Department of Pharmacy

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Subject: search.filters.subject.Pharmacokinetics

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    Basic nitrogen (BaN): a ‘privileged element’ in medicinal chemistry
    (Taylor & Francis, 2024-10) Sundriyal, Sandeep
    Medicinal chemists continuously search for small molecules with ideal pharmacokinetic and pharmacodynamic (PKPD) profiles. This quest has resulted in several efforts to understand and define ‘druglikeness’ or ‘drug-like chemical space’. Favorable drug-living system interactions ultimately depend on a compound's chemical structure. Hence, studying patterns and correlations between compound structure and PKPD parameters to derive common denominators is an obvious strategy [Citation1]. Since the publication of ‘Lipinski’s rule of five’ [Citation2], our understanding of the correlation between druglikeness and different physicochemical properties has evolved. Consequently, several guidelines have been suggested for selecting ‘quality’ compounds to improve success rates in preclinical and clinical studies.
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    Effects of acute and repeated dose toxicity profiling of chelidonic acid in rats: in silico and in vivo evidence
    (Wiley, 2023-11) Murugesan, Sankaranarayanan
    Chelidonic acid is a phytoconstituent found in rhizomes of the perennial plant celandine. The current study aims to evaluate the acute and repeated dose oral toxicity study of chelidonic acid as per the OECD guidelines 425 and 407. The pharmacokinetic and toxicity profile of chelidonic acid was predicted using online servers and tools. A single dose of chelidonic acid (2000 mg/kg) was administered to female Wistar rats in an acute toxicity study, and the animals were monitored for 14 days. We studied the toxicity profile of chelidonic acid at 10, 20, and 40 mg/kg doses in Wistar rats for repeated dose toxicity (28 days). Clinical biochemistry, haematological, and urine parameters were estimated. A gross necropsy and histopathology were performed. A single oral dose of chelidonic acid (2000 mg/kg) showed no signs of toxicity or mortality. The Administration of chelidonic acid showed no significant alterations in haematological, biochemical, and urine parameters. The histopathology showed normal structure and architecture in all the vital organs. A gross necropsy of vital organs showed no signs of toxicity. The chelidonic acid was found to be safe at all selected dose levels in the acute and repeated dose toxicity study in rats.
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    Pharmacokinetic and Biodistribution Studies of Camel Milk Casein Nanoparticles Loaded Sorafenib in Swiss Albino Mice
    (Springer, 2024-06) Taliyan, Rajeev; Dubey, Uma S.
    Sorafenib, a multikinase inhibitor, is used for the treatment of advanced stages of hepatic and renal carcinoma patients. However, sorafenib’s low solubility, low bioavailability, unfavorable pharmacokinetic properties, and undesirable side effects are barriers that restrict its utility. This study aims to overcome these problems by encapsulating sorafenib in a novel camel milk casein nanoparticles. Calcium chloride–linked casein nanoparticles were prepared, lyophilized, and characterized for size distribution, zeta potential, and polydispersity index by using a zeta sizer. Drug encapsulation efficiency and drug loading efficiency of these nanoparticles were also determined by UV spectroscopy. Further, in vivo pharmacokinetic and biodistribution studies were conducted in healthy Swiss albino mice. Bioanalytical method was developed by HPLC for quantitative evaluation of the drug in mice plasma, liver, lungs, kidney, heart, and spleen. Multiple pharmacokinetic parameters like T1/2, AUC, clearance, etc. were analyzed through Phoenix Winolin software. Our pharmacokinetic study showed that sorafenib encapsulation within casein nanoparticles (SFN-CasNPs) significantly increased its bioavailability, as exhibited by an enhanced Cmax (3.8-fold) and AUC (1.42-fold). Also, the half-life (t1/2)) of the encapsulated drug increased by 2 h as compared to free drug. Furthermore, biodistribution study showed an increased accumulation of SFN-CasNPs in the liver and kidney as compared to all other tissues, whereas the free drug showed its maximum accumulation in the heart indicating cardiotoxicity. This accumulation of sorafenib was significantly reduced when it was encapsulated within the camel milk casein nanoparticle. This study has highlighted the significance of using camel milk casein nanoparticles for drug delivery owing to an enhanced bioavailability of the sorafenib in an encapsulated form. The reduced accumulation of sorafenib in an encapsulated form also indicates a reduced risk of cardiotoxicity. In the future, clinical trials may be performed on hepatocellular caricinoma patients, after enhancing the selectivity of the drug towards the liver.
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    Macrophage derived Exosomal Docetaxel (Exo-DTX) for pro-metastasis suppression: QbD driven formulation development, validation, in-vitro and pharmacokinetic investigation
    (Elsevier, 2024-02) Chitkara, Deepak
    Exosomes, biogenic nano-vesicles, are renowned for their ability to encapsulate diverse payloads, however the systematic development and validation of exosomal formulation with significant biological implications have been overlooked. Herein, we developed and validated Exo-DTX, a QbD-driven optimized RAW 264.7 cell derived exosomal anti-cancer formulation of docetaxel (DTX) and evaluate its anti-metastatic and apoptotic efficacy in TNBC 4T1 cells. RAW264.7-derived exosomes were having particle size (112.5 ± 21.48 nm) and zeta-potential (−10.268 ± 3.66 mV) with polydispersity (PDI:0.256 ± 0.03). The statistical optimization of exosomes (200 μg) with Exo: DTX ratio 4:1 confirmed encapsulation of 23.60 ± 1.54 ng DTX/ µg exosomes. Exo-DTX (∼189 nm, −11.03 mV) with 100 ng/ml DTX as payload exhibited ∼5 folds’ improvement in IC50 of DTX and distinct cytoskeletal deformation in TNBC 4T1 cells. It also has shown enormous Filamentous actin (F-actin) degradation and triggered apoptosis explained Exo-DTX's effective anti-migratory impact with just 2.6 ± 6.33 % wound closure and 4.56 ± 1.38 % invasion. The western blot confirmed that Exo-DTX downregulated migratory protein EGFR and β1-integrin but raised cleaved caspase 3/caspase 3 (CC3/C3) ratio and BAX/BCL-2 ratio by about 2.70 and 4.04 folds respectively. The naive RAW 264.7 exosomes also contributed positively towards the effect of Exo-DTX formulation by suppressing β1-integrin expression and increasing the CC3/C3 ratio in TNBC 4T1 cells as well. Additionally, significant improvement in PK parameters of Exo-DTX was observed in comparison to Taxotere, 6-folds and 3.04-folds improved t1/2 and Vd, proving the translational value of Exo-DTX formulation. Thus, the Exo-DTX so formulated proved beneficial in controlling the aggressiveness of TNBC wherein, naive exosomes also demonstrated beneficial synergistic anti-proliferative effect in 4T1.
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    Potent anti-inflammatory and anti-apoptotic activities of electrostatically complexed C-peptide nanospheres ameliorate diabetic nephropathy
    (Elsevier, 2024-10) Chitkara, Deepak
    In the present era of “Diabetic Pandemic”, peptide-based therapies have generated immense interest however, are facing odds due to inevitable limitations like stability, delivery complications and off-target effects. One such promising molecule is C-peptide (CPep, 31 amino acid polypeptide with t1/2 30 min); it is a cleaved subunit of pro-insulin, well known to suppress microvascular complications in kidney but has not been able to undergo translation to the clinic till date. Herein, a polymeric CPep nano-complexes (NPX) was prepared by leveraging electrostatic interaction between in-house synthesized cationic, polyethylene carbonate (PEC) based copolymer (Mol. wt. 44,767 Da) and negatively charged CPep (Mol. wt. 3299 Da) at pH 7.4 and further evaluated in vitro and in vivo. NPX exhibited a spherical morphology with a particle size of 167 nm and zeta potential equivalent to +10.3, with 85.70 % of CPep complexation efficiency. The cellular uptake of FITC-tagged CPep NPX was 95.61 % in normal rat kidney cells, NRK-52E. Additionally, the hemocompatible NPX showed prominent cell-proliferative, anti-oxidative (1.8 folds increased GSH; 2.8 folds reduced nitrite concentration) and anti-inflammatory activity in metabolic stress induced NRK-52E cells as well. The observation was further confirmed by upregulation of anti-apoptotic protein BCl2 by 3.5 folds, and proliferative markers (β1-integrin and EGFR) by 3.5 and 2.3 folds, respectively, compared to the high glucose treated control group. Pharmacokinetic study of NPX in Wistar rats revealed a 6.34 folds greater half-life than free CPep. In in-vivo efficacy study in STZ-induced diabetic nephropathy animal model, NPX reduced blood glucose levels and IL-6 levels significantly by 1.3 and 2.5 folds, respectively, as compared to the disease control group. The above findings suggested that NPX has tremendous potential to impart sustained release of CPep, resulting in enhanced efficacy to treat diabetes-induced nephropathy and significantly improved renal pathology.
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    Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect
    (Elsevier, 2017-02) Shrivastava, Richa
    Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40 mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40 mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress.
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    Histone methyltransferase inhibitors: orally bioavailable, fast acting molecules with activity against different human malaria species
    (OUP, 2014) Sundriyal, Sandeep
    Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity with IC50 values <50 nM against drug sensitive laboratory strains and multi-drug resistant field isolates including artemisinin refractory P. falciparum isolates. Activity against ex vivo clinical isolates of both P. falciparum and P. vivax were similar with potencies of 300-400 nM. Sexual stage gametocyte inhibition occurs at micromolar levels, however, mature gametocyte progression to gamete formation is inhibited at sub-micromolar concentrations. Parasite reduction ratio analysis confirms a fast asexual stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of P. berghei and P. falciparum infection. The discovery of a rapid and broad-acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
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    Controlled release effervescent buccal discs of buspirone hydrochloride: in vitro and in vivo evaluation studies
    (Taylor & Francis, 2014-06) Pandey, Murali Monohar
    In the present study controlled release effervescent buccal discs of buspirone hydrochloride (BS) were designed using HPMC as rate controlling and bioadhesive polymer by direct compression method. Sodium bicarbonate and citric acid were used in varying amounts as effervescence forming agents. Carbon dioxide evolved due to reaction of sodium bicarbonate and citric acid was explored for its potential as buccal permeation enhancer. The designed buccal discs were evaluated for physical characteristics and in vitro drug release studies. Bioadhesive behavior of designed buccal discs was assessed using texture analyzer. In vivo animal studies were performed in rabbits to study bioavailability of BS in the designed buccal discs and to establish permeation enhancement ability of carbon dioxide. It was observed that effervescent buccal discs have faster drug release compared to non-effervescent buccal discs in vitro and effervescent buccal discs demonstrated significant increase in bioavailability of drug when compared to non-effervescent formulation. Hence, effervescent buccal discs can be used as an alternative to improve the drug permeation resulting in better bioavailability. However, the amount of acid and base used for generation of carbon dioxide should be selected with care as this may damage the integrity of bioadhesive dosage form.
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    Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles
    (Elsevier, 2013-12) Roy, Aniruddha
    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided.
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    Prediction of in vivo plasma concentration–time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method
    (Taylor & Francis, 2013-10) Singhvi, Gautam
    The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50 mg and IR 100 mg) and matrix based controlled release (CR 100 mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (Cmax and AUC) predicted from convolution method were found to be 106.90 ng/mL, 1138.96 ng/mL h for IR 50 mg and 209.80 ng/mL, 2280.61 ng/mL h for IR 100 mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for Cmax and AUC were found to be 7.04 and −7.35 for IR 50 mg and 11.10 and −8.21 for IR 100 mg formulations. The Cmax, Tmax, and AUC for CR 100 mg were found to be 120 ng/mL, 10 h and 2112.60 ng/mL h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24 h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies.