Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.938
Filtrar
1.
Adv Clin Exp Med ; 28(10): 1409-1418, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31638745

RESUMO

BACKGROUND: Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to polymorphic ventricular tachycardia and ventricular fibrillation. OBJECTIVES: This study investigated the effect of an intracoronary (IC) bolus of high adenosine triphosphate (ATP) and nicorandil doses for IMR measurement and explored the possibility of inducing maximal hyperemia with an IC alprostadil bolus. MATERIAL AND METHODS: Index of coronary microcirculatory resistance was measured in a hyperemic state induced by 7 experimental conditions in 21 pigs (IC bolus of papaverine (18 mg), ATP (40 µg, 80 µg, 160 µg, and 240 µg), and nicorandil (2 mg and 4 mg)). The 7 conditions were induced sequentially, and the average IMR was calculated. Because of the long-term hyperemic condition in the pilot experiments, the IMR was measured 1, 3, 5, 8, and 10 min after an IC bolus of alprostadil (10 µg) in another 7 pigs. RESULTS: The IMR induced by 240 µg of ATP or 4 mg of nicorandil was not significantly different from that induced by 18 mg of papaverine (both p > 0.05). A strong linear correlation was observed between IMRs with papaverine (18 mg) and nicorandil (4 mg) (R2 = 0.936, p < 0.001) and with papaverine (18 mg) and ATP (240 µg) (R2 = 0.838, p < 0.05). The IC bolus of nicorandil (4 mg) produced the smallest changes, whereas papaverine caused the most significant changes in mean blood pressure and heart rate (p < 0.05). Tachypnea and transient ST depression were more common with increasing ATP dosages (especially 240 µg). Alprostadil (5 min) yielded a significant hyperemic response but reduced baseline blood pressure by almost 40% for a long time. CONCLUSIONS: Intracoronary bolus administration of 4 mg of nicorandil was better than 18 mg of papaverine or 240 µg of ATP for induction of maximal hyperemia and IMR measurement in a pig model, whereas alprostadil was not suitable for IMR measurement.


Assuntos
Trifosfato de Adenosina/administração & dosagem , Alprostadil/administração & dosagem , Circulação Coronária/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Nicorandil/administração & dosagem , Papaverina/administração & dosagem , Vasodilatadores/administração & dosagem , Trifosfato de Adenosina/farmacologia , Alprostadil/farmacologia , Animais , Papaverina/farmacologia , Suínos , Vasodilatadores/farmacologia
2.
J Bras Nefrol ; 41(2): 185-192, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31498862

RESUMO

BACKGROUND: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. METHOD: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. RESULTS: Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). CONCLUSION: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.


Assuntos
Derivação Arteriovenosa Cirúrgica/métodos , Falência Renal Crônica/cirurgia , Papaverina/farmacologia , Vasodilatadores/farmacologia , Adolescente , Adulto , Idoso , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Feminino , Seguimentos , Hematoma/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Papaverina/administração & dosagem , Estudos Prospectivos , Diálise Renal , Trombose/etiologia , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Pressão Venosa , Adulto Jovem
3.
PLoS One ; 14(5): e0216358, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31100066

RESUMO

The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Papaverina/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Proteína HMGB1/metabolismo , Xenoenxertos , Humanos , Camundongos , Alcaloides Opiáceos , Papaverina/farmacologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Temozolomida/farmacologia
4.
J Mol Neurosci ; 68(1): 111-119, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852743

RESUMO

Studies have shown that papaverine can inhibit lipopolysaccharide (LPS)-induced microglial activation. The retinal primary microglia of newborn SD rats were isolated and purified, and a LPS-induced microglia activation model was established. The protein phosphorylation level of the signaling pathway was detected by western blotting. The transcription and expression of TNF-α, IL-1ß, and IL-10 were respectively detected by RT-PCR and ELISA to observe the abnormal activation of primary microglia. The cAMP inhibitor Rp-isomer, PKA inhibitor H89, and MEK inhibitor U0126 were separately added to further investigate the role of MEK/Erk in PAP inhibition of primary microglial activation and the relationship between cAMP/PKA and MEK/Erk. It was found that the level of MEK phosphorylation was upregulated after LPS stimulation, which was blocked by 10 µg/ml of papaverine.10µM U0126 significantly inhibited TNF-α and IL-1ß and increased IL-10 transcription and expression in retinal microglia (P < 0.01). Both Rp-isomer and H89 upregulated the phosphorylation levels of MEK and Erk. Papaverine may inhibit inflammatory factors and promote the expression of anti-inflammatory factors through the cAMP/PKA and MEK/Erk pathway, thereby inhibiting LPS-induced activation of primary retinal microglia, and the MEK/Erk pathway may be partially regulated by cAMP/PKA, which can provide theoretical basis and experimental basis for its protection of the central nervous system.


Assuntos
Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases , Microglia/metabolismo , Retina/metabolismo , Animais , Células Cultivadas , Citocinas/genética , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Papaverina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Ratos , Ratos Sprague-Dawley , Retina/citologia
5.
J Cardiothorac Surg ; 14(1): 15, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30665449

RESUMO

BACKGROUND: Radial artery (RA) is widely used in coronary artery bypass (CABG) surgery and the prevention of spasm is crucial for graft patency. Botulinum toxin A (BTX-A) and B are commonly used for aesthetic reasons and neuromuscular disorders. They are proven to raise blood flow and increase survival of ischemic skin flaps. In this study we evaluated and compared the vasodilator effects of BTX-A and papaverine on human RA grafts. METHODS: After resting 60 min in isolated organ baths, human RA grafts were examined. Contraction responses for different doses of serotonin (5-HT) and endothelin-1 (ET-1) were evaluated as a percent of maximum contraction response elicited by 80 mM potassium chloride (KCl). The inhibitory effects of BTX-A and papaverine on contraction responses taken at the 0th hour were compared with the 1st and 2nd hour responses. Inhibitory effects of BTX-A and papaverine against the contractile agent were evaluated by comparing the results of the first and last (0th and 2nd hour) application. RESULTS: In low concentrations, when we compared the effects of BTX-A (10- 8 M) and papaverine (10- 6 M) on 5-HT, papaverine was found to be more effective at both the 0th and 2nd hour (p < 0.05). Both BTX-A and papaverine inhibited the maximum contractile effect of ET-1 to the same extent at the 0th hour; but, the inhibitory effect of BTX-A was significantly stronger at the 2nd hour (p < 0.05). In high concentrations, when we compared the effects of BTX-A (10- 6 M) and papaverine (10- 4 M) on 5-HT, papaverine showed stronger inhibition (p < 0.05), whereas both agents had similar action of inhibition on ET-1 mediated maximum contraction responses. CONCLUSION: BTX-A inhibits both ET-1 and 5-HT induced contractions and its effectiveness does not decrease over time as observed with papaverine. This study is the first in the literature using human RA for prevention of vasospasm by BTX-A.


Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/cirurgia , Papaverina/farmacologia , Artéria Radial/transplante , Vasoconstrição/efeitos dos fármacos , Adulto , Idoso , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/farmacologia , Artéria Radial/efeitos dos fármacos , Artéria Radial/fisiologia , Vasodilatadores/farmacologia
6.
Am J Respir Cell Mol Biol ; 60(5): 532-540, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30365340

RESUMO

Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides their coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) extracellular signal-related kinase 1/2 (ERK1/2), but the cellular effects are not known. In the present study, we show in HASM cells that TAS2R agonists initially stimulate phosphorylated ERK1/2 (pERK1/2) but by 24 hours cause a marked (50-70%) downregulation of pERK1/2 without a change in total ERK1/2. It was hypothesized that TAS2R agonists suppress cell growth through this pERK1/2 downregulation. Agonist-dependent inhibition of cell proliferation was indeed found in HASM cells derived from normal and asthmatic human lungs, as well as in an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2 (mitogen-activated protein kinase/extracellular signal-regulated kinase). Various structurally diverse TAS2R agonists evoked a range of inhibition of HASM proliferation, the magnitude of which directly correlated with the downregulation of pERK1/2 (R2 = 0.86). Some TAS2R agonists were as effective as pharmacological inhibitors of Raf1 and MEK1/2 in suppressing growth. siRNA silencing of TAS2Rs (subtypes 10, 14, and 31) ablated the pERK1/2 and growth-inhibitory effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G protein Gαi and by knocking down ß-arrestin 1/2, indicating a dual pathway, although there may be additional mechanisms involved in this HASM TAS2R multidimensional signaling. Thus, TAS2R agonist structure can be manipulated to maintain the relaxation response and can be biased toward suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, in which an increase in smooth muscle mass contributes to airway obstruction.


Assuntos
Broncodilatadores/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Miócitos de Músculo Liso/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/genética , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Asma/patologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Cálcio/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Emodina/análogos & derivados , Emodina/farmacologia , Famotidina/farmacologia , Humanos , Transporte de Íons/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Papaverina/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , beta-Arrestina 1/genética , beta-Arrestina 1/metabolismo , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
7.
Neurocrit Care ; 30(2): 467-477, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30386963

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is an important contributor to morbidity and mortality. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) and ET-1 are upregulated and contribute to impairment of cerebral autoregulation and histopathology after porcine fluid percussion brain injury (FPI). Recent studies show that inhaled nitric oxide (iNO) prevents impairment of cerebral autoregulation and histopathology after FPI in pigs. Unrelated studies indicated an association between ERK and increased IL-6 after FPI. However, the role of IL-6 in central nervous system (CNS) pathology is not well understood. We investigated whether iNO protects autoregulation and limits histopathology after FPI in pigs due to modulation of brain injury associated upregulation of ET-1, ERK MAPK, and IL-6. METHODS: Lateral FPI was produced in anesthetized pigs equipped with a closed cranial window and iNO administered at 30 min or 2 h post injury. RESULTS: CSF ET-1, ERK MAPK, and IL-6 were increased by FPI, but release was blocked by iNO administered at 30 min or 2 h after TBI. The IL-6 antagonist LMT-28 prevented impairment of cerebral autoregulation and hippocampal CA1 and CA3 neuronal necrosis after FPI. Papaverine induced dilation was unchanged by FPI and LMT-28. Protection lasted for at least 2 h after iNO administration was stopped. CONCLUSIONS: These data indicate that iNO protects cerebral autoregulation and reduces hippocampal necrosis after traumatic brain injury through inhibition of ET-1, ERK MAPK, and IL-6 upregulation in pigs.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Endotelina-1/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Interleucina-6/líquido cefalorraquidiano , Óxido Nítrico/farmacologia , Vasodilatadores/farmacologia , Administração por Inalação , Animais , Animais Recém-Nascidos , Lesões Encefálicas Traumáticas/líquido cefalorraquidiano , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Endotelina-1/líquido cefalorraquidiano , MAP Quinases Reguladas por Sinal Extracelular/líquido cefalorraquidiano , Feminino , Hipocampo/patologia , Interleucina-6/antagonistas & inibidores , Masculino , Necrose/patologia , Necrose/prevenção & controle , Óxido Nítrico/administração & dosagem , Oxazolidinonas/farmacologia , Papaverina/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Suínos , Regulação para Cima/efeitos dos fármacos , Vasodilatadores/administração & dosagem
8.
Nat Neurosci ; 21(12): 1689-1703, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397325

RESUMO

Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.


Assuntos
Comportamento Animal/fisiologia , MicroRNAs/genética , Diester Fosfórico Hidrolases/metabolismo , Comportamento Social , Comportamento Estereotipado/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Papaverina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 115(42): 10756-10761, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30201710

RESUMO

Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells' demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine's complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Neoplasias Pulmonares/radioterapia , Mitocôndrias/efeitos dos fármacos , NADH Desidrogenase/antagonistas & inibidores , Oxigênio/metabolismo , Papaverina/farmacologia , Radiossensibilizantes/farmacologia , Animais , Sistemas CRISPR-Cas , Hipóxia Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , NADH Desidrogenase/genética , Inibidores de Fosfodiesterase/farmacologia , Tolerância a Radiação , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Noise Health ; 20(93): 47-52, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29676295

RESUMO

Introduction: Noise exposure, the main cause of hearing loss in countries with lot of industries, may result both in temporary or permanent hearing loss. The goal of this study was to investigate the effects of parenteral papaverine and piracetam administration following an acoustic trauma on hearing function with histopathologic correlation. Materials and Methods: Eighteen Wistar albino rats exposed to noise for 8 h in a free environment were included. We divided the study population into three groups, and performed daily intraperitoneal injections of papaverine, piracetam, and saline, respectively, throughout the study. We investigated the histopathologic effects of cellular apoptosis on inner hair cells (IHCs) and outer hair cells (OHCs) and compared the distortion product otoacoustic emissions (DPOAEs) thresholds among the groups. Results and Discussion: On the 3rd and 7th days, DPOAE thresholds at 8 kHz were significantly higher both in papaverine and piracetam groups compared with the control group (P = 0.004 for 3rd day, P = 0.016 and P = 0.028 for 7th day, respectively). On the 14th day, piracetam group had significantly higher mean thresholds at 8 kHz (P = 0.029); however, papaverine group had similar mean thresholds compared to the control group (P = 0.200). On the 3rd and 7th days following acoustic trauma, both IHC and OHC loss were significantly lower in both papaverine and piracetam groups. On the 7th day, the mean amount of apoptotic IHCs and OHCs identified using Caspase-3 method were significantly lower in both groups, but the mean amount identified using terminal deoxynucleotidyl transferase dUTP nick end labeling method were similar in both groups compared to the control group. Conclusion: We demonstrated the effects of papaverine and piracetam on the recovery of cochlear damage due to acoustic trauma on experimental animals using histopathologic and electrophysiologic examinations.


Assuntos
Células Ciliadas Auditivas Internas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Papaverina/farmacologia , Piracetam/farmacologia , Animais , Apoptose , Eletrofisiologia , Células Ciliadas Auditivas Internas/patologia , Células Ciliadas Auditivas Internas/fisiologia , Células Ciliadas Auditivas Externas/patologia , Células Ciliadas Auditivas Externas/fisiologia , Perda Auditiva Provocada por Ruído/patologia , Injeções Intraperitoneais , Masculino , Fármacos Neuroprotetores/administração & dosagem , Emissões Otoacústicas Espontâneas , Papaverina/administração & dosagem , Piracetam/administração & dosagem , Ratos Wistar
11.
Int Braz J Urol ; 44(3): 617-622, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29617080

RESUMO

OBJECTIVE: To investigate the effect of papaverine and alprostadil on testicular torsion-detorsion injury in rats. MATERIALS AND METHODS: A total of 40 male Wistar-Albino rats were used in this study. Four hours of right testicular torsion was applied to each group, excluding sham operated group. The torsion-detorsion (T/D), T/D + papaverine and T/D + alprostadil groups received saline, papaverine and alprostadil at the same time as surgical detorsion, respectively. At 14 days after the surgical detorsion, ischaemic changes and the degree of damage were evaluated with Cosentino scoring and the Johnson tubular biopsy score (JTBS). RESULTS: JTBS was determined as 8.8±2.7 in the Sham group, 5.08±1.9 in the T/ D+papaverine group, 5.29±2.3 in the T/D +alprostadil group and 2.86±1.9 in the TD group. The JTBS was determined to be statistically significantly high in both the T/D + papaverine group and the T/D + alprostadil group compared to the T/D group (p=0.01, p=0.009). In the T/D + papaverine group, 3 (43 %) testes were classified as Cosentino 2, 3 (43%) as Cosentino 3 and 1 (14 %) as Cosentino 4. In the T/D +alprostadil group, 5 (50 %) testes were classified as Cosentino 2, 3 (30 %) as Cosentino 3 and 2 (20%) as Cosentino 4. CONCLUSION: The present study indicated that spermatic cord administration of alprostadil and papaverine showed a protective effect against ischemia/reperfusion injury after right-side testes torsion and histological changes were decreased after testicular ischemia reperfusion injury.


Assuntos
Alprostadil/farmacologia , Papaverina/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Torção do Cordão Espermático/prevenção & controle , Testículo/irrigação sanguínea , Vasodilatadores/farmacologia , Alprostadil/uso terapêutico , Animais , Biópsia , Isquemia/prevenção & controle , Masculino , Papaverina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Torção do Cordão Espermático/patologia , Testículo/patologia , Resultado do Tratamento , Vasodilatadores/uso terapêutico
12.
Pharmacology ; 101(3-4): 163-169, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29301136

RESUMO

BACKGROUND: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3',5'-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. SUMMARY: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations. It was found that drotaverine not only relaxed the precontracted tracheal preparations but also decreased mediator-induced contraction. These effects of drotaverine were concentration dependent, with a significantly higher potency on the KCl-induced response, than on either the histamine or methacholine induced one. A similar result was noted for nifedipine. The PDE inhibitor, theophylline, also relaxed the precontracted preparations but was ineffective on the mediator-induced contraction in a physiologically relevant concentration range. Moreover, theophylline did not show selectivity and was the least potent relaxant among the 3 tested molecules. Key Message: These results show that drotaverine is a more potent airway smooth muscle relaxant molecule than theophylline. This enhanced potency on relaxation and inhibition of the constrictor response, at least partly, may be explained by the combined L-VOCC blocking and PDE inhibitory potential of drotaverine.


Assuntos
Músculo Liso/efeitos dos fármacos , Papaverina/análogos & derivados , Traqueia/efeitos dos fármacos , Animais , Cobaias , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Papaverina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Teofilina/farmacologia , Traqueia/fisiologia
13.
Microsurgery ; 38(5): 524-529, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29341294

RESUMO

BACKGROUND: Papaverine remains a popular agent to treat intraoperative microsurgical vasospasm. However, the recent shortage has forced surgeons to trial antispasmodic agents unproven in microsurgery, but commonly used in other areas. During this shortage we have trialed topical nitroglycerin to break intraoperative vasospasm. This study aims to analyze the outcomes of this medication on flap complications compared with papaverine. METHODS: All consecutive free flaps performed for breast reconstruction at a single institution were reviewed. Data collected included patient demographics, co-morbidities, complications and type of antispasmodic agent. Rates of re-exploration, complications and flap salvage were compared between patients receiving nitroglycerin and papaverine. RESULTS: Over 10 years, 991 flaps were treated with antispasmodics: 18 of which were treated with topical nitroglycerin. Patients treated with nitroglycerin tended to have higher BMI (32.1 vs. 27.9, P < 0.01), higher rates of pre-operative chemotherapy (83.3% vs. 51.3%, P < 0.01) and shorter follow-up duration (735 vs. 1691 days, P < 0.01). However, no differences in complications were observed, including: unplanned return to the operating room, flap loss, fat necrosis, infection, hematoma, or seroma. Subgroup analysis with a time-matched cohort of papaverine patients revealed minimal difference in comorbidities and no difference in complications. CONCLUSIONS: Substituting topical nitroglycerin for papaverine to treat vasospasm during the shortage did not demonstrate an increased rate of flap loss or return to the operating room, making these medications a safe alternative to papaverine.


Assuntos
Isquemia/etiologia , Mamoplastia/efeitos adversos , Microcirurgia/efeitos adversos , Nitroglicerina/farmacologia , Retalho Perfurante/irrigação sanguínea , Retalho Perfurante/patologia , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Administração Tópica , Adulto , Anastomose Cirúrgica/efeitos adversos , Mama/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Período Intraoperatório , Isquemia/prevenção & controle , Pessoa de Meia-Idade , Necrose/etiologia , Necrose/prevenção & controle , Nitroglicerina/administração & dosagem , Nitroglicerina/efeitos adversos , Papaverina/administração & dosagem , Papaverina/farmacologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos
14.
Cardiovasc Interv Ther ; 33(2): 116-124, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28110424

RESUMO

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 µg/kg/min (normal dose) and 170 µg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.


Assuntos
Trifosfato de Adenosina/farmacologia , Angina Pectoris/fisiopatologia , Cafeína/farmacologia , Estenose Coronária/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico/efeitos dos fármacos , Neurotransmissores/farmacologia , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/antagonistas & inibidores , Idoso , Angina Pectoris/etiologia , Cateterismo Cardíaco , Café , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Feminino , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Hemodinâmica , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neurotransmissores/administração & dosagem , Neurotransmissores/antagonistas & inibidores , Papaverina/administração & dosagem , Papaverina/farmacologia , Estudos Prospectivos , Vasodilatadores/administração & dosagem , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacologia
15.
Braz J Cardiovasc Surg ; 33(6): 553-558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30652743

RESUMO

OBJECTIVE: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. METHODS: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. RESULTS: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. CONCLUSION: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.


Assuntos
Doença da Artéria Coronariana/cirurgia , Vasoespasmo Coronário/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Papaverina/administração & dosagem , Artéria Radial/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Idoso , Ponte de Artéria Coronária/métodos , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Masculino , Papaverina/efeitos adversos , Papaverina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Vasodilatadores/farmacologia
16.
Zhonghua Jie He He Hu Xi Za Zhi ; 40(12): 931-935, 2017 Dec 12.
Artigo em Chinês | MEDLINE | ID: mdl-29224304

RESUMO

Objective: To establish a standardized method for isolated pulmonary artery and vein rings with different diameter, pressure and length, which could provide a more scientific method for in vitro study of pulmonary vessel diseases. Methods: Male SD rats were anesthetized, and the right ventricular systolic pressure were measured. Small pulmonary artery and vein rings with 200-400 µm in diameter and 2 mm in length were prepared by dissecting pulmonary arteries and veins. The pulmonary vessel rings were mounted in the organ bath by 2 stainless steel wires with diameter of 40 µm. Then the internal circumference of the vessel rings was increased gradually with 100 µm per step. At the same time the vascular tension was recorded by the Myograph System and Acknowledgement data acquisition system, and subsequently the passive length-tension exponential curve was made. The initial tension of the rings was set, equilibrated for another 30 min, and then stimulated with 60 mmol/L KCl 3 times, and the best contractile reactivity was achieved. The contractile reactivity of pulmonary artery rings and endothelial integrity were detected by exposure to 1 µmol/L phenylephrine(PE) and 10 µmol/L acetylcholine(Ach), while the contractile reactivity of pulmonary vein rings was detected by exposure to 1 µmol/L U46619 and 10 µmol/L papaverine. Results: The contraction and relaxation effects of the pulmonary artery rings reached 0.39 mg and 92% when they were stimulated by 1 µmol/L PE and 10 µmol/L Ach. The contraction and relaxation effects of pulmonary vein rings were up to 0.13 mg and 84% when they were exposed to 1 µmol/L U46619 and 10 µmol/L papaverine, respectively. Conclusion: Pulmonary artery and vein rings with appropriate basal tension and optimal vasodilator activity were prepared, and a standardized method of tension experiment for isolated pulmonary artery and vein rings established.


Assuntos
Endotélio Vascular/fisiologia , Papaverina/farmacologia , Artéria Pulmonar , Vasodilatadores/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Masculino , Músculo Liso Vascular , Ratos , Ratos Sprague-Dawley , Veia Safena/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
17.
Hum Mol Genet ; 26(24): 4929-4936, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29040550

RESUMO

Inherited mitochondrial optic neuropathies, such as Leber's hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA) are caused by mutant mitochondrial proteins that lead to defects in mitochondrial complex 1-driven ATP synthesis, and cause specific retinal ganglion cell (RGC) loss. Complex 1 defects also occur in patients with primary open angle glaucoma (POAG), in which there is specific RGC loss. The treatment of mitochondrial optic neuropathy in the US is only supportive. The Ndufs4 knockout (Ndufs4 KO) mouse is a mitochondrial complex 1-deficient model that leads to RGC loss and rapid vision loss and allows for streamlined testing of potential therapeutics. Preceding RGC loss in the Ndufs4 KO is the loss of starburst amacrine cells, which may be an important target in the mechanism of complex 1-deficient vision loss. Papaverine and zolpidem were recently shown to be protective of bioenergetic loss in cell models of optic neuropathy. Treatment of Ndufs4 KO mice with papaverine, zolpidem, and rapamycin-suppressed inflammation, prevented cell death, and protected from vision loss. Thus, in the Ndufs4 KO mouse model of mitochondrial optic neuropathy, papaverine and zolpidem provided significant protection from multiple pathophysiological features, and as approved drugs in wide human use could be considered for the novel indication of human optic neuropathy.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Doenças do Nervo Óptico/metabolismo , Animais , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/deficiência , Complexo I de Transporte de Elétrons/genética , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Inflamação/metabolismo , Complexo Mediador/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Doenças Mitocondriais/metabolismo , Doenças do Nervo Óptico/genética , Papaverina/farmacologia , Piridinas/farmacologia , Células Ganglionares da Retina/metabolismo , Zolpidem
18.
Biol Pharm Bull ; 40(10): 1654-1660, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28966237

RESUMO

OTC drugs have an important role in self-medication. However, the pharmacokinetic properties of some OTC drugs have not been fully investigated and reports concerning their drug interactions are insufficient. Several gastrointestinal drugs are available as OTC drugs. Because of their pharmacological properties, these drugs are often used concomitantly with other drugs. Therefore, it is important to predict the possible drug interactions among these drugs. In the current study, we investigated the inhibitory effects of five gastrointestinal drugs, namely loperamide, oxethazaine, papaverine, pirenzepine, and trimebutine, on CYP activities in human liver microsomes. Furthermore, we calculated the ratio of the intrinsic clearance of each CYP substrate in the presence or absence of the gastrointestinal drugs. The possibility of drug interactions in vivo was predicted by cut-off criteria. CYP3A4 activity was markedly inhibited by trimebutine, papaverine, and oxethazaine. Their inhibitory properties were competitive and the Ki values were 6.56, 12.8, and 3.08 µM, respectively. Alternative R values of CYP3A4 exceeded the cut-off level. These results suggested that drug interactions mediated by CYP3A4 may occur during treatment with these gastrointestinal drugs, necessitating the confirmation of the clinical significance of these drug interactions to prevent unexpected adverse effects.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Fármacos Gastrointestinais/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Etanolaminas/farmacologia , Humanos , Loperamida/farmacologia , Microssomos Hepáticos/enzimologia , Medicamentos sem Prescrição/farmacologia , Papaverina/farmacologia , Pirenzepina/farmacologia , Trimebutina/farmacologia
19.
Braz J Cardiovasc Surg ; 32(3): 197-201, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28832798

RESUMO

Objective:: Ischemia-reperfusion injury after acute ischemia treatment is a serious condition with high mortality and morbidity. Ischemia-reperfusion injury may result in organ failure particularly in kidney, lung, liver, and heart. In our study, we investigated the effects of papaverine and vitamin C on ischemia-reperfusion injury developed in the rat liver after occlusion-reperfusion of rat aorta. Methods:: 32 Sprague-Dawley female rats were randomized into four groups (n=8). Ischemia was induced with infrarenal aortic cross-clamping for 60 minutes; then the clamp was removed and reperfusion was allowed for 120 minutes. While the control group and the ischemia-reperfusion group did not receive any supplementary agent, two other groups received vitamin C and papaverine hydrochloride (papaverine HCL). Liver tissues were evaluated under the light microscope. Histopathological examination was assessed by Suzuki's criteria and results were compared between groups. Results:: In ischemia-reperfusion group, severe congestion, severe cytoplasmic vacuolization, and parenchymal necrosis over 60% (score 4) were observed. In vitamin C group, mild congestion, mild cytoplasmic vacuolization and parenchymal necrosis below 30% (score 2) were found. In papaverine group, moderate congestion, moderate cytoplasmic vacuolization and parenchymal necrosis below 60% (score 3) were observed. Conclusion:: An ischemia of 60 minutes induced on lower extremities causes damaging effects on hepatic tissue. Vitamin C and papaverine are helpful in reducing liver injury after acute ischemia reperfusion and may partially avoid related negative conditions.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Papaverina/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Vasodilatadores/farmacologia , Animais , Antioxidantes/uso terapêutico , Aorta Abdominal , Ácido Ascórbico/uso terapêutico , Constrição , Modelos Animais de Doenças , Feminino , Fígado/patologia , Necrose , Papaverina/uso terapêutico , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/uso terapêutico
20.
Cell Signal ; 39: 55-65, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28754627

RESUMO

Intracellular cyclic AMP and/or cyclic GMP are characterized in the 1960th. These second messengers, hydrolysed specifically by cyclic nucleotide phosphodiesterase (PDE), play a major role in intracellular signalling. Natural products have been a rich source of drug discovery, Theophylline and Methylxanthine originated from tea leaves used for asthma treatment, whereas, Papaverine, a natural isoquinolein originated from Papaver somniferum traditionally used in impotency, altogether as caffeine where firstly described as PDE-inhibiting compounds. Since that time, the knowledge in PDE field has been drastically increased, allowing the design and development of new therapeutic drugs acting against different pathologies in the nanomolar range. During this period some natural compounds have been identified as PDE inhibitors and used in that context to investigate their therapeutic potential effects. The aim of this literature review is to point out the reported data and demonstrating the contribution of natural characterized molecules as PDE inhibitors in various pathologies that can open new fields of research for drug discovery, notably in epigenetic regulation.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Epigênese Genética/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Asma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Neovascularização Patológica/tratamento farmacológico , Papaverina/farmacologia , Papaverina/uso terapêutico , Teofilina/farmacologia , Teofilina/uso terapêutico , Xantinas/farmacologia , Xantinas/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA