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 IS01957, a para-coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy.

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.

Liquid Chromatography Based Methods for Analysis of Disease-Modifying Antirheumatic Drugs (DMARDs) in Biological Matrices.

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.

Erasmus Syndrome: Association of Silicosis and Systemic Sclerosis.

Silicosis is an inflammatory disease of the lung characterized by irreversible lung fibrosis which develops from prolonged pulmonary inhalation and retention of crystalline silica and immune reaction. It mainly appears as an occupational hazard in persons involved in stone-quarrying, mining, and sand blasting. Crystalline silica is not only known to be responsible for silicosis but also for other autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)-Caplan syndrome, systemic sclerosis (SSc), and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis. Erasmus syndrome is the association of silica exposure and subsequent development of SSc. The limited numbers of cases reported in the literature were miners and only sporadically involved in other professionals. Here, we report a case of a 52 -year-old stone cutter who developed silicosis and SSc after 25 years of exposure.

Intervention of curcumin on oral pharmacokinetics of daclatasvir in rat: A possible risk for long-term use.

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.

DCE-MRI and parametric imaging in monitoring response to neoadjuvant chemotherapy in breast carcinoma: a preliminary report.

PURPOSE: Neoadjuvant chemotherapy is recommended in patients with locally advanced breast cancer. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enables evaluation of the tumour neovasculature that occurs prior to any volume change, which helps identify early treatment failures and allows prompt implementation of second-line therapy. MATERIAL AND METHODS: We conducted a prospective study in 14 patients with histopathologically proven breast cancer. DCE-MRI data were acquired using multisection, T1-weighted, 3D vibe sequences with fat suppression before, during, and after IV bolus injection (0.1 mmol/kg body weight, Gadoversetamide, Optimark). Post-processing of dynamic contrast perfusion data was done with the vendor's Tissue 4D software to generate various dynamic contrast parameters, i.e. Ktrans, Kep, Ve, initial area under the time signal curve (IAUC), apparent diffusion coefficient (ADC), and enhancement curve. Patients underwent MRI examinations at baseline, and then after two cycles, and finally at completion of chemotherapy. RESULTS: Based on Sataloff criteria for pathological responses, four patients out of 14 were responders, and 10 were non-responders. At the 2nd MRI examination, IAUC was significantly smaller in responders than in non-responders (p = 0.023). When the results of the first and second MRI examinations were compared, Kep decreased from baseline to the second MRI (p = 0.03) in non-responders and in responders (p = 0.04). This change was statistically significant in both groups. The ADC values increased significantly in responders from baseline to the third MRI (p = 0.012). CONCLUSIONS: In our study, IAUC and ADC were the only parameters that reliably differentiated responders from non-responders after two and three cycles of chemotherapy.

Physicochemical, pharmacokinetic, efficacy and toxicity profiling of a potential nitrofuranyl methyl piperazine derivative IIIM-MCD-211 for oral tuberculosis therapy via in-silico-in-vitro-in-vivo approach.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 µM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception.

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.

Development and validation of a highly sensitive LC-ESI-MS/MS method for estimation of IIIM-MCD-211, a novel nitrofuranyl methyl piperazine derivative with potential activity against tuberculosis: Application to drug development.

In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode. Elution was achieved in gradient mode on High Resolution Chromolith RP-18e column with mobile phase comprised of acetonitrile and 0.1% (v/v) formic acid in water at the flow rate of 0.4mL/min. Precursor to product ion transitions (m/z 344.5/218.4 and m/z 237.3/194.2) were used to measure analyte and IS, respectively. All validation parameters were well within the limit of acceptance criteria. The method was successfully applied to assess the pharmacokinetics of the candidate in mice following oral (10mg/kg) and intravenous (IV; 2.5mg/kg) administration. It was also effectively used to quantitate metabolic stability of the compound in mouse liver microsomes (MLM) and human liver microsomes (HLM) followed by its in-vitro-in-vivo extrapolation.

Push-out bond strength of different endodontic obturation material at three different sites - In-vitro study.

BACKGROUND: The key to success of any root canal therapy is adequate obturation of the prepared root canal space. Root canal sealers are not dimensionally stable and might dissolve partially over a period of time. The objective of this in vitro study is to evaluate the push-out bond strength to intraradicular dentin of two endodontic obturation materials. MATERIAL AND METHODS: Forty extracted single rooted permanent teeth were used. Canals orifice was explored, teeth were instrumented. The samples were divided into two groups each containing twenty specimens obturated with different obturation material (Group1 Epiphany/Resilon and Group 2 Gutta Percha/AH Plus).The obturation systems used in this study was Element Obturation unit (Sybron Endo). Each tooth root was horizontally sectioned in approximately 2-mm thick slices from the coronal 1/3rd, middle 1/3rd and apical 1/3rd. The push-out bond strength of each specimen was calculated using Universal Testing Machine. The statistical analysis was done using two way analysis of variance (ANOVA) and tukey's test. RESULTS: There was significant difference between push out bond strength of Resilon/Epiphany and AH Plus/Gutta Percha. Gutta percha group was superior with push out bond strength of 2.22 (± 0.16) Mpa in comparison to Resilon/Epiphany group with 1.61 (±0.14) Mpa (p<0.001). CONCLUSIONS: The interfacial bond strength achieved with Resilon/Epiphany self-etch (SE) to intraradicular dentine was not superior to that of AH Plus/Gutta Percha. Key words:AH Plus, Apical leakage, Epiphany, Gutta percha, Push-out test Resilon.

Synthesis of Ofornine mimics from natural product l-vasicine as anti-hypertensive agents.

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.