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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-β, 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 is chemically an isoflavane class of natural phenols and is found mainly in the roots of

Andrographolide is one of the main active principles of

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.

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.

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.

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.

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.

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.

A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration.

Rheumatoid arthritis (RA) is a common chronic disease with inflammatory and immunological background where treatments can only improve the symptoms and slow down the progress of the disease. Although there are several drugs with different therapeutic targets available in the market for the treatment of RA, conventional synthetic disease-modifying antirheumatic drugs (DMARDs) are the most effective option to date. Methotrexate, azathioprine, hydroxychloroquine, sulfasalazine, leflunomide, minocycline are commonly prescribed DMARDs by rheumatologists but they have the limitations of severe toxicity for which therapeutic drug monitoring is necessary. Many chromatographic methods are available for analysis of these drugs including their metabolites. However, they have not been critically reviewed for pre-chromatographic sample preparation, chromatographic separation and sensitive detection. This review article can be handy for quantitation of DMARDs in diverse biological matrices as it provides comprehensive information on the reported liquid chromatographic methods for last three decades covering all the aspects required for preclinical and clinical studies.

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.

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.

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.

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

Alzheimer disease (AD) is usually accompanied by two prominent pathological features, cerebral accumulation of amyloid-β (Aβ) plaques and presence of MAPT/tau neurofibrillary tangles. Dysregulated clearance of Aβ 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 Aβ. Failure of autophagic clearance of Aβ is currently acknowledged as a contributing factor to increased accumulation of Aβ 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 Aβ 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 Aβ 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: Aβ: amyloid-β; 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/CaMKKβ: 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/GSK3β: 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.

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

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.

Sickle cell anemia (SCA) is an inherited disorder in the β-globin chain of hemoglobin that affects millions of people around the world, especially children. This disease prevalently occurs in some Mediterranean and Saharan Africa. For the treatment of SCA patients, a wide range of drugs have been explored by targeting antisickling activity, γ-globulin induction, antiplatelet effect, etc., but hardly a few drugs have shown potential to combat with this complex disease phenomenon. In spite of unprecedented advances in modern system of medicine, people in the disease-prone area have been taking traditional medicinal plants or plant-derived products to increase the life span of patients. Moreover, numerous clinical trials have been going on for the use of natural products under the purview of symptomatic management of SCA. This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization. This summarized information will be beneficial for further exploration of new therapeutics in the treatment arena of SCA.

Curcumin, a natural diarylheptanoid, is extensively used as a food additive or dietary supplement on the regular basis. It is known to have potential to encumber the drug transporters and hepatic drug metabolizing enzymes that lead to pharmacokinetic interactions with drug or food. Daclatasvir is a new orally acting drug for the treatment of chronic Hepatitis C Virus infections. This is a substrate of P-glycoprotein and CYP3A4 that are involved in the major pharmacokinetic interaction. Hence, the studies' aim is to assess for any possible pharmacokinetic interactions. Pharmacokinetic studies of daclatasvir in presence or absence of curcumin were carried out in Wistar rats following oral administration. Parallelly, the oral pharmacokinetics of daclatasvir was also determined in the presence of ketoconazole or quinidine. Studies revealed that plasma level of daclatasvir was not altered significantly during concomitant single dose administration of curcumin, whereas significantly decreased upon pretreatment for 7 days with curcumin at high dose level. Ketoconazole and quinidine markedly increase daclatasvir exposure following concomitant administration with daclatasvir. It can be concluded that dose adjustment is unlikely to be required for intermittent use of curcumin at low dose but cautious for chronic and concomitant use of curcumin at a high dose.

Diclofenac is one of the world's largest selling nonsteroidal anti-inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti-inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti-inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in-situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4-hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.

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.

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.

Curcumin, a natural diarylheptanoid, is extensively used as a food additive or dietary supplement on the regular basis. It is known to have potential to encumber the drug transporters and hepatic drug metabolizing enzymes that lead to pharmacokinetic interactions with drug or food. Daclatasvir is a new orally acting drug for the treatment of chronic Hepatitis C Virus infections. This is a substrate of P-glycoprotein and CYP3A4 that are involved in the major pharmacokinetic interaction. Hence, the studies' aim is to assess for any possible pharmacokinetic interactions. Pharmacokinetic studies of daclatasvir in presence or absence of curcumin were carried out in Wistar rats following oral administration. Parallelly, the oral pharmacokinetics of daclatasvir was also determined in the presence of ketoconazole or quinidine. Studies revealed that plasma level of daclatasvir was not altered significantly during concomitant single dose administration of curcumin, whereas significantly decreased upon pretreatment for 7 days with curcumin at high dose level. Ketoconazole and quinidine markedly increase daclatasvir exposure following concomitant administration with daclatasvir. It can be concluded that dose adjustment is unlikely to be required for intermittent use of curcumin at low dose but cautious for chronic and concomitant use of curcumin at a high dose.

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.