Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.273
Filtrar
1.
J Pharmacol Exp Ther ; 388(1): 190-200, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37863485

RESUMO

This study aimed to evaluate the effects of cytochrome P450 3A4 (CYP3A4) gene polymorphism and drug interaction on the metabolism of blonanserin. Human recombinant CYP3A4 was prepared using the Bac-to-Bac baculovirus expression system. A microsomal enzyme reaction system was established, and drug-drug interactions were evaluated using Sprague-Dawley rats. Ultra-performance liquid chromatography-tandem mass spectrometry was used to detect the concentrations of blonanserin and its metabolite. Compared with wild type CYP34A, the relative clearance of blonanserin by CYP3A4.29 significantly increased to 251.3%, while it decreased notably with CYP3A4.4, 5, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 23, 24, 28, 31, 33, and 34, ranging from 6.09% to 63.34%. Among 153 tested drugs, nimodipine, felodipine, and amlodipine were found to potently inhibit the metabolism of blonanserin. Moreover, the inhibitory potency of nimodipine, felodipine, and amlodipine varied with different CYP3A4 variants. The half-maximal inhibitory concentration and enzymatic kinetics assay demonstrated that the metabolism of blonanserin was noncompetitively inhibited by nimodipine in rat liver microsomes and was inhibited in a mixed manner by felodipine and amlodipine in both rat liver microsomes and human liver microsomes. When nimodipine and felodipine were coadministered with blonanserin, the area under the blood concentration-time curve (AUC)(0-t), AUC(0-∞), and C max of blonanserin increased. When amlodipine and blonanserin were combined, the C max of blonanserin C increased remarkably. The vast majority of CYP3A4 variants have a low ability to catalyze blonanserin. With combined administration of nimodipine, felodipine, and amlodipine, the elimination of blonanserin was inhibited. This study provides the basis for individualized clinical use of blonanserin. SIGNIFICANCE STATEMENT: The enzyme kinetics of novel CYP3A4 enzymes for metabolizing blonanserin were investigated. Clearance of blonanserin by CYP3A4.4, 5, 7-10, 12-14, 16-18, 23-24, 28, 31, 33, and 34 decreased notably, but increased with CYP3A4.29. Additionally, we established a drug interaction spectrum for blonanserin, in which nimodipine, felodipine, and amlodipine kinetics exhibited mixed inhibition. Moreover, their inhibitory potencies decreased with CYP3A4.4 and 5 compared to CYP3A4.1. This study provides essential data for personalized clinical use of blonanserin.


Assuntos
Citocromo P-450 CYP3A , Nimodipina , Humanos , Ratos , Animais , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Nimodipina/metabolismo , Nimodipina/farmacologia , Felodipino/metabolismo , Felodipino/farmacologia , Ratos Sprague-Dawley , Interações Medicamentosas , Anlodipino/metabolismo , Anlodipino/farmacologia , Microssomos Hepáticos/metabolismo , Metaboloma
2.
Pharm Res ; 40(9): 2229-2237, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37552386

RESUMO

OBJECTIVES: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. METHODS: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf  and by X-ray diffraction. RESULTS: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. CONCLUSIONS: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers.


Assuntos
Felodipino , Polímeros , Polímeros/química , Cristalização , Cetoconazol/química , Reologia , Solubilidade , Povidona/química
3.
Exp Anim ; 72(4): 505-512, 2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-37316263

RESUMO

Felodipine is a calcium channel blocker with antioxidant and anti-inflammatory properties. Researchers have stated that oxidative stress and inflammation also play a role in the pathophysiology of gastric ulcers caused by nonsteroidal anti-inflammatory drugs. The aim of this study was to investigate the antiulcer effect of felodipine on indomethacin-induced gastric ulcers in Wistar rats and compare it with that of famotidine. The antiulcer activities of felodipine (5 mg/kg) and famotidine were investigated biochemically and macroscopically in animals treated with felodipine (5 mg/kg) and famotidine in combination with indomethacin. The results were compared with those of the healthy control group and the group administered indomethacin alone. It was observed that felodipine suppressed the indomethacin-induced malondialdehyde increase (P<0.001); reduced the decrease in total glutathione amount (P<0.001), reduced the decrease superoxide dismutase (P<0.001), and catalase activities (P<0.001); and significantly inhibited ulcers (P<0.001) at the tested dose compared with indomethacin alone. Felodipine at a dose of 5 mg/kg reduced the indomethacin-induced decrease in cyclooxygenase-1 activity (P<0.001) but did not cause a significant reduction in the decrease in cyclooxygenase-2 activity. The antiulcer efficacy of felodipine was demonstrated in this experimental model. These data suggest that felodipine may be useful in the treatment of nonsteroidal anti-inflammatory drug-induced gastric injury.


Assuntos
Indometacina , Úlcera Gástrica , Ratos , Animais , Indometacina/efeitos adversos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Famotidina/efeitos adversos , Felodipino/efeitos adversos , Ratos Wistar , Anti-Inflamatórios não Esteroides/efeitos adversos , Antioxidantes/farmacologia
4.
Int J Pharm ; 642: 123153, 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37339688

RESUMO

Glaucoma may cause irreversible eyesight loss and damage to the optic nerve. Trabecular meshwork obstruction may raise intraocular pressure (IOP) in open-angle and/or closed-angle type inflammatory glaucoma. Ocular delivery of felodipine (FEL) has been undertaken for the management of intraocular pressure and inflammation. FEL film was formulated using different plasticizers, and IOP has been assessed using a normotensive rabbit eye model. Ocular acute inflammation induced by carrageenan has also been monitored. Drug release has been enhanced significantly (93.9 % in 7 h) in the presence of DMSO (FDM) as a plasticizer in the film compared to others (59.8 to 86.2 % in 7 h). The same film also exhibited the highest ocular permeation of 75.5 % rather than others (50.5 to 61.0 %) in 7 h. Decreased IOP was maintained up to 8 h after ocular application of FDM compared to the solution of FEL only up to 5 h. Ocular inflammation has almost been disappeared within 2 h of using the film (FDM), whereas inflammation has been continued even after 3 h of the induced rabbit without film. DMSO plasticized felodipine film could be used for the better management of IOP and associated inflammation.


Assuntos
Glaucoma , Pressão Intraocular , Animais , Coelhos , Plastificantes , Felodipino , Dimetil Sulfóxido , Glaucoma/tratamento farmacológico , Malha Trabecular
5.
Georgian Med News ; (337): 138-145, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37354687

RESUMO

The problem of contamination of the most commonly used medicines with nitrosamines is worsening worldwide. According to recent literature data, this "contamination" is the cause not only of skin cancer (keratinocytic/melanoma) but also of gastrointestinal neoplasms, brain tumours, neuroblastoma, rectal carcinoma, acute lymphoblastic leukaemia, and many others. It is these clinical manifestations that are associated with/ or already directly linked to the nitrosamine content of drugs and food products used by patients in previous periods. And it is this permissive availability/contamination that could prove to be the most likely, powerful inducer of acquired mutations underlying the worldwide cancer pandemic. Of further concern is the evidence of contamination of newer classes of medications by nitrosamines- namely: beta blockers, calcium antagonists and selective serotonin reuptake inhibitors (SSRIs). In practice, mankind faces the problem of certainly over 1 billion patients taking nitrosamine-contaminated drugs: 280 million patients with depression (antidepressants), over 1 billion patients with arterial hypertension (antihypertensive drugs), over half a billion patients with type 2 diabetes mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4 billion patients with gastritis (ranitidine), over 5 million with tuberculosis (rifampicin), and probably a number of others. The calculations are apocalyptic, since even if only 20-30% of the groups were affected, the number of patients taking these drugs would, by a rough calculation, currently amount to over 1 billion. And there are certainly other classes of drugs yet to be announced. It is for this reason that we should not be surprised that the data on the development of keratinocyte cancer after intake of nitrosamine-contaminated preparations is growing at a breakneck pace. This data indirectly but strongly confirms the importance of a newly introduced concept in the medical science : Nitrosogenesis of skin cancer. A concept, until recently unknown, incomprehensible, but at the same time frightening and gradually accepted, imposing itself and which with each passing day is gaining more and more scientific significance and "visibility", "scientific tangibility, receptivity, and acceptability." This article presents, for the first time in the world literature, patients who developed single/multiple forms of keratinocytic cancer (partly in combination with melanoma precursors-dysplastic moles) after administration of two new classes of potentially nitrosamine-contaminated antihypertensive drugs: beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine). For the first time in the scientific literature, the contributory pro-carcinogenic role of another potentially nitrosamine-contaminated ACE inhibitor- lisinopril , as well as that of candesartan: in the development of keratinocytic cancer is also discussed. For the first time in the world literature, the conclusion regarding the pathogenetic relationship between the intake of potentially contaminated drugs (from different drug groups) and cancer development is based on the model of the equivalent clinical manifestation of skin tumors (rather than on controlled long-term prospective analyses). Nitrosamine contamination in these drug groups appears to be the sole and major unifying factor or causative agent for these manifestations.


Assuntos
Diabetes Mellitus Tipo 2 , Melanoma , Nitrosaminas , Neoplasias Cutâneas , Humanos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina , Anlodipino , Perindopril , Metoprolol , Bisoprolol , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Lisinopril , Felodipino , Inibidores de Simportadores de Cloreto de Sódio , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nitrosaminas/efeitos adversos , Estudos Prospectivos , Cálcio , Tiazidas
6.
Cell Mol Immunol ; 20(4): 351-364, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36864189

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.


Assuntos
COVID-19 , Receptores de Antígenos Quiméricos , Humanos , SARS-CoV-2/metabolismo , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Caspofungina , Felodipino , Síndrome da Liberação de Citocina/tratamento farmacológico , Inflamação , Citocinas/metabolismo
7.
CPT Pharmacometrics Syst Pharmacol ; 12(6): 808-820, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36855819

RESUMO

In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically-based pharmacokinetic (PBPK) population for different severities of CeD was developed. Gastrointestinal physiology parameters, such as luminal pH, transit times, morphology, P-gp, and CYP3A4 expression were included in development of the CeD population. Data on physiological difference between healthy and CeD subjects were incorporated into the model as the ratio of celiac to healthy. A PBPK model was developed and verified for felodipine extended-release tablet in healthy volunteers (HVs) and then utilized to verify the CeD populations. Plasma concentration-time profile and PK parameters were predicted and compared against those observed in both groups. Sensitivity analysis was carried out on key system parameters in CeD to understand their impact on drug exposure. For felodipine, the predicted mean concentration-time profiles and 5th and 95th percentile intervals captured the observed profile and variability in the HV and CeD populations. Predicted and observed clearance was 56.9 versus 56.1 (L/h) in HVs. Predicted versus observed mean ± SD area under the curve for extended release felodipine in different severities of CeD were values of 14.5 ± 9.6 versus 14.4 ± 2.1, 14.6 ± 9.0 versus 17.2 ± 2.8, and 28.1 ± 13.5 versus 25.7 ± 5.0 (ng.h/mL), respectively. Accounting for physiology differences in a CeD population accurately predicted the PK of felodipine. The developed CeD population can be applied for determining the drug concentration of CYP3A substrates in the gut as well as for systemic levels, and for application in drug-drug interaction studies.


Assuntos
Doença Celíaca , Felodipino , Humanos , Felodipino/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Inibidores do Citocromo P-450 CYP3A , Modelos Biológicos
8.
Mol Pharm ; 20(1): 409-418, 2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36529939

RESUMO

Inhomogeneity is a key factor that significantly influences the dissolution behavior of amorphous solid dispersion (ASD). However, the underlying mechanisms of the effects of inhomogeneous phase on the dissolution characteristics as well as the bioavailability of ASDs are still unclear. In this study, two types of felodipine/PVPVA based ASDs with 30 wt % drug loading but different homogeneity were prepared: homogeneous "30 wt % ASD" prepared by spray drying, as well as inhomogeneous "30 wt % PM" prepared by physically mixing the sprayed dried 70 wt % ASD with PVPVA. We aimed to investigate (1) drug-polymer interaction mechanism and "apparent" interaction strength within the two ASDs and (2) dissolution mechanism as well as in vivo performance of the two ASDs. DSC thermogram revealing a single Tg in 30 wt % ASD confirmed its homogeneous phase. 1H NMR, FT-IR, and DVS studies collectively proved that strong hydrogen bonding interactions formed between felodipine and PVPVA in ASDs. Moreover, homogeneous "30 wt % ASD" has more numbers of interacting drug-polymer pairs, and thus exhibits stronger "apparent" interaction strength comparing with that of inhomogeneous "30 wt % PM". Unexpectedly,in the in vitro dissolution studies, inhomogeneous "30 wt % PM" showed much faster dissolution and also generated drug concentration ∼4.4 times higher than that of homogeneous "30 wt % ASD". However, drug precipitate recrystallized much slower in homogeneous "30 wt % ASD", presumably because much more polymer coprecipitated with amorphous drug in this system, which helps inhibiting drug crystallization. Surprisingly, homogeneous "30 wt % ASD" showed a significantly higher bioavailability in the in vivo pharmacokinetic studies, with the maximum plasma concentrations (Cmax) and the area under the curve (AUC) values of about 2.7 and 2.3 times higher than those of inhomogeneous "30 wt % PM". The above findings indicated that the amorphous state of drug precipitate contributes significantly to increase bioavailability of ASDs, while traditional in vitro dissolution studies, for instance, if we only compare the dissolved drug in solution or the capability of an ASD to generate supersaturation, are inadequate to predict in vivo performance of ASDs. In conclusion, the phase behavior of ASDs directly impact the formation of drug-polymer interaction, which controls not only drug supersaturation in solution but also drug crystallization in precipitate, and ultimately affect the in vivo performance of ASDs.


Assuntos
Felodipino , Polímeros , Felodipino/química , Solubilidade , Disponibilidade Biológica , Espectroscopia de Infravermelho com Transformada de Fourier , Polímeros/química , Liberação Controlada de Fármacos
9.
Int J Mol Sci ; 23(21)2022 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-36362394

RESUMO

Ca2+ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca2+ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca2+ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1ß levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases.


Assuntos
Lipopolissacarídeos , Memória Espacial , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Camundongos Endogâmicos C57BL , Felodipino/efeitos adversos , Espinhas Dendríticas , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Microglia
10.
Int J Pharm ; 628: 122295, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36244562

RESUMO

Poly(latic-co-glycolic) acid (PLGA) nanoparticles loaded with felodipine (FEL) were embedded in a mucoadhesive matrix of poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) to prepare micro-nanoparticulate composites by particle engineering. Composites were characterized for physical and rheological properties and formulated with inhalable grade lactose. In-vitro characterization studies such as drug release kinetics, and mucoadhesive, and aerodynamic properties were performed. The in-vivo efficacy was evaluated by administering the optimized composites by nebulization in hypertensive rats. The obtained FEL-PLGA-PVM/MA composites of 1,069 ± 82 nm showed sustained drug release and mucoadhesive properties. Bulk and tapped densities of composites mixed with lactose were 0.08-0.13 g/mL and 0.18-0.30 g/mL, respectively, with mass median aerodynamic diameters (MMAD) in a range of 1.29-12.0 µm. After pulmonary administration of the composites, a decrease in systolic and diastolic blood pressure was observed within the first 3 h, of -9.0 ± 1.3 % and -13.9 ± 3.3 %, respectively, with a maximal effect at 12 h (sustained during 144 h), in contrast to pure FEL, which showed no significant decrease in blood pressure (1.6 ± 2.7 % and 4.1 ± 4.1 %). Findings suggest that novel mucoadhesive FEL-PLGA-PVM/MA composites are a promising strategy formulation to treat systemic diseases by pulmonary route.


Assuntos
Nanocompostos , Nanopartículas , Ratos , Animais , Felodipino , Tamanho da Partícula , Lactose , Portadores de Fármacos
11.
J Am Psychoanal Assoc ; 70(4): 813-816, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36047622
12.
Int J Pharm ; 626: 122158, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36058407

RESUMO

Amorphization is a powerful approach for improving the aqueous solubility and bioavailability of poorly water-soluble compounds. However, it can cause chemical and physical instability, the latter of which can lead to crystallization during storage, diminishing the solubility advantage of the amorphous state. As there is no standard method for predicting the physical stability of amorphous materials, a long-term stability study is needed in drug development. This study investigated the correlation between the physical stability of amorphous compounds and molecular mobility based on the assumption that physical stability is governed by the diffusional motion of a molecule. Model compounds were evaluated for crystallization onset time, structural relaxation time, fragility, and fictive temperature. The crystallization onset time of acetaminophen glass correlated with its relaxation time calculated from the Adam-Gibbs-Vogel equation; however, that of felodipine glass correlated with the relaxation time calculated from the Vogel-Tammann-Fulcher equation. The different crystallization tendencies of these compounds can be explained by the differences in the rate limiting steps in their crystallization processes, indicating the importance of distinguishing the critical process associated with crystallization. These findings will be useful for more accurate prediction of long-term physical stability of amorphous materials.


Assuntos
Acetaminofen , Felodipino , Varredura Diferencial de Calorimetria , Cristalização , Estabilidade de Medicamentos , Preparações Farmacêuticas , Água
14.
Cell Mol Biol (Noisy-le-grand) ; 67(6): 174-180, 2022 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-35818198

RESUMO

This study aimed to analyze the effect of felodipine combined with enalapril in the treatment of patients with essential hypertension and coronary artery disease. Also, the effect of these medicines was evaluated on the peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression. For this purpose, 110 patients with essential hypertension combined with coronary heart disease, admitted to the hospital from January 2019 to January 2021, were selected and randomly divided into two groups. The control group was given felodipine treatment alone, and the study group was treated with combined application of felodipine and enalapril. The treatment effect, peripheral blood Salusin-ß, Apelin, PON1 gene expression, and the safety of medication were compared between the two groups. The results showed that the post-treatment systolic blood pressure in the study group was 119.77 ± 5.23 mm Hg and diastolic blood pressure was 86.84 ± 5.42 mm Hg, both of which were significantly lower than those in the control group (127.81 ± 6.92 mm Hg and 95.13 ± 6.08 mm Hg), with statistically significant differences (p<0.05). The effective rates of the study group and the control group were 92.73% and 74.54% respectively, with statistically significant differences (P<0.05). The post-treatment peripheral blood Salusin-ßlevel in the study group was 3.77±0.53mmol/L, and Apelin was 1.94±0.58µg/L, with statistically significant differences compared to the control group (P<0.05). The PON1 gene expression in the study group was higher than those in the control group after treatment (P<0.05). Also, the results showed that there was no statistical difference in adverse reactions between the two groups (P>0.05). According to these results, the combination of felodipine and enalapril in patients with essential hypertension combined with coronary artery disease can effectively lower the patients' blood pressure and improve their peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression, thus enhancing the patients' therapeutic effect with few adverse effects and high safety.


Assuntos
Doença da Artéria Coronariana , Hipertensão , Apelina/genética , Apelina/farmacologia , Arildialquilfosfatase , Pressão Sanguínea , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Enalapril/farmacologia , Enalapril/uso terapêutico , Hipertensão Essencial/induzido quimicamente , Hipertensão Essencial/tratamento farmacológico , Hipertensão Essencial/genética , Felodipino/farmacologia , Felodipino/uso terapêutico , Expressão Gênica , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/genética
15.
Mol Pharm ; 19(8): 2888-2899, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35759395

RESUMO

Drug-polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug-polymer interactions were studied using the melting point depression method and the Flory-Huggins model fitting. The Flory-Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, -0.55 ± 0.20, and -1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug-polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.


Assuntos
Felodipino , Polímeros , Cristalização/métodos , Felodipino/química , Polímeros/química , Solubilidade , Água/química
16.
J Food Drug Anal ; 30(1): 111-127, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35647719

RESUMO

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1,000 personyears) than the subgroup without SMS treatment (51.10 per 1,000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1-60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11-1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62-2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1-60 g SMS: HR: 0.67; 95% CI: 0.47-0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37-0.79; p = 0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.


Assuntos
Citocromo P-450 CYP3A , Nifedipino , Animais , Citocromo P-450 CYP3A/genética , Combinação de Medicamentos , Medicamentos de Ervas Chinesas , Felodipino , Cefaleia , Humanos , Nifedipino/farmacocinética , Ratos , Estudos Retrospectivos
17.
Sci Total Environ ; 836: 155643, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35513148

RESUMO

Soil Aquifer Treatment (SAT) can provide supplementary treatment of trace organic compounds (TrOCs) such as pharmaceutical and industrial compounds present in Secondary Treated Wastewater (STWW). Concern on presence of unregulated TrOCs in natural systems has raised recently as well as the interest in SAT systems for remediation. The present study quantifies, at the field scale over35 m of lateral groundwater flow, the effectiveness of the Agon-Coutainville SAT system (Manche, Normandy, France) for TrOCs removal by sorption and biodegradation through monitoring of seven TrOCs (oxazepam, carbamazepine, benzotriazole, tolyltriazole, caffein, paracetamol, ibuprofen) and major inorganic compounds as intrinsic tracers in STWW and groundwater during a 34-day STWW infiltration experiment during operational use of the SAT. Cationic exchanges and mixing between groundwater and STWW during the experiment were highlighted by major ions and geochemical simulations. Due to the low thickness of the unsaturated zone, a 1D analytical solution of the advection-dispersion equation (ADE) was applied on chloride data. Chloride was used as conservative intrinsic tracer to calibrate the horizontal flow and transport parameters such as the aquifer dispersion coefficient (D) and the average pore water velocity (ν) allowing estimation of the groundwater residence time. Transport and attenuation of the TrOCs were simulated assuming first-order degradation constant (µ) and linear retardation coefficient (R), calibrated to simulate the observed temporal changes in the breakthrough of TrOCs. Sorption was found to play a role in the transport of TrOCs, notably for oxazepam with a higher linear retardation coefficient value of 2.2, whereas no significant differences of retardation were observed for carbamazepine, tolyltriazole, benzotriazole (1.37, 1.35, 1.36 respectively). Estimated first order degradation rate constants, between 0.03d-1 for carbamazepine and 0.09d-1 for tolyltriazole, were generally high compared to the literature, possibly due to favourable redox conditions and important microbial activities within the system. This study provides evidence of the efficiency of the Agon-Coutainville SAT system for the removal of TrOCs.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Carbamazepina , Cloretos , Felodipino , Água Subterrânea/química , Compostos Orgânicos , Oxazepam , Solo/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise
18.
Curr Pharm Des ; 28(24): 2010-2021, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35619254

RESUMO

BACKGROUND: The dissolution method for certain drugs needs specialized conditions. Dissolution testing for felodipine extended release (ER) tablets (Plendil® 5 mg) and amlodipine-indapamide fixed dose (Natrilam®, 5/1.5 mg) ER tablets requires the use of a stationary (felodipine) basket in USP Apparatus II. OBJECTIVE: The study aimed to develop simple methods for Plendil® and Natrilam® without the use of a felodipine basket. METHODS: The dissolution profiles obtained from different media and paddle speeds were used to compute miscellaneous dissolution parameters and were compared to those obtained from standard (existing) methods using a felodipine basket. RESULTS: The f1, f2, and bootstrap f2 (5th % percentile) values for Plendil® 2.47, 88.17, and 54.62, respectively, and all other dissolution factors revealed similarity between standard and the selected test method with 1% Tween 20 at 50 rpm. For Natrilam®, f1 and f2 and bootstrap f2 5.13, 72.92, and 62.67, respectively, and all other dissolution parameters showed similarity of the standard and selected test method using 0.1N HCl media having 0.38 gm/L EDTA with a sinker at 100 rpm. Release of products assumed zero-order and Weibull model, respectively. CONCLUSION: Test dissolution methods for Plendil® and Natrilam® tablets produced equivalent dissolution profiles compared to their respective standard methods with stationary basket USP Apparatus II.


Assuntos
Felodipino , Indapamida , Anlodipino , Humanos , Solubilidade , Comprimidos
19.
Pharm Res ; 39(9): 2033-2047, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35386014

RESUMO

The aim of this work is to present a modeling tool to describe drying kinetics and delineate evolving physical and chemical behavior of multicomponent droplets during drying. Conservation equations coupled with population balance equations (PBE) are used to achieve this goal. Modeling results are gauged with single salt-water droplet drying from literature and show congruent trends. This model is then extended to a more complex system: various droplet sizes containing methanol (solvent), Felodipine (active ingredient), and PVP (polyvinylpyrrolidone as excipient). The FIB-SEM (Focused-Ion Beam Scanning Electron Microscopy) imaging results from spray-dried particles produced with similar formulation and processing conditions are consistent with phase behavior predicted by the model. The results show competing impacts of transport phenomena on the intermittent shell formation process and final particle structure and chemical heterogeneity. Solute diffusion, solvent efflux, and intra-drop flow impact the model system. It is found that shell formation follows a fluctuating profile where the initial precipitation of the dissolved species on the droplet surface is dampened, and nucleated particles become dispersed periodically until the shell becomes strong enough to withstand internal circulations. These internal effects are dependent on droplet size and are pronounced for larger droplets. That is, the particle phase behavior and physical nature are functions of the atomized droplet size. Stemming understating from this study would inform an optimized unit, operating in target design space. This would provide better product quality control and minimize discrepancies observed in process development during the early phase vs. commercial scale.


Assuntos
Excipientes , Povidona , Excipientes/química , Felodipino , Metanol , Tamanho da Partícula , Pós/química , Solventes/química , Água
20.
AAPS PharmSciTech ; 23(4): 93, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35314906

RESUMO

The 1H nuclear magnetic resonance (NMR) relaxometry method was applied to investigate the physical stability of an active pharmaceutical ingredient (API) and, for the first time, its recrystallization process in an amorphous solid dispersion system (ASD). The ASD of felodipine and polyvinylpyrrolidone (PVP) was prepared using the solvent evaporation method in a mass ratio of 50:50. In the first stage of the study (250 days), the sample was stored at 0% relative humidity (RH). The recovery of magnetization was described by one-exponential function. In the second stage (300 days in 75% relative humidity), the recrystallization process of felodipine was studied, showing in the sample three components of equilibrium magnetization related to (i) crystalline felodipine, (ii) water, and (iii) felodipine and PVP remaining in the ASD. The study shows that the 1H NMR relaxometry method is a very useful tool for analysing the composition of a three-phase system mixed at the molecular level and for the investigation of recrystallization process of API in amorphous solid dispersion system.


Assuntos
Felodipino , Povidona , Cristalização , Estabilidade de Medicamentos , Felodipino/química , Espectroscopia de Ressonância Magnética/métodos , Povidona/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...