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1.
Eur J Pharm Sci ; 141: 105083, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634557

RESUMO

One of the greatest problems of pre-clinical development of new chemical entities is their poor aqueous solubility. Herein, we focus our attention on MD20 - a novel calcium channel blocker that selectively blocks T-type calcium channel (Cav3.2) over L-type calcium channel (Cav1.2). To avoid future problems with limited solubility of this compound, an amorphous form of MD20 was obtained and thoroughly investigated by various experimental techniques. The thermal properties of both crystalline and amorphous MD20 were examined by differential scanning calorimetry and thermogravimetry. Dielectric spectroscopy studies of MD20 at T < Tg revealed that this compound possesses as many as four secondary relaxation processes. The molecular dynamics of the supercooled sample was investigated by dielectric and mechanical spectroscopies. In this paper, a comparison of the relaxation dynamics of supercooled MD20 obtained from both of these experimental techniques is presented. On the basis of the dielectric studies, the time of physical stability of the investigated material (at T = 298 K) was predicted as 150 years. Finally, we have performed experimental long-term stability tests, which showed that amorphous MD20 did not reveal any signs of re-crystallization for at least 260 days.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Di-Hidropiridinas/química , Canais de Cálcio Tipo T , Estabilidade de Medicamentos , Elasticidade , Simulação de Dinâmica Molecular , Viscosidade
2.
Biomed Pharmacother ; 121: 109592, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706101

RESUMO

Intervertebral disc degeneration (IVDD) is a major cause of many spinal diseases characterized mainly by nucleus pulposus degradation. 1,4-dihydropyridine (DHP), a new activator of sirtuin-1 (sirt1), has been reported to have anti-oxidative effects. The aim of this study is to investigate the effect of DHP on nucleus pulposus (NP) cells in vitro. NP cells were pretreated with IL-1ß to establish a degenerated model, and then treated with DHP alone or DHP combined with selisistat (an inhibitor of sirt1). ROS level was analyzed by flow cytometry. Production of IL-6 and TNF-α were evaluated by the enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and sirt1. We found that DHP inhibited IL-1ß-induced upregulation of ROS, TNF-α, IL-6, MMP-3, ADAMTS-5. Besides, DHP remarkably increased the sirt1 and anti-oxidative protein SOD-1 level. Furthermore, DHP significantly protected the IL-1ß-induced degradation of collagen-II and aggrecan. However, the inhibitory effect of DHP was obvious abolished by selisistat, suggesting that DHP exerts these effects in NP cells through activating sirt1. Taken together, we found that DHP inhibited the ROS, inflammatory response and ECM degradation through activating Sirt1 in human NP cells.


Assuntos
Di-Hidropiridinas/farmacologia , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Adulto , Bloqueadores dos Canais de Cálcio/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Masculino , Estresse Oxidativo/fisiologia
3.
Enzyme Microb Technol ; 132: 109411, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731971

RESUMO

Biocatalytic oxidations mediated by laccases are gaining importance due to their versatility and beneficial environmental effects. In this study, the oxidation of 1,4-dihydropyridines has been performed using three different types of bacterial laccase-based catalysts: purified laccase from Bacillus licheniformis ATCC 9945a (BliLacc), Escherichia coli whole cells expressing this laccase, and bacterial nanocellulose (BNC) supported BliLacc catalysts. The catalysts based on bacterial laccase were compared to the commercially available Trametes versicolor laccase (TvLacc). The oxidation product of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained within 7-24 h with good yields (70-99%) with all three biocatalysts. The substrate scope was examined with five additional 1,4-dihydropyridines, one of which was oxidized in high yield. Whole-cell biocatalyst was stable when stored for up to 1-month at 4 °C. In addition, evidence has been provided that multicopper oxidase CueO from the E. coli expression host contributed to the oxidation efficiency of the whole-cell biocatalyst. The immobilized whole-cell biocatalyst showed satisfactory activity and retained 37% of its original activity after three biotransformation cycles.


Assuntos
Bacillus/enzimologia , Biocatálise , Di-Hidropiridinas/metabolismo , Lacase/metabolismo , Enzimas Imobilizadas/metabolismo , Concentração de Íons de Hidrogênio , Oxirredução , Temperatura
4.
AAPS PharmSciTech ; 21(1): 21, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823090

RESUMO

Hypertension shows circadian blood pressure rhythms (day-night pattern) that urge the delivery of antihypertensive drugs at the right time in the desired levels. Thus, a bilayered core-in-cup buccoadhesive tablet was formulated that immediately releases olmesartan, to give a burst effect, and controls azelnidipine release, to prolong its therapeutic effect. The main challenge was the poor bioavailability of azelnidipine due to its poor aqueous solubility and first-pass effect. Hence, liquisolid compact buccoadhesive tablets were prepared to enhance solubility, dissolution profiles, and bypass the oral route. Two factorial designs were conducted to study the type and concentration effect of the mucoadhesive polymers on the dissolution and mucoadhesion of olmesartan and azelnidipine. Characterization studies were conducted regarding drug content, surface pH, water uptake, mucoadhesive strength, in vitro release, and ex vivo permeability. The core-in-cup olmesartan/azelnidipine buccoadhesive tablet showed similar release profile to the statistically optimized formulae of each drug. In vitro dissolution study showed enhanced release of azelnidipine than the directly compressed tablets, to comply with the regulatory standards of controlled release systems. In vivo pharmacokinetic study of olmesartan and azelnidipine conducted on human volunteers against Rezaltas® 10/8 mg tablet showed percentage relative bioavailability of 106.12 and 470.82%, respectively. Graphical Abstract.


Assuntos
Anti-Hipertensivos/administração & dosagem , Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas/administração & dosagem , Imidazóis/administração & dosagem , Tetrazóis/administração & dosagem , Adulto , Ácido Azetidinocarboxílico/administração & dosagem , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Disponibilidade Biológica , Preparações de Ação Retardada/química , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacocinética , Composição de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Comprimidos/química , Tetrazóis/química , Tetrazóis/farmacocinética
5.
Int J Mol Sci ; 20(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817163

RESUMO

The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells. In addition, the combination of Btz and Ler triggers mitochondrial Ca2+ overload, critically contributing to mitochondrial dilation and subsequent paraptotic events, including mitochondrial membrane potential loss and ER dilation. Taken together, our results suggest that a combined regimen of PI and Ler may effectively kill cancer cells via structural and functional perturbations of the ER and mitochondria.


Assuntos
Bortezomib/farmacologia , Cálcio/metabolismo , Di-Hidropiridinas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Íons/química , Mitocôndrias/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
6.
Urologiia ; (5): 48-52, 2019 Dec.
Artigo em Russo | MEDLINE | ID: mdl-31808632

RESUMO

OBJECTIVE: to evaluate the nephroprotective effect of lercanidipine, its effect on the dynamics of creatinine clearance and blood cytokine levels in patients with nephrolithiasis with obstructive uropathy during renal drainage. MATERIAL AND METHODS: 66 patients were included in the study with concretions of the pelvic segment and the presence of obstruction according to instrumental methods of examination. In order to prevent the occurrence of infectious complications before lithotripsy patients the first stage was performed installation of nephrostomic drainage, followed by antibacterial, anti-inflammatory therapy. Patients were divided into 2 groups: the first (33 patients) received standard therapy, the second (33 people) additionally received lercanidipine at a dose of 10 mg per day for 1 month. Determined the concentration of IL-8, VEGF, MCP-1, G-CSF and GM-CSF in the blood serum by the method of solid-phase ELISA. The glomerular filtration rate was calculated using the CKD-EPI formula. All studies were performed at the preoperative stage, on 7, 14, 21 and 28 days after renal drainage. RESULTS: In the appointment of lercanidipine, there was a more rapid decrease in levels of IL-8, VEGF, MS-1, GM-CSF in serum (21 days), and an improvement in renal function, compared with the group that did not receive nephroprotective therapy. CONCLUSION: The administration of lercanidipine may contribute to a more rapid recovery of renal function and normalization of blood cytokine levels. This drug can be used in the complex treatment of patients with nephrolithiasis with obstructive uropathy.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Citocinas/sangue , Di-Hidropiridinas/uso terapêutico , Rim/efeitos dos fármacos , Nefrolitíase/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Urolitíase/cirurgia , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Di-Hidropiridinas/administração & dosagem , Taxa de Filtração Glomerular , Humanos , Fármacos Neuroprotetores/administração & dosagem , Resultado do Tratamento
7.
JAMA Netw Open ; 2(12): e1918425, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31880802

RESUMO

Importance: Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics. Objective: To assess the magnitude and characteristics of the DH CCB prescribing cascade. Design, Setting, and Participants: This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019. Exposures: Initiation of DH CCB or negative control medications. Main Outcomes and Measures: The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs. Results: Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29). Conclusions and Relevance: This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Di-Hidropiridinas/efeitos adversos , Edema/induzido quimicamente , Edema/tratamento farmacológico , Adulto , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/tratamento farmacológico , Perna (Membro) , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Pharmacol Rep ; 71(6): 1264-1272, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31675672

RESUMO

BACKGROUND: Anxiety is a disorder of multi-factorial pathogenesis involving interrelated pathways of neurotransmitters, oxidative stress and metamorphosed calcium-signaling that negatively affects brain functions. Modulation of Ca2+-channels outlines a promising strategy to curb the progression of anxiety-like disorders through attenuation of redox-imbalance. The current research scheme was designed to explore the anxiolytic effects of lacidipine (L-type Ca2+-channel blocker; LCD) pretreatment in caffeine-induced anxiety-like symptom model in mice. METHODS: Forty-two Swiss albino mice (25-30 g) were distributed to 7 groups (n = 6): Vehicle control, caffeine, alprazolam + caffeine, lacidipine(0.3, 1 and 3 mg/kg, ip)+caffeine and Bay-K8644+LCD(3)+caffeine. Caffeine (25 mg/kg, ip) was administered from day 8 to 14 to induce anxiety-like symptoms in mice. Lacidipine (0.3, 1 and 3 mg/kg, ip) and alprazolam (0.25 mg/kg, ip) were administered from day 1 to 14 in separate groups. Bay-K8644 (Ca2+-channel agonist) was injected on day 14 to delineate the role of Ca2+ in anti-anxiety effect of LCD in caffeine-treated mice. Elevated zero maze and mirror chamber test were employed to assess anxiety-like behavior. Afterwards, the mice were sacrificed and whole brains were harvested for estimation of biomarkers of oxido-nitrosative stress, such as TBARS, GSH, SOD, catalase and total nitrite content. RESULTS: An increase in brain oxido-nitrosative stress and anxiety-like behavior was observed in caffeine treated mice. LCD pretreatment attenuated the brain oxido-nitrosative stress and anxiety-like behavior in mice in caffeine treated mice. Anxiolytic effect of LCD was attenuated by Bay-K8644 (0.5 mg/kg) in caffeine treated mice. CONCLUSION: LCD (L-type Ca2+-channel antagonist) pretreatment attenuated caffeine-induced oxido-nitrosative stress and anxiety-like behavior.


Assuntos
Ansiedade/tratamento farmacológico , Cafeína/farmacologia , Cálcio/metabolismo , Di-Hidropiridinas/farmacologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Feminino , Masculino , Camundongos
9.
Life Sci ; 239: 116878, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669736

RESUMO

AIMS: We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition. MAIN METHODS: Mice from both wild-type (WT) and ß-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month. KEY FINDINGS: HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine. SIGNIFICANCE: These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.


Assuntos
Deferiprona/farmacologia , Di-Hidropiridinas/farmacologia , Ferro/toxicidade , Nitrofenóis/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Deferiprona/metabolismo , Di-Hidropiridinas/metabolismo , Modelos Animais de Doenças , Ferro/metabolismo , Quelantes de Ferro/farmacologia , Sobrecarga de Ferro/patologia , Camundongos , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Nitrofenóis/metabolismo , Compostos Organofosforados/metabolismo , Compostos Organofosforados/farmacologia , Talassemia/patologia
10.
Curr Top Med Chem ; 19(29): 2676-2686, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31702500

RESUMO

AIM: The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives. BACKGROUND: An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process. MATERIALS & METHODS: In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N-dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. RESULTS: Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties. CONCLUSION: The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.


Assuntos
Antioxidantes/farmacologia , Di-Hidropiridinas/farmacologia , Animais , Quelantes/farmacologia , Simulação por Computador , Di-Hidropiridinas/química , Hemólise/efeitos dos fármacos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
12.
Mini Rev Med Chem ; 19(15): 1219-1254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31735158

RESUMO

Nowadays, heterocyclic compounds act as a scaffold and are the backbone of medicinal chemistry. Among all of the heterocyclic scaffolds, 1,4-Dihydropyridine (1,4-DHP) is one of the most important heterocyclic rings that possess prominent therapeutic effects in a very versatile manner and plays an important role in synthetic, medicinal, and bioorganic chemistry. The main aim of the study is to review and encompass relevant studies related to 1,4-DHP and excellent therapeutic benefits of its derivatives. An extensive review of Pubmed-Medline, Embase and Lancet's published articles was done to find all relevant studies on the activity of 1,4-DHP and its derivatives. 1,4-DHP is a potent Voltage-Gated Calcium Channel (VGCC) antagonist derivative which acts as an anti-hypertensive, anti- anginal, anti-tumor, anti-inflammatory, anti-tubercular, anti-cancer, anti-hyperplasia, anti-mutagenic, anti-dyslipidemic, and anti-ulcer agent. From the inferences of the study, it can be concluded that the basic nucleus, 1,4-DHP which is a voltage-gated calcium ion channel blocker, acts as a base for its derivatives that possess different important therapeutic effects. There is a need of further research of this basic nucleus as it is a multifunctional moiety, on which addition of different groups can yield a better drug for its other activities such as anti-convulsant, anti-oxidant, anti-mutagenic, and anti-microbial. This review would be significant for further researches in the development of several kinds of drugs by representing successful matrix for the medicinal agents.


Assuntos
Di-Hidropiridinas/farmacologia , Compostos Heterocíclicos/farmacologia , Neoplasias/tratamento farmacológico , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/química , Antiulcerosos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/metabolismo , Di-Hidropiridinas/química , Compostos Heterocíclicos/química , Úlcera/tratamento farmacológico
13.
J Pharmacol Exp Ther ; 371(3): 675-683, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31585986

RESUMO

Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2α (HIF-2α), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, we examined whether liver-derived EPO improved anemia in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2α and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2α level from 0.27 to 1.53 fmol/mg and the EPO mRNA expression level by 1300-fold in the livers of healthy rats. After administration of TP0463518 at 20 mg/kg, the total EPO mRNA expression level in the whole liver was 22-fold that in the whole kidney. In bilaterally nephrectomized rats, TP0463518 raised the serum EPO concentration from 0 to 180 pg/ml at 20 mg/kg. Furthermore, repeated administration of TP0463518 at 10 mg/kg increased the reticulocyte count in 5/6 Nx rats on day 7 and raised the hemoglobin level on day 14. The present study revealed that TP0463518 specifically induced EPO production in the liver and improved anemia. The characteristic feature of TP0463518 would lead to not only a more detailed understanding of the PHD-HIF2α-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver; however, their effects on renal EPO production have been shown to vary depending on the experimental conditions. The authors found that 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518), a PHD 1/2/3 pan inhibitor, specifically induced EPO production in the liver and that the liver-derived EPO was pharmacologically effective. Investigation of the effects of TP0463518 may pave the way for the development of a new therapeutic alternative for renal anemia patients.


Assuntos
Di-Hidropiridinas/farmacologia , Eritropoetina/metabolismo , Fígado/efeitos dos fármacos , Inibidores de Prolil-Hidrolase/farmacologia , Piridinas/farmacologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Eritropoetina/genética , Células Hep G2 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações Medicamentosas , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
16.
Mutat Res ; 845: 403077, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31561891

RESUMO

1,4-Dihydropyridines (1,4-DHP) possess important biochemical and pharmacological properties, including antioxidant and antimutagenic activities. AV-153-Na, an antimutagenic and DNA-repair enhancing compound was shown to interact with DNA by intercalation. Here we studied DNA binding of several AV-153 salts to evaluate the impact of AV-153 modifications on its DNA binding capacity, the ability to scavenge the peroxynitrite, to protect HeLa and B-cells cells against DNA damage. Affinity of the AV-153 salts to DNA measured by a fluorescence assay was dependent on the metal ion forming a salt in position 4 of the 1,4-DHP, and it decreased as follows: Mg > Na > Ca > Li > Rb > K. AV-153-K and AV-153-Rb could not react chemically with peroxynitrite as opposed to AV-153-Mg and AV-153-Ca, the latter increased the decomposition rate of peroxynitrite. AV-153-Na and AV-153-Ca effectively reduced DNA damage induced by peroxynitrite in HeLa cells, while AV-153-K and AV-153-Rb were less effective, AV-153-Li did not protect the DNA, and AV-153-Mg even caused DNA damage itself. The Na, K, Ca and Mg AV-153 salts were also shown to reduce the level of DNA damage in human B-cells from healthy donors. Thus, metal ions modify both DNA-binding and DNA-protecting effects of the AV-153 salts.


Assuntos
Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Substâncias Intercalantes/farmacologia , Metais/farmacologia , Niacina/análogos & derivados , Antioxidantes/toxicidade , Linfócitos B/efeitos dos fármacos , Ensaio Cometa , Quebras de DNA de Cadeia Simples , Reparo do DNA , Di-Hidropiridinas/toxicidade , Interações Medicamentosas , Células HeLa , Humanos , Substâncias Intercalantes/toxicidade , Niacina/farmacologia , Niacina/toxicidade , Estresse Oxidativo , Ácido Peroxinitroso/toxicidade , Proteínas Recombinantes/farmacologia , Análise de Célula Única , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia
17.
Ultrason Sonochem ; 59: 104737, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473427

RESUMO

A convenient strategy for synthesis of the various derivatives of 1,4-dihydropyridine (1,4-DHP), as one of the most important pharmaceutical compounds, is presented in this study. For this purpose, firstly, magnetic iron oxide nanoparticles (Fe3O4 NPs) were fabricated and suitably coated by silica network (SiO2) and trimethoxy vinylsilane (TMVS). Then, their surfaces were well functionalized with pyrimidine-2,4-diamine (PDA) as the main active sites for catalyzing the synthesis reactions. In this regard, the performance of three different methods including reflux, microwave (MW) and ultrasound wave (USW) irradiations have been comparatively monitored via studying various analyses on the fabricated nanocatalyst (Fe3O4/SiO2-PDA). Concisely, high efficiency of the USW irradiation (in an ultrasound cleaning bath with a frequency of 50 kHz and power of 250 W/L) has been well proven through the investigation of the main factors such as excellent surface-functionalization, core/shell structure conservation, particle uniformity, close size distribution of the particles, and great inhibition of the particle aggregation. Then, the effectiveness of the USW irradiation as a promising co-catalyst agent has been clearly demonstrated in the 1,4-DHP synthesis reactions. It has been concluded that the USW could provide more appropriate conditions for activation of the catalytic sites of Fe3O4/SiO2-PDA NPs. However, high reaction yields (89%) have been obtained in the short reaction times (10 min) due to the substantial synergistic effect between the presented nanocatalyst and USW.


Assuntos
Di-Hidropiridinas/química , Di-Hidropiridinas/síntese química , Nanopartículas de Magnetita/química , Pirimidinas/química , Ondas Ultrassônicas , Catálise , Técnicas de Química Sintética , Dióxido de Silício/química
18.
Eur J Pharm Sci ; 139: 105043, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415903

RESUMO

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6-7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0-∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.


Assuntos
Di-Hidropiridinas/administração & dosagem , Portadores de Fármacos/administração & dosagem , Excipientes/administração & dosagem , Polietilenoglicóis/administração & dosagem , Polivinil/administração & dosagem , Dodecilsulfato de Sódio/administração & dosagem , Tensoativos/administração & dosagem , Animais , Disponibilidade Biológica , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Excipientes/química , Excipientes/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polivinil/química , Polivinil/farmacocinética , Ratos Sprague-Dawley , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Tensoativos/química , Tensoativos/farmacocinética
19.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
20.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398786

RESUMO

The number of effective antituberculotic drugs is strongly limited to four first-line drugs in standard therapy. In case of resistances second-line antibiotics are used with a poor efficacy and tolerability. Therefore, novel antituberculotic drugs are urgently needed. We synthesized novel nonclassical 1,4-dihydropyridines and evaluated their antituberculotic properties depending on substituent effects. Preferred substituents could be identified. As related classical 1,4-dihydropyridines are known as inhibitors of the transmembrane efflux pump ABCB1 in cancer cells, we wondered whether a use of our compounds may be of favour to enhance the antituberculotic drug efficacy of the second-line antituberculotic drug clofazimine, which is a known substrate of ABCB1 by a suggested inhibition of a corresponding efflux pump in Mycobacterium tuberculosis (Mtb). For this, we determined the ABCB1 inhibiting properties of our compounds in a mouse T-lymphoma cell line model and then evaluated the drug-enhancing properties of selected compounds in a co-application with clofazimine in our Mtb strain. We identified novel enhancers of clofazimine toxicity which could prevent clofazimine resistance development mediated by an efflux pump activity.


Assuntos
Antituberculosos/farmacologia , Clofazimina/farmacologia , Di-Hidropiridinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antituberculosos/química , Clofazimina/química , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Análise Espectral
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