Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 16.234
Filtrar
1.
Int J Mol Sci ; 23(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35409146

RESUMO

Some hearing, vestibular, and vision disorders are imputable to voltage-gated Ca2+ channels of the sensory cells. These channels convey a large Ca2+ influx despite extracellular Na+ being 70-fold more concentrated than Ca2+; such high selectivity is lost in low Ca2+, and Na+ can permeate. Since the permeation properties and molecular identity of sensory Ca2+ channels are debated, in this paper, we examine the Na+ current flowing through the L- and R-type Ca2+ channels of labyrinth hair cells. Ion currents and cytosolic free Ca2+ concentrations were simultaneously monitored in whole-cell recording synchronous to fast fluorescence imaging. L-type and R-type channels were present with different densities at selected sites. In 10 nM Ca2+, the activation and deactivation time constants of the L-type Na+ current were accelerated and its maximal amplitude increased by 6-fold compared to physiological Ca2+. The deactivation of the R-type Na+ current was not accelerated, and its current amplitude increased by 2.3-fold in low Ca2+; moreover, it was partially blocked by nifedipine in a voltage- and time-dependent manner. In conclusion, L channel gating is affected by the ion species permeating the channel, and its selectivity filter binds Ca2+ more strongly than that of R channel; furthermore, external Ca2+ prevents nifedipine from perturbing the R selectivity filter.


Assuntos
Cálcio , Nifedipino , Animais , Cálcio/metabolismo , Cátions , Cabelo/metabolismo , Nifedipino/farmacologia , Permeabilidade , Sódio/metabolismo , Vertebrados/metabolismo
2.
Hypertens Pregnancy ; 41(2): 126-138, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35361052

RESUMO

OBJECTIVES: This network meta-analysis aimed to compare the efficacy and safety of intravenous (IV) hydralazine, oral nifedipine, and IV labetalol with different dosage regimens in the treatment of severe hypertension during pregnancy. METHODS: A comprehensive literature search was performed on PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) exploring the effects of hydralazine, nifedipine, and labetalol in the treatment of severe hypertension during pregnancy. RESULTS: A total of 21 RCTs with 2183 patients comparing 7 regimens (oral nifedipine 50,60,90 mg; hydralazine 15,25 mg; and labetalol 220,300 mg) were identified. Compared with IV labetalol 300 mg, nifedipine 50,60, and 90 mg significantly improved the successful treatment rate of severe hypertension during pregnancy, nifedipine 50 and 90 mg and IV hydralazine 25 mg required significantly fewer doses to achieve target blood pressure (BP), and nifedipine 50 mg took significantly shorter time to achieve target BP. Subgroup analysis showed that only nifedipine 50 mg tablets, not capsules, required a significantly shorter time and fewer doses to achieve target BP than IV labetalol 300 mg. Moreover, nifedipine 60,90 mg showed superior effectiveness than IV hydralazine 15,25 mg in the successful treatment rate of severe hypertension during pregnancy. SUCRA analysis suggested that nifedipine 50,60,90 mg as the better regimens with the lower rates of overall ADR and neonatal complications. CONCLUSION: These findings demonstrated the superiority of oral nifedipine 50,60,90 mg, especially oral nifedipine 50 mg tablets, in the treatment of severe hypertension during pregnancy than IV labetalol 300 mg, while oral nifedipine 60,90 mg also showed superiority in the successful treatment rate of severe hypertension during pregnancy than IV hydralazine 15,25 mg. However, the limitations of the underlying data indicate that future large-scale and rigorous RCTs are needed to confirm such findings.


Assuntos
Hipertensão Induzida pela Gravidez , Hipertensão , Labetalol , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Feminino , Humanos , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Recém-Nascido , Labetalol/efeitos adversos , Metanálise em Rede , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
J Chem Phys ; 156(14): 144504, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35428390

RESUMO

Crystal nucleation rates have been measured in the supercooled melts of two richly polymorphic glass-forming liquids: ROY and nifedipine (NIF). ROY or 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile is known for its crystals of red, orange, and yellow colors and many polymorphs of solved structures (12). Of the many polymorphs, ON (orange needles) nucleates the fastest with the runner up (Y04) trailing by a factor of 103 when compared under the same mobility-limited condition, while the other unobserved polymorphs are slower yet by at least 5 orders of magnitude. Similarly, of the six polymorphs of NIF, γ' nucleates the fastest, ß' is slower by a factor of 10, and the rest are slower yet by at least 5 decades. In both systems, the faster-nucleating polymorphs are not built from the lowest-energy conformers, while they tend to have higher energies and lower densities and thus greater similarity to the liquid phase by these measures. The temperature ranges of this study covered the glass transition temperature Tg of each system, and we find no evidence that the nucleation rate is sensitive to the passage of Tg. At the lowest temperatures investigated, the rates of nucleation and growth are proportional to each other, indicating that a similar kinetic barrier controls both processes. The classical nucleation theory provides an accurate description of the observed nucleation rates if the crystal growth rate is used to describe the kinetic barrier for nucleation. The quantitative rates of both nucleation and growth for the competing polymorphs enable prediction of the overall rate of crystallization and its polymorphic outcome.


Assuntos
Vidro , Nifedipino , Cristalização , Vidro/química , Nifedipino/química , Temperatura , Temperatura de Transição
4.
Se Pu ; 40(3): 266-272, 2022 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-35243836

RESUMO

A method based on ultra high performance liquid chromatography-electrostatic field orbitrap high resolution mass spectrometry (UHPLC-Orbitrap HRMS) was established for the determination of genotoxic impurities 2, 6, and 12 in nifedipine. After extraction with methanol, the sample was injected into the UHPLC-Orbitrap HRMS system for analysis. An ACE EXCELTM 3 C18-AR column (150 mm×4.6 mm, 3 µm) was used for chromatographic separation. The mobile phase was methanol-0.1% formic acid aqueous solution (65∶35, v/v). The flow rate was 0.6 mL/min, while the column temperature and autosampler temperature were set as 35 ℃ and 8 ℃, respectively. The divert valve switching technique was used to protect the mass spectrometer. The six-way valve was set to divert the eluent of 7.5-11.6 min to waste and the rest of the eluent into the mass spectrometer. The Orbitrap mass spectrometer was coupled with the UHPLC system by an electrospray ion (ESI) source. The sheath gas and auxiliary gas flow rates were 60 and 20 arb (arbitrary units), respectively. The spray voltage was 3.5 kV, while the capillary temperature and auxiliary gas heater temperature were set as 350 ℃ and 400 ℃, respectively. The positive ion parallel reaction monitoring (PRM) scanning mode was adopted, and the mass spectral resolution was set to 35000 FWHM. The accurate masses of the [M+H]+ precursor ions of impurities 2, 6, and 12 were m/z 347.1230, 361.1026, and 347.1230, respectively. The accurate masses of the extracted [M+H]+ fragment ions of impurities 2, 6, and 12 were m/z 315.0968, 298.1069, and 315.0968, respectively. The normalized collision energies (NCEs) were optimized to 10%, 42%, and 10% for impurities 2, 6, and 12, respectively. The external standard method was utilized for quantitative analysis. The established method was validated in detail by investigating the specificity, linear range, limit of detection (LOD), limit of quantification (LOQ), recovery, precision, and stability. This method had good specificity, and the solvent did not interfere with the determination of impurities. The peak areas of impurities 2, 6, and 12 as well as their concentrations showed good linear relationships in the ranges of 0.2-100 ng/mL, with all correlation coefficients (r)≥0.9998. The recoveries of impurities 2, 6, and 12 at three levels (low, medium, and high) were in the range of 96.9%-105.0%, while the RSDs were between 1.21% and 5.12%. The LODs were 0.05 ng/mL and the LOQs were 0.2 ng/mL for all three impurities. This analytical method was used to determine impurities 2, 6, and 12 in three batches of nifedipine samples. Impurity 6 was not detected in the three batches, but impurities 2 and 12 were detected in all the three samples, and the detection amount was within the limit. The developed method is sensitive, fast, accurate, and easy to operate. It can provide a reference for the quality control of nifedipine by pharmaceutical companies and extend strong technical support for the supervision by drug regulatory authorities.


Assuntos
Nifedipino , Espectrometria de Massas em Tandem , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Cromatografia Líquida de Alta Pressão , Dano ao DNA , Eletricidade Estática
5.
Int J Mol Sci ; 23(6)2022 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-35328753

RESUMO

During injuries in the central nervous system, intrinsic protective processes become activated. However, cellular reactions, especially those of glia cells, are frequently unsatisfactory, and further exogenous protective mechanisms are necessary. Nimodipine, a lipophilic L-type calcium channel blocking agent is clinically used in the treatment of aneurysmal subarachnoid haemorrhage with neuroprotective effects in different models. Direct effects of nimodipine on neurons amongst others were observed in the hippocampus as well as its influence on both microglia and astrocytes. Earlier studies proposed that nimodipine protective actions occur not only via calcium channel-mediated vasodilatation but also via further time-dependent mechanisms. In this study, the effect of nimodipine application was investigated in different time frames on neuronal damage in excitotoxically lesioned organotypic hippocampal slice cultures. Nimodipine, but not nifedipine if pre-incubated for 4 h or co-applied with NMDA, was protective, indicating time dependency. Since blood vessels play no significant role in our model, intrinsic brain cell-dependent mechanisms seems to strongly be involved. We also examined the effect of nimodipine and nifedipine on microglia survival. Nimodipine seem to be a promising agent to reduce secondary damage and reduce excitotoxic damage.


Assuntos
Fármacos Neuroprotetores , Hipocampo , Microglia , Neurônios , Fármacos Neuroprotetores/farmacologia , Nifedipino/farmacologia , Nimodipina/farmacologia
6.
Anal Sci ; 38(2): 359-368, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35314982

RESUMO

Nifedipine is an antihypertensive chemical. The illegal addition of this chemical into Chinese traditional patent medicine (CTPM) is unstandardized and lacks regulation. It could bring serious side effects to patients, causing various symptoms. Therefore, accurate detection of nifedipine is very important for human health and the prevention of illegal additives. Surface-enhanced Raman spectroscopy (SERS) is a fast and sensitive fingerprint spectroscopic technique, which has been shown to be promising in drug detection. In this study, nifedipine in CTPM was determined qualitatively and quantitatively with SERS. Linear relationships between the concentrations of nifedipine and the intensities of the characteristic peaks were established. The results showed a linear relationship within the concentration range of 0.5-10 mg/L, and the lowest detectable concentration of nifedipine in CTPM was 0.1 mg/L (equivalent to 0.03% doping of nifedipine in CTPM). This method has shown a great potential in the detection of drugs illegally added to CTPM.


Assuntos
Nifedipino , Análise Espectral Raman , China , Humanos , Medicina Tradicional Chinesa , Medicamentos sem Prescrição , Análise Espectral Raman/métodos
7.
Anal Sci ; 38(2): 393-399, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35314986

RESUMO

A simple and fast microwave synthesis method was applied for the preparation of several carbon dots (CDs) from various combinations of urea, phosphoric acid, and B-alanine as nitrogen, phosphorus, and carbon precursors. The maximum quantum yield (44%) was obtained for nitrogen and phosphorus co-doped carbon dots (N, P-CDs) prepared from urea, B-alanine, and phosphoric acid. Furthermore, N, P-CDs were exploited to synthesize a simple and sensitive fluorometric probe to determine nifedipine (NFD). We determined that the analytical response of the designed sensor could be affected by the kind of dopant and synthesis precursors. It is worth mentioning that the fluorescence intensity of N, P-CDs was weakened by NFD, and no fluorescence quenching was observed for other prepared CDs. The NFD-developed sensor demonstrated a linear response range of 3.3 × 10-8-3.2 × 10-5 mol/L, with the detection limit of 1.0 × 10-8 mol/L. The sensor was successfully applied to measure NFD in human biological fluids.


Assuntos
Carbono , Pontos Quânticos , Corantes Fluorescentes , Humanos , Micro-Ondas , Nifedipino
8.
Geriatr Gerontol Int ; 22(5): 449-454, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35355383

RESUMO

AIM: Dosage adjustment is essential in older individuals because they are prone to experience a decline in liver function and changes in body composition. However, quantitative tests or equations for evaluating the activity of hepatic drug metabolism have not yet been clearly established. We examined hepatic drug metabolism activities in older individuals, focusing on changes in body composition parameters. METHODS: Lansoprazole and nifedipine, substrates of the metabolic enzymes cytochrome P450 (CYP) 2C19 and 3A4, respectively, were selected to study hepatic drug metabolism. Residual samples from blood test for older patients were evaluated to determine drug metabolism. The body composition of relevant patients was determined by analyzing characteristic parameters of skeletal muscle mass index (SMI), handgrip strength (HGS) and hepatic steatosis index (HSI). The differences in hepatic drug metabolism were studied statistically among categories in terms of the cut-off value of these parameters. RESULTS: Older male patients receiving lansoprazole and nifedipine in the low SMI (<7.0 kg/m2 ) category showed an 85-90% reduction in respective CYP2C19 and CYP3A4 metabolic activities compared with the normal SMI category. For the female patients, CYP2C19 and CYP3A4 metabolic activities showed no significant correlation with SMI and HGS. Fatty liver disease (HSI ≥36) was found to reduce CYP2C19 metabolic activity particularly in older female patients. CONCLUSIONS: Low CYP2C19 metabolic activity was statistically correlated with low SMI in male patients and high HSI in female patients, whereas low CYP3A4 metabolic activity was statistically correlated with low HGS in male patients. Geriatr Gerontol Int 2022; 22: 449-454.


Assuntos
Citocromo P-450 CYP3A , Sarcopenia , Idoso , Composição Corporal , Citocromo P-450 CYP2C19 , Feminino , Força da Mão , Humanos , Lansoprazol , Fígado , Masculino , Nifedipino
9.
Colloids Surf B Biointerfaces ; 214: 112474, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35338963

RESUMO

Nifedipine is a potent anti-hypertensive, which is poorly orally bioavailable on account of first-pass metabolism, short half-life, and low water solubility. This study aimed to develop a microemulsified system with low surfactant concentration and to evaluate the influence of microemulsion (ME) phase behavior on skin permeation of nifedipine, as drug model. Thereafter, MEs were obtained using PPG-5-CETETH-20, oleic acid, and phosphate buffer at pH 5.0. The selected MEs were isotropic, with droplet diameters less than 10 nm, polydispersity index < 0.25, and pH between 5.0 and 5.2. MEs presented low viscosity and Newtonian behavior. SAXS results confirmed bicontinuous and oil-in-water (o/w) MEs formation. The presence of the drug promoted only very slight modifications in the ME structure. The MEs presented ability to deliver nifedipine via the transdermal route when in comparison with the control. Nevertheless, the skin permeated and retained amounts from the o/w and bicontinuous formulations did not differ significantly. The ATR-FTIR demonstrated that both formulations promoted fluidization and disorganization of lipids and increased the drug diffusion and partition coefficients in the skin. In conclusion, PPG-5-CETETH-20 MEs obtained proved to be effective skin permeation enhancers, acting by rising the coefficients of partition and diffusion of the nifedipine in the skin.


Assuntos
Nifedipino , Pele , Administração Cutânea , Emulsões/química , Nifedipino/metabolismo , Espalhamento a Baixo Ângulo , Pele/metabolismo , Tensoativos/química , Água/química , Difração de Raios X
10.
J Ethnopharmacol ; 290: 115099, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35167934

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The species Lippia origanoides Kunth, popularly known as "salva-de-marajó", is used in Brazilian traditional "quilombola" communities to treat menstrual cramps and uterine inflammation. AIM OF THE STUDY: Evaluate the spasmolytic activity of Lippia origanoides essential oil (LOO) on experimental models of uterine conditions related to menstrual cramps and investigate its mechanism of action. MATERIALS AND METHODS: Virgin rat-isolated uterus was mounted in the organ bath apparatus to evaluate the spasmolytic effect of LOO on basal tonus and contractions induced by carbachol, KCl, or oxytocin. We used pharmacological agents to verify the relaxation mechanism of LOO. The evaluation of uterine contractility in virgin rats, after treatment with LOO for three consecutive days, was carried out by the construction of a concentration-response curve with oxytocin or carbachol. The primary dysmenorrhea animal model was replicated with an injection of estradiol cypionate in female mice for three consecutive days, followed by intraperitoneal application of oxytocin. RESULTS: LOO relaxed the rat uterus precontracted with 10-2 IU/mL oxytocin (logEC50 = 1.98 ± 0.07), 1 µM carbachol (logEC50 = 1.42 ± 0.07) or 60 mM KCl (logEC50 = 1.53 ± 0.05). It was also able relax uterus on spontaneous contractions (logEC50 = 0.41 ± 0.05). Preincubation with glibenclamide, propranolol, phentolamine or L-NAME in contractions induced by carbachol did not alter significantly the relaxing effect of LOO. However, in the presence of 4-aminopyridine, CsCl or tetraethylammonium there was a reduction of LOO potency, whereas the blockers methylene blue, ODQ, aminophylline and heparin potentiated the LOO relaxing effect. Preincubation with LOO in a Ca2+ free medium at concentrations of 27 µg/mL or 81 µg/mL reduced the contraction induced by carbachol. The administration of LOO for 3 days did not alter uterus contractility. The treatment with LOO at 30 or 100 mg/kg intraperitoneally, or 100 mg/kg orally, inhibited writhing in female mice. The association of LOO at 10 mg/kg with nifedipine or mefenamic acid potentiated writhing inhibition in mice. CONCLUSIONS: The essential oil of L. origanoides has tocolytic activity in rat isolated uterus pre-contracted with KCl, oxytocin, or carbachol. This effect is possibly related to the opening of potassium channels (Kir, KV, and KCa), cAMP increase, and diminution of intracellular Ca2+. This relaxant effect, probably, contributed to reduce the number of writhings in an animal model of dysmenorrhea being potentiated by nifedipine or mefenamic acid. Taken together, the results here presented indicate that this species has a pharmacological potential for the treatment of primary dysmenorrhea, supporting its use in folk medicine.


Assuntos
Dismenorreia/patologia , Lippia , Óleos Voláteis/farmacologia , Tocolíticos/farmacologia , Útero/efeitos dos fármacos , Animais , Cálcio/metabolismo , Carbacol/farmacologia , AMP Cíclico/metabolismo , Feminino , Ácido Mefenâmico/farmacologia , Contração Muscular/efeitos dos fármacos , Nifedipino/farmacologia , Ocitocina/farmacologia , Canais de Potássio/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Ratos , Contração Uterina/efeitos dos fármacos
11.
J Oral Sci ; 64(1): 99-104, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-34980825

RESUMO

PURPOSE: The aim of this study was to establish an in vitro model of nifedipine-induced gingival overgrowth and characterize the anti-fibrotic effect of hepatocyte growth factor (HGF) using this model. METHODS: Human gingival fibroblasts were cultured-treated with 0.1, 1, or 10 µg/mL nifedipine or 10 ng/mL IL-1ß + 0.1, 1, or 10 µg/mL nifedipine (0.1N, 1N, 10N, IL + 0.1N, IL + 1N, IL + 10N). Cell proliferation and levels of type I collagen, TGF-ß1, CCN2/CTGF, and α-SMA were measured 48 h after the simultaneous addition of 10 and 50 ng/mL HGF (10 and 50HGF) along with IL-1ß and nifedipine. Type I collagen was measured after administration of anti-HGF neutralizing antibody. RESULTS: Significant increases in type I collagen, TGF-ß1, and CCN2/CTGF were observed after treatment in the 1N and IL + 0.1N groups. Levels of type I collagen and CCN2/CTGF differed significantly between the IL + 0.1N group and the IL + 0.1N + 50HGF group. Production of type I collagen increased significantly following addition of anti-HGF antibody. CONCLUSION: This study demonstrated the establishment of an in vitro model of nifedipine-induced gingival overgrowth by showing increased collagen levels. Experiments using this model suggested that HGF exerts anti-fibrotic effects.


Assuntos
Crescimento Excessivo da Gengiva , Nifedipino , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo , Fibroblastos , Gengiva , Crescimento Excessivo da Gengiva/induzido quimicamente , Crescimento Excessivo da Gengiva/tratamento farmacológico , Fator de Crescimento de Hepatócito , Humanos
13.
J Cell Physiol ; 237(3): 1980-1991, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34988986

RESUMO

Nifedipine, an L-type voltage-gated Ca2+ channel (L-VGCC) blocker, is one of the most used tocolytics to treat preterm labor. In clinical practice, nifedipine efficiently decreases uterine contractions, but its efficacy is limited over time, and repeated or maintained nifedipine-based tocolysis appears to be ineffective in preventing preterm birth. We aimed to understand why nifedipine has short-lasting efficiency for the inhibition of uterine contractions. We used ex vivo term pregnant human myometrial strips treated with cumulative doses of nifedipine. We observed that nifedipine inhibited spontaneous myometrial contractions in tissues with high and regular spontaneous contractions. By contrast, nifedipine appeared to increase contractions in tissues with low and/or irregular spontaneous contractions. To investigate the molecular mechanisms activated by nifedipine in myometrial cells, we used the pregnant human myometrial cell line PHM1-41 that does not express L-VGCC. The in vitro measurement of intracellular Ca2+ showed that high doses of nifedipine induced an important intracellular Ca2+ entry in myometrial cells. The inhibition or downregulation of the genes encoding for store-operated Ca2+ entry channels from the Orai and transient receptor potential-canonical (TRPC) families in PHM1-41 cells highlighted the implication of TRPC1 in nifedipine-induced Ca2+ entry. In addition, the use of 2-APB in combination with nifedipine on human myometrial strips tends to confirm that the pro-contractile effect induced by nifedipine on myometrial tissues may involve the activation of TRPC channels.


Assuntos
Contração Muscular , Miométrio , Nifedipino , Canais de Cátion TRPC , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular , Feminino , Humanos , Contração Muscular/efeitos dos fármacos , Miométrio/efeitos dos fármacos , Nifedipino/farmacologia , Gravidez , Nascimento Prematuro/metabolismo , Nascimento Prematuro/prevenção & controle , Canais de Cátion TRPC/metabolismo , Contração Uterina
14.
Cell Biochem Biophys ; 80(1): 171-190, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34643835

RESUMO

Cardiovascular and cancer illnesses often co-exist, share pathological pathways, and complicate therapy. In the context of the potential oncological role of cardiovascular-antihypertensive drugs (AHD), here we examine the role of calcium-channel blocking drugs on mechanics of extravasating cancer cells, choosing two clinically-approved calcium-channel blockers (CCB): Verapamil-hydrochloride and Nifedipine, as model AHD to simultaneously target cancer cells (MCF7 and or MDA231) and an underlying monolayer of endothelial cells (HUVEC). First, live-cell microscopy shows that exposure to Nifedipine increases the spreading-area, migration-distance, and frequency of transmigration of MCF-7 cells through the HUVEC monolayer, whereas Verapamil has the opposite effect. Next, impedance-spectroscopy shows that for monolayers of either endothelial or cancer cells, Nifedipine-treatment alone decreases the impedance of both cases, suggesting compromised cell-cell integrity. Furthermore, upon co-culturing MCF-7 on the HUVEC monolayers, Nifedipine-treated MCF-7 cells exhibit weaker impedance than Verapamil-treated MCF-7 cells. Following, fluorescent staining of CCB-treated cytoskeleton, focal adhesions, and cell-cell junction also indicated that Nifedipine treatment diminished the cell-cell integrity, whereas verapamil treatment preserved the integrity. Since CCBs regulate intracellular Ca2+, we next investigated if cancer cell's exposure to CCBs regulates calcium-dependent processes critical to extravasation, specifically traction and mechanics of plasma membrane. Towards this end, first, we quantified the 2D-cellular traction of cells in response to CCBs. Results show that exposure to F-actin depolymerizing drug decreases traction stress significantly only for Nifedipine-treated cells, suggesting an actin-independent mechanism of Verapamil activity. Next, using an optical tweezer to quantify the mechanics of plasma membrane (PM), we observe that under constant, externally-applied tensile strain, PM of Nifedipine-treated cells exhibits smaller relaxation-time than Verapamil and untreated cells. Finally, actin depolymerization significantly decreases MSD only for Verapamil treated cancer-cells and endothelial cells and not for Nifedipine-treated cells. Together, our results show that CCBs can have varied, mechanics-regulating effects on cancer-cell transmigration across endothelial monolayers. A judicious choice of CCBs is critical to minimizing the pro-metastatic effects of antihypertension therapy.


Assuntos
Bloqueadores dos Canais de Cálcio , Neoplasias , Cálcio , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diltiazem , Células Endoteliais , Neoplasias/tratamento farmacológico , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Verapamil/farmacologia , Verapamil/uso terapêutico
15.
Burns ; 48(2): 372-380, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34103198

RESUMO

As a calcium antagonist, the mechanism of nifedipine for treating chilblain has not been reported. In the present study, we established the chilblain model by using -20 ℃ 95% ethanol to freeze the right back foot of SD rats, and investigated the effects of this drug. Hematoxylin-eosin (HE) examination indicated most of pannus in the skin tissue of chilblain rats had disappeared, and the local inflammatory cells were also greatly reduced when given nifedipine at 15.0 mg/kg/d. The enzyme-linked immunosorbent assay (ELISA) revealed that nifedipine inhibited release of inflammatory factors TNF-α, IL-6, IL-1ß and VEGF in serum. The RT-PCR analysis showed that nifedipine down regulated mRNA levels of TRPC-6 and VEGF in skin tissue. Furthermore, immunohistochemical examination showed nifedipine inhibited expression of IL-1ß, IL-6, and TNF-α inflammatory protein and further inhibited expression of TRP (transient receptor potential) family proteins TRPM-7, TRPC-1, TRPC-3 and TRPC-6 and reduced expression of VEGF in skin and relieved erythema and oedema. This study demonstrated that nifedipine as an old medicine can be new use for the treatment of chilblain by acting on TRPs family and inflammatory proteins.


Assuntos
Queimaduras , Pérnio , Animais , Humanos , Interleucina-6 , Nifedipino/farmacologia , Nifedipino/uso terapêutico , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular
16.
J Orthop Res ; 40(2): 310-322, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33719091

RESUMO

Inorganic polyphosphates (polyP) are polymers composed of phosphate residues linked by energy-rich phosphoanhydride bonds. As polyP can bind calcium, the hypothesis of this study is that polyP enters chondrocytes and exerts its anabolic effect by calcium influx through calcium channels. PolyP treatment of cartilage tissue formed in 3D culture by bovine chondrocytes showed an increase in proteoglycan accumulation but only when calcium was also present at a concentration of 1.5 mM. This anabolic effect could be prevented by treatment with either ethylene glycol-bis(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid or the calcium channel inhibitors gadolinium and nifedipine. Calcium and polyP cotreatment of chondrocytes in monolayer culture resulted in calcium oscillations that were polyP chain length specific and were inhibited by gadolinium and nifedipine. The calcium influx resulted in increased gene expression of sox9, collagen type II, and aggrecan which was prevented by treatment with either calphostin, an inhibitor of protein kinase C, and W7, an inhibitor of calmodulin; suggesting activation of the protein kinase C-calmodulin pathway. Tracing studies using  4',6-diamidino-2-phenylindole, Mitotracker Red, and/or Fura-AM staining showed that polyP was detected in the nucleus, mitochondria, and intracellular vacuoles suggesting that polyP may also enter the cell. PolyP colocalizes with calcium in mitochondria. This study demonstrates that polyP requires the influx of calcium to regulate chondrocyte matrix production, likely via activating calcium signaling. These findings identify the mechanism regulating the anabolic effect of polyP in chondrocytes which will help in its clinical translation into a therapeutic agent for cartilage repair.


Assuntos
Anabolizantes , Condrócitos , Anabolizantes/farmacologia , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Calmodulina/metabolismo , Calmodulina/farmacologia , Bovinos , Condrócitos/metabolismo , Gadolínio , Nifedipino/farmacologia , Polifosfatos/farmacologia , Proteína Quinase C
17.
Neurogastroenterol Motil ; 34(3): e14220, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34337829

RESUMO

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effects of pharmacological agents for neurogenic oropharyngeal dysphagia based on evidence from randomized controlled trials (RCTs). METHODS: Electronic databases were systematically searched between January 1970 and March 2021. Two reviewers independently extracted and synthesized the data. The outcome measure was changed in (any) relevant clinical swallowing-related characteristics. KEY RESULTS: Data from 2186 dysphagic patients were collected from 14 RCT studies across a range of pharmacotherapies. The pooled effect size of transient receptor potential (TRP) channel agonists was large compared to placebo interventions (SMD[95%CI] =1.27[0.74,1.80], p < 0.001; I2  = 79%). Data were limited for other pharmacological agents and the overall pooled effect size of these agents was non-significant (SMD [95% CI] =0.25 [-0.24, 0.73]; p = 0.31; I2  = 85%). When analyzed separately, large effect sizes were observed with Nifedipine (SMD[95%CI] =1.13[0.09,2.18]; p = 0.03) and Metoclopramide (SMD[95%CI] =1.68[1.08,2.27]; p < 0.001). By contrast, the effects of angiotensin-converting enzyme (ACE) inhibitors (SMD[95%CI] = -0.67[-2.32,0.99]; p = 0.43; I2  = 61%), Physostigmine (SMD[95%CI] = -0.05[-1.03,0.93]; p = 0.92) and Glyceryl Trinitrate (GTN) (SMD [95% CI] = -0.01 [-0.11, 0.08]; p = 0.78) were non-significant. Within stroke patients, subgroup analysis showed that TRP channel agonists had a moderate pooled effect size (SMD[95%CI] =0.74[0.10,1.39]; p = 0.02; I2  = 82%) whereas the effects of other agents were non-significant (SMD[95%CI] =0.40[-0.04,0.84]; p = 0.07; I2  = 87%). CONCLUSIONS & INFERENCES: Our results showed that TRP channel agonists, Nifedipine and Metoclopromide may be beneficial for neurogenic dysphagic patients. Large scale, multicenter clinical trials are warranted to fully explore their therapeutic effects on swallowing.


Assuntos
Transtornos de Deglutição , Acidente Vascular Cerebral , Deglutição , Transtornos de Deglutição/tratamento farmacológico , Humanos , Estudos Multicêntricos como Assunto , Nifedipino
18.
J Pharm Pharmacol ; 74(1): 94-102, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109981

RESUMO

OBJECTIVES: This study aimed to identify the effect of trimetazidine (TMZ), an antianginal drug, on detrusor smooth muscle (DSM) contractility and its possible mechanisms of action. METHODS: We performed in-vitro contractility studies on isolated mouse DSM strips and investigated the effect of TMZ on Ca2+ levels in fura-2-loaded A7r5 cells. KEY FINDINGS: TMZ (300 or 1000 µM) inhibited carbachol (CCh)- and KCl-induced contractions and produced a concentration-dependent (10-1000 µM) relaxation in KCl-precontracted DSM strips. TMZ-induced relaxation was markedly decreased by BaCl2, an inward-rectifying K+ channel blocker, but was not altered by preincubation with tetraethylammonium, glibenclamide, 4-aminopyridine, propranolol, L-NAME or methylene blue. TMZ (300 or 1000 µM) reduced both the CaCl2-induced contraction of depolarized DSM strips under Ca2+-free conditions and the CCh-induced contraction of DSM strips preincubated with nifedipine in Ca2+-containing Krebs solution. Furthermore, TMZ (1000 µM) significantly decreased the Ca2+ levels in fura-2-loaded A7r5 cells. CONCLUSIONS: TMZ decreased DSM contractility and caused a concentration-dependent relaxation of the tissue possibly through its actions on Ca2+ transients and K+ channels. Our results provide preclinical evidence that TMZ would be a potential candidate to treat disorders related to the overactivity of the bladder.


Assuntos
Reposicionamento de Medicamentos/métodos , Trimetazidina/farmacologia , Bexiga Urinária Hiperativa , Bexiga Urinária , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Canais Iônicos/metabolismo , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/fisiopatologia , Vasodilatadores/farmacologia
19.
Biomed Chromatogr ; 36(1): e5244, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34528268

RESUMO

An experimental combination of analytical quality by design and green analytical chemistry approaches is introduced to develop an high-performance thin-layer chromatography (HPTLC) approach to quantify barnidipine hydrochloride in the pharmaceutical matrix. The analytical quality by design approach was introduced to green analytical chemistry to enhance protocol knowledge while ensuring efficiency and reducing environmental impacts, energy consumption and analyst visibility. This analytical approach was systematically addressed by exploring failure mode effect analysis, risk assessment and optimization design. Subsequently, a screening of primary variables was performed to select the aptest proportion of solvents in the mobile phase resulting from the principles of green analytical chemistry. Failure mode effect analysis and a risk assessment study were attempted to estimate the critical method parameters (CMPs). The influence of the CMPs on critical analytical attributes, i.e. retention factor and peak area, was assessed through a screening design. A response surface methodology was then executed for the critical analytical attributes as a concern of the determined CMPs, and the conditions for excellent resolution were determined using a desirability procedure. The established protocol was validated in compliance with the International Conference on Harmonization guideline Q2(R1) and showed excellent specificity and sensitivity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Química Verde/métodos , Nifedipino/análogos & derivados , Limite de Detecção , Modelos Lineares , Nifedipino/análise , Reprodutibilidade dos Testes , Projetos de Pesquisa
20.
Mol Pharm ; 19(2): 568-583, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35060741

RESUMO

In the present study, the oxidative degradation behavior of nifedipine (NIF) in amorphous solid dispersions (ASDs) prepared with poly(vinyl pyrrolidone) (PVP) with a short (K30) and a long (K90) chain length was investigated. The ASDs were prepared via dry ball-milling and analyzed using Fourier transform infrared (IR) spectroscopy, X-ray scattering, and differential scanning calorimetry. The ASDs were exposed to accelerated thermal-oxidative conditions using a pressurized oxygen headspace (120 °C for 1 day) and high temperatures at atmospheric pressure (60-120 °C for a period of 42 days). Additionally, solution-state oxidative degradation studies showed that pure NIF degrades to a greater extent than in the presence of PVP. Electronic structure calculations were performed to understand the impact of drug-polymer intermolecular interactions on the autoxidation of drugs. While no drug degradation was observed in freshly prepared ASD samples, alkyl free radicals were detected via electron paramagnetic resonance (EPR) spectroscopy. The free radicals were found to be consumed to a greater extent by PVP K30- than PVP K90-based ASDs upon exposure to high oxygen pressures. This was consistent with the greater solid-state oxidative degradation of NIF observed in ASDs with PVP K30 than with PVP K90. As no drug recrystallization occurred during this study period, the lower glass-transition temperature and presumed greater molecular mobility of PVP K30 and its ASD as compared to the PVP K90 system appear to contribute to the greater drug degradation in PVP-K30-based ASDs. The extent and the rate of oxidative degradation were higher in the case of PVP-K30-based ASD as compared to that in PVP-K90-based ASD, and the overall degradation increased with an increase in temperature. IR spectral analysis of drug-polymer interactions supports the electronic calculations of the oxidation process. We infer that, apart from the initial free radical content, the difference in the extent of drug-polymer intermolecular interactions in ASDs and amorphous stabilization during the forced oxidation experiments contribute to the observed differences in the autoxidative reactivity of the drug in ASDs with different PVP chain lengths. Overall, the chemical degradation of NIF in ASDs with two PVP chain lengths obtained from accelerated solid-state oxidation studies was in qualitative agreement with that obtained from long-term (3 years) storage under ambient conditions. The study highlights the ability of accelerated processes to determine the oxidative degradation behavior of polymeric ASDs and suggests that the polymer chain length could factor into chemical as well as physical stability considerations.


Assuntos
Nifedipino , Povidona , Varredura Diferencial de Calorimetria , Polímeros/química , Povidona/química , Solubilidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...