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Background: Polycystic ovarian syndrome is a metabolic disorder majorly caused by the hormonal fluctuations in female and the current scenario explains that adolescents remain predominantly affected with this disorder. Bauhinia variegata assist in the treatment of various ailments and are used as an ingredient in targeting uterine disorders, yet the exact constituent that contributes on activity remains unknown. Aim: The main aim of our study is to determine the potent phytoconstituent of Bauhinia variegata to fight against the symptoms of PCOS through computational techniques. Materials and Methods: Five in silico techniques like Molecular docking analysis, Pharmacokinetics, toxicity prediction of the compounds, Biological activity and Molecular dynamics simulation studies were performed to identify the potent phytoconstituent. Results and Discussion: Molecular docking studies show that the major constituent lupeol had a good binding interaction and high docking score of -10.31 Kcal/mol and -11.52 Kcal/mol with both the proteins 3RUK and 1E3K. Pharmacokinetics, toxicity and biological activity studies reveal that it had ideal drug likeliness properties with proper biological activity values and were found to non-toxic in the analysed parameters. Lupeol complex was found to be potentially stable throughout the molecular dynamic’s simulation for 100 ns. Conclusion: Thus, through in silico analysis it is evident that from the list of phytoconstituents of Bauhinia variegata, lupeol possess potent activities in mitigating the symptoms of PCOS. Further in vitro and in vivo analysis on PCOS model is expected to yield favourable results. [ABSTRACT FROM AUTHOR]

Simple Summary: This multicenter, retrospective study assessed the added value of magnetic resonance dispersion imaging (MRDI), a quantitative analysis of dynamic contrast-enhanced MRI (DCE-MRI), alongside standard multiparametric MRI (mpMRI) for detecting clinically significant prostate cancer (csPCa). Seventy-six patients, including fifty-one with csPCa, who underwent mpMRI and radical prostatectomy, were included. Two radiologists evaluated mpMRI, MRDI and a combination of both, with histopathology serving as the reference standard. The study found that MRDI improved inter-observer agreement and enhanced csPCa detection when combined with mpMRI. MRDI enabled the detection of up to 20% more cases compared to mpMRI alone. With the role of DCE-MRI in the context of mpMRI being debated, this study suggests that quantitative analysis of DCE-MRI by MRDI could enhance csPCa detection and reduce variability between observers. In this multicenter, retrospective study, we evaluated the added value of magnetic resonance dispersion imaging (MRDI) to standard multiparametric MRI (mpMRI) for PCa detection. The study included 76 patients, including 51 with clinically significant prostate cancer (csPCa), who underwent radical prostatectomy and had an mpMRI including dynamic contrast-enhanced MRI. Two radiologists performed three separate randomized scorings based on mpMRI, MRDI and mpMRI+MRDI. Radical prostatectomy histopathology was used as the reference standard. Imaging and histopathology were both scored according to the Prostate Imaging-Reporting and Data System V2.0 sector map. Sensitivity and specificity for PCa detection were evaluated for mpMRI, MRDI and mpMRI+MRDI. Inter- and intra-observer variability for both radiologists was evaluated using Cohen's Kappa. On a per-patient level, sensitivity for csPCa for radiologist 1 (R1) for mpMRI, MRDI and mpMRI+MRDI was 0.94, 0.82 and 0.94, respectively. For the second radiologist (R2), these were 0.78, 0.94 and 0.96. R1 detected 4% additional csPCa cases using MRDI compared to mpMRI, and R2 detected 20% extra csPCa cases using MRDI. Inter-observer agreement was significant only for MRDI (Cohen's Kappa = 0.4250, p = 0.004). The results of this study show the potential of MRDI to improve inter-observer variability and the detection of csPCa. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of distribution kinetics is a neglected aspect of pharmacokinetics. This study examines the utility of the model-independent parameter whole body distribution clearance (CLD) in this respect. Methods: Since mammillary compartmental models are widely used, CLD was calculated in terms of parameters of this model for 15 drugs. The underlying distribution processes were explored by assessment of relationships to pharmacokinetic parameters and covariates. Results: The model-independence of the definition of the parameter CLD allowed a comparison of distributional properties of different drugs and provided physiological insight. Significant changes in CLD were observed as a result of drug-drug interactions, transporter polymorphisms and a diseased state. Conclusion: Total distribution clearance CLD is a useful parameter to evaluate distribution kinetics of drugs. Its estimation as an adjunct to the model-independent parameters clearance and steady-state volume of distribution is advocated. [ABSTRACT FROM AUTHOR]

Background and Objectives: Gemcitabine has been used to treat various solid cancers, including, since 1997, metastatic pancreatic cancer. Here, we developed an HPLC-UV method to determine serum gemcitabine levels and use it in pharmacokinetic studies. Materials and Methods: The analysis was performed after a single protein precipitation step on a reversed-phase column, isocratically eluted with sodium phosphate buffer and methanol. For the pharmacokinetic study, NOD/SCID mice received a single dose of gemcitabine at 100 mg/kg by either subcutaneous (SC) or intraperitoneal (IP) administration. Blood samples were collected at 5, 15, and 30 min and 1, 2, 4, and 6 h after the administration of gemcitabine for further analysis. Results: The duration of the analysis was ~12.5 min. The calibration curve was linear (r2 = 0.999) over the range of 1–400 μM. The mean recovery of GEM was 96.53% and the limit of detection was 0.166 μΜ. T1/2, Tmax, Cmax, AUC0–t, and clearance were 64.49 min, 5.00 min, 264.88 μmol/L, 9351.95 μmol/L*min, and 0.0103(mg)/(μmol/L)/min, respectively, for the SC administration. The corresponding values for the IP administration were 59.34 min, 5.00 min, 300.73 μmol/L, 8981.35 μmol/L*min and 0.0108(mg)/(μmol/L)/min (not statistically different from the SC administration). Conclusions: A simple, valid, sensitive, and inexpensive method for the measurement of gemcitabine in serum has been developed. This method may be useful for monitoring gemcitabine levels in cancer patients as part of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

For the treatment of lung cancer, erlotinib is used as primary treatment. Erlotinib is an epidermal growth factor receptor inhibitor, however it is deposited in normal cells also and clinicians do not prefer it. This constraint opens the way for development of targeted therapy. Mixed micelles via self-assembly have the functionality to improve the delivery of hydrophobic drugs, and improve the pharmacokinetics of the loaded drug. Pluronic® F127 and tocopheryl polyethylene glycol succinate were used to prepare micelles. Box- Behnken design was applied to optimize formulation. With optimum ratio, micelles were characterized, and pharmacokinetic parameters were predicted. Design batches F1 to F15, showed the range of 42-133 nm size and 55-82 % of entrapment. Critical micelles concentration was found to be 3 x 10-5 M. Drug release of optimized mixed micelles was found 84.91± 1.58 % in 72 h. In a nutshell, self-assembled mixed micelles would be a suitable delivery platform for targeting anticancer agents. [ABSTRACT FROM AUTHOR]

Purpose: The optimal temporal resolution for free-breathing dynamic contrast-enhanced MRI (FBDCEMRI) of the pancreas has not been determined. This study aimed to evaluate the appropriate temporal resolution to achieve good image quality and to perform pharmacokinetic analysis in FBDCE-MRI of the pancreas using golden-angle radial sparse parallel (GRASP). Methods: Sixteen participants (53 ± 15 years, eight females) undergoing FBDCE-MRI were included in this prospective study. Images were retrospectively reconstructed at four temporal resolutions (1.8, 3.0, 4.8, and 7.8s). Two radiologists (5 years of experience) evaluated the image quality of each reconstructed image by assessing the visualization of the celiac artery (CEA), the common hepatic artery, the splenic artery, each area of the pancreas, and artifacts using a 5-point scale. Using Tissue-4D, pharmacokinetic parameters were calculated for each area in the reconstructed images at each temporal resolution for 16 examinations, excluding two with errors in the pharmacokinetic modeling analysis. Friedman and Bonferroni tests were used for analysis. A P value < 0.05 was considered statistically significant. Results: During vascular assessment, only scores for the CEA at 7.8s were significantly lower than the other temporal resolutions. Scores of all pancreatic regions and artifacts were significantly lower at 1.8s than at 4.8s and 7.8s. In the pharmacokinetic analysis, all volume transfer coefficients (Ktrans), rate constants (Kep), and the initial area under the concentration curve (iAUC) in the pancreatic head and tail were significantly lower at 4.8s and 7.8s than at 1.8s. iAUC in the pancreatic body and extracellular extravascular volume fraction (Ve) in the pancreatic head were significantly lower at 7.8s than at 1.8s. Conclusion: A temporal resolution of 3.0s is appropriate to achieve image quality and perform pharmacokinetic analysis in FBDCE-MRI of the pancreas using GRASP. [ABSTRACT FROM AUTHOR]

Copyright of Klinická Farmakologie a Farmacie is the property of Solen sro and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In the pharmacokinetic analysis of ethanol after oral administration, only single- or two-compartment models are used, but their precision in estimating pharmacokinetic parameters might be insufficient. In a recent study, pharmacokinetic analysis using a modified Norberg three-compartment model was performed after oral administration of differently sweetened alcoholic solutions and compared to pharmacokinetic analysis using the classic Widmark model. On three occasions, eight male volunteers consumed differently sweetened alcoholic solutions: non-sweetened, sweetened with sucrose, and sweetened with steviol glycoside. Blood ethanol concentration was determined from samples obtained at t = 15, 30, 60, 90, 120, 180 min after consumption. Pharmacokinetic analysis was performed model independently, using the classic Widmarks model and using the modified Norberg model. Results showed that estimated pharmacokinetic parameters depend on the type of model used. The classic Widmark model in particular overestimated the fraction of absorbed ethanol from the gastrointestinal system to systemic circulation. Furthermore, the type of sweetener also affected pharmacokinetic parameters, although the difference was not statistically significant. In conclusion, the novel pharmacokinetic model, while being more physiological, fits experimental data better and hence is more suitable for modelling real-life alcohol consumption. In addition, the effect of natural non-caloric sweetener steviol glycoside on ethanol pharmacokinetics, analysed for the first time in the current research, might be different when compared to the common-used sweetener sucrose. [ABSTRACT FROM AUTHOR]

N-(4-hydroxyphenyl) retinamide (4-HPR, or fenretinide) has promising in vitro and in vivo antiviral activity against a range of flaviviruses and an established safety record, but there are challenges to its clinical use. This study evaluated the in vivo exposure profile of a 4-HPR dosage regime previously shown to be effective in a mouse model of severe dengue virus (DENV) infection, comparing it to an existing formulation for human clinical use for other indications and developed/characterised self-emulsifying lipid-based formulations of 4-HPR to enhance 4-HPR in vivo exposure. Pharmacokinetic (PK) analysis comprising single-dose oral and IV plasma concentration-time profiles was performed in mice; equilibrium solubility testing of 4-HPR in a range of lipids, surfactants and cosolvents was used to inform formulation approaches, with lead formulation candidates digested in vitro to analyse solubilisation/precipitation prior to in vivo testing. PK analysis suggested that effective plasma concentrations could be achieved with the clinical formulation, while novel lipid-based formulations achieved > 3-fold improvement. Additionally, 4-HPR exposure was found to be limited by both solubility and first-pass intestinal elimination but could be improved through inhibition of cytochrome P450 (CYP) metabolism. Simulated exposure profiles suggest that a b.i.d dosage regime is likely to maintain 4-HPR above the minimum effective plasma concentration for anti-DENV activity using the clinical formulation, with new formulations/CYP inhibition viable options to increase exposure in the future. [ABSTRACT FROM AUTHOR]

The synthesis of (E)-isobutyl2-(2-(4-chlorophenyl)hydrazono)-3-oxobutanoate derivatives has been achieved by condensation of 4-chloroaniline and isobutyl 3-oxobutanoate using benzene diazonium chloride. Physicochemical and spectroscopic methods such as IR, 1H-NMR, 13C-NMR, and melting point measurements were used for the examination of the synthesized compound. Density functional theory was used along with the basic set of B3LYP/6-311 G (d, p) for optimizing the geometrical structure. The stability of the molecule as well as charge delocalization was examined using natural bond orbital analysis. The frontier molecular orbital energies give a description of the transfer of charge that occurs within the molecule. Analysis has been done on molecular electrostatic potential. Since the reported molecule has a high hyperpolarizability value, it is considered a potential nonlinear optical material. To conduct studies on drug similarity and oral activity, Lipinski's rule of five was used. The binding energy of the drug to several Covid receptors is examined using molecular docking experiments and it is determined that this compound is a superior antiviral agent. [ABSTRACT FROM AUTHOR]

Current PET datasets are becoming larger, thereby increasing the demand for fast and reproducible processing pipelines. This paper presents a freely available, open source, Python-based software package called NiftyPAD, for versatile analyses of static, full or dual-time window dynamic brain PET data. The key novelties of NiftyPAD are the analyses of dual-time window scans with reference input processing, pharmacokinetic modelling with shortened PET acquisitions through the incorporation of arterial spin labelling (ASL)-derived relative perfusion measures, as well as optional PET data-based motion correction. Results obtained with NiftyPAD were compared with the well-established software packages PPET and QModeling for a range of kinetic models. Clinical data from eight subjects scanned with four different amyloid tracers were used to validate the computational performance. NiftyPAD achieved R 2 > 0.999 correlation with PPET, with absolute difference ∼ 10 - 2 for linearised Logan and MRTM2 methods, and R 2 > 0.999999 correlation with QModeling, with absolute difference ∼ 10 - 4 for basis function based SRTM and SRTM2 models. For the recently published SRTM ASL method, which is unavailable in existing software packages, high correlations with negligible bias were observed with the full scan SRTM in terms of non-displaceable binding potential ( R 2 = 0.96 ), indicating reliable model implementation in NiftyPAD. Together, these findings illustrate that NiftyPAD is versatile, flexible, and produces comparable results with established software packages for quantification of dynamic PET data. It is freely available (https://github.com/AMYPAD/NiftyPAD), and allows for multi-platform usage. The modular setup makes adding new functionalities easy, and the package is lightweight with minimal dependencies, making it easy to use and integrate into existing processing pipelines. [ABSTRACT FROM AUTHOR]

This prospective study investigated the impact of cabozantinib exposure on proteinuria and muscle toxicity, in a cohort of 14 Japanese patients with unresectable hepatocellular carcinoma (uHCC). We measured the trough concentration of cabozantinib (Ctrough) weekly for 6 weeks after starting treatment. Although the initial dose was less than 60 mg in most cases, dose interruption occurred in 79%, primarily because of proteinuria and/or malaise. The median and coefficient of variation of maximum Ctrough at 7–42 d were 929.0 ng/mL and 59.2%, respectively. The urinary protein-to-creatinine ratio (UPCR), serum creatine kinase, and serum aldolase values were all significantly elevated following treatment. Moreover, maximum changes in serum creatine kinase and aldolase were significantly associated with maximum Ctrough (r = 0.736, p < 0.01; r = 0.798, p < 0.001; respectively). Receiver operating characteristic (ROC) curve analysis showed that changes in serum creatine kinase ≥70.5 U/L and aldolase ≥6.1 U/L from baseline relatively accurately predicted inclusion in the high-maximum Ctrough (≥929.0 ng/mL) group, with an area under the ROC of 0.929 and 0.833, respectively. Measurement of serum creatine kinase and aldolase may increase the clinical usefulness of cabozantinib treatment for uHCC and help alleviate difficulties with dose adjustments. [ABSTRACT FROM AUTHOR]

Chalcones are organic compounds with numerous biotic activities such as anticancer, antibacterial, and antifungal. Using the Claisen-Schmidt condensation reaction, three methoxy substituted chalcone derivatives were synthesized and crystallized using the slow evaporation method. Cytotoxicity evaluation showed that all three compounds were almost inoffensive to VERO cell lines and exhibited excellent anticancer activity on breast cancer (MCF-7) cell lines. Molecular docking analysis confirmed that all three molecules fit well at the active site of the target protein with PDB ID: 1M17. In silico pharmacokinetic analysis reveals that the compounds satisfied Lipinski’s rule of five and can be recommended as oral drug candidates. ADMET properties of the organic synthesized compounds revealed the efficacy of the compounds to be considered as drug candidates for treating breast cancer after in-vivo experiments and clinical authentication [ABSTRACT FROM AUTHOR]

Voxtalisib, is a specific, effective, and reversible dual inhibitor, which inhibits both pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). To date, voxtalisib has been studied in trials for melanoma, lymphoma, glioblastoma, breast cancer, and other cancers. In this study, a highly sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technology was applied to the quantitative methodology and pharmacokinetic analysis of voxtalisib in rat plasma. After protein precipitation of the analyte by acetonitrile, the chromatographic separation was performed by gradient elution on an Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with acetonitrile (solvent A) and 0.1% formic acid (solvent B) as the mobile phase. In the positive ion mode, the mass transfer detection of the analyte and IS was m/z 270.91 > 242.98 and m/z 572.30 > 246.10, respectively. In the concentration range of 1–2000 ng/ml, a good linear relationship of voxtalisib was successfully established by the UPLC-MS/MS technology, and the lower limit of quantification (LLOQ) of the analyte was identified as 1 ng/ml. Intra-day and inter-day precisions for voxtalisib were 7.5–18.7% and 13.0–16.6%, respectively, and the accuracies were in the ranges of −14.0–2.0% and −7.2–3.1%, respectively. The matrix effect, extraction recovery, carryover and stability of the analyte were all in compliance with the acceptance criteria of bioassays recommended by FDA. Finally, the pharmacokinetic profile of the analyte had been availably studied by the UPLC-MS/MS bio-analytical method after rats were treated by intragastric administration with voxtalisib (5 mg/kg). The results indicated that the UPLC-MS/MS technology can effectively and quickly quantify the analyte, and this method can also be used for the pharmacokinetic study of voxtalisib, which can provide reference for the optimization of clinical drug management in the later period. [ABSTRACT FROM AUTHOR]

Background and purpose: Morphologic magnetic resonance imaging (MRI) for characterization of salivary gland tumors has limited utility, and the use of perfusion MRI data in the clinical setting is controversial. We examined the potential of tissue-normalized dynamic contrast-enhanced (DCE) MRI pharmacokinetic parameters of salivary gland tumors as imaging biomarkers for characterization and differentiation between benign and malignant lesions. Materials and methods: DCE-MR images acquired from 60 patients with parotid and submandibular gland tumors were retrospectively reviewed. Pharmacokinetic parameters as transfer constant (Ktrans), rate constant (Kep), extracellular space volume (Ve), fractional plasma volume (Vp), and AEC (area of all times enhancement curve) were measured on both the lesion and the normal contralateral salivary gland parenchyma. Lesion/parenchyma ratio (L/P) for each parameter was calculated. Results: Five groups of lesions were identified (reference: histopathology): pleomorphic adenomas(n = 20), Warthin tumors(n = 16), other benign entities(n = 4), non-Hodgkin lymphomas(n = 4), and malignancies(n = 16). Significant differences were seen for mean values of L/PKtrans (higher in malignancies), L/PKep (lower in adenomas than Warthin tumors), L/PVe (lower in Warthin tumors and lymphomas), L/PVp (higher in Warthin tumors and malignancies than adenomas), and L/PAEC (higher in malignancies). Significant differences were found between benign and malignant (non-lymphoproliferative) lesions in mean value of L/PKtrans (0.485 and 1.581), L/PVp (1.288 and 2.834), and L/PAEC (0.682 and 1.910). ROC analysis demonstrated the highest AUC (0.96) for L/PAEC, with sensitivity and specificity for malignancy of 93.8% and 97.5% (cutoff value = 1.038). Conclusion: Lesion/parenchyma ratio of DCE-MRI pharmacokinetic data could be helpful for recognizing the principal types of salivary gland tumors; L/PAEC seems a valuable biomarker for differentiating benign from malignant tumors. [ABSTRACT FROM AUTHOR]

Background Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is an oral potassium binder for the treatment of hyperkalemia in adults. SZC acts in the gastrointestinal tract and additionally binds hydrogen ions in acidic environments like the stomach, potentially transiently increasing gastric pH and leading to drug interactions with pH-sensitive drugs. This study assessed potential pharmacokinetic (PK) interactions between SZC and nine pH-sensitive drugs. Methods In this single-dose, open-label, single-sequence cross-over study in healthy adults, amlodipine, atorvastatin, clopidogrel, dabigatran, furosemide, glipizide, levothyroxine, losartan or warfarin were each administered alone and, following a washout interval, with SZC 10 g. Maximum plasma concentration (C max), area under the plasma concentration–time curve from 0 to the last time point (AUC0– t ) and AUC extrapolated to infinity (AUCinf) were evaluated. No interaction was concluded if the 90% confidence interval for the geometric mean ratio (SZC coadministration versus alone) of the PK parameters was within 80–125%. Results During SZC coadministration, all PK parameters for amlodipine, glipizide, levothyroxine and losartan showed no interaction, while reductions in clopidogrel and dabigatran C max, AUC0– t and AUCinf (basic drugs) were <50% and increases in atorvastatin, furosemide and warfarin C max (acidic drugs) exceeded the no-interaction range by ˂2-fold. Conclusions SZC coadministration was associated with small changes in plasma concentration and exposure of five of the nine drugs evaluated in this study. These PK drug interactions are consistent with transient increases in gastric pH with SZC and are unlikely to be clinically meaningful. [ABSTRACT FROM AUTHOR]

Background: Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics "drug-likeliness" properties of the new compounds before they could proceed to pre-clinical trials. Results: The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R2) = 0.6715, (R2adj) = 0.61920, (Q2) = 0.5460 and (R2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions: The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line). [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the usefulness of high-temporal-resolution dynamic contrast-enhanced (DCE) MRI and quantitative pharmacokinetic analysis to differentiate the normal-appearing pituitary gland from a pituitary macroadenoma.Materials and Methods: Twenty-seven patients with macroadenomas underwent preoperative DCE-MRI with a temporal resolution of 5 s using compressed sensing to obtain pharmacokinetic parameters. Two independent observers localized the normal-appearing pituitary gland on post-contrast T1-weighted images before and after referring to the corresponding Ktrans maps. Agreements between the localizations and intraoperative findings were evaluated using the kappa statistics. The Mann-Whitney U test was used to compare the pharmacokinetic parameters of the normal-appearing pituitary gland and adenoma.Results: For both observers, the agreement between the MRI-based localization and the intraoperative findings increased after referring to the Ktrans maps (observer 1, 0.930-1; observer 2, 0.636-0.855). The normal-appearing pituitary gland had significantly higher Ktrans [/min] (1.50 ± 0.80 vs 0.58 ± 0.49, P < 0.0001), kep [/min] (3.19 ± 1.29 vs 2.15 ± 1.18, P = 0.0049), and ve (0.43 ± 0.15 vs 0.25 ± 0.17, P = 0.0003) than adenoma.Conclusion: High-temporal-resolution DCE-MRI and quantitative pharmacokinetic analysis help accurately localize the normal-appearing pituitary gland in patients with macroadenomas. The normal-appearing pituitary gland was characterized by higher Ktrans, kep, and ve than macroadenoma. Dynamic contrast-enhanced MRI with high-temporal-resolution using compressed sensing was used for quantitative pharmacokinetic analysis of pituitary macroadenomas. An observer study, the use of Ktrans maps improved accuracy in localizing the normal-appearing pituitary gland. As compared to an adenoma, the normal-appearing pituitary gland had significantly higher Ktrans, kep, and ve values. [ABSTRACT FROM AUTHOR]

Introduction: Worldwide, cancer of the breast is the most commonly diagnosed disease and the second leading cause of cancer-related mortality amongst women yearly (Miller et al., 2016). Computer-aided drug discovery (CADD) is a fundamental shortcut in drug discovery arena. CADD tools ascertain key molecule for testing, predicting the effectiveness, the possible side effect, and also assist in upgrading drug-likeliness of drug molecules (Leelananda and Lindert, 2016). The propose of carrying out this research is to design new 2-anilinopyrimidine derivative compounds based on the interaction of the derivative compounds (ligand) and thyroid hormone receptor (TRβ1), and also analyze their pharmacokinetic properties as drug compounds that would be used by the pharmaceuticals against triple-negative breast cancer (MDA-MB-468 cell line). Results: Three compounds (12, 17, and 18) had the highest docking score ranging from − 7.3 to − 7.4 kcal/mol. This showed that the compounds (ligands) bind tightly with the active site of the thyroid hormone receptor (TRβ1). Based on their tight interactions with the receptor, the compounds were chosen as lead compounds in the design of fourteen new compounds by incorporating some fragments found to bind intensely with the active site of the thyroid hormone receptor (TRβ1). All the newly designed compounds passed the pharmacokinetic analysis (adsorption, distribution, metabolism, excretion, and other physicochemical test) passed the drug-likeness test, and they also adhered to the Lipinski rule of five. Conclusions: New derivative compounds of 2-anilinopyrimidine against MDA-MB-468 cell line were designed based on the information obtained from the molecular docking studies. Furthermore, the pharmacokinetics analysis (adsorption, distribution, metabolism, excretion (ADME) and other physicochemical properties) carried out on the newly designed compounds showed this compounds can be made into oral drugs for patients with triple-negative breast cancer (MBA-MD-468 cell line) as they serve as most promising inhibitors against thyroid hormone receptor (TRβ1). [ABSTRACT FROM AUTHOR]

Objectives: To study the pharmacokinetics, biodistribution, and injection doses of 99mTc-TRODAT-1 in healthy adults.Methods: Thirty healthy individuals comprising 15 females and 15 males were randomly divided into three groups and the injection doses of 99mTc-TRODAT-1 of group 1, 2, and 3 were 370 MBq, 740 MBq, and 1110 MBq, respectively. Assessments of subjective symptoms and tests were performed before and after injection. Blood and urine collections and whole-body planar imaging were analyzed at various time points. Bilateral brain striatal SPECT images obtained at 3.5 h PI were assessed visually and semiquantitatively.Results: No serious adverse events or deaths were observed in our study. The pharmacokinetic analysis showed that 99mTc-TRODAT-1 was eliminated rapidly from the circulation, with just about 4% of the injected dose remaining in blood at 1 h post-injection. The mean cumulative urinary excretion over 24 h was just 2.96 ± 0.96%ID. The time-activity curve demonstrated that the radioactivity was mainly in liver and abdomen. The highest absorbed dose was in the dose-limiting organ, liver (20.88 ± 4.45 × 10-3 mSv/MBq). The average effective dose was 5.22 ± 1.05 × 10-3 mSv/MBq. The clarity of striatal images assessed visually in group 1 was worse than that in group 2 and 3. The semiquantitative analysis showed that there were no differences in striatum/cerebellum between the three groups (group 1: 1.77 ± 0.11, group 2: 1.62 ± 0.14, and group 3: 1.75 ± 0.20; P = 0.088).Conclusions: 99mTc-TRODAT-1 was safe to use in humans and showed the status of dopaminergic neurons specifically and clearly. The injection dose we suggested was 740 MBq. [ABSTRACT FROM AUTHOR]

This prospective, Phase 3, open-label, study (EudraCT: 2016-001631-12) evaluated pharmacokinetic (PK) characteristics of 3-/4-weekly Privigen® (IgPro10, CSL Behring, King of Prussia, PA, USA) in Japanese patients with PID. PK parameters including serum trough immunoglobulin (IgG) level before next infusion during the wash-in/wash-out phase (Ctrough), area under the concentration-time curve from time point zero to the last time point with quantifiable concentration (AUC0–last), dose-adjusted AUC0–last (dAUC), lowest and highest observed IgG levels (Cmin, Cmax), time to reach Cmax (Tmax), and total clearance (CL) were analyzed for both regimens of Privigen® (dose: 138–554 mg/kg body weight). Ten patients were included in this analysis (3-/4-weekly: n = 2/n = 8). Ctrough levels achieved ranged 7.96–10.05 g/L. Cmax was observed approximately 1 h after the start of the infusion in both regimens. Mean (SD [not applicable for 3-weekly data]) PK parameters: Cmax, 16.60 and 14.20 (5.53) g/L; Cmin, 10.60 and 8.53 (3.89) g/L; AUC0–last, 5971 and 6591 (2633) g*h/L; dAUC, 0.41 and 0.46 (0.19) g*h/L/mg; CL, 2.53 and 2.53 (1.00) mL/h and median Tmax was 1.19 and 1.14 h, for 3-/4-weekly dosing regimens, respectively. Privigen® PK characteristics in Japanese patients were similar between dosing regimens and to previously-reported results in non-Japanese patients with PID. [ABSTRACT FROM AUTHOR]

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Objectives: To validate and adapt a modified two-compartment model, originally developed for magnetic resonance imaging, for measuring human single-kidney glomerular filtration rate (GFR) and perfusion using dynamic contrast-enhanced computed tomography (DCE-CT). Methods: This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. Thirty-eight patients with essential hypertension (EH, n = 13) or atherosclerotic renal artery stenosis (ARAS, n = 25) underwent renal DCE-CT for GFR and perfusion measurement using a modified two-compartment model. Iothalamate clearance was used to measure reference total GFR, which was apportioned into single-kidney GFR by renal blood flow. Renal perfusion was also calculated using a conventional deconvolution algorithm. Validation of GFR and perfusion and inter-observer reproducibility, were conducted by using the Pearson correlation and Bland-Altman analysis. Results: Both the two-compartment model and iothalamate clearance detected in ARAS patients lower GFR in the stenotic compared to the contralateral and EH kidneys. GFRs measured by DCE-CT and iothalamate clearance showed a close match (r = 0.94, P<0.001, and mean difference 2.5±12.2mL/min). Inter-observer bias and variation in model-derived GFR (r = 0.97, P<0.001; mean difference, 0.3±7.7mL/min) were minimal. Renal perfusion by deconvolution agreed well with that by the compartment model when the blood transit delay from abdominal aorta to kidney was negligible. Conclusion: The proposed two-compartment model faithfully depicts contrast dynamics using DCE-CT and may provide a reliable tool for measuring human single-kidney GFR and perfusion. [ABSTRACT FROM AUTHOR]

Coincidence detector neurons transmit timing information by responding preferentially to concurrent synaptic inputs. Principal cells of the medial superior olive (MSO) in the mammalian auditory brainstem are superb coincidence detectors. They encode sound source location with high temporal precision, distinguishing submillisecond timing differences among inputs. We investigate computationally how dynamic coupling between the input region (soma and dendrite) and the spike-generating output region (axon and axon initial segment) can enhance coincidence detection in MSO neurons. To do this, we formulate a two-compartment neuron model and characterize extensively coincidence detection sensitivity throughout a parameter space of coupling configurations. We focus on the interaction between coupling configuration and two currents that provide dynamic, voltage-gated, negative feedback in subthreshold voltage range: sodium current with rapid inactivation and low-threshold potassium current, IKLT. These currents reduce synaptic summation and can prevent spike generation unless inputs arrive with near simultaneity. We show that strong soma-to-axon coupling promotes the negative feedback effects of sodium inactivation and is, therefore, advantageous for coincidence detection. Furthermore, the feedforward combination of strong soma-to-axon coupling and weak axon-to-soma coupling enables spikes to be generated efficiently (few sodium channels needed) and with rapid recovery that enhances high-frequency coincidence detection. These observations detail the functional benefit of the strongly feedforward configuration that has been observed in physiological studies of MSO neurons. We find that IKLT further enhances coincidence detection sensitivity, but with effects that depend on coupling configuration. For instance, in models with weak soma-to-axon and weak axon-to-soma coupling, IKLT in the axon enhances coincidence detection more effectively than IKLT in the soma. By using a minimal model of soma-to-axon coupling, we connect structure, dynamics, and computation. Although we consider the particular case of MSO coincidence detectors, our method for creating and exploring a parameter space of two-compartment models can be applied to other neurons. [ABSTRACT FROM AUTHOR]

Modulating the complement system is a promising strategy in drug discovery for disorders with uncontrolled complement activation. Although some of these disorders can be effectively treated with an antibody that inhibits complement C5, the high plasma concentration of C5 requires a huge dosage and frequent intravenous administration. Moreover, a conventional anti-C5 antibody can cause C5 to accumulate in plasma by reducing C5 clearance when C5 forms an immune complex (IC) with the antibody, which can be salvaged from endosomal vesicles by neonatal Fc receptor (FcRn)-mediated recycling. In order to neutralize the increased C5, an even higher dosage of the antibody would be required. This antigen accumulation can be suppressed by giving the antibody a pH-dependent C5-binding property so that C5 is released from the antibody in the acidic endosome and then trafficked to the lysosome for degradation, while the C5-free antibody returns back to plasma. We recently demonstrated that a pH-dependent C5-binding antibody, SKY59, exhibited long-lasting neutralization of C5 in cynomolgus monkeys, showing potential for subcutaneous delivery or less frequent administration. Here we report the details of the antibody engineering involved in generating SKY59, from humanizing a rabbit antibody to improving the C5-binding property. Moreover, because the pH-dependent C5-binding antibodies that we first generated still accumulated C5, we hypothesized that the surface charges of the ICs partially contributed to a slow uptake rate of the C5–antibody ICs. This idea motivated us to engineer the surface charges of the antibody. Our surface-charge engineered antibody consequently exhibited a high capacity to sweep C5 and suppressed the C5 accumulation in vivo by accelerating the cycle of sweeping: uptake of ICs into cells, release of C5 from the antibody in endosomes, and salvage of the antigen-free antibody. Thus, our engineered anti-C5 antibody, SKY59, is expected to provide significant benefits for patients with complement-mediated disorders. [ABSTRACT FROM AUTHOR]

We present a method to efficiently separate signal in magnetic resonance imaging (MRI) into a base signal S0, representing the mainly T1-weighted component without T2*-relaxation, and its T2*-weighted counterpart by the rapid acquisition of multiple contrasts for advanced pharmacokinetic modelling. This is achieved by incorporating simultaneous multislice (SMS) imaging into a multi-contrast, segmented echo planar imaging (EPI) sequence to allow extended spatial coverage, which covers larger body regions without time penalty. Simultaneous acquisition of four slices was combined with segmented EPI for fast imaging with three gradient echo times in a preclinical perfusion study. Six female domestic pigs, German-landrace or hybrid-form, were scanned for 11 minutes respectively during administration of gadolinium-based contrast agent. Influences of reconstruction methods and training data were investigated. The separation into T1- and T2*-dependent signal contributions was achieved by fitting a standard analytical model to the acquired multi-echo data. The application of SMS yielded sufficient temporal resolution for the detection of the arterial input function in major vessels, while anatomical coverage allowed perfusion analysis of muscle tissue. The separation of the MR signal into T1- and T2*-dependent components allowed the correction of susceptibility related changes. We demonstrate a novel sequence for dynamic contrast-enhanced MRI that meets the requirements of temporal resolution (Δt < 1.5 s) and image quality. The incorporation of SMS into multi-contrast, segmented EPI can overcome existing limitations of dynamic contrast enhancement and dynamic susceptibility contrast methods, when applied separately. The new approach allows both techniques to be combined in a single acquisition with a large spatial coverage. [ABSTRACT FROM AUTHOR]

Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron’s output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two “modes” of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can “self-regulate” the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract. [ABSTRACT FROM AUTHOR]

Abstract: Men have two practical choices for contraception; the condom which has a high typical use failure rate or vasectomy. New male hormonal and non-hormonal contraceptives are under development that target either the production of sperm (spermatogenesis) or the delivery of sperm. One particular target is the sperm protein EPPIN, which is present on the surface of human spermatozoa. EP055 is a small organic compound that targets EPPIN on the surface of sperm and inhibits motility. EP055 was tested in cynomolgus (Macaca fascicularis) males to determine its plasma half-life after intravenous (i.v.) infusion of a single dose and for binding to its target tissues. Our initial study demonstrated a plasma half-life for EP055 of 10.6 minutes. In a second study examination of macaque testis, epididymis, and plasma after i.v. infusion of a single dose of compound EP055 (63.25 mg/kg) demonstrated that EP055 was detected in testis and epididymis two hours and six hours post-infusion. We initiated a trial in rhesus (Macaca mulatta) males to assess the availability of EP055 in semen and its effect on sperm motility as a measure of the drug's efficacy. Four macaques were infused with a low dose (75–80 mg/kg) followed by a recovery period and a subsequent high dose (125–130 mg/kg) of EP055. After high dose administration, sperm motility fell to approximately 20% of pretreatment levels within 6 hours post-infusion; no normal motility was observed at 30 hours post-infusion. Recovery of sperm motility was obvious by 78 hours post-infusion; with full recovery in all animals by 18 days post-infusion. EP055 has the potential to be a male contraceptive that would provide a reversible, short-lived pharmacological alternative. [ABSTRACT FROM AUTHOR]

Prolonged seizure activity or status epilepticus (SE) is one of the most critical manifestations of organophosphate exposure. Previous studies in our laboratory have demonstrated that oxidative stress is a critical mediator of SE-induced neuronal injury. The goal of this study was to determine if diisopropylflurorphoshate (DFP) exposure in rats resulted in oxidative stress and whether scavenging reactive oxygen species attenuated DFP-induced neurotoxicity. DFP treatment increased indices of oxidative stress in a time- and region-dependent manner. Neuronal loss measured by Fluoro-Jade B staining was significantly increased in the hippocampus, piriform cortex and amygdala following DFP. Similarly, levels of the proinflammatory cytokines, particularly TNF-α, IL-6, and KC/GRO were significantly increased in the piriform cortex and in the hippocampus following DFP treatment. The catalytic antioxidant AEOL10150, when treatment was initiated 5 min after DFP-induced SE, significantly attenuated indices of oxidative stress, neuroinflammation and neuronal damage. This study suggests that catalytic antioxidant treatment may be useful as a novel therapy to attenuate secondary neuronal injury following organophosphate exposure. [ABSTRACT FROM AUTHOR]

Effective inhibitors of invasion and metastasis represent a serious unmet clinical need. We have recently identified 4-fluoro-3’,4’,5’-trimethoxychalcone or C16 as a potent anti-invasive molecule. In this paper, we report on the development of an optimized vehicle for oral administration of C16. We also explore its pharmacokinetic and toxicity profile in rodents as a prelude to a broad-scope evaluation as a pharmacological tool in animal models of disease. C16 showed suboptimal pharmacokinetics with limited oral bioavailability and whole blood stability. Rapid metabolism with elimination via glutathione conjugation was observed. An oral dosing routine using medicated gels was developed to overcome bioavailability issues and yielded sustained whole blood levels above the half maximal effective concentration (EC50) in a 7-day study. The compound proved well-tolerated in acute and chronic experiments at 300 mg/kg PO dosing. The medicated gel formulation is highly suitable for evaluation of C16 in animal models of disease. [ABSTRACT FROM AUTHOR]

Background & aims: Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A. Methods: Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds. Results: It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person’s pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity. Conclusion: The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A. [ABSTRACT FROM AUTHOR]

We consider a microfluidic molecular communication (MC) system, where the concentration-encoded molecular messages are transported via fluid flow-induced convection and diffusion, and detected by a surface-based MC receiver with ligand receptors placed at the bottom of the microfluidic channel. The overall system is a convection-diffusion-reaction system that can only be solved by numerical methods, e.g., finite element analysis (FEA). However, analytical models are key for the information and communication technology (ICT), as they enable an optimisation framework to develop advanced communication techniques, such as optimum detection methods and reliable transmission schemes. In this direction, we develop an analytical model to approximate the expected time course of bound receptor concentration, i.e., the received signal used to decode the transmitted messages. The model obviates the need for computationally expensive numerical methods by capturing the nonlinearities caused by laminar flow resulting in parabolic velocity profile, and finite number of ligand receptors leading to receiver saturation. The model also captures the effects of reactive surface depletion layer resulting from the mass transport limitations and moving reaction boundary originated from the passage of finite-duration molecular concentration pulse over the receiver surface. Based on the proposed model, we derive closed form analytical expressions that approximate the received pulse width, pulse delay and pulse amplitude, which can be used to optimize the system from an ICT perspective. We evaluate the accuracy of the proposed model by comparing model-based analytical results to the numerical results obtained by solving the exact system model with COMSOL Multiphysics. [ABSTRACT FROM AUTHOR]

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

An HPLC-DAD method combined with second-order calibration based on the alternating trilinear decomposition (ATLD) algorithm with the aid of region selection was developed to simultaneously and quantitatively characterize the synergistic relationships and cumulative excretion of the four bioactive ingredients of Radix Gentianae Macrophyllae in vivo. Although the analytes spectra substantially overlapped with that of the biological matrix, the overlapping profiles between analytes and co-eluting interferences can be successfully separated and accurately quantified by the ATLD method on the basis of the strength of region selection. The proposed approach not only determined the content change but also revealed the synergistic relationships and the cumulative excretion in vivo of the four ingredients in urine and feces samples collected at different excretion time intervals. In addition, several statistical parameters were employed to evaluate the accuracy and precision of the method. Quantitative results were confirmed by HPLC-mass spectrometry. Satisfactory results indicated that the proposed approach can be utilized to investigate the pharmacokinetics of Radix Gentianae Macrophyllae excretion in vivo. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Objective: M10 is a ten amino acid peptide generated from the intracellular cytoplasmic tail of the hepatocyte growth factor (HGF) receptor c-Met following cleavage by caspase-3. Recently we reported that M10 interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo and can be advanced into a novel antifibrotic remedy. The current study was undertaken to develop an immunoassay to measure M10 concentration in biological specimens. Experimental design: An Indirect Enzyme-Linked Immunosorbent Assay (ELISA) for detection of M10 in biological fluids was developed using pharmaceutical grade synthetic M10 as a calibrator and commercially available anti-c-Met C12 antibody. Results: M10 ELISA specifically detected in plasma M10, but not a scrambled peptide, following a single intraperitoneal administration of M10 (1mg/kg) to mice. The detection limit was 9.6 ng/ml, and the measuring limit was between 15 ng/ml and 200 ng/ml. The recovery limits of M10 were between 80% and 120%; intra-assay coefficient of variation was between 5.3% and 6.3%; inter-assay coefficient of variation was between 5.0% and 8.0% over the buffer concentration tested in the range from 15 ng /ml to 250 ng /ml. The peak of M10 concentration following a single intraperitoneal injection (1mg/kg) was achieved within 6 hours and declined to minimal levels by 48 hours. The experimentally obtained half-life for M10 was comparable to the theoretically predicted half-life for M10. Conclusions: We have established a highly sensitive ELISA to detect the antifibrotic peptide M10 in plasma samples, which should prove to be a novel tool to study the pharmacokinetics and efficacy of M10 in the treatment of fibroproliferative disorders. [ABSTRACT FROM AUTHOR]

This pilot study investigates the construction of an Adaptive Neuro-Fuzzy Inference System (ANFIS) for the prediction of the survival time of patients with glioblastoma multiforme (GBM). ANFIS is trained by the pharmacokinetic (PK) parameters estimated by the model selection (MS) technique in dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) data analysis, and patient age. DCE-MRI investigations of 33 treatment-naïve patients with GBM were studied. Using the modified Tofts model and MS technique, the following physiologically nested models were constructed: Model 1, no vascular leakage (normal tissue); Model 2, leakage without efflux; Model 3, leakage with bidirectional exchange (influx and efflux). For each patient, the PK parameters of the three models were estimated as follows: blood plasma volume ( vp) for Model 1; vp and volume transfer constant ( Ktrans) for Model 2; vp, Ktrans and rate constant ( kep) for Model 3. Using Cox regression analysis, the best combination of the estimated PK parameters, together with patient age, was identified for the design and training of ANFIS. A K-fold cross-validation ( K = 33) technique was employed for training, testing and optimization of ANFIS. Given the survival time distribution, three classes of survival were determined and a confusion matrix for the correct classification fraction (CCF) of the trained ANFIS was estimated as an accuracy index of ANFIS's performance. Patient age, kep and ve ( Ktrans/ kep) of Model 3, and Ktrans of Model 2, were found to be the most effective parameters for training ANFIS. The CCF of the trained ANFIS was 84.8%. High diagonal elements of the confusion matrix (81.8%, 90.1% and 81.8% for Class 1, Class 2 and Class 3, respectively), with low off-diagonal elements, strongly confirmed the robustness and high performance of the trained ANFIS for predicting the three survival classes. This study confirms that DCE-MRI PK analysis, combined with the MS technique and ANFIS, allows the construction of a DCE-MRI-based fuzzy integrated predictor for the prediction of the survival of patients with GBM. [ABSTRACT FROM AUTHOR]

Proteolytic degradation of peptide-based drugs is often considered as major weakness limiting systemic therapeutic applications. Therefore, huge efforts are typically devoted to stabilize sequences against proteases present in serum or plasma, obtained as supernatants after complete blood coagulation or centrifugation of blood supplemented with anticoagulants, respectively. Plasma and serum are reproducibly obtained from animals and humans allowing consistent for clinical analyses and research applications. However, the spectrum of active or activated proteases appears to vary depending on the activation of proteases and cofactors during coagulation (serum) or inhibition of such enzymes by anticoagulants (plasma), such as EDTA (metallo- and Ca2+-dependent proteases) and heparin (e.g. thrombin, factor Xa). Here, we studied the presumed effects on peptide degradation by taking blood via cardiac puncture of CD-1 mice using a syringe containing a peptide solution. Due to absence of coagulation activators (e.g. glass surfaces and damaged cells), visible blood clotting was prevented allowing to study peptide degradation for one hour. The remaining peptide was quantified and the degradation products were identified using mass spectrometry. When the degradation rates (half-life times) were compared to serum derived freshly from the same animal and commercial serum and plasma samples, peptides of three different families showed indeed considerably different stabilities. Generally, peptides were faster degraded in serum than in plasma, but surprisingly all peptides were more stable in fresh blood and the order of degradation rates among the peptides varied among the six different incubation experiments. This indicates, that proteolytic degradation of peptide-based therapeutics may often be misleading stimulating efforts to stabilize peptides at degradation sites relevant only in vitro, i.e., for serum or plasma stability assays, but of lower importance in vivo. [ABSTRACT FROM AUTHOR]

Background and aim: Estimation of a PET tracer’s non-displaceable distribution volume (VND) is required for quantification of specific binding to its target of interest. VND is generally assumed to be comparable brain-wide and is determined either from a reference region devoid of the target, often not available for many tracers and targets, or by imaging each subject before and after blocking the target with another molecule that has high affinity for the target, which is cumbersome and involves additional radiation exposure. Here we propose, and validate for the tracers [11C]DASB and [11C]CUMI-101, a new data-driven hybrid deconvolution approach (HYDECA) that determines VND at the individual level without requiring either a reference region or a blocking study. Methods: HYDECA requires the tracer metabolite-corrected concentration curve in blood plasma and uses a singular value decomposition to estimate the impulse response function across several brain regions from measured time activity curves. HYDECA decomposes each region’s impulse response function into the sum of a parametric non-displaceable component, which is a function of VND, assumed common across regions, and a nonparametric specific component. These two components differentially contribute to each impulse response function. Different regions show different contributions of the two components, and HYDECA examines data across regions to find a suitable common VND. HYDECA implementation requires determination of two tuning parameters, and we propose two strategies for objectively selecting these parameters for a given tracer: using data from blocking studies, and realistic simulations of the tracer. Using available test-retest data, we compare HYDECA estimates of VND and binding potentials to those obtained based on VND estimated using a purported reference region. Results: For [11C]DASB and [11C]CUMI-101, we find that regardless of the strategy used to optimize the tuning parameters, HYDECA provides considerably less biased estimates of VND than those obtained, as is commonly done, using a non-ideal reference region. HYDECA test-retest reproducibility is comparable to that obtained using a VND determined from a non-ideal reference region, when considering the binding potentials BPP and BPND. Conclusions: HYDECA can provide subject-specific estimates of VND without requiring a blocking study for tracers and targets for which a valid reference region does not exist. [ABSTRACT FROM AUTHOR]

In most vertebrate neurons, spikes initiate in the axonal initial segment (AIS). When recorded in the soma, they have a surprisingly sharp onset, as if sodium (Na) channels opened abruptly. The main view stipulates that spikes initiate in a conventional manner at the distal end of the AIS, then progressively sharpen as they backpropagate to the soma. We examined the biophysical models used to substantiate this view, and we found that spikes do not initiate through a local axonal current loop that propagates along the axon, but through a global current loop encompassing the AIS and soma, which forms an electrical dipole. Therefore, the phenomenon is not adequately modeled as the backpropagation of an electrical wave along the axon, since the wavelength would be as large as the entire system. Instead, in these models, we found that spike initiation rather follows the critical resistive coupling model proposed recently, where the Na current entering the AIS is matched by the axial resistive current flowing to the soma. Besides demonstrating it by examining the balance of currents at spike initiation, we show that the observed increase in spike sharpness along the axon is artifactual and disappears when an appropriate measure of rapidness is used; instead, somatic onset rapidness can be predicted from spike shape at initiation site. Finally, we reproduce the phenomenon in a two-compartment model, showing that it does not rely on propagation. In these models, the sharp onset of somatic spikes is therefore not an artifact of observing spikes at the incorrect location, but rather the signature that spikes are initiated through a global soma-AIS current loop forming an electrical dipole. [ABSTRACT FROM AUTHOR]

Purpose: Non-invasive response monitoring can potentially be used to guide therapy selection for breast cancer patients. We employed dynamic 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG PET) to evaluate changes in three breast cancer xenograft lines in mice following three chemotherapy regimens.Procedures: Sixty-six athymic nude mice bearing bilateral breast cancer xenografts (two basal-like and one luminal-like subtype) underwent three 60 min [18F]FDG PET scans. Scans were performed prior to and 3 and 10 days after treatment with doxorubicin, paclitaxel, or carboplatin. Tumor growth was monitored in parallel. A pharmacokinetic compartmental model was fitted to the tumor uptake curves, providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Early and late standardized uptake values (SUVE and SUVL, respectively); the rate constants k 1, k 2, and k 3, and the intravascular fraction v B were estimated. Changes in tumor volume were used as a response measure. Multivariate partial least-squares regression (PLSR) was used to assess if PET parameters could model tumor response and to identify PET parameters with the largest impact on response.Results: Treatment responders had significantly larger perfusion-related parameters (k 1 and k 2) and lower metabolism-related parameter (k 3) than non-responders 10 days after the start of treatment. These findings were further supported by the PLSR analysis, which showed that k 1 and k 2 at day 10 and changes in k 3 explained most of the variability in response to therapy, whereas SUVL and particularly SUVE were of lesser importance.Conclusions: Overall, rate parameters related to both tumor perfusion and metabolism were associated with tumor response. Conventional metrics of [18F]FDG uptake such as SUVE and SUVL apparently had little relation to tumor response, thus necessitating full dynamic scanning and pharmacokinetic analysis for optimal evaluation of chemotherapy-induced changes in breast cancers. [ABSTRACT FROM AUTHOR]

The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies. [ABSTRACT FROM AUTHOR]

Hansen’s disease (HD), or leprosy, is still considered a public health risk in much of Brazil. Understanding the dynamics of the infection at a regional level can aid in identification of targets to improve control. A compartmental continuous-time model for leprosy dynamics was designed based on understanding of the biology of the infection. The transmission coefficients for the model and the rate of detection were fit for each region using Approximate Bayesian Computation applied to paucibacillary and multibacillary incidence data over the period of 2000 to 2010, and model fit was validated on incidence data from 2011 to 2012. Regional variation was noted in detection rate, with cases in the Midwest estimated to be infectious for 10 years prior to detection compared to 5 years for most other regions. Posterior predictions for the model estimated that elimination of leprosy as a public health risk would require, on average, 44–45 years in the three regions with the highest prevalence. The model is easily adaptable to other settings, and can be studied to determine the efficacy of improved case finding on leprosy control. [ABSTRACT FROM AUTHOR]

5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 μg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 μg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 μg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). [ABSTRACT FROM AUTHOR]

We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives. [ABSTRACT FROM AUTHOR]

Arterial transit time (ATT) is most crucial for measuring absolute cerebral blood flow (CBF) by arterial spin labeling (ASL), a noninvasive magnetic resonance (MR) perfusion assessment technique, in patients with chronic occlusive cerebrovascular disease. We validated ASL-CBF and ASL-ATT maps calculated by pulsed continuous ASL (pCASL) with multiple post-label delay acquisitions in patients with occlusive cerebrovascular disease. Fifteen patients underwent MR scans, including pCASL, and positron emission tomography (PET) scans with 15O-water to obtain PET-CBF. MR acquisitions with different post-label delays (1.0, 1.5, 2.0, 2.5 and 3.0 sec) were also obtained for ATT correction. The theoretical framework of 2-compartmental model (2CM) was also used for the delay compensation. ASL-CBF and ASL-ATT were calculated based on the proposed 2CM, and the effect on the CBF values and the ATT correction characteristics were discussed. Linear regression analyses were performed both on pixel-by-pixel and region-of-interest bases in the middle cerebral artery (MCA) territory. There were significant correlations between ASL-CBF and PET-CBF both for voxel values (r = 0.74 ± 0.08, slope: 0.87 ± 0.22, intercept: 6.1 ± 4.9) and for the MCA territorial comparison in both affected (R2 = 0.67, y = 0.83x + 6.3) and contralateral sides (R2 = 0.66, y = 0.74x + 6.3). ASL-ATTs in the affected side were significantly longer than those in the contralateral side (1.51 ± 0.41 sec and 1.12 ± 0.30 sec, respectively, p <0.0005). CBF measurement using pCASL with delay compensation was feasible and fairly accurate even in altered hemodynamic states. [ABSTRACT FROM AUTHOR]

The dermal and transdermal delivery of protein pharmaceuticals faces enormous challenges, and at the same time, has very significant potential for the non-invasive treatment of both localized and systemic diseases. To demonstrate the pharmaceutical usefulness of dissolving microneedles (MNs) containing interferon-α-2b (IFN), IFN MNs were prepared using a new method. IFN were encapsulated in MNs with dose from 4.94 ± 0.64 to 23.79 ± 2.48 μg, andin vitrorelease test showed the efficiency reached 49.2%. After percutaneous administration of IFN MNs to rats, serum IFN levels were measured for 12 h. The peak serum IFN level, maximum drug concentration (Cmax), and the time to reach maximum concentration (Tmax), were 11.58 ± ng/ml and 40 min, respectively, for high-dose MNs group. The area under the curve (AUC) of MNs group was 28.85 ng·h/ml, while intramuscular injection (IM) group with equal dose was 31.17 ng·h/ml. Immunogenicity analysis showed the anti-IFN antibody got back to normal level at ninth week, and there was no difference between male and female rats. IFN MNs showed good stability for 2 months and no damage to the administered rats’ skin. The results demonstrated the IFN MNs have a great potential to provide an alternative to IM. [ABSTRACT FROM PUBLISHER]

Signal transduction through the Mitogen Activated Protein Kinase (MAPK) pathways is evolutionarily highly conserved. Many cells use these pathways to interpret changes to their environment and respond accordingly. The pathways are central to triggering diverse cellular responses such as survival, apoptosis, differentiation and proliferation. Though the interactions between the different MAPK pathways are complex, nevertheless, they maintain a high level of fidelity and specificity to the original signal. There are numerous theories explaining how fidelity and specificity arise within this complex context; spatio-temporal regulation of the pathways and feedback loops are thought to be very important. This paper presents an agent based computational model addressing multi-compartmentalisation and how this influences the dynamics of MAPK cascade activation. The model suggests that multi-compartmentalisation coupled with periodic MAPK kinase (MAPKK) activation may be critical factors for the emergence of oscillation and ultrasensitivity in the system. Finally, the model also establishes a link between the spatial arrangements of the cascade components and temporal activation mechanisms, and how both contribute to fidelity and specificity of MAPK mediated signalling. [ABSTRACT FROM AUTHOR]

Streptokinase (SK) remains a favored thrombolytic agent in the developing world as compared to the nearly 10-fold more expensive human tissue-plasminogen activator (tPA) for the dissolution of pathological fibrin clots in myocardial infarction. However, unlike the latter, SK induces systemic activation of plasmin which results in a greater risk of hemorrhage. Being of bacterial origin, it elicits generation of unwanted antibody and has a relatively short half-life in vivo that needs to be addressed to make it more efficacious clinically. In order to address these lacunae, in the present study we have incorporated cysteine residues specifically at the N- and C-termini of partially truncated SK and these were then PEGylated successfully. Some of the obtained derivatives displayed enhanced plasmin resistance, longer half-life (upto several hours), improved fibrin clot-specificity and reduced immune-reactivity as compared to the native SK (nSK). This paves the way for devising next-generation SK-based thrombolytic agent/s that besides being fibrin clot-specific are endowed with an improved efficacy by virtue of an extended in vivo half-life. [ABSTRACT FROM AUTHOR]

Purpose: SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods: This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results: Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions: SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]