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1.
Int J Mol Sci ; 22(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445763

RESUMO

Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4'-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand-protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1-5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Descoberta de Drogas/métodos , Inibidores de Proteases/farmacologia , Antivirais/uso terapêutico , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Ensaios Enzimáticos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Serina Endopeptidases/metabolismo
2.
Int J Pharm ; 606: 120877, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34252522

RESUMO

Resveratrol (RVT) is one of the potent anticancer phytochemicals which has shown promising potential for breast cancer therapy. However, its short half-life and low bioavailability is a major hurdle in its effective use. In this study, we have developed nanostructured lipid carriers (NLCs) of RVT to enable localized delivery of the drug to the breast tissues using microneedle arrays to improve effectiveness. The NLCs were optimized using the Design of Experiments approach and characterized for their particle size, polydispersity index, zeta potential and entrapment efficiency. The RVT-NLCs delivered using microneedle array 1200 showed a higher permeation of RVT across the skin with lower skin retention compared to pure RVT. Further, RVT-NLCs showed higher anticancer activity on MDA-MB-231 breast cancer cell lines and enhanced internalization compared to pure RVT. Moreover, the RVT-NLCs were found to inhibit the migration of MDA-MB-231 breast cancer cell lines. Preclinical studies in rats showed that RVT-NLCs delivered via microneedles demonstrated a remarkable increase in the Cmax, Tmax and AUC0-inf, and a higher localization in breast tissue compared to pure RVT administered orally. These results suggests that the RVT-NLCs administered by microneedle array system is an effective strategy for the local delivery of RVT for breast cancer therapy.


Assuntos
Nanoestruturas , Neoplasias , Animais , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Lipídeos , Tamanho da Partícula , Ratos , Resveratrol
3.
Eur J Pharm Biopharm ; 167: 127-139, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34329710

RESUMO

Recent preclinical studies have shown that resveratrol (RSV), is a promising remedy for osteoporosis owing to its estrogenic, anti-inflammatory, and antioxidant properties. However, RSV has met limited success due to its poor oral bioavailability and inefficient systemic delivery. In this study, we prepared the inclusion complex of RSV with sulfo-butyl ether ß-cyclodextrin (SBE-ß-CD) to enhance the aqueous solubility of RSV. The in-silico docking studies and Physico-chemical characterization assays were performed to understand the interaction of RSV inside the SBE-ß-CD cavity. The in vivo safety assessment of RSV-SBE-ß-CD inclusion complex (R-CDIC) was performed in healthy Wistar rats. The efficacy of the inclusion complex against postmenopausal osteoporosis was further investigated in ovariectomized (OVX) rat model. The alteration in the bone micro-architectural structure was evaluated by microcomputed tomographic scanning, serum biochemical estimations, biomechanical strength and histopathological investigation. Administration of RSV-SBE-ß-CD inclusion complex was found to be safe and significantly improved micro-architectural deterioration induced by estrogen withdrawal. Results of bone morphometry and biomechanics study further emboldened the efficacy claim of the RSV-SBE-ß-CD complex. Thus, the present study demonstrated the efficacy of the RSV-SBE-ß-CD inclusion complex for treating osteolytic degradation in osteoporosis.

4.
J Food Biochem ; 45(4): e13690, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33749834

RESUMO

This study evaluates the modulation of inflammatory markers by petroleum ether fraction of Trigonella foenum-graecum L. (PE-TFG) seed extract in ovariectomized rats. The HPTLC method was used for standardization and to quantify the diosgenin in PE-TFG. For testing PE-TFG in rats, the total duration of treatment was 12-weeks, and the rats were sacrificed on week 12. The tissue samples such as blood, liver, heart, and aorta were isolated for testing inflammatory markers such as adiponectin, leptin, PPAR-γ, TNF-α, lipid profile, hepatic markers, antioxidants, and oxidative stress markers. The PE-TFG treatment decreased the elevation of total cholesterol, triglyceride, AST, and ALT. Upon PE-TFG treatment, there was a significant increase in adiponectin and PPAR-γ mRNA expression. Leptin and TNF-α were normal after treatment with PE-TFG seed extract. Further, micro-steatosis of hepatocytes marked glomerular hypertrophy in the kidney and increased thickness of tunica intima and media of common carotid artery was reversed after treatment with PE-TFG. PRACTICAL APPLICATIONS: Trigonella foenum-graecum L. is a curative plant used to treat inflammatory conditions like diabetes, obesity, dyslipidemia, arthritis, cancer, and digestive disorders. In our study, PE-TFG supplementation has a protective effect on OVX-induced inflammation, oxidative stress, mRNA expression of adiponectin and PPAR-γ, hepatic steatosis, and decreased thickness of tunica intima and media of common carotid artery.


Assuntos
Petróleo , Trigonella , Alcanos , Animais , Extratos Vegetais/farmacologia , Ratos
5.
Carbohydr Polym ; 261: 117893, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766378

RESUMO

Glycosylated pH-sensitive mesoporous silica nanoparticles (MSNs) of capecitabine (CAP) were developed for targeting colorectal cancer. The MSNs possessed an average pore diameter of 8.12 ± 0.43 nm, pore volume of 0.73 ± 0.21 cm3/g, and particle size of 245.24 ± 5.75 nm. A high loading of 180.51 ± 5.23 mg/g attributed to the larger pore volume was observed. The surface of the drug-loaded MSNs were capped with chitosan-glucuronic acid (CHS-GCA) conjugate to combine two strategies viz. pH-sensitive, and lectin receptor mediated uptake. In vitro studies demonstrated a pH-sensitive and controlled release of CAP which was further enhanced in the presence of rat caecal content. Higher uptake of the (CAP-MSN)CHS-GCA was observed in HCT 116 cell lines. The glycosylated nanoparticles revealed reduction in the tumors, aberrant crypt foci, dysplasia and inflammation, and alleviation in the toxic features. This illustrated that the nanoparticles showed promising antitumor efficacy with reduced toxicity and may be used as a effective carrier against cancer.


Assuntos
Capecitabina/administração & dosagem , Quitosana/química , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/síntese química , Ácido Glucurônico/química , Dióxido de Silício/química , Animais , Capecitabina/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/uso terapêutico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/química , Nanopartículas/uso terapêutico , Tamanho da Partícula , Porosidade , Ratos , Ratos Wistar , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Pharmacol ; 896: 173922, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33539819

RESUMO

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , COVID-19 , Doxorrubicina/análogos & derivados , Lopinavir/farmacologia , SARS-CoV-2 , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Inibidores da Topoisomerase II/farmacologia
7.
Arch Med Res ; 52(1): 38-47, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32962867

RESUMO

BACKGROUND AND AIMS: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) induced Novel Coronavirus Disease (COVID-19) has currently become pandemic worldwide. Though drugs like remdesivir, favipiravir, and dexamethasone found beneficial for COVID-19 management, they have limitations clinically, and vaccine development takes a long time. The researchers have reported key proteins which could act as druggable targets. Among them, the major protease Mpro is first published, plays a prominent role in viral replication and an attractive drug-target for drug discovery. Hence, to target Mpro and inhibit it, we accomplished the virtual screening of US-FDA approved drugs using well-known drug repurposing approach by computer-aided tools. METHODS: The protein Mpro, PDB-ID 6LU7 was imported to Maestro graphical user interphase of Schrödinger software. The US-FDA approved drug structures are imported from DrugBank and docked after preliminary protein and ligand preparation. The drugs are shortlisted based on the docking scores in the Standard Precision method (SP-docking) and then based on the type of molecular interactions they are studied for molecular dynamics simulations. RESULTS: The docking and molecular interactions studies, five drugs emerged as potential hits by forming hydrophilic, hydrophobic, electrostatic interactions. The drugs such as arbutin, terbutaline, barnidipine, tipiracil and aprepitant identified as potential hits. Among the drugs, tipiracil and aprepitant interacted with the Mpro consistently, and they turned out to be most promising. CONCLUSIONS: This study shows the possible exploration for drug repurposing using computer-aided docking tools and the potential roles of tipiracil and aprepitant, which can be explored further in the treatment of COVID-19.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/enzimologia , Antivirais/química , Antivirais/farmacologia , COVID-19/virologia , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Descoberta de Drogas/métodos , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos
8.
F1000Res ; 9: 1166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204411

RESUMO

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (M pro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.


Assuntos
Antivirais , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , COVID-19 , Domínio Catalítico , Humanos , Simulação de Acoplamento Molecular , Pandemias , Ácidos Pentanoicos/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Quinolonas/farmacologia , SARS-CoV-2
9.
Pharmacol Rep ; 72(4): 799-813, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32666476

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitors represent the first-line therapy regimen for non-small cell lung cancer (NSCLC). Most of these inhibitors target the ATP-site to stop the aggressive development of NSCLC. Stabilization of the ATP-binding on EGFR is difficult due to autophosphorylation of the EGFR domain. This leads to activation of nonintrinsic influence of the tumor microenvironment and expression of anti-apoptotic pathways and drug resistance. METHODS: The NSCLC related literature search was carried out using online databases such as Scopus, Web of Sciences, PubMed, Protein Data Bank and UniPort for the last ten years and selected articles are referred for discussion in this review. RESULTS: To overcome the problem of mutations in NSCLC, the allosteric site of EGFR was targeted, which shows significant therapeutic outcome without causing resistance. Compounds like EAI001, EAI045 JBJ-04-125-02, DDC4002 and a series of small molecules with an affinity towards the EGFR allosteric site are reported and are under the investigational stage. These compounds are categorized under fourth-generation anti-NSCLC agents. CONCLUSION: Composition of this review highlights the advantage of inhibiting allosteric site in the EGFRTK receptor domains and presents a comparative analysis of the new fourth-generation anti-NSCLC agents to overcome the drug resistance.


Assuntos
Sítio Alostérico/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Sítio Alostérico/fisiologia , Animais , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Estrutura Secundária de Proteína
10.
Pharmaceutics ; 12(6)2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521684

RESUMO

Breast cancer has become one of the biggest concerns for oncologists in the past few decades because of its unpredictable etiopathology and nonavailability of personalized translational medicine. The number of women getting affected by breast cancer has increased dramatically, owing to lifestyle and environmental changes. Besides, the development of multidrug resistance has become a challenge in the therapeutic management of breast cancer. Studies reveal that the use of monotherapy is not effective in the management of breast cancer due to high toxicity and the development of resistance. Combination therapies, such as radiation therapy with adjuvant therapy, endocrine therapy with chemotherapy, and targeted therapy with immunotherapy, are found to be effective. Thus, multimodal and combination treatments, along with nanomedicine, have emerged as a promising strategy with minimum side effects and drug resistance. In this review, we emphasize the multimodal approaches and recent advancements in breast cancer treatment modalities, giving importance to the current data on clinical trials. The novel treatment approach by targeted therapy, according to type, such as luminal, HER2 positive, and triple-negative breast cancer, are discussed. Further, passive and active targeting technologies, including nanoparticles, bioconjugate systems, stimuli-responsive, and nucleic acid delivery systems, including siRNA and aptamer, are explained. The recent research exploring the role of nanomedicine in combination therapy and the possible use of artificial intelligence in breast cancer therapy is also discussed herein. The complexity and dynamism of disease changes require the constant upgrading of knowledge, and innovation is essential for future drug development for treating breast cancer.

11.
J Taibah Univ Med Sci ; 14(4): 383-389, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31488972

RESUMO

Objective: The present study was carried out to assess the effects of fenugreek seed extract on various biochemical and haematological parameters in high-fat diet (HFD)-fed rats. Methods: Female Wistar rats were allocated into five groups (n = 6): 1) control rats, 2) HFD-fed control rats 3) rats fed with HFD and fenugreek (FG) seed extract at doses of 200 mg/kg/day, 300 mg/kg/day, and 400 mg/kg/day for 12 weeks. Blood was collected to examine the biochemical and haematological parameters using a veterinary blood cell counter; blood indices such as MCV, MCH, MCHC, red blood cell distribution width, haemoglobin (Hb) levels, haematocrit, and platelet counts were measured. Blood samples were centrifuged at 3000 rpm for 10 min at room temperature to obtain serum for the estimation of lipid profiles, and aspartate transaminase and alanine transaminase levels. Results: Rats fed with FG at a dose of 400 mg/kg/day showed a significant increase in the red blood cell count, Hb levels, haematocrit, and MCV, and a significant decrease in the lymphocyte count. The total cholesterol, triglyceride, and low-density lipoprotein levels increased significantly (p < 0.05) in rats from the HFD control group, compared to those in the normal control group, but decreased significantly in rats fed with 400 mg/kg/day of FG. Conclusion: The results of the current study suggest that FG seed extract exhibits hypolipidaemic activity and significantly improves the activity of hepatic enzymes, and the blood counts and indices in rats with HFD-induced obesity.

12.
Psychopharmacology (Berl) ; 235(5): 1557-1570, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29502275

RESUMO

RATIONALE AND OBJECTIVES: 5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes. METHODS: In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ. RESULTS: Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible. CONCLUSION: The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.


Assuntos
Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Estreptozocina/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Estreptozocina/administração & dosagem
13.
Life Sci ; 183: 11-20, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28647214

RESUMO

AIMS: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. MATERIALS AND METHODS: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. KEY FINDINGS: The mean particle size was found to be in the range of 126.6 to 306.2nm with PDI of 0.340-1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of -18.1 to -20.2mv. Biotinylated proliposomes (LIP-5B) were in the size of 149.8±6.8nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP-5) and biotin proliposomes (LIP-5B) were executed. SIGNIFICANCE: The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site.


Assuntos
Biotina/química , Linfócitos T CD4-Positivos/metabolismo , Sistemas de Liberação de Medicamentos , Inibidores da Protease de HIV/administração & dosagem , Ritonavir/administração & dosagem , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Inibidores da Protease de HIV/farmacocinética , Lipídeos , Lipossomos , Tamanho da Partícula , Pró-Fármacos , Ratos , Ratos Wistar , Ritonavir/farmacocinética , Baço/metabolismo , Timo/metabolismo , Distribuição Tecidual
14.
Neurochem Res ; 42(5): 1571-1579, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28271324

RESUMO

Beta-amyloid peptide (Aß) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer's disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aß-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aß25-35 (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aß25-35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aß25-35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aß25-35 induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Fragmentos de Peptídeos/toxicidade , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Indóis/farmacologia , Células PC12 , Piperazinas/farmacologia , Piridinas/farmacologia , Ratos , Sulfonamidas/farmacologia
15.
Life Sci ; 163: 38-45, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27593571

RESUMO

The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.


Assuntos
Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Risperidona/administração & dosagem , Risperidona/farmacocinética , Administração Intranasal , Administração Intravenosa , Aminas/química , Animais , Desenho Assistido por Computador , Liberação Controlada de Fármacos , Lipossomos/administração & dosagem , Lipossomos/síntese química , Lipossomos/farmacocinética , Masculino , Tamanho da Partícula , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Ratos , Risperidona/sangue
16.
Recent Pat Nanotechnol ; 10(2): 116-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27502389

RESUMO

BACKGROUND: HIV infection persists for a longer time in AIDS patient compared to many other viral diseases. This is mainly because the HIV resides maximally in lymphatic system mainly the lymph nodes. Most of the present anti-HIV drugs have very poor bioavailability at lymphatic tissue. Hence, pharmaceutical scientists have made many efforts to formulate anti-HIV drugs for targeting lymphatic system. The exploration of nanoparticulate drug delivery systems have been popularly investigated for lymphatic targeting and for improving therapeutic efficacy. METHODS: An electronic search was undertaken to review the recent publications and patents from the available resources on nanoformulations of anti-HIV drugs for lymphatic delivery. RESULTS: Various carrier systems such as liposomes, polymeric nanoparticles, solid-lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, dendrimers, and nanocrystals have been tried for lymphatic targeting. These nanoparticles are widely studied as passive targeting carriers for lymphatic systems. There is dearth of active targeting for anti-HIV drugs. The studies on surface modified nanoparticles have shown promising results for lymphatic targeting. CONCLUSION: One of the reasons for low success rate in targeting the lymphatic tissue is poor-understanding of pharmacokinetic interactions of novel delivery systems in disease pathology. Apart from this, there are several hurdles in biological screening models and clinical trials. These issues should never be neglected in developing newer targeted delivery systems for treatment of AIDS.


Assuntos
Fármacos Anti-HIV/química , Sistemas de Liberação de Medicamentos , Sistema Linfático , Nanopartículas/química , Infecções por HIV , Humanos , Patentes como Assunto
17.
Chem Biol Interact ; 244: 71-83, 2016 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-26549477

RESUMO

A synthetic small molecule, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH) was conveniently synthesised by a one-step reaction, purified and characterised by chromatographic and spectroscopic methods. HMPH scavenged free radicals and inhibited lipopolysaccharide (LPS)-induced ROS generation and NO release in RAW-264.7 cells without signs of any detectable cytotoxicity. HMPH inhibited lipid peroxidation (LPO) with IC50 of 135 ± 9 as against 58 ± 8 µM for α-tocopherol. Further, HMPH (>50 µM) significantly reduced the LPS-induced TNF-α release in mouse peritoneal macrophages and in human peripheral blood mononuclear cells (PBMCs). HMPH did not show any visible signs of toxicity in rats up to 400 mg/kg/intraperitoneal and 2000 mg/kg/oral. HMPH at 25 and 50 mg/kg attenuated neutrophil infiltration in air-pouch lavage and bronchoalveolar lavage (BAL) in rat models. HMPH also reduced myeloperoxidase (MPO), nitrite and TNF-α in air-pouch lavage in addition to MPO in plasma. HMPH reduced acute paw-inflammation in carrageenan-induced paw-edema. HMPH consistently decreased both ipsilateral and contralateral paw inflammation, minimised the clinical scores of arthritis, prevented body weight (B.wt.) loss, attenuated serum C-reactive protein (C-RP) and rheumatoid factors (RF) in rat model of adjuvant-induced arthritis. Histopathology and radio-graphical reports show that HMPH reduced bone erosion in both ipsilateral and contralateral paw joints. Failure to inhibit COX suggests that effectiveness of HMPH in both acute and chronic inflammation is mediated by a multimodal mechanism involving modulation of immunity, attenuating TNF-α, protecting bone attrition and reducing oxidative stress.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Hidrazonas/farmacologia , Indóis/farmacologia , Inflamação/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Carragenina , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Indóis/síntese química , Indóis/química , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
18.
ScientificWorldJournal ; 2014: 854267, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25548795

RESUMO

Benzopyrones are proven antidiabetic drug candidate in diabetic drug discovery. In this view novel synthetic benzopyrone analogues were selected for testing in experimental diabetes. Type 2 diabetes (T2D) was induced in Wistar rats by streptozotocin (60 mg/kg, i.p.) followed by nicotinamide (120 mg/kg i.p.). Rats having fasting blood glucose (FBG)>200 mg/dL, 7 days after T2D-induction, are selected for the study. Test compounds and standard treatment were continued for 15 days. FBG, oral glucose tolerance test (OGTT), and insulin tolerance test (ITT) were determined on 21st day after induction of T2D. Plasma lipids and serum insulin were estimated. Homeostatic model assessment (HOMA-IR) was then calculated from serum insulin. Rats were sacrificed and pancreas was isolated for histopathological observations. Oxidative stress markers were estimated in liver homogenate. Quercetin, a natural product with benzopyrone ring, showed significant hypoglycemic activity comparable to glibenclamide. Treatment with test compounds lowered the FBG and insulin resistance was significant alleviated as determined by OGTT, HOMA-IR, and ITT. There was significant normalisation of liver antioxidant enzymes compared to diabetic rats indicating that all the synthesised benzopyrone analogues are beneficial in reducing oxidative stress and are on par with the standard quercetin and glibenclamide in experimental T2D.


Assuntos
Cumarínicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Cumarínicos/química , Cumarínicos/farmacologia , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Jejum/sangue , Teste de Tolerância a Glucose , Produtos Finais de Glicação Avançada/sangue , Glicogênio/metabolismo , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/sangue , Resistência à Insulina , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Niacinamida , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos Wistar , Estreptozocina
19.
EXCLI J ; 13: 1055-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26417321

RESUMO

Synthetic 3-hydroxyflavone analogues (JY-1, JY-2, JY-3, JY-4), were tested for antidiabetic activity in high-fructose-diet-fed (66 %, for 6 weeks) insulin-resistant Wistar rats (FD-fed rats). The fasting blood glucose, insulin, creatinine and AGEs were decreased to near normal upon treatment with test compounds. Insulin resistance markers such as HOMA-IR, K-ITT, plasma triglycerides, lipids, endogenous antioxidant defense and glycogen were restored in FD-fed rats after treatment with 3-hydroxyflavones. It is known that insulin resistance is partly because of oxidative stress and hence antioxidant activity was determined. They exhibited significant in vitro DPPH and ABTS radical scavenging activity (IC50: 10.66-66.63 µM). Test compounds inhibited ROS and NO production in RAW 264.7 cells (IC50: 10.39-42.63 µM) and they were found as potent as quercetin. Further, the test compounds inhibited lipid peroxidation at low concentrations (IC50: 99.61-217.47 µM). All test compounds at concentrations 100-200 µM protected calf thymus DNA-damage by Fenton reaction. In addition, test compounds inhibited protein glycation in different in vitro antiglycation assays. JY-2 showed maximum potency in all the stages of glycation which was comparable to the standard quercetin and aminoguanidine. Test compounds also enhanced the glucose uptake by L6 myotubes at an EC50 much lower than that of quercetin. Thus the synthetic 3-hydroxyflavones were found to have good antidiabetic activity by pleotropic and multimodal suppression of insulin resistance and enhancement of glucose uptake by skeletal muscles. These compounds are non-toxic at the doses tested. Further, the combined antioxidant and antiglycation activities of these molecules have complementary benefits in management of diabetes.

20.
Cancer Biother Radiopharm ; 26(6): 737-43, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22087607

RESUMO

The current study investigated the radioprotective effect of Ocimum sanctum on the salivary gland of rats administered radioiodine ((131)I) and compared its efficacy with a known radioprotectant, amifostine. The experimental rats were divided in four groups and sacrificed in three different batches at 1, 3, and 6 months of time interval after 18.5 MBq/100g (i.p.) (131)I exposure. Six months duration batch received (131)I exposure twice with the gap of 3 months. Two groups of experimental rats were presupplemented with O. sanctum (40 mg/kg for 5 days, orally) and amifostine (200 mg/kg, s.c) before (131)I exposure separately. Increased Technetium-99m-pertechnetate ((99m)TcO(4)(-)) uptake at 30 minutes post injection in salivary glands of only (131)I exposed rats may imply delay in clearance at 6 months of exposure in comparison to their counterparts sacrificed at 1 month. Parotid gland histology showed atrophy with lipomatosis in only (131)I exposed rats at 3 and 6 months of duration. O. sanctum and amifostine presupplemented and subsequently exposed to (131)I rats at 3 and 6 months duration exhibited comparable histopathology with controls. Our study indicates possible radioprotective effect of O. sanctum and amifostine against high-dose (131)I exposure.


Assuntos
Amifostina/farmacologia , Radioisótopos do Iodo/farmacologia , Ocimum/química , Glândula Parótida/efeitos dos fármacos , Glândula Parótida/efeitos da radiação , Preparações de Plantas/farmacologia , Protetores contra Radiação/farmacologia , Amifostina/farmacocinética , Animais , Feminino , Glândula Parótida/metabolismo , Glândula Parótida/patologia , Fitoterapia/métodos , Preparações de Plantas/farmacocinética , Protetores contra Radiação/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Radioterapia/métodos , Ratos , Ratos Wistar , Pertecnetato Tc 99m de Sódio/farmacocinética , Pertecnetato Tc 99m de Sódio/farmacologia , Distribuição Tecidual
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