Development of Mupirocin-Impregnated Bacterial Cellulosic Transdermal Patches for the Management of Skin Infection.

The present study reports the production of bacterial cellulose (BC) membranes using Komagataeibacter hansenii for the development of transdermal wound healing patches. BC-based transdermal patches were developed by impregnating varied concentrations of antibiotic mupirocin and characterized by SEM, FTIR, TGA, and DSC to study the interaction of BC with antibiotic. Developed patches were evaluated for antimicrobial activity, in vitro drug release study, in vivo efficacy, and acute dermal toxicity studies. The antibacterial activity of mupirocin-impregnated patches (mup-BC) showed an inhibition zone from 26.16 ± 0.76 to 35.86 ± 0.61 mm. The in vivo efficacy of mup-BC patches on the superficial abrasion mouse model infected with MRSA 15187 was determined. A single application of the mup-BC (Batch-3) showed a significant decrease up to 2.5 log10 colony-forming units (CFUs) in the infected skin. Acute dermal toxicity study showed no notable sign of toxicity. Pharmacokinetic study indicated that an application of mup-BC (Batch-3) showed a peak plasma concentration of around 1.5 µg/mL mupirocin. The overall preparation, ease of application, and efficacy results clearly indicate that the patches developed in the present study find immense application in the healthcare sector, especially for the treatment of burn or dermal wound infections.

Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction.

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO2 permeability was also excellent for compound 18.

Ameliorating effect of rutin against diclofenac-induced cardiac injury in rats with underlying function of FABP3, MYL3, and ANP.

Diclofenac is a widely prescribed anti-inflammatory drug having cardiovascular complications as one of the main liabilities that restrict its therapeutic use. We aimed to investigate for any role of rutin against diclofenac-induced cardiac injury with underlying mechanisms as there is no such precedent to date. The effect of rutin (10 and 20 mg/kg) was evaluated upon concomitant oral administration for fifteen days with diclofenac (10 mg/kg). Rutin significantly attenuated diclofenac-induced alterations in the serum cardiac markers (LDH, CK-MB, and SGOT), serum cytokine levels (TNF-α and IL-6), and oxidative stress markers (MDA and GSH) in the cardiac tissue. Histopathological examination and Scanning Electron Microscopy (SEM) findings displayed a marked effect of rutin to prevent diclofenac-mediated cardiac injury. Altered protein expression of myocardial injury markers (cTnT, FABP3, and ANP) and apoptotic markers (Bcl-2 and Caspase-3) in the cardiac tissue upon diclofenac treatment was considerably shielded by rutin treatment. MYL3 was unaffected due to diclofenac or rutin treatment. Rutin also significantly improved diclofenac-induced gastrointestinal and hepatic alterations based on the observed ameliorative effects in key mediators, oxidative stress markers, histopathology examination, and SEM findings. Overall results suggest that rutin can protect the diclofenac-induced cardiac injury by lowering oxidative stress, inhibiting inflammation, and reducing apoptosis. Further research work directs toward the development of phytotherapeutics for cardioprotection.

Ayurveda-based phytochemical composition attenuates lung inflammation and precipitates pharmacokinetic interaction with favipiravir: an in vivo investigation using disease-state of acute lung injury.

Acute respiratory distress syndrome (ARDS) is a critical form of acute lung injury (ALI). Here, we investigated the effect of a defined combination of ten pure phytochemicals in equal proportions of weight (NPM) from plants, recommended by Ayurveda for any protective action against lipopolysaccharide (LPS)-induced ALI. Results indicate that NPM markedly improved protein and neutrophil contents, myeloperoxidase and hydroxyproline levels, oxidative stress markers (glutathione and malonaldehyde), inflammatory cytokines, and genes (IL-6, TNF-α, TGF-ß, and NF-κB/IκBα) in BALF/lung tissue. The histopathological examination of the lung revealed the shielding effect of NPM against ALI. NPM exhibited a protective effect on the lung by reducing oxidative stress and inhibiting inflammation. A substantial drop in favipiravir's oral exposure was observed in ALI-state compared to normal-state, but oral exposure upon NPM treatment in ALI-state followed similar behaviour of favipiravir alike normal-state without NPM treatment. Overall, results offer potential insight into Ayurvedic recommendations for immunity boosting during ALI situations.

Glabridin Plays Dual Action to Augment the Efficacy and Attenuate the Hepatotoxicity of Methotrexate in Arthritic Rats.

Glabridin is chemically an isoflavane class of natural phenols and is found mainly in the roots of Glycyrrhiza glabra. It has several beneficial pharmacological actions for the management of inflammatory disorders as well as can counteract drug-induced toxic effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. However, its treatment is associated with major side effects like hepatotoxicity. In the quest to explore a suitable combination therapy that can improve the efficacy and reduce the hepatotoxicity of MTX, we hypothesized that glabridin might serve the purpose for which there is no literature precedent to date. We explored the antiarthritic efficacy of MTX in the presence or the absence of glabridin using Mycobacterium-induced arthritic model in rats. The results of reduction in paw swelling, inhibition of serum cytokines (TNF-α, IL-6, and IL-1ß), and improvement in the bone joints from radiological and histopathological findings suggest that glabridin can substantially augment the antiarthritic efficacy of MTX. Further, results of concomitant glabridin treatment with MTX in the experimental time frame demonstrate that glabridin could considerably prevent the MTX-induced hepatic alteration in serum biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde (MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a marked effect in impeding the regulation of NF-κB/IκBα and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous administration of glabridin with MTX in the rat model indicate that glabridin had no pronounced effect of causing severe alteration in the pharmacokinetic behavior of MTX. In summary, glabridin can significantly potentiate the antiarthritic efficacy of MTX and can also minimize its hepatotoxicity via the inhibition of inflammation and oxidative stress. Further research should be performed to develop glabridin as a phytotherapeutics for the improved efficacy and better tolerability of MTX at the reduced dose level of MTX.

Epicatechin exerts dual action to shield sickling and hydroxyurea-induced myelosuppression: Implication in sickle cell anemia management.

Hydroxyurea (HU) is the key drug to treat Sickle cell anemia (SCA). However, its treatment is associated with the liability of myelosuppression. The present study aimed to investigate the potential of epicatechin as a supplementation therapy for the symptomatic management of SCA under HU therapy. A panel of experiments were performed at first to observe epicatechin's effect on sickling and hemolytic behaviour using SCA patient's blood (ex vivo). Thereafter, the effect of HU in the presence or absence of epicatechin was investigated on cytokine inhibition in rat splenocytes (ex vivo) as well as alterations in hematological parameters and kidney function tests in rats (in vivo). Then, any effect of epicatechin on pharmacokinetic modulation of HU in rats was elucidated along with the underlying mechanism using a battery of in vitro and in vivo models. Epicatechin exhibited potent action on anti-sickling, polymerization inhibition, and erythrocyte membrane stability. It did not show any inherent hemolytic activity and reduced TNF-α level during concomitant administration with HU. Based on hematological changes in rats, epicatechin treatment aided to the beneficial effect of HU and prevented the treatment-linked disadvantageous effects of HU like neutropenia. The plasma exposure of HU was significantly augmented in rats upon simultaneous oral administration of epicatechin with HU. Down-regulation of Oatp1b2 and catalase possibly contributed to the pharmacokinetic interaction of HU. Epicatechin is found to be a promising candidate and should be explored at a reduced dose level of HU towards offsetting the dose-dependent myelosuppressive effect of HU under the frame of supplementation therapy in SCA.

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches.

Myricetin, a bioflavonoid, is widely used as functional food/complementary medicine and has promising multifaceted pharmacological actions against therapeutically validated anticancer targets. On the other hand, CYP2C8 is not only crucial for alteration in the pharmacokinetics of drugs to cause drug interaction but also unequivocally important for the metabolism of endogenous substances like the formation of epoxyeicosatrienoic acids (EETs), which are considered as signaling molecules against hallmarks of cancer. However, there is hardly any information known to date about the effect of myricetin on CYP2C8 inhibition and, subsequently, the CYP2C8-mediated drug interaction potential of myricetin at the preclinical/clinical level. We aimed here to explore the CYP2C8 inhibitory potential of myricetin using in silico, in vitro, and in vivo investigations. In the in vitro study, myricetin showed a substantial effect on CYP2C8 inhibition in human liver microsomes using CYP2C8-catalyzed amodiaquine-N-deethylation as an index reaction. Considering the Lineweaver-Burk plot, the Dixon plot, and the higher α-value, myricetin is found to be a mixed type of CYP2C8 inhibitor. Moreover, in vitro-in vivo extrapolation data suggest that myricetin is likely to cause drug interaction at the hepatic level. The molecular docking study depicted a strong interaction between myricetin and the active site of the human CYP2C8 enzyme. Moreover, myricetin caused considerable elevation in the oral exposure of amodiaquine as a CYP2C8 substrate via a slowdown of amodiaquine clearance in the rat model. Overall, the potent action of myricetin on CYP2C8 inhibition indicates that there is a need for further exploration to avoid drug interaction-mediated precipitation of obvious adverse effects as well as to optimize anticancer therapy.

Investigating the Potential Use of Andrographolide as a Coadjuvant in Sickle Cell Anemia Therapy.

Andrographolide is one of the main active principles of Andrographolide paniculata and has been extensively explored for its therapeutic use. Current studies focus on phytotherapeutics-based adjuvant therapy to symptomatically treat sickle cell anemia (SCA) as there is no specific drug/gene therapy available to date. The present study aimed to explore the potential of andrographolide as an adjuvant therapy for SCA in the presence or absence of hydroxyurea (HU), a key drug for SCA treatment. A panel of ex vivo and in vivo experimentations was performed to explore the antisickling activity of andrographolide, followed by evaluating pharmacokinetic and pharmacodynamic (PK/PD) activities in the presence of HU. Andrographolide showed significant antisickling activity using blood from SCA patients (ex vivo) and did not show any deleterious effect to cause hemolysis using rat blood (ex vivo). It displayed a substantial decrease in HU-induced decline in splenic lymphocyte proliferation and cytokine level (TNF-α and IFN-γ) using rat splenocytes (ex vivo). Concomitant oral administration of andrographolide with HU in rats for 15 days exhibited a noticeable improvement in the RBC count and hemoglobin levels comparable to the efficacy of l-glutamine (in vivo). Simultaneous administration of andrographolide with HU caused no marked effect on any pharmacokinetic parameters of HU except the highest plasma concentration of HU and its corresponding time point, which significantly dropped and delayed, respectively (in vivo). No considerable effect of andrographolide was observed on urease and horseradish peroxidase activity (in vitro). Overall, results suggest that andrographolide has several beneficial actions to be an adjuvant therapy to symptomatically manage SCA, but it should be avoided during the prescribed therapy of HU.

Apportionment of long-term trends in different sections of total ozone column over tropical region.

The additive time-series decomposition analysis was performed on National Oceanic and Atmospheric Administration Solar Backscatter Ultraviolet Instrument Merge satellite dataset version 8.6 for the period January 1979 to December 2019 with an objective to detect and apportion long-term trends present in the total ozone column (TOC) and the long-term trends exist in the respective ozone contents present in the vertical sub-columns constituting the TOC viz. upper, middle and lower stratosphere as well as near-surface for the tropical region. Linear regression analysis was performed on the deseasonalized monthly mean time series of TOC and corresponding ozone contents present in each partitioned layer for three different time spans, viz. 1979-2019 (complete time series), 1979-1998 (pre-inflection years), and 1999-2019 (post-inflection years), where 1998 was taken as inflection year. For the complete time-series, statistically significant negative trends were observed in TOC and corresponding ozone contents in the sub-columns over most of the tropical region. Expectedly, during pre-inflection years, strong negative trends were noted for TOC and ozone contents in the partitioned vertical layers. In contrast, during the post-inflection year time span, long-term trends in TOC were statistically insignificant over two-third of the tropical region, but one-third of the subtropical region exhibited negative trends in TOC. During this time span, positive trends were observed in the ozone contents present in the upper stratospheric sub-column. However, negative trends in ozone contents persisted in the middle and the lower stratosphere. It was interesting to note that the ozone contents confined in near-surface layer manifested strong negative trends during pre-inflection years and the same reversed into strong positive trends that in post-inflection span. The observed, contrasting, long-term trends and variability in the respective partitioned layer of the TOC confounded any clear sign of recovery in the TOC over the tropical region. The continuation of declining trends in the middle stratosphere and increasing trends in the near-surface layer of ozone contents is a matter of concern.

Glabridin attenuates paracetamol-induced liver injury in mice via CYP2E1-mediated inhibition of oxidative stress.

CYP2E1 plays a crucial role in the bio-activation of toxic substances leading to liver damage. In this context, CYP2E1 converts paracetamol (PCM) to N-acetyl-p-benzoquinone imine (NAPQI), which is prone to cause hepatotoxicity. Hence, we aimed to explore the protective effect of glabridin on widely used PCM-induced liver injury model in the present study and, after that, correlated with the role of CYP2E1 toward its efficacy. Glabridin was isolated from Glycyrrhiza glabra and characterized before the investigation in an in-vivo mice model of PCM-induced liver injury. Glabridin after oral treatment at 5-20 mg/kg showed a considerable improvement in serum biochemical parameters (ALT and AST) and oxidative stress markers (MDA, GSH, SOD, and catalase) in comparison to only PCM-treatment. Histopathological examination of the liver depicted that glabridin exhibited substantial protection from PCM-induced liver injury compared to the disease control group. Significant down-regulation of CYP2E1 protein and its mRNA expression levels were observed in the glabridin-treated groups compared to PCM-induced respective elevation of CYP2E1. Moreover, activation of NF-κB was significantly inhibited by glabridin. Therefore, glabridin has the potential to protect PCM-induced liver injury through CYP2E1 inhibition-mediated normalization of oxidative stress. Further research is warranted to establish glabridin as a phytotherapeutics for liver protection for which no effective and safe oral drug is available to date.

Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches.

Hydroxyurea (HU) is the first-ever approved drug by USFDA for sickle cell anemia (SCA). However, its treatment is associated with severe side effects like myelosuppression. Current studies are focused on the supplementation therapy for symptomatic management of SCA. In the present study, we aimed to explore rutin's and gallic acid's potential individually, for concomitant therapy with HU using pharmacokinetic and pharmacodynamic approaches since there is no such precedent till date. In vivo pharmacokinetic studies of HU in rats showed that rutin could be safely co-administered with HU, while gallic acid significantly raised the plasma concentration of HU. Both the phytochemicals did not have any marked inhibitory effect on urease but have considerable effects on horseradish peroxidase enzyme. The experimental phytoconstituents displayed a very low propensity to cause in vitro hemolysis. Gallic acid markedly enhanced the HU-induced decrease in lymphocyte proliferation. A substantial improvement by rutin or gallic acid was observed in HU-induced reduction of the main hematological parameters in rats. Combined treatment of HU with rutin and gallic acid reduced serum levels of both IL-6 and IL-17A. Overall, both rutin and gallic acid are found to have promising phytotherapy potential with HU. Further exploration needs to be done on both candidates for use as phytotherapeutics for SCA.

Glabridin ameliorates methotrexate-induced liver injury via attenuation of oxidative stress, inflammation, and apoptosis.

Despite unprecedented advances in modern medicine, no safe and effective drug is available to date for oral administration to combat drug-induced liver injury, which is a vital concern nowadays. The present study deals with the hepatoprotective effect of pure glabridin, a key phytoconstituent from Glycyrrhiza glabra with mechanistic investigations using an in-vivo methotrexate-induced liver injury model as there is no such precedent. The study was performed in the Swiss mice model where a single dose of methotrexate (40 mg/kg) was given on the 7th day through an intraperitoneal route to induce hepatotoxicity, and glabridin as a test compound was administered orally for eleven consecutive days at 10 to 40 mg/kg. Glabridin markedly improved serum biochemical parameters (SGPT, SGOT), proinflammatory cytokine (TNF-α) level, oxidative stress markers (MDA, GSH, SOD, CAT) as compared to methotrexate alone. Alterations in methotrexate-induced liver architecture were considerably prevented by glabridin treatment as suggested by liver histopathological examination and SEM investigation. Glabridin substantially prevented methotrexate-induced down-regulation of Nrf2, & activation of NF-κB, and caused up-regulation of BAX at different dose levels. Overall, glabridin is found to protect methotrexate-induced hepatotoxicity by improving important factors for oxidative stress, inflammation, and apoptosis.

Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats.

Bedaquiline (TMC-207) is a key anti-tubercular drug to fight against multidrug resistance tuberculosis. Little information is available till date on the impact of any disease state toward its pharmacokinetic behavior. The present research work aimed to investigate the effect of renal impairment and diabetes mellitus on the oral pharmacokinetics of bedaquiline in the rat model. Renal impairment and diabetes mellitus were induced in the Wistar rat model separately using cisplatin and streptozotocin, respectively, and thereafter, an oral pharmacokinetic study of bedaquiline was carried out in the individual disease models as well as in the normal rat model. Pharmacokinetic parameters of bedaquiline were not altered markedly in cisplatin-induced renal-impaired rats compared to normal rats except an area under the curve (AUC) for plasma concentration of bedaquiline in the experimental time frame (AUC0-t ) reduced to 3477 ± 228 from 4984 ± 1174 ng h/mL, respectively. Maximum plasma concentrations of bedaquiline (259 ± 77 ng/mL), AUC0-t (3112 ± 1046 ng h/mL), and AUC0-∞ (3673 ± 1493 ng h/mL) were significantly reduced along with an increase in the clearance of bedaquiline (3.1 ± 1.1 L/h/kg) in the case of streptozotocin-induced diabetic rats compared to respective pharmacokinetic parameters of bedaquiline (482 ± 170 ng/mL, 4984 ± 1174 ng h/mL, and 6137 ± 1542 ng h/mL) in the normal rats. Preclinical findings suggest that dose adjustment of bedaquiline is required in the diabetes mellitus condition to prevent the therapeutic failure of bedaquiline treatment, but clinical exploration is needed to establish the fact. It is the first report for the consequence of renal impairment and diabetes mellitus on the pharmacokinetics of bedaquiline in the preclinical model.

Amalgamation of in-silico, in-vitro and in-vivo approach to establish glabridin as a potential CYP2E1 inhibitor.

CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using in-silico, in-vitro and in-vivo approaches.Results of in-vitro CYP2E1 inhibitory studies using CYP2E1-mediated chlorzoxazone 6-hydroxylation in human liver microsomes showed that glabridin have the highest potential than fisetin, epicatechin, nobiletin, and chrysin to inhibit CYP2E1 enzyme. Mechanistic investigations indicate that glabridin is a competitive CYP2E1 inhibitor. Molecular docking study results demonstrate that glabridin strongly interacted with the active site of human CYP2E1 enzyme. Pharmacokinetics of a CYP2E1 substrate in mice model indicates a significant alteration of chlorzoxazone and 6-hydroxychlorzoxazone plasma levels in the presence of glabridin. Further studies are needed to confirm the results at clinical level.Overall, glabridin is found to be a potential CYP2E1 inhibitor.

Crocetin promotes clearance of amyloid-ß by inducing autophagy via the STK11/LKB1-mediated AMPK pathway.

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-ß (Aß) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aß largely contributes to its accumulation and plaque formation in the brain. Macroautophagy/autophagy is a lysosomal degradative process, which plays an important role in the clearance of Aß. Failure of autophagic clearance of Aß is currently acknowledged as a contributing factor to increased accumulation of Aß in AD brains. In this study, we have identified crocetin, a pharmacologically active constituent from the flower stigmas of Crocus sativus, as a potential inducer of autophagy in AD. In the cellular model, crocetin induced autophagy in N9 microglial and primary neuron cells through STK11/LKB1 (serine/threonine kinase 11)-mediated AMP-activated protein kinase (AMPK) pathway activation. Autophagy induction by crocetin significantly increased Aß clearance in N9 cells. Moreover, crocetin crossed the blood-brain barrier and induced autophagy in the brains' hippocampi of wild-type male C57BL/6 mice. Further studies in transgenic male 5XFAD mice, as a model of AD, revealed that one-month treatment with crocetin significantly reduced Aß levels and neuroinflammation in the mice brains and improved memory function by inducing autophagy that was mediated by AMPK pathway activation. Our findings support further development of crocetin as a pharmacological inducer of autophagy to prevent, slow down progression, and/or treat AD.Abbreviations: Aß: amyloid-ß; ABCB1/P-gp/P-glycoprotein: ATP-binding cassette, subfamily B (MDR/TAP), member 1; AD: Alzheimer disease; AMPK/PRKAA: AMP-activated protein kinase; APP: amyloid beta (A4) precursor protein; ATG: autophagy related; BBB: blood-brain barrier; BECN1: beclin 1, autophagy related; CAMKK2/CaMKKß: calcium/calmodulin-dependent protein kinase kinase 2, beta; CSE: Crocus sativus extract; CTSB: cathepsin B; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GFAP: glial fibrillary acidic protein; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; Kp: brain partition coefficient; LRP1: low density lipoprotein receptor-related protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MAPK/ERK: mitogen-activated protein kinase; MAPT/tau: microtubule-associated protein tau; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTOR: mechanistic target of rapamycin kinase; MWM: Morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NMDA: N-methyl-d-aspartic acid; RPTOR: regulatory associated protein of MTOR; RPS6KB1/p70S6K: ribosomal protein S6 kinase 1; SQSTM1: sequestosome 1; SRB: sulforhodamine B; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TSC2: TSC complex subunit 2; ULK1: unc-51 like kinase 1.

A highly sensitive UPLC-MS/MS method for hydroxyurea to assess pharmacokinetic intervention by phytotherapeutics in rats.

Hydroxyurea (HU) is the first-ever approved drug by the United States Food and Drug Administration (USFDA) for the management of sickle cell anemia (SCA). However, its treatment is associated with severe liabilities like myelosuppression. Therefore, the aim of the present investigation was to identify phytotherapeutics through assessment of the pharmacokinetic interaction of HU with dietary bioflavonoids followed by elucidation of the same phytoconstituents for their ability to protect HU-induced toxicity in hematological profile. In this direction, we developed a sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to estimate HU in rat plasma at first and then validated as per USFDA guidelines as there is no such precedent in the literature. A simple plasma protein precipitation method was employed for plasma sample processing. The separation was achieved in gradient mode using Syncronis HILIC column (100 × 4.6 mm, 3 µm) with a mobile phase composition of water containing 0.1% (v/v) formic acid and acetonitrile. Ionization was carried out in positive heated-electrospray ionization (H-ESI) mode. Detection was done in selected reaction monitoring (SRM) mode with m/z 77.1 > 44.4 and m/z 75.1 > 58.2 for HU and methylurea (internal standard), respectively. All the validation parameters were within the acceptable criteria. This bioanalytical method was found to be useful in assessing the preclinical pharmacokinetic interaction of HU. Concomitant administration of chrysin or quercetin with HU in rats significantly enhanced the oral exposure of HU. Lowering of total red blood cells (RBC) and hemoglobin (Hb) level by HU in rats was significantly improved in the presence of chrysin, quercetin, and naringenin. Overall, both chrysin and quercetin showed potential to be a promising phytotherapeutics for concomitant therapy with HU to combat its dose-dependent side effects.

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure.

Safranal, a plant secondary metabolite isolated from saffron, has been reported for several promising pharmacological properties toward the management of Alzheimer's disease. In the present study, we observe and report for the first time about several druglike attributes of safranal, such as adherence to Lipinski's rule of five; optimum lipophilicity; high permeability; low blood-to-plasma ratio; less to moderate propensity to interact with P-glycoprotein (P-gp) or breast cancer-resistant protein (BCRP) transporters; and high plasma protein binding as common to most of the marketed drugs using in vitro and ex vivo models. In spite of the above attributes, in vivo oral absorption was found to be very poor, which is linked to the structural integrity of safranal in simulated gastric fluid, simulated intestinal fluid, plasma, and liver microsomes. Moreover, the presence of unsaturated aldehyde moiety in safranal remains in equilibrium with its hydroxylated acetal form. Further research work is required to find out the stable oral absorbable form of safranal by derivatization of its aldehyde group without losing its potency.

Effect of rutin on pharmacokinetic modulation of diclofenac in rats.

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug interaction. The aim of the present research work was to investigate the role of rutin on pharmacokinetic modulation and the consequent efficacy of diclofenac. At first, pharmacodynamics and pharmacokinetics of diclofenac as alone and in the presence of rutin were investigated orally in a rat model. Then, mechanistic studies were performed to explain the effect of rutin on improvement in oral exposure as well as the efficacy of diclofenac using a battery of in-vitro/in-situ/in-vivo studies. Results displayed that rutin enhanced efficacy as well as oral bioavailability of diclofenac in rats. A marked increase in permeability of diclofenac by rutin was displayed that is linked to inhibition of Breast Cancer Resistance Protein (BCRP) transporters. There was no significant effect of rutin on the modulation of intestinal transit, CYP2C9 inhibition in human liver microsomes, and CYP2C9/CYP2C11 expression in rat liver tissues to boost the oral exposure of diclofenac. Rutin is found to be an inhibitor for BCRP transporters and can act as an oral bioavailability enhancer for a drug like diclofenac.

Effect of Natural Phenolics on Pharmacokinetic Modulation of Bedaquiline in Rat to Assess the Likelihood of Potential Food-Drug Interaction.

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 plant-based natural products, typically phenolics, on in vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3',5-dihydroxyflavone-7-O-ß-d-galacturonide-4'-O-ß-d-glucopyranoside), and 6-gingerol should not be coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.

Consistent production of kojic acid from Aspergillus sojae SSC-3 isolated from rice husk.

A consistent kojic acid producing fungal strain has been isolated from rice husk using glucose-peptone medium. The isolate was identified as Aspergillus sojae SSC-3 on 18S rDNA analysis. A. sojae was capable of producing substantially good amount of kojic acid, however the production was varying from batch to batch. In order to obtain consistent, repeated and high levels of kojic acid, monospore isolation procedures was adopted. The highest production of kojic acid obtained was 12 ± 2 g/L in 120 h with sucrose (10%) and yeast extract (0.5%) as carbon and nitrogen source respectively. The process was scale up to 10 L fermenter size which repeatedly resulted in the production of 18 ± 2 g/L of kojic acid in 96 h. Kojic acid was recovered (> 82%) from the fermentation broth with > 99% purity. Best to our knowledge this is the first report were kojic acid production is reported from Aspergillus sojae strain.