared with the C, 5S, and 10S wounds. 5S wounds had a total wound area 0.7 ± 0.3 cm2 larger than 10S wounds. No significant differences were present when C wounds were compared with 5S and 10S wounds for total wound area, contraction, or epithelialization. Histologic acute inflammatory scores were higher for 5S and 10S wounds in the early and late stages of wound healing, with higher reparative scores on day 7. Neovascularization was higher for 10S wounds on day 7 and 14. CLINICAL RELEVANCE: The topical sildenafil hydrogel promoted early granulation tissue, which may be beneficial for secondary wound closure in clinical settings.


Assuntos
Hidrogéis , Cicatrização , Animais , Bandagens/veterinária , Cães , Tecido de Granulação , Hidrogéis/uso terapêutico , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico
11.
BMC Res Notes ; 15(1): 244, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35799272

RESUMO

OBJECTIVES: To determine the efficacy and safety of sildenafil citrate to improve outcomes in pregnancies complicated by early-onset, dismal prognosis, fetal growth restriction (FGR). Eligibility: women ≥ 18 years, singleton, 18 + 0-27 + 6 weeks' gestation, estimated fetal weight < 700 g, low PLFG, and ≥ 1 of (i) abdominal circumference < 10th percentile for gestational age (GA); or (ii) reduced growth velocity and either abnormal uterine artery Doppler or prior early-onset FGR with adverse outcome. Ineligibility criteria included: planned termination or reversed umbilical artery end-diastolic flow. Eligibility confirmed by placental growth factor (PLGF) < 5 th percentile for GA measured post randomization. Women randomly received (1:1) either sildenafil 25 mg three times daily or matched placebo until either delivery or 31 + 6 weeks. PRIMARY OUTCOME: delivery GA. The trial stopped early when Dutch STRIDER signalled potential harm; despite distinct eligibility criteria and IRB and DSMB support to continue, because of futility. NCT02442492 [registered 13/05/2015]. RESULTS: Between May 2017 and June 2018, 21 (90 planned) women were randomised [10 sildenafil; 11 placebo (1 withdrawal)]. Baseline characteristics, PLGF levels, maternal and perinatal outcomes, and adverse events did not differ. Delivery GA: 26 + 6 weeks (sildenafil) vs 29 + 2 weeks (placebo); p = 0.200. Data will contribute to an individual participant data meta-analysis.


Assuntos
Retardo do Crescimento Fetal , Artérias Umbilicais , Canadá , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Retardo do Crescimento Fetal/tratamento farmacológico , Idade Gestacional , Humanos , Fator de Crescimento Placentário/uso terapêutico , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Citrato de Sildenafila/uso terapêutico , Ultrassonografia Pré-Natal/efeitos adversos , Artérias Umbilicais/diagnóstico por imagem
12.
J Cell Mol Med ; 26(16): 4556-4565, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35810384

RESUMO

Radiation-induced oral mucositis is a common and dose-limiting complication of head and neck radiotherapy with no effective treatment. Previous studies revealed that sildenafil, a phosphodiesterase 5 inhibitor, has anti-inflammatory and anti-cancer effects. In this study, we investigated the effect of sildenafil on radiation-induced mucositis in rats. Two doses of radiation (8 and 26 Gy X-ray) were used to induce low-grade and high-grade oral mucositis, separately. A control group and three groups of sildenafil citrate-treated rats (5, 10, and 40 mg/kg/day) were used for each dose of radiation. Radiation increased MDA and activated NF-κB, ERK and JNK signalling pathways. Sildenafil significantly decreased MDA level, nitric oxide (NO) level, IL1ß, IL6 and TNF-α. The most effective dose of sildenafil was 40 mg/kg/day in this study. Sildenafil also significantly inhibited NF-κB, ERK and JNK signalling pathways and increased bcl2/bax ratio. In addition, high-dose radiation severely destructed the mucosal layer in histopathology and led to mucosal cell apoptosis in the TUNEL assay. Sildenafil significantly improved mucosal structure and decreased inflammatory cell infiltration after exposure to high-dose radiation and reduced apoptosis in the TUNEL assay. These findings show that sildenafil can improve radiation-induced oral mucositis and decrease the apoptosis of mucosal cells via attenuation of inflammation and oxidative stress.


Assuntos
NF-kappa B , Estomatite , Animais , Apoptose , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Estomatite/tratamento farmacológico , Estomatite/etiologia , Estomatite/metabolismo
13.
Inflammopharmacology ; 30(4): 1351-1362, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35834151

RESUMO

The current work explored the influences of time dependent Sildenafil (SILD) administration, and the possible outcomes from its concomitant administration with dexamethasone against acetic acid-induced ulcerative colitis in rats. Rats were assigned into six random groups: diseased group (AA), injected once with 2 ml acetic acid (3%) intrarectally, 2 days before sacrification. SILD + AA, received sildenafil (25 mg/kg, orally) for 6 days starting 3 days pre-injection of AA; SILD-t + AA, received sildenafil (25 mg/kg, orally), starting at time of AA injection and continued for 3 days; DEXA + AA, received dexamethasone (2 mg/kg, i.p.) for 3 days, starting at time of AA injection; SILD-t + DEXA + AA, received sildenafil (25 mg/kg, orally) and dexamethasone (2 mg/kg, i.p.), as mentioned. Sildenafil markedly ameliorated disease activity index (DAI), ulcer scores, colon length shortening and colonic histopathological changes. Mechanistically, Sildenafil markedly attenuated immunoexpression of NF-κB p65/ TNF-α and COX-2, diminished oxidative stress (↓ MDA/NO levels and ↑ GSH level and SOD activity), increased levels of Nrf-2/HO-1, compared to untreated group. Taken together, Sildenafil treatment suppressed acetic acid-induced ulcerative colitis, probably via inhibiting NF-κB/TNF-α signaling dependent of Nrf-2/HO-1 pathway, reducing oxidative stress and attenuating inflammation. Surprisingly, effects of sildenafil were unpromoted in a time dependant manner. Short term treatment with sildenafil was sufficient to exert its coloprotective effect, while longer term pretreatment was only superior among other treatments in the macroscopical changes. Moreover, concurrent administration of sildenafil and dexamethasone had the preference in boosting the antioxidant defense and anti-inflammatory mechanisms, visualized by histopathological/immunohistochemical changes.


Assuntos
Colite Ulcerativa , Ácido Acético/farmacologia , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo , Dexametasona/farmacologia , NF-kappa B/metabolismo , Ratos , Citrato de Sildenafila/efeitos adversos , Citrato de Sildenafila/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Placenta ; 126: 46-53, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35764022

RESUMO

INTRODUCTION: There is a lack of effective therapeutic interventions for preeclampsia. A central factor in the etiology of the disease is the development of placental hypoxia due to abnormal vascular remodeling. However, methods to assess the impact of potential therapies on placental growth and remodeling are currently lacking. Here, we develop and validate ultrasound-guided photoacoustic imaging methods to monitor the placental response to therapeutic intervention. Establishing non-invasive tools to image placental function opens up previously unachievable understandings of placental therapeutic response. METHODS: Studies were performed in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. Preclinical research has identified tempol, a superoxide dismutase mimetic, and the phosphodiesterase inhibitor sildenafil as potential therapeutics for preeclampsia, as both improve in vivo maternal outcomes. PA images of the placental environment were acquired in RUPP rats receiving tempol (n = 8) or sildenafil (n = 8) to assess the longitudinal effects of treatment on placental oxygenation and vascular remodeling. Imaging measurements were validated with ex vivo histological analysis. RESULTS: Spectral photoacoustic imaging non-invasively measured placental hypoxia and impaired vascular growth two days after the RUPP procedure was implemented. Sildenafil significantly improved (p < 0.05) placental oxygenation and promoted vascular remodeling in RUPP animals, while RUPP animals treated with tempol had a diminished placental therapeutic response. DISCUSSION: We demonstrate that photoacoustic imaging provides in vivo measures of placental oxygenation and vascular remodeling, a previously unobtainable assessment of preeclamptic therapeutic response. These imaging tools have tremendous potential to accelerate the search for effective therapies for preeclampsia.


Assuntos
Técnicas Fotoacústicas , Pré-Eclâmpsia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hipóxia , Isquemia , Técnicas Fotoacústicas/efeitos adversos , Placenta/irrigação sanguínea , Pré-Eclâmpsia/diagnóstico por imagem , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/etiologia , Gravidez , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/farmacologia , Remodelação Vascular
17.
Apoptosis ; 27(7-8): 606-618, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35725975

RESUMO

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.


Assuntos
Cisplatino , Linfoma de Células T , Apoptose , Linhagem Celular Tumoral , Cisplatino/farmacologia , Glucose/metabolismo , Glicólise , Humanos , Linfoma de Células T/metabolismo , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Citrato de Sildenafila/farmacologia
18.
Drug Dev Ind Pharm ; 48(2): 41-51, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35754330

RESUMO

Two simple and validated chromatographic studies were performed for simultaneous estimation of sildenafil citrate (SIL) and alfuzosin hydrochloride (ALF) in bulk, pharmaceuticals, and in the presence of their main degradation products. Two systems of mobile phase were applied isocratically for their first chromatographic separation using conventional and micellar mobile phases. Methanol, acetonitrile, and 0.02 M potassium dihydrogen phosphate (43:14:43 v/v; pH 4.66) were pumped at 1.3 mL/min in method I. Meanwhile, method II was based on less hazardous micellar mobile phase of nonionic surfactant (0.005 M Brij-35 in water; pH 2.5 adjusted with 0.1% orthophosphoric acid) with a flow rate of 1 mL/min. Both methods were carried on C18 column and coupled with UV detection at 225 nm at ambient temperature. The first method was rectilinear over the concentration range of 5-62.5 µg/mL for both drugs, while the second method showed higher linearity ranges of 0.5-40, 2.5-62.5 µg/mL for ALF and (SIL), respectively. The developed methods successfully enabled the quantification of the studied binary mixture in their tablets dosage form and evaluation their stabilities. Validation of the proposed methods according to ICH guidelines and system suitability were ascertained. Moreover, the applied methods were evaluated and compared from the perspective of green analytical chemistry, employing the National Environmental Methods Index, analytical Eco-Scale score, and Green Analytical Procedure Index, as three assessment tools.


Assuntos
Micelas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Quinazolinas , Citrato de Sildenafila
19.
Life Sci ; 303: 120691, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35671809

RESUMO

AIMS: The present study aimed to investigate the effect of nano selenium, sildenafil, and their combination on inflammation, oxidative stress, and apoptosis in streptozotocin-induced diabetic nephropathy in rats. Herein, a new anti-inflammatory pathway for sildenafil as a high-mobility group box (HMGB1) inhibitor was proposed using the molecular docking technique. MATERIALS AND METHODS: Rats were divided into 7 groups: normal control, control nano selenium, control sildenafil, control diabetic, diabetic+ nano selenium, diabetic+ sildenafil, diabetic+ nano selenium+ sildenafil. The effects of drugs were evaluated by measuring serum urea, creatinine, lactate dehydrogenase (LDH), levels of tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1ß), HMGB1, receptor advanced glycation end product (RAGE), malondialdehyde (MDA), thioredoxin reductase (TrxR) by biochemical assays, nuclear factor-kappa b (NF-κB), toll-like receptor (TLR4) by immunohistochemistry, gene expressions of caspase 3 and monocyte chemoattractant protein (MCP-1) besides histopathological investigations of renal cells. KEY FINDINGS: Results showed beneficial effects of 8 weeks of treatment by nano selenium and sildenafil supported by improvement in kidney function, histopathological changes, and reduction in all of these parameters. These results supported molecular docking that indicated sildenafil had a high binding score and interactions with the HMGB1 receptor. SIGNIFICANCE: The current study demonstrated a renoprotective effect of nano­selenium and sildenafil by interfering at multiple pathways, especially the HMGB1/NF-κB signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Proteína HMGB1 , Selênio , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Proteína HMGB1/metabolismo , Rim/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Selênio/metabolismo , Selênio/farmacologia , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Estreptozocina/farmacologia
20.
Vascul Pharmacol ; 145: 107017, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35680060

RESUMO

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.


Assuntos
Hipertensão Pulmonar , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Catepsina B/farmacologia , Catepsina B/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/terapia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/prevenção & controle , Hipóxia/tratamento farmacológico , Inflamassomos , Inflamação/patologia , Monocrotalina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Artéria Pulmonar , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêutico , Remodelação Vascular
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