Tratamiento farmacológico en la restricción del crecimiento fetal: revisión de la bibliografía / Pharmacological management for fetal growth restriction: literature review

Resumen OBJETIVO: Explorar las diferentes estrategias de tratamiento farmacológico de la restricción del crecimiento fetal propuestas a lo largo del tiempo. METODOLOGÍA: Revisión cuasi-sistemática de la evidencia científica histórica disponible acerca del tratamiento médico descrito para la atención de mujeres embarazadas con restricción del crecimiento fetal. RESULTADOS: Entre los tratamientos médicos descritos para tratar la restricción del crecimiento fetal, los donadores de óxido nítrico, las estatinas y la aspirina asociada con omega 3, han tenido desenlaces no consistentes en estudios con limitado tamaño de muestra. Por lo que se refiere a los inhibidores de la 5-fosfodiesterasa, el sildenafilo no se ha asociado con un aumento de la velocidad de crecimiento fetal pero sí con alarmas respecto de su seguridad debidas al incremento de los casos de hipertensión pulmonar fetal y mortalidad perinatal. Por su parte, el tadalafilo ha mostrado desenlaces iniciales favorables y se esperan estudios con mayor tamaño de muestra que permitan emitir recomendaciones claras con respecto a su indicación. También se esperan los desenlaces de estudios clínicos en curso, para definir la indicación de la heparina de bajo peso molecular en este escenario en virtud de sus prometedores resultados iniciales. Los procedimientos más invasivos, como la inyección de factor de crecimiento endotelial vascular y la plasmaféresis, permanecen en estudio como propuestas terapéuticas por los resultados de estudios preclínicos y clínicos con pocos pacientes. CONCLUSIÓN: Por ahora, ninguna estrategia farmacológica propuesta ha conseguido generar recomendaciones fuertes para su indicación; sin embargo, se esperan nuevos estudios con alta calidad metodológica que generen evidencia científica lo suficientemente contundente para recomendar su indicación.

Abstract OBJECTIVE: To explore the different pharmacological treatment strategies for fetal growth restriction proposed over time. METHODOLOGY: Quasi-systematic review of the available historical scientific evidence on the medical treatment described for the care of pregnant women with fetal growth restriction. RESULTS: Among the medical treatments described to treat fetal growth restriction, nitric oxide donors, statins, and aspirin associated with omega-3 have had inconsistent outcomes in studies with limited sample size. As for 5-phosphodiesterase inhibitors, sildenafil has not been associated with an increase in fetal growth velocity, but there have been alarms regarding its safety due to the increase in cases of fetal pulmonary hypertension and perinatal mortality. On the other hand, tadalafil has shown favorable initial outcomes and studies with a larger sample size are awaited to issue clear recommendations regarding its indication. The results of ongoing clinical studies are also awaited to define the indication of low molecular weight heparin in this setting, given its promising initial results. More invasive procedures, such as vascular endothelial growth factor injection and plasmapheresis, remain under study as therapeutic proposals due to the results of preclinical and clinical studies with few patients. CONCLUSION: For now, no proposed pharmacological strategy has managed to generate strong recommendations for its indication; however, new studies with high methodological quality are expected to generate scientific evidence strong enough to recommend its indication.

Effect of topical nitric oxide donors on epidermal hyperplasia in mice with impaired barrier function / 中华皮肤科杂志

Objective:To evaluate the effect of nitric oxide on epidermal hyperplasia in mice with impaired barrier function.Methods:Fifteen SKH1 hairless mice were divided into 4 groups by using a random number table: normal control group (3 mice) , S-nitroso-N-acetyl-DL-penicillamine (SNAP) group (4 mice) , barrier-impaired group (4 mice) , SNAP-treated barrier-impaired group (4 mice) . Fifteen C57BL/6J mice were randomly and equally divided into 3 groups: normal control group, barrier-impaired group and sodium nitroprusside (SNP) -treated barrier-impaired group. Mice in the two normal control groups were both topically treated with propylene glycol-ethanol mixtures on the back; those in the SNAP group were topically treated with SNAP solution alone; those in the two barrier-impaired groups were both treated with repeated tape peeling followed by topical application of propylene glycol-ethanol mixtures on the back twice a day; those in the SNAP-or SNP-treated barrier-impaired group were treated with repeated tape peeling followed by topical application of 10-mmol/L SNAP or SNP solution on the back twice a day. After 4 consecutive days of treatment, all the mice were sacrificed on day 5, and skin tissues were resected from the back of mice followed by preparation of paraffin sections. Hematoxylin-eosin (HE) staining was performed to measure the epidermal thickness, and proliferating cell nuclear antigen (PCNA) staining was conducted to detect proliferating cells in the epidermis. Two-way analysis of variance and one-way analysis of variance were used for comparisons among groups, and least significant difference- t test was used for multiple comparisons. Results:No significant difference in the epidermal thickness or number of PCNA-positive cells was observed between the SNAP group and normal control group ( t=0.33, 1.25, P=0.748, 0.246, respectively) . Compared with the corresponding normal control groups, the barrier-impaired groups showed significantly increased epidermal thickness and number of PCNA-positive cells (all P < 0.01) . Compared with the corresponding barrier-impaired groups, SNAP-treated barrier-impaired group and SNP-treated barrier-impaired group both showed significantly increased epidermal thickness (SKH1: 127.5 ± 12.0 μm vs. 50.4 ± 5.4 μm; C57BL/6J: 78.1 ± 7.6 μm vs. 45.9 ± 3.7 μm; both P < 0.001) and number of PCNA-positive cells (SKH1: 120.0 ± 5.0 cells/mm vs. 87.3 ± 3.8 cells/mm; C57BL/6J: 285.0 ± 15.0 cells/mm vs. 232.0 ± 19.3 cells/mm; both P < 0.01) . Conclusion:Topical nitric oxide donors did not affect normal epidermis, but could aggravate epidermal hyperplasia in barrier-impaired skin, suggesting that skin condition affects the effect of topical nitric oxide donors on epidermal hyperplasia.

Neoplasms chemosensitization enhancing effects of nitric oxide donor compounds / 国际肿瘤学杂志

The chemosensitivity enhancive mechanism on nitric oxide includes three routes:adjust the expression level of hypoxia-inducible factor-1 α(HIF-1 α),classical nitric oxide signal pathway and combine with the reaction products of other molecules.Traditional nitric oxide donor compounds include nitroferricya-nide,organic nitrates,s-nitrosothiols,azo onium diol aldoxide,non-steroids anti-inflammatory drugs,whose function of antitumor and chemotherapy sensitization caused extensive attention.

Assessment of ocular surface toxicity after topical instillation of nitric oxide donors / Avaliação da toxicidade na superfície ocular após instilação tópica de doadores de óxido nítrico

PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.

OBJETIVO: Avaliar a toxidade na superfície ocular de dois compostos doadores de óxido nítrico em modelos ex vivo e in vivo: S-nitrosoglutationa (GSNO) e S-nitroso-N-acetilcisteína (SNAC), em uma matriz de hidroxipropil metilcelulose (HPMC) nas concentrações finais de 1,0 and 10,0 mM. MÉTODOS: As toxicidades de GSNO e SNAC foram avaliadas clinicamente e histologicamente em modelo ex vivo usando globos oculares porcinos recém excisados. Experimentos in vivo foram realizados com 20 coelhos albinos que foram randomizados em 4 grupos (5 animais em cada): Os grupos 1 e 2 receberam instilações de 150 µL de solução aquosa de HPMC contendo GSNO 1,0 e 10,0 mM, respectivamente, em um dos olhos; Os grupos 3 e 4 receberam instilações de 150 µL de solução aquosa de HPMC contendo SNAC 1,0 and 10,0 mM, respectivamente, em um dos olhos. Os olhos contralaterias em cada grupo receberam solução aquosa de HPMC como controle. Todos os animais foram clinicamente avaliados em lâmpada de fenda e os olhos foram pontuados de acordo com o teste de Draize modificado e analisados histologicamente. RESULTADOS: Os globos oculares porcinos não apresentaram sinais de perfuração, erosão, opacidade da córnea ou outros danos graves. Esses resultados foram confirmados pela análise histológica. Não houve diferença entre os olhos dos coelhos tratados e controles de acordo com a pontuação do teste de Draize em todos os grupos (p>0,05). Todas as formulações apresentaram um escore médio menor do que 1 e foram classificadas como "não-irritantes". Não houve evidência de toxicidade tecidual nas análises histológicas em todos os animais. CONCLUSÃO: Soluções aquosas de HPMC contendo GSNO e SNAC em concentrações até 10,0 mM não induzem irritação ocular.

Estudo do efeito do TERPY [Ru(terpy)(bdq)NO+]3+, um novo doador de óxido nítrico, na reatividade vascular e na pressão arterial de ratos espontaneamente hipertensos (SHR) / Study of the effect of TERPY [Ru (terpy) (bdq) NO +] 3 +, a new nitric oxide donor, vascular reactivity and blood pressure in spontaneously hypertensive rats (SHR)

O uso clínico de drogas que liberam óxido nítrico (NO) é limitado por seus efeitos colaterais. A hipotensão induzida pelo doador clássico de NO, nitroprussiato de sódio (NPS) é rápida, transiente e induz à taquicardia reflexa, o que pode ser um efeito indesejável em pacientes com doença cardíaca e uma limitação para a terapia anti-hipertensiva. Este estudo avaliou o efeito hipotensor e vasodilatador do novo doador de NO [Ru(terpy)(bdq)NO+]3+ (TERPY) e comparou com os resultados obtidos com o NPS em ratos Wistar e ratos espontaneamente hipertensos (SHR). Em outra parte do estudo, foram estudadas diferenças no mecanismo de ação desta droga entre aortas de SHR jovens e velhos. Diferente do observado para o NPS, a hipotensão induzida pelo TERPY é lenta, duradoura e não leva a alterações da frequência cardíaca. Além disso, o TERPY libera quantidades semelhantes de NO em aortas de SHR e Wistar, induzindo relaxamento parcialmente dependente de GCs em ambos os grupos, ao contrário do NPS, que libera mais NO em aortas de SHR e também é mais potente e eficaz em aortas desses animais. Fatores como o estresse oxidativo e a atividade da PDE5 são importantes para o relaxamento do TERPY em SHR, mas a inibição da PDE5 não aumenta a potência do TERPY em aortas de ratos Wistar. Além disso, o relaxamento induzido pelo TERPY é mais potente em anéis de aorta de SHR velhos do que novos. Os mecanismos de ação do TERPY são semelhantes nas aortas desses animais, mas, interessantemente, a incubação com Apocinina aumenta a potência do TERPY em aortas de SHR jovens, mas não de velhos. Em conjunto, estes dados demonstram que o composto TERPY é um doador de NO que possui vantagens em relação ao NPS. Além disso, é mais potente em aortas de animais hipertensos velhos, o que é mais uma vantagem para sua utilização e um incentivo para a realização de novos estudos que possam contribuir para entender melhor seu mecanismo de ação

The clinical use of nitric oxide (NO) releasing drugs is limited by their harmful effects. The hypotension induced by the classic NO donor, sodium nitroprusside (SNP) is fast, transient and induces reflex tachycardia, which can be an undesirable effect in patients with heart disease and a limitation for the anti-hypertensive therapy. This study evaluated the hypotensive and vasodilatory effects of the new NO donor [Ru(terpy)(bdq)NO+]3+ (TERPY) in Wistar rats and spontaneously hypertensive rats (SHR). In another part of the study, we investigated the differences in the mechanism of action of this drug between aortas of young and old SHR. Different from what is observed for SNP, the hypotension induced by TERPY is slow, long lasting and doesn’t lead to alterations in the heart rate. Besides, TERPY releases similar amounts of NO in SHR and Wistar aortas, inducing a relaxation partially dependent on GCs in both groups, contrary to SNP, which releases more NO in aortas of SHR and is also more potent and efficient in the aortas of these animals. Factors as oxidative stress and the activity of PDE5 are important to the relaxation of TERPY in SHR, but the inhibition of PDE5 doesn’t increase the potency of TERPY in aortas of Wistar rats. Furthermore, the relaxation induced by TERPY is more potent in aortas of old SHR than of young ones. The mechanisms of action of TERPY are similar in the aortas of both groups, but, interestingly, the incubation with Apocynin increases the potency of TERPY in aortas of young SHR, but not of old ones. Taken together, these data show that the compound TERPY is a NO donor that has advantages in relation to SNP. Moreover, it’s more potent in aortas of old hypertensive animals, which is another advantage for its use and an incentive for the elaboration of new studies that could contribute to understand its mechanism of action

Effects of exogenous NO on cell proliferation and cell cycle of gastric cancer cell line SGC-7901 / 肿瘤

Objective:To investigate the effect of exogenous nitric oxide(NO) on the growth and proliferation of gastric cancer cell line SGC-7901. Methods:The inhibitory effects of NO donor sodium nitroprusside (SNP) and nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methylester(L-NAME) on the proliferation of SGC-7901 cells were analyzed by MTT assay. The changes of mRNA and protein expression of proliferating cell nuclear antigen(PCNA) and caspase-3 were examined by RT-PCR and Western blotting. The cell cycle was measured using flow cytometry. Results:Compared with control group, more cells in the SNP group were arrested at G_1 and G_0 phases (P<0.05) and fewer cells were at S phases (P<0.05). SNP decreased the speed of cell-cycle progression from G_0/G_1 phase into S phase. SNP inhibited the proliferation of SGC-7901 cells and reduced the mRNA and protein expressions of PCNA and caspase-3. NOS inhibitor L-NAME reversed the effects of SNP. Conclusion:NO inhibited cell growth and proliferation, but accelerated apoptosis of gastric cancer cells.

Nitroglicerina transdérmica versus nifedipina oral para inibição do trabalho de parto prematuro: ensaio clínico randomizado / Transdermal nitroglycerin versus oral nifedipine administration for tocolysis: a randomized clinical trial

OBJETIVO: comparar a efetividade da nitroglicerina transdérmica com a nifedipina oral na inibição do trabalho de parto prematuro. MÉTODOS: foi realizado um ensaio clínico com 50 mulheres em trabalho de parto prematuro, randomizadas em dois grupos, 24 para nifedipina oral (20 mg) e 26 para nitroglicerina transdérmica (patch 10 mg). Foram selecionadas as pacientes com gestação única, entre a 24ª e 34ª semanas e diagnóstico de trabalho de parto prematuro. Foram excluídas pacientes com malformações fetais e com doenças clínicas ou obstétricas. As variáveis analisadas foram tocólise efetiva, tempo necessário para tocólise, frequência de recorrência, progressão para parto prematuro e efeitos colaterais. RESULTADOS: a eficácia da tocólise nas primeiras 12 horas foi semelhante entre os grupos (nitroglicerina: 84,6 por cento versus nifedipina: 87,5 por cento; p=0,5). A média do tempo para tocólise também foi semelhante (6,6 versus 5,8 horas; p=0,3). Não houve diferença entre os grupos quanto à recorrência de parto prematuro (26,9 versus 16,7 por cento; p=0,3) e nem na frequência de parto prematuro dentro de 48 horas (15,4 versus 12,5 por cento; p=0,5). Entretanto, a frequência de cefaleia foi significativamente maior no grupo que usou nitroglicerina (30,8 versus 8,3 por cento; p=0,04). CONCLUSÕES: a nitroglicerina transdérmica apresentou efetividade semelhante à nifedipina oral para inibição do trabalho de parto prematuro nas primeiras 48 horas, porém com maior frequência de cefaleia.

PURPOSE: to compare the effectiveness of transdermal nitroglycerin with oral nifedipine in the inhibition of preterm delivery. METHODS: a clinical essay has been performed with 50 women in preterm delivery, randomly divided into two groups, 24 receiving oral nifedipine (20 mg), and 26, transdermal nitroglycerin (10 mg patch). Patients with a single gestation, between the 24th and the 34th weeks and diagnosis of preterm delivery were selected. Women with fetal malformation and clinical or obstetric diseases were excluded. The variables analyzed were: effective tocolysis, time needed for tocolysis, recurrence frequency, progression to preterm delivery, and side effects. RESULTS: tocolysis efficacy in the first 12 hours was similar between the groups (nitroglycerin: 84.6 percent versus nifedipine: 87.5 percent; p=0.50). The time average time needed for tocolysis was also similar (6.6 versus 5.8 hours; p=0.30). There was no difference between the groups, concerning the recurrence of preterm delivery (26.9 versus 16.7 percent; p=0.30), and neither in the rate of preterm delivery within 48 hours (15.4 versus 12.5 percent; p=0.50). Nevertheless, the cephalea rate was significantly higher in the Nitroglycerin Group (30.8 versus 8.3 percent; p=0.04). CONCLUSIONS: transdermal nitroglycerin has presented similar effectiveness to oral nifedipine to inhibit preterm delivery in the first 48 hours, however with higher cephalea frequency.

Evaluation of the protective function of NO precursor/donator on cerebral ischemia injury with DWI and PWI / 中国医师杂志

Objective To establish a rat model of middle cerebral artery occlusion (MCAO)by blockage or obstruction of middle cerebral artery. NO precursor L-Arginine (L-ARG) and NO donator Nitroglycerine (NG)are administrated from intraearotid arteries. DWI and PWI are applied to evaluate blood circulation and brain damage of the effected region to elucidate the piotective function of L-ARG and NG in the early stage of brain ischemia. Methods The middle cerebral artery was occluded by insertion of a suture through the internal carotid artery of SD male rats to duplicate ischemia-reperfusion model. Reperfusion was established by suture withdrawal. After 2 hours of blockage, reperfusion and administrate L-ARG,NG by interventional therapy through the internal carotid artery simultaneously. Image indexes such as T1WI, T2WI, DWI and PWI are utilized to assess the changes in different time points. These indexes, Longa score and TTC stain were compared. Results There were obvious decrease in DWI high signal region and Trc pale region in drugs groups, compared with MCAO group(P＜0.01).ADC and rADC values in DWI high signal region increased gradually from 2 hours after ischemia to 24 hours after reperfusion in each group. ADC and rADC values in DWI high signal region of the drugs groups increased obviously(P＜0.01).Conclusion Interventional therapy with NO precursor/donator showed significant protective function in the early stage of brain ischemia.

Sodium nitroprusside preventing pulmonary ischemia-reperfusion injury / 中华器官移植杂志

Objective To study the role of sodium nitroprusside in preventing pulmonary ische-mia-reperfusion injury and the possible mechanism. Methods Fourteen pigs were randomly divided into 2 groups: control group underwent controlled reperfusion with reperfusion solution (leukocyte-depleting blood modified buckberg perfusate = 4:1) for 10 min at lower pressure of 18 mm Hg and 37℃? 1℃ before removing the pulmonary artery clamp; experimental group were subjected to controlled reperfusion with reperfusion solution before removing the pulmonary artery clamp, followed by infusion of sodium nitroprusside (10?g?kg-1?min 1 for 10 min) via pulmonary artery. Blood oxygen pressure, pulmonary vascular resistance, pulmonary compliance and the changes in pulmonary oxygen-ation function were assessed 0. 5, 1 and 2 h later. After the trail, the contents of water, NO and MDA in pulmonary tissues were measured. Results In the experimental group, left lung oxygenation function and pulmonary compliance was significantly better (P