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1.
Impact of Truncated Area on Point Estimate and Intra-Subject Variability in Bioequivalence of Dutasteride with Long Half-Life.
Prasaja, B, Harahap, Y, Lusthom, W, Yumi, L, Sofiana, A, Sandra, M, Safira, F, Chilmi, U
Drug research. 2018;(4):238-240
Abstract
PURPOSE To investigate the effect of using truncated area under the curve (AUC0-72) on bioequivalence of dutasteride with long half-life in point estimate and intra-subject variability. METHODS Fifteen subjects were enrolled in this single-dose, open-label, randomized two-way crossover design following an overnight fasting with five-week washout period. Plasma samples were collected to 72 h and 144 h following drug administration and dutasteride were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The pharmacokinetic parameters for bioequivalence assessment were AUC0-72 and AUC0-144. RESULTS The estimated point and the 90% confidence intervals were 91.07% (84.54-98.11%) for AUC0-72 and 91.43% (84.65-98.75%) for AUC0-144, that is, within the ranges for acceptance of bioequivalence. The intra-subject variability's were 11.45% for AUC0-72 and 11.87% for AUC0-144. CONCLUSIONS There was no statistically significant difference in point estimated and intra-subject variability between truncated AUC at 72 h and 144=h and the truncated AUC (AUC0-72) approach could be considered for bioequivalence assessment for dutasteride.
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2.
Low colonic absorption drugs: risks and opportunities in the development of oral extended release products.
Xu, J, Lin, Y, Boulas, P, Peterson, ML
Expert opinion on drug delivery. 2018;(2):197-211
Abstract
INTRODUCTION Currently numerous drugs have been observed with lower colonic absorption than small intestine absorption, which can significantly impact in vivo performance of their oral extended release (ER) products. AREAS COVERED We reviewed over 300 publications, patents, book chapters, and commercial reports of drug products from regulatory agencies for low colonic absorption (LCA) drugs and critical findings are discussed. The focuses of this article are (1) current findings on the causes of low colonic absorption to support early assessment of LCA candidates, and (2) current knowledge on successful ER strategies and technical platforms used for LCA drugs in commercial drug products to facilitate oral ER product development. EXPERT OPINION Colonic drug absorption is one of the critical considerations in successful development of oral ER products. The root causes of low colonic absorption in many LCA drugs are still unclear. It is recommended to evaluate colonic drug absorption of drug candidate at early stage of oral ER product development. After evaluation, the selection of a formulation platform to develop an oral ER product needs to be carefully considered for LCA drugs. Based on the current commercial oral ER formulation platforms for LCA drugs, compounds are first divided into five types (I-V) and different ER formulation approaches with higher success rate are recommended for each type.
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3.
Physiological and Pharmaceutical Knowledge in "Ninja" Society: Suggestions for Modern Anesthesiologists and Intensivists.
Takazawa, T, Tobe, M, Kimura, M, Suto, T, Ohta, J, Matsuoka, H, Yano, H, Saito, S
Journal of anesthesia history. 2018;(4):209-213
Abstract
Anesthesiologists and intensivists are modern professionals who provide conscious sedation and respiratory care and prescribe medicines with potential toxicity. Similarly, ninjas, covert agent soldiers who carried out special operations in medieval Japan, also had ample knowledge of toxicology, psychology, human consciousness and respiration. Although the extent of their knowledge remains largely unknown, that which has been described in the literature appears to be practical and scientifically explainable from the standpoint of modern medical science.
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4.
Cell Penetrating Peptides: A Promising Tool for the Cellular Uptake of Macromolecular Drugs.
Zhu, P, Jin, L
Current protein & peptide science. 2018;(2):211-220
Abstract
The lipid bilayer of the plasma membrane is a selective impermeable barrier for the internalization of most macromolecules. Cell penetrating peptides (CPPs) could cross the plasma membrane barrier to deliver various molecules into cells and are considered as a promising tool to deliver macromolecular drugs. However, the exact cellular uptake mechanisms of CPPs are still ambiguous. It was reported that the exact cellular uptake pathway was determined by numerous factors such as the amino acid sequences (hydrophobicity and net charge), extracellular CPP concentration, cargoes' properties, cell type and the temperature. No matter what kind of mechanisms, the electrostatic interaction between the positive charged amino acids and the membrane with negatively charged glycosaminoglycans (GAGs), especially heparan sulphate proteoglycans (HSPGs), was supposed to be the first crucial step for CPPs uptake. The first recognition triggers cytoskeletal remodeling via activating Rho/Rac GTPases and kinase C, followed by the cell surface microdomains changing, ligand binding and cellular uptake. This review briefly discusses the classification, structure-activity relationships, cellular uptake mechanisms and biomedical applications of CPPs.
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Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity.
Li, AP, Alam, N, Amaral, K, Ho, MD, Loretz, C, Mitchell, W, Yang, Q
Drug metabolism and disposition: the biological fate of chemicals. 2018;(11):1562-1571
Abstract
We report here a novel in vitro enteric experimental system, cryopreserved human intestinal mucosa (CHIM), for the evaluation of enteric drug metabolism, drug-drug interaction, drug toxicity, and pharmacology. CHIM was isolated from the small intestines of four human donors. The small intestines were first dissected into the duodenum, jejunum, and ileum, followed by collagenase digestion of the intestinal lumen. The isolated mucosa was gently homogenized to yield multiple cellular fragments, which were then cryopreserved in a programmable liquid cell freezer and stored in liquid nitrogen. After thawing and recovery, CHIM retained robust cytochrome P450 (P450) and non-P450 drug-metabolizing enzyme activities and demonstrated dose-dependent induction of transcription of CYP24A1 (approximately 300-fold) and CYP3A4 (approximately 3-fold) by vitamin D3 as well as induction of CYP3A4 (approximately 3-fold) by rifampin after 24 hours of treatment. Dose-dependent decreases in cell viability quantified by cellular ATP content were observed for naproxen and acetaminophen, with higher enterotoxicity observed for naproxen, consistent with that observed in humans in vivo. These results suggest that CHIM may be a useful in vitro experimental model for the evaluation of enteric drug properties, including drug metabolism, drug-drug interactions, and drug toxicity.
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6.
Uptake of pharmaceuticals by plants grown under hydroponic conditions and natural occurring plant species: A review.
Madikizela, LM, Ncube, S, Chimuka, L
The Science of the total environment. 2018;:477-486
Abstract
Sizeable amount of research has been conducted on the possible uptake of pharmaceuticals by plants from contaminated soil and water used for irrigation of crops. In most cases, pharmaceuticals are taken by roots and translocated into various tissues by transpiration and diffusion. Due to the plant uptake, the occurrence of pharmaceuticals in food sources such as vegetables is a public concern. Few review papers focusing on the uptake of pharmaceuticals, in particular antibiotics, and their translocation in plant tissues have been published. In the current review paper, the work conducted on the uptake of pharmaceuticals belonging to different therapeutic groups such as antibiotics, non-steroidal anti-inflammatory drugs, β-blockers and antiepileptics is reviewed. Such work includes the occurrence of pharmaceuticals in plants, translocation once taken by plants, toxicity studies as well as implications and future studies. Furthermore, the advantages and drawbacks associated with the detection and uptake of these pharmaceuticals by plants are discussed. In addition, the physico-chemical properties that could influence the plant uptake of pharmaceuticals are deliberated.
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7.
Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations.
Bedada, W, de Andrés, F, Engidawork, E, Hussein, J, LLerena, A, Aklillu, E
Scientific reports. 2018;(1):12726
Abstract
In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.
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8.
Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis.
Elfaki, I, Mir, R, Almutairi, FM, Duhier, FMA
Asian Pacific journal of cancer prevention : APJCP. 2018;(8):2057-2070
Abstract
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.
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9.
Effects of pharmaceuticals on microbial communities and activity of soil enzymes in mesocosm-scale constructed wetlands.
Yan, Q, Xu, Y, Yu, Y, Zhu, ZW, Feng, G
Chemosphere. 2018;:245-253
Abstract
Cyperus alternifolius based mesocosm-scale constructed wetland was employed to remove pharmaceuticals. We investigated the microbial community composition using phosphor lipid fatty acids (PFLAs) analysis and substrate enzyme activity during long-term exposure to pharmaceuticals in mesocosm-scale constructed wetlands. The results showed that there was no visible inhibition effect of pharmaceuticals on CW substrate enzymes activities in the experimental range (0-500 μg/L). Microbial communities, as revealed by PFLAs, were enhanced by the presence of plants, while the PFLAs content was highest when the pharmaceutical concentration was 10 μg/L or 30 μg/L at CWs. Except for anaerobic bacteria and Saturated fatty acids, the maximum PLFAs levels were reached when the pharmaceuticals were 10 μg/L or 30 μg/L, while Bacteria, G (-), fungal bacteria, Aerobic bacteria and Monounsaturated fatty acids were remarkably affected by high pharmaceuticals (100-500 μg/L). However, the main microbial florae were not changed among the treatments. In this study, the removal efficiencies of the studied pharmaceuticals in Planted (30) was greatest, which could be attributed to the higher microbial biomass. These results indicate that C. alternifolius can phytoremediate pharmaceutical-contaminated waters in CWs. Individual fatty acid cannot be used to represent specific species; therefore, more approaches to species identification such as rRNA-based methods must be included in future studies to better understand the metabolic mechanisms of microorganisms involved in the removal of studied pharmaceuticals and improve the performance of CWs.
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10.
Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects.
Garimella, T, Tao, X, Sims, K, Chang, YT, Rana, J, Myers, E, Wind-Rotolo, M, Bhatnagar, R, Eley, T, LaCreta, F, et al
Drugs in R&D. 2018;(1):55-65
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Abstract
BACKGROUND A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. OBJECTIVE The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. METHODS We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection). RESULTS Daclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration-time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8-1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration-time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23-0.55) and 0.34 (0.25-0.46), respectively] than without [0.57 (0.42-0.78), 0.48 (0.39-0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration-time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50-0.65), 0.53 (0.47-0.60); metoprolol 1.40 (1.20-1.64), 1.71 (1.49-1.97); digoxin 1.23 (1.12-1.35), 1.23 (1.17-1.29); pravastatin 2.01 (1.63-2.47), 1.68 (1.43-1.97)]. CONCLUSIONS No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.