Pharmacokinetic-pharmacodynamic modeling analysis and anti-inflammatory effect of Wangbi capsule in the treatment of adjuvant-induced arthritis.

Clinically, Wangbi Capsule (WBC) is widely used in the treatment of Rheumatoid arthritis (RA) because of its remarkable therapeutic effect. To reveal the mechanism, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed for the first time to assess the relationship between time-concentration (dose)-effect. Freund's Complete Adjuvant was used to induce the adjuvant-induced arthritis model. Multi-indices were used to evaluate the therapeutic effect and an S-Imax PK-PD model was established based on the concentrations of osthole, 5-O-methylvisamminoside, cimifugin, albiflorin, paeoniflorin and icariin and the levels of interleukin-1ß and prostaglandin E2 using a two-compartment PK model together with a PD model with an effect-site compartment. The results suggest that WBC can treat RA by regulating the levels of prostaglandin E2 and interleukin-1ß. For the PK-PD model, the parameters indicated that WBC had a large safety margin and all six bioactive ingredients of WBC have therapeutic effects on RA. Among them icariin, osthole and 5-O-methylvisamminoside may be the main effective substances. This study provided a scientific basis for further study of population pharmacokinetics / population pharmacodynamics (PPK/PPD), to develop a reasonable administration plan and improve individualized drug therapy.

Visual stimuli induce serotonin release in occipital cortex: A simultaneous positron emission tomography/magnetic resonance imaging study.

Endogenous serotonin (5-HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5-HT levels in living humans. Here, we study the neural responses to a visual stimulus using simultaneous PET/MRI. In a cross-over design, 11 healthy individuals were PET/MRI scanned with the 5-HT1B receptor radioligand [11 C]AZ10419369, which is sensitive to changes in endogenous 5-HT. During the last part of the scan, participants either viewed autobiographical images with positive valence (n = 11) or kept their eyes closed (n = 7). The visual stimuli increased cerebral blood flow (CBF) in the occipital cortex, as measured with pseudo-continuous arterial spin labeling. Simultaneously, we found decreased 5-HT1B receptor binding in the occipital cortex (-3.6 ± 3.6%), indicating synaptic 5-HT release. Using a linear regression model, we found that the change in 5-HT1B receptor binding was significantly negatively associated with change in CBF in the occipital cortex (p = .004). For the first time, we here demonstrate how cerebral 5-HT levels change in response to nonpharmacological stimuli in humans, as measured with PET. Our findings more directly support a link between 5-HT signaling and visual processing and/or visual attention.

Garcinoic acid prevents ß-amyloid (Aß) deposition in the mouse brain.

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in ß-amyloid (Aß) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aß oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aß aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aß deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aß oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.

A pH-responsive dissociable mesoporous silica-based nanoplatform enabling efficient dual-drug co-delivery and rapid clearance for cancer therapy.

The balance between tumor accumulation and renal clearance has severely limited the efficacy of mesoporous silica-based drug nanocarriers in cancer therapy. Herein, a pH-responsive dissociable mesoporous silica-based nanoplatform with efficient dual-drug co-delivery, tumor accumulation and rapid clearance for cancer therapy is achieved by adjusting the wetting of the mesoporous silica surface. At pH 7.4, the synthesized spiropyran- and fluorinated silane-modified ultrasmall mesoporous silica nanoparticles (SP-FS-USMSN) self-assemble to form larger nanoclusters (denoted as SP-FS-USMSN cluster) via hydrophobic interactions, which can effectively co-deliver anticancer drugs, doxorubicin hydrochloride (Dox) and curcumin (Cur), based on the mesopores within SP-FS-USMSN and the voids among the stacked SP-FS-USMSN. At pH 4.5-5.5, the conformational conversion of spiropyran from a "closed" state to an "open" state causes the wetting of the SP-FS-USMSN surface, leading to the dissociation of the SP-FS-USMSN cluster for drug release and renal clearance. The in vitro and in vivo studies demonstrate that the Cur and Dox co-loaded SP-FS-USMSN cluster (Cur-Dox/SP-FS-USMSN cluster) possesses great combined cytotoxicity, and can accumulate into tumor tissue by its large size-favored EPR effect and potently suppress tumor growth in HepG2-xenografted mice. This research demonstrates that the SP-FS-USMSN cluster may be a promising drug delivery system for cancer therapy and lays the foundation for practical mesoporous silica-based nanomedicine designs in the future.

Study on preparation and controlled release in vitro of bergenin-amino polylactic acid polymer.

The efficacy of traditional tablets, drop pills and soft capsules of bergenin is far lower than expected. Therefore, bergenin was modified in this paper to connect with amino polylactic acid, a kind of biodegradable material, for chemical immobilization. The bergenin-amino PLA thus obtained was controllable with small molecular weight and excellent thermal stability. Its release in vitro could be extended with the increase in molecular weight. According to tests of biological compatibility and anti-tumor in vitro, bergenin-amino PLA at a proportion of 1 to 100 was characterized by better biological compatibility and lower cytotoxicity than control group at a concentration of 0.4 µ g/m L. The chemical immobilization of bergenin not only provides patients with an excellent way of drug administration but lays a good foundation for sustained drug release.

Development and Validation of Analytical Method for SH-1242 in the Rat and Mouse Plasma by Liquid Chromatography/Tandem Mass Spectrometry.

SH-1242, a novel inhibitor of heat shock protein 90 (HSP90), is a synthetic analog of deguelin: It was previously reported that the treatment of SH-1242 led to a strong suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retinas by inhibiting the hypoxia-induced upregulation of expression in hypoxia-inducible factor 1α (HIF-1ɑ) and vascular endothelial growth factor (VEGF). In this study, an analytical method for the quantification of SH-1242 in biological samples from rats and mice was developed/validated for application in pharmacokinetic studies. SH-1242 and deguelin, an internal standard of the assay, in plasma samples from the rodents were extracted with methanol containing 0.1% formic acid and analyzed at m/z transition values of 368.9→151.0 and 395.0→213.0, respectively. The method was validated in terms of accuracy, precision, dilution, matrix effects, recovery, and stability and shown to comply with validation guidelines when it was used in the concentration ranges of 1-1000 ng/mL for rat plasma and of 2-1000 ng/mL for mouse plasma. SH-1242 levels in plasma samples were readily determined using the developed method for up to 480 min after the intravenous administration of 0.1 mg/kg SH-1242 to rats and for up to 120 min to mice. These findings suggested that the current method was practical and reliable for pharmacokinetic studies on SH-1242 in preclinical animal species.

Green chemistry appended synthesis, metabolic stability and pharmacokinetic assessment of medicinally important chromene dihydropyrimidinones.

A green chemistry approach has been developed for the synthesis of chromene dihydropyrimidinone (CDHPM) using recyclable Fe/Al pillared clay catalyst. Pharmacokinetic parameters like aqueous solubility, lipophilicity, P-glycoprotein (P-gp) ATPase activity, permeability, plasma protein binding, red blood cell (RBC) partitioning, metabolic stability in liver microsomes and in silico computations have been studied for the most potent anticancer chromene dihydropyrimidinone hybrid 1. This compound exhibited low solubility, optimum lipophilicity, no P-gp inhibitory activity, intermediate permeability, high plasma protein binding, low RBC partitioning, acceptable metabolic stability in rat liver microsomes (RLM) as well as human liver microsomes (HLM) with transitional hepatic extraction ratio.

Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota.

CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 µg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-ß-cyclodextrin Complex Suitable for Parenteral Administration.

The chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-ß-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-ß-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-ß-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-ß-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

Formulation and Pharmacokinetic Evaluation of Phosal Based Zaltoprofen Solid Self-Nanoemulsifying Drug Delivery System.

BACKGROUND: Phosal based excipients are liquid concentrates containing phospholipids. They are used to solubilize water-insoluble drug and also act as an emulsifier to get the smallest droplet size of the formed emulsion after administration. OBJECTIVE: The aim is to prepare phosal based self nanoemulsifying drug delivery system (SNEDDS) for water insoluble drug zaltoprofen. METHODS: The various parameters like solubility of drug in different vehicles, ternary phase diagram are considered to formulate the stable emulsion which is further characterized by Self emulsification time and globule size analysis to optimize liquid SNEDDS of Zaltoprofen. Optimized L-SNEDDS was converted into free-flowing powder Solid-SNEDDS (S-SNEDDS). S-SNEDDS was evaluated for Globule size analysis after reconstitution, in vitro dissolution study and in vivo pharmacokinetic study in rats. RESULTS: Phosal 53 MCT with highest drug solubility was used as oil along with Tween 80 and PEG 400 as surfactant and cosurfactant respectively to prepare liquid SNEDDS. Neusilin us2 was used as an adsorbent to get free-flowing S-SNEDDS. S-SNEDDS showed improved dissolution profile of the drug as compared to pure drug. In vivo study demonstrated that there is a significant increase in Cmax and AUC of S-SNEDDS compared to zaltoprofen powder. CONCLUSION: Phosal based SNEDDS formation can be successfully used to improve the dissolution and oral bioavailability of poorly soluble drug zaltoprofen.

In vitro investigation of permeability and metabolism of licoricidin.

Aim Licoricidin has multiple pharmacological activities. The present study was designed to investigate the permeability and pharmacokinetic behavior of licoricidin using in vitro models. MATERIAL AND METHODS: First, human liver microsomes and recombinant human supersomes were used to investigate the interactions between metabolic enzymes and licoricidin. In addition, rat, minipig, rabbit, dog, monkey, and human liver microsomes were used to determine metabolic differences among species. The parallel artificial membrane permeability assay (PAMPA) was used to explore licoricidin permeability behavior. KEY FINDINGS: At 100 µM, licoricidin strongly inhibited CYP2C9, CYP2C19, CYP3A4, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17. Licoricidin metabolism exhibited considerable differences among species; dog, pig, and rat liver microsomes showed higher metabolic capacity than the other species. Seven licoricidin metabolites were identified by liquid chromatography-tandem mass spectrometry, and hydration and hydroxylation were the major metabolic pathways. The PAMPA permeability of licoricidin was moderate at both pH 4.0 and 7.4. SIGNIFICANCE: The present study will support further pharmacological or toxicological research on licoricidin.

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials.

BACKGROUND: Several treatment approaches in cystic fibrosis (CF) aim to correct CF transmembrane conductance regulator (CFTR) function; the efficacy of each approach is dependent on the mutation(s) present. A need remains for more effective treatments to correct functional deficits caused by the F508del mutation. METHODS: Two placebo-controlled, phase 2a studies evaluated GLPG2222, given orally once daily for 29 days, in subjects homozygous for F508del (FLAMINGO) or heterozygous for F508del and a gating mutation, receiving ivacaftor (ALBATROSS). The primary objective of both studies was to assess safety and tolerability. Secondary objectives included assessment of pharmacokinetics, and of the effect of GLPG2222 on sweat chloride concentrations, pulmonary function and respiratory symptoms. RESULTS: Fifty-nine and 37 subjects were enrolled into FLAMINGO and ALBATROSS, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.2% (14/48) of subjects in FLAMINGO and 40.0% (12/30) in ALBATROSS; most were mild to moderate in severity and comprised primarily respiratory, gastrointestinal, and infection events. There were no deaths or discontinuations due to TEAEs. Dose-dependent decreases in sweat chloride concentrations were seen in GLPG2222-treated subjects (maximum decrease in FLAMINGO: -17.6 mmol/L [GLPG2222 200 mg], p < 0.0001; ALBATROSS: -7.4 mmol/L [GLPG2222 300 mg], p < 0.05). No significant effects on pulmonary function or respiratory symptoms were reported. Plasma GLPG2222 concentrations in CF subjects were consistent with previous studies in healthy volunteers and CF subjects. CONCLUSIONS: GLPG2222 was well tolerated. Sweat chloride reductions support on-target enhancement of CFTR activity in subjects with F508del mutation(s). Significant improvements in clinical endpoints were not demonstrated. Observed safety results support further evaluation of GLPG2222, including in combination with other CFTR modulators. FUNDING: Galapagos NV. Clinical trial registration numbers FLAMINGO, NCT03119649; ALBATROSS, NCT03045523.

Pharmacokinetics of a novel microtubule inhibitor mHA11 in rats.

mHA11, a 2-amino-4-phenyl-4H-chromene-3-carboxylate analog, is a microtubule-targeting agent discovered by our group through the modification of the Bcl-2 inhibitor HA14-1. mHA11 exhibits cytotoxicities against tumor cells with nM IC50 values, whereas it has only a minimal effect on normal cells. We explored the plasma pharmacokinetics, tissue distribution, and excretion of mHA11 in rats using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Next, we identified the metabolites of mHA11 and assessed the influence of cytochrome P450 (CYP) isozymes on mHA11 metabolism. We also examined the in vitro stability in rat plasma and rat liver microsomes (RLMs), the blood-to plasma (B/P) ratio, and the inhibitory effect on CYP isozyme activities. After oral administration at 5, 15, and 45 mg/kg, mHA11 was absorbed and eliminated rapidly. There was a linear correlation between the area under the concentration-time curve (AUC0-∞) and the dose (R2 = 0.983). The bioavailability of mHA11 was 4.1% at the oral dose of 15 mg/kg mHA11 was extensively distributed in various tissues and exhibited a high penetration into the brain. No significant parent drug was detected in urine or bile, and only 0.74% was recovered in feces, whereas two demethylated metabolites, M1 and M2, were found in the urine and feces, and further studies showed that CYP2C19 primarily contributed to metabolites formation. mHA11 was stable in rat plasma but degraded significantly in RLMs; its B/P ratio was 1.05 in rat blood. In addition, mHA11 dose-dependently inhibited the activities of rat CYP isozymes, including CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1 and CYP3A2. The present study is the first report on the disposition of mHA11 in rats and provides important data for further research and development of this inhibitor.

Pharmacokinetics and excretion study of bergenin and its phase II metabolite in rats by liquid chromatography tandem mass spectrometry.

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of bergenin and its phase II metabolite in rat plasma, bile and urine has been developed. Biological samples were pretreated with protein precipitation extraction procedure and enzymatic hydrolysis method was used for converting glucuronide metabolite to its free form bergenin. Detection and quantitation were performed by MS/MS using electrospray ionization and multiple reaction monitoring. Negative electrospray ionization was employed as the ionization source. Sulfamethoxazole was used as the internal standard. The separation was performed on a reverse-phase C18 (250 × 4.6 mm, 5 µm) column with gradient elution consisting of methanol and 0.5% aqueous formic acid. The concentrations of bergenin in all biological samples were in accordance with the requirements of validation of the method. After oral administration of 12 mg/kg of the prototype drug, bergenin and its glucuronide metabolite were determined in plasma, bile and urine. Bergenin in bile was completely excreted in 24 h, and the main excreted amount of bergenin was 97.67% in the first 12 h. The drug recovery in bile within 24 h was 8.97%. In urine, the main excreted amount of bergenin was 95.69% in the first 24 h, and the drug recovery within 24 h was <22.34%. Total recovery of bergenin and its glucuronide metabolite was about 52.51% (20.31% in bile within 24 h, 32.20% in urine within 48 h). The validated method was successfully applied to pharmacokinetic and excretion studies of bergenin.

Short Communication: Discovery and molecular docking simulation of 7-hydroxy-6-methoxy-2H-chromen-2-one as a LOX Inhibitor.

Millettia ovalifolia is traditionally used in variety of diseases including inflammation. In our investigation in to the phytochemical constituents of Millettia ovalifolia an effort was made to find out bioactive constituent from medicinal Plant M. ovalifolia to scientifically validate its use in inflammatory disorders. The compound 7-hydroxy-6-methoxy-2H-chromen-2-one was isolated from the bark of M. ovalifolia and was found to exhibited significant lipoxygenase (LOX) inhibitory activity with (IC50 value: 116.83±0.02µM). The Standard compounds Baicalein and Tenidap sodium revealed IC50 value being 22.1±0.03µM and 41.6±0.02µM. Molecular docking study further displayed significant molecular interactions between 7-hydroxy-6-methoxy-2H-chromen-2-one and LOX showed potential for further optimization as a possible anti-inflammatory lead compound.

A liquid chromatography-tandem mass spectrometry method for preclinical pharmacokinetics and tissue distribution of hydrolyzable tannins chebulinic acid and chebulagic acid in rats.

A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of chebulinic acid and chebulagic acid in rat plasma and tissues and well used in the pharmacokinetic and tissue distribution studies after intraperitoneal injection administration. Samples were processed with methanol by protein precipitation, and chromatographic separation was performed on an Agilent Zorbax SB-C18 column (50 × 2.1 mm, 1.8 µm) with a mobile phase consisting of methanol and water containing 0.1% formic acid (60:40, v/v). Quantification was performed by selected reaction monitoring with m/z 977.1 → 806.8 for chebulagic acid, m/z 979.0 → 808.7 for chebulinic acid and m/z 851.2 → 704.9 for the internal standard. Good linearity was observed over their respective concentration range. The pharmacokinetic study showed that both compounds reached their peak concentration values (605.8 ± 35.6 ng/mL for chebulinic acid and 1327.1 ± 118.6 ng/mL for chebulagic acid) at the same time of 0.9 h following intraperitoneal injection administration. The two compounds could be detected in blood-abundant tissues. The kidney had the highest concentrations (462.6 ± 138.5 ng/g for chebulinic acid and 1651.7 ± 167.7 ng/g for chebulagic acid) at 1 h post-dose, followed by the heart, liver, spleen and lung.

Preliminary assessment of galaxolide bioaccessibility in raw and cooked FISH.

Generally, dietary intake assessment and risk characterization are evaluated using contaminant concentration in raw fish while it is usually ingested cooked, which can cause an overestimation because one of the essential issues for risk-benefit analysis is to determine the maximum amount of a contaminant that can be released from the food matrix and be absorbed by the human body, called bioaccessibility. Moreover, despite most seafood products are cooked before consumption, risk assessment is still evaluated in raw products, strongly affecting public health guidelines. In the present study, an in vitro bioaccessibility assay was performed for Galaxolide (HHCB) in fish samples. Raw spiked hake samples were in vitro digested and aliquots of each fraction of the digestion process were analysed. HHCB was quantitatively present in the bioaccessibility fraction. The effect of fish cooking on HHCB was also evaluated in cod and mackerel samples. Results demonstrate that steaming and grilling processes lead to a loss of 50-70% HHCB in fish.

Fabrication and statistical optimization of starch-κ-carrageenan cross-linked hydrogel composite for extended release pellets of zaltoprofen.

The current study was aimed to develop extended release (ER) pellets formulations containing zaltoprofen as a model drug and cross-linked starch-κ-carrageenan (Sκ-C) hydrogel composite as a binder and extended release polymer. The Sκ-C cross-linked hydrogel composites were prepared using a 32 full factorial design approach and characterized by FTIR, DSC, XRD and SEM analysis. The matrix pellets were prepared by extrusion-spheronization technique and characterized production yield, FTIR, DSC, XRD, SEM, optical microscopy, flow characteristics, mucoadhesiveness, in-vitro dissolution and in-vivo pharmacokinetic parameter. The FTIR interpretation of Sκ-C cross-linked hydrogel composite provides the significant result as a formation of hemiacetal group and keton group of glyoxal is abolished; hence it could be satisfied that Sκ-C cross-linked hydrogel composite was formed. The optimized formulation (Sκ-C2) was contained 4:2 ratio of starch and κ-carrageenan of Sκ-C cross-linked hydrogel composite showed in-vitro drug release up to 99.15 ±â€¯2.20% up to 12h, and mucoadhesion of 94.00 ±â€¯2.00 up to 12 h, respectively and in-vivo parameter were showed decrease in C max and increase in t1/2 significantly and drug release >12 h. Hence it was concluded that optimized formulation (Sκ-C2) showed acceptable release pattern, hence would be the viable alternative to ER type formulations.

Pranoprofen quantification in ex vivo corneal and scleral permeation samples: Analytical validation.

The investigation of the ocular permeability and/or distribution of pranoprofen (PF), a non-steroidal antiinflamatory drug, demands for the selective analysis of its transit through specific ocular membranes. Therefore, customised ex vivo permeation experiments through external ocular tissues (cornea and sclera) have been validated for this drug in addition to its HPLC-UV quantification following standard bioanalytical guidelines. Chromatographic conditions consist of an isocratic system to elute the drug with a C18 column with UV detection at 245 nm. Precision, expressed as the relative standard deviation (% RSD), ranged between 4.89 and 0.79% (intra-day) and between 9.02 and 2.14% (interday). Accuracy ranged between 5.15 and -1.92% in intra-day experiments and between 6.25 and -4.89% in inter-day experiments. Drug recovery from tissue samples was reproducible around 90% and considered satisfactory to adequately assess drug levels in target tissues. Results indicate that the procedure is valid for the quantitation of PF in those ophthalmic samples in the range of 6.5 µg/mL to 100 µg/ml. As a proof of concept, PF permeation profiles through porcine cornea and sclera with vertical diffusion cells have been generated and analyzed. Pilot experiments demonstrate its applicability to investigate permeation levels of PF from 22.31 µg/cm2 (about a 20% of the dose) until 500 µg/cm2 if required. Additionally, real tissue-retention samples were also generated to verify the goodness of this experimental setup.

Deuterium Kinetic Isotope Effect Studies of a Potential in Vivo Metabolic Trapping Agent for Monoamine Oxidase B.

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[11C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([11C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [11C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [11C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [11C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.