Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.

BACKGROUND: The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. OBJECTIVE: This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. METHODS: Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. RESULTS: In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2nd hr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. CONCLUSION: This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.

Small-molecule oligonucleotides as smart modality for antiviral therapy: a medicinal chemistry perspective.

Small-molecule oligonucleotides could be exploited therapeutically to silence the expression of viral infection-causing genes, and a few of them are now in clinical trials for the management of viral infections. The most challenging aspect of these oligonucleotides' therapeutic success involves their delivery. Thus medicinal chemistry strategies are inevitable to avoid degradation by serum nucleases, avoid kidney clearance and improve cellular uptake. Recently small-molecule oligonucleotide design has opened up new avenues to improve the treatment of drug-resistant viral infections, along with the development of COVID-19 medicines. This review is directed toward the recent advances in rational design, mechanism of action, structure-activity relationships and future perspective of the small-molecule oligonucleotides targeting viral infections, including COVID-19.

Green Synthesis of Silver Nanoparticles of Vernonia cinerea Leaf Extract and their In vitro Cytotoxicity Activity against Neuroblastoma SHSY-5Y Cell Lines, Antimicrobial and Antioxidant Studies.

BACKGROUND: Green syntheses of silver nanoparticles using plant extracts have potential anti- cancer, antimicrobial, and antioxidant properties, among other aspects. The aim of the present patent study was to synthesize silver nanoparticles (AgNPs) using Vernonia cinerea plant extract. METHODS: The AgNPs were successfully prepared and characterized using UV-Vis Spectrophotometer, particle size, Zeta potential, Transmission electron microscopy (TEM), Energy-dispersive x-ray analysis (EDAX), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectrometry. The in vitro cytotoxicity study was performed using neuroblastoma SHSY-5Y cell lines. Moreover, antimicrobial and antioxidant activity studies were also performed for AgNPs. RESULTS: The size of AgNPs determined through the dynamic light scattering (DLS) technique was 49.5 nm and the zeta potential was -36.8 mV. The synthesized AgNPs were checked using UV-Visible spectroscopy at ƛmax 439 nm. The color was changed from green to dark brown, indicating the formation of AgNPs. The TEM study revealed that the nanoparticles were spherical in shape. The XRD pattern of AgNPs produced in this experiment was apparently crystalline. The results of FTIR study revealed that the majority of the obtained peaks correspond to the polyphenols, triterpenoids, and alkaloids which were abundant in the corresponding to the V. cinerea leaf extract and support to the formation of AgNPs. The cytotoxicity effect of the V. cinerea plant extract and biosynthesized AgNPs was found to be dosedependent. From the results of antimicrobial studies, it was reported that the gram negative bacteria were found to be more susceptible compared to the gram positive bacteria. Moreover, the results of antioxidant study revealed that the AgNPs showed good antioxidant activity (77.21%) in comparison to the V. cinerea plant extract (56.13%). CONCLUSION: Based on the results, it could be concluded that the green synthesized silver nanoparticles showed promising anticancer, antioxidant, and anti-bacterial activities as compared to the plain V. cineria plant extract.

Ameliorative Potential of Rosuvastatin on Doxorubicin-induced Cardiotoxicity by Modulating Oxidative Damage in Rats

Objectives: The study aimed to explore the in vivo protective potential of rosuvastatin (ROSS), an oral antihyperlipidemic drug against doxorubicin (DOXO) induced cardio toxicity in rats. Materials and Methods: Cardiac toxicity was induced by DOXO injection (10 mg/kg, i.p.), once on the 20th day of the experiment. Except for the control rats, all were received DOXO and the study was continued for up to 21 days. The influence of ROSS on acute treatment was analyzed by quantification of cardiac marker enzymes such as creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and liver marker enzymes like aspartate aminotransferase (AST), alanine aminotransferase (ALT) along with the measurement of in vivo antioxidants like superoxide dismutase and catalase. To observe histological changes of myocardial tissue hematoxylin and eosin staining were used. Results: Acute administration of DOXO resulted in a marked rise of cardiac marker enzymes that confirms the myocardial damage compared to control animals whereas administration of ROSS (10 mg/kg, p.o.) resulted in the significant reduction of CK-MB, LDH levels (p<0.05) and AST, ALT levels to a remarkable extent. Moreover, ROSS administration significantly increased the activities of various in vivo antioxidant levels. Conclusion: From the results, the acute administration of ROSS showed significant cardioprotective property, which was evidenced by a significant reduction of cardiac and liver marker enzymes along with significant improvement of in vivo antioxidant activities. Furthermore the results were supported with histopathological observations. Hence, it can be concluded that cardioprotective potential of ROSS may be through attenuation of oxidative stress by modulating oxidative damage in rats.

Formulation and Characterization of Rutin Loaded Chitosan-alginate Nanoparticles: Antidiabetic and Cytotoxicity Studies.

BACKGROUND: The rutin loaded chitosan-alginate nanoparticles (RCANP) were prepared using an ion gelation method. The optimized RCANP4 formulation composed of rutin: alginate: chitosan with the ratio of 1.24:5:2. The particle size, zeta potential, and entrapment efficiency of RCANP4 formulation were found to be 168.4 ± 11.23 nm, -24.7 ± 1.5 mV, and 91.23 ± 1.1%, respectively. The in vitro drug release of RCANP4 formulation was found to be 88.89 ± 2.9% within 24 h. The Fourier transform infrared spectroscopy (FT-IR) of RCANP4 revealed all characteristic groups of rutin, confirming the successful loading of rutin into the nanoparticles. METHODS: Due to rutin entrapment in the chitosan sodium alginate matrix, a broad curve was observed in the Differential Scanning Calorimetry (DSC) study of RCANP4. The RCANP4 was found to be uniform and spherical revealed from Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). RCANP4 showed 3.54 times more bioavailability than free rutin, resulting in more internalization of rutin in systemic circulation. The results of plasma glucose levels of diabetic rats administered with RCANP4 and rutin were evident that RCANP4 showed effective antidiabetic activity compared to rutin. RESULTS: The results obtained for glucose uptake in HepG2 cells, the RCANP4 caused a significant (P < 0.05) increase in glucose uptake in contrast to rutin. In vitro cytotoxicity results explained that RCANP4 could significantly (P < 0.05) reduce the cells viability rate compared with rutin. It may be due to the internalization of RCANP4 formulations in systemic circulation. CONCLUSION: The results also showed that RCANP4 could significantly reduce cell viability over 24 h and 48 h compared to free rutin.

Quality by design (Qbd) approach to develop stability indicating HPLC method for estimation of rutin in chitosan-sodium alginate nanoparticles

Rutin is a flavonoid glycoside, mainly consists of phenolic compounds, responsible for many biological activities. The objective of the present study was to develop and validate a precise, simple, robust, rapid and reliable reverse phase high -performance liquid chromatography (RP-HPLC) technique by using Qbd approach for evaluating the rutin in nanoparticles. Central composite design (CCD) was employed for optimizing the experimental conditions of RP-HPLC method. Buffer pH, methanol content in the mobile phase composition, flow rate, and wavelength were selected as independent variables whereas retention time, peak area, and asymmetry factor was selected as dependent variables. The retention time, peak area and asymmetric factor of rutin by using optimized independent variables were found to be 3.75 min, 1014.79 mV, and 1.26 respectively. The limit of detection and limit of quantitation values were found to be 0.005 µg/mL and 0.15 µg/mL respectively. For confirming linearity, accuracy, precision, and robustness, the optimized assay condition was validated as per ICH guidelines. The proposed method, which was optimized by QbD approach was found to be a suitable method for analyzing the rutin in chitosan-sodium alginate nanoparticles.

Solid lipid nanoparticles of Annona muricata fruit extract: formulation, optimization and in vitro cytotoxicity studies.

The present study was aimed to develop Annona muricata fruit extract loaded solid lipid nanoparticles (SLNs) and explore its cytotoxic potential in vitro model of breast cancers. Extract loaded SLNs were successfully prepared by high-pressure homogenization followed by ultrasonication method and optimized using 23 full factorial design. The extract loaded SLNs were characterized using different parameters such as particle size (PS), % entrapment efficiency (EE), zeta potential (ZP) and % cumulative drug release (CDR). The SLNs formulation was optimized on the basis of software analysis with an overall desirability factor. The PS and %EE of the optimized formulation were found to be 134.8 nm and 83.26%, respectively. The optimized formulation showed a CDR of 79.83% up to 48 h. In vitro cytotoxicity efficacy of extract loaded SLNs was determined using MTT and Apoptosis assay and compared to that of a free extract. The SLNs showed a notable apoptotic effect and better efficacy to kill MCF7 cancer cells as compared to free extract. Thus, extract loaded SLNs could be an alternative dosage form which possibly controls therapeutic action with reducing side effect.

Sorbitan ester niosomes for topical delivery of rofecoxib.

The aim of the present investigation is to encapsulate rofecoxib in niosomes and incorporate the prepared niosomes into dermal gel base for sustained therapeutic action. Niosomes were prepared by lipid film hydration technique and were analyzed for size, entrapment efficiency and drug retention capacity. Niosomal vesicles were then incorporated into blank carbopol gel to form niosomal gel. The in vitro permeation study across pig skin was performed using Keshary-Chien glass diffusion cell. The size and entrapment efficiency of the niosomal vesicles increased with gradual increase in HLB value of nonionic surfactants used. Maximum drug entrapment was observed with Span 20 with HLB value of 8.6 and drug leakage from vesicles was less at refrigerated condition than at the room temperature. Higher proportion of cholesterol made the niosomal formulation more stable with high drug retention properties. The niosomal gel showed a prolong drug release behavior compared to plain drug gel. Differential scanning calorimetric study of drug loaded gel and pig skin after permeation study confirmed inertness of carbopol gel base toward rofecoxib and absence of drug metabolism in the skin during permeation study, respectively. The niosomal formulations were successfully prepared by lipid film hydration technique using cholesterol and Span as nonionic surfactant. Presence of cholesterol made niosomes more stable with high drug entrapment efficiency and retention properties. The lower flux value of niosomal gel as compared to plain drug gel across pig skin assured the prolong drug release behavior with sustained action.

Influence of etoricoxib on anticonvulsant activity of phenytoin and diazepam in experimental seizure models in mice.

OBJECTIVES: Our aim was to investigate the effect of etoricoxib on the anticonvulsant activity of phenytoin and diazepam against seizure models in mice. In addition the acute adverse effect of etoricoxib was assessed with a chimney test. METHODS: The maximal seizure pattern was induced in mice by giving an alternating current of 50 mA for 0.2 s, while chemical seizures were induced by intraperitoneal injection of pentylenetetrazole at its CD97 dose (97% convulsive dose for the clonic phase). Test drug was administered 45 min before the electrical or chemical induction of seizures in combination with conventional antiepileptics. The ability of the test drug to reduce or abolish the extensor phase of maximal electroshock and clonic-type seizures in the chemical induction method was selected as anti-seizure criteria. KEY FINDINGS: Concurrent treatment with etoricoxib at an oral dose of 10 mg/kg reduced the anticonvulsant potency of phenytoin. The protective effects of diazepam against pentylenetetrazole-induced convulsions was significantly increased and the mortality rate was reduced by concurrent treatment with etoricoxib (10 mg/kg p.o.) when compared with diazepam groups. No neurotoxic effect was observed with etoricoxib (10 mg/kg p.o.) and it had no impact on motor coordination in the chimney test in mice. Etoricoxib applied at its highest dose (10 mg/kg) significantly enhanced the free plasma levels of diazepam whereas the free plasma levels of phenytoin were significantly reduced. CONCLUSIONS: The obtained results suggest that the preferential cyclooxygenase-2 inhibitor etoricoxib significantly reduced the anticonvulsant action of phenytoin and significantly increased the beneficial action of diazepam against maximal electroshock and pentylenetetrazole-induced convulsions in a mouse model.