Video-based learning can improve the understanding of pharmacists’ contributions during the COVID-19 pandemic: A cross-sectional survey of pharmacy students in Japan

Backgound: It has been challenging to conduct university education in face-to-face and large group settings during the COVID-19 pandemic. Accordingly, there is a pressing need for online educational videos. Objective: To create educational videos to highlight community pharmacists’ efforts during the COVID-19 pandemic in Japan and investigate pharmacy students’ awareness of community pharmacists’ efforts. Methods: To assess the importance of five educational videos, we conducted a cross-sectional survey. In July 2020, first-year pharmacy students (n = 120) were invited to watch these educational videos, which dealt with infection control measures for COVID-19 in pharmacies and the questions received from patients on COVID-19. Subsequently, the students were asked to respond to a questionnaire to assess the impact of the videos on them. Results: Seventy percent of the students revealed that after watching the videos, they, for the first time, realized the contributions of community pharmacists toward healthcare during the COVID-19 pandemic. Many of the students reported that their image of the pharmacist profession changed to “a familiar medical professional who is close to patients.” Furthermore, 102 of the participants (85%) were satisfied with the videos and more than 60% said they gave them confidence for their future studies. Conclusions: Creating these five educational videos provided the first-year pharmacy students with an improved understanding of the role played by pharmacists in public health. Through the videos, the role of pharmacists during the COVID-19 pandemic was particularly highlighted. This helped students feel closer to pharmacists, whose role is rarely reported in the media. Moreover, their future goal of becoming a pharmacist was concretized. (AU)

[Preparation, Confidence, and Attitude to Sell Emergency Contraceptive Pills at Pharmacies: A Web Survey of Japanese Community Pharmacists].

Emergency contraceptive (EC) pills are used to prevent pregnancy after unprotected sexual intercourse. Levonorgestrel is an EC pill, which has been only approved in Japan; it is more effective the sooner it is used after intercourse and safe without serious side effects. EC pills are already available at accessible community pharmacies in more than 90 countries around the world. In Japan, citizens have signed a petition calling for the sale of emergency contraceptives at community pharmacies. However, little is known about the thoughts of pharmacists who engage with patients and sell medicines at pharmacies. Therefore, we conducted a web-based cross-sectional survey to determine the level of preparation in community pharmacies and the awareness of pharmacists regarding the sale of EC pills. A total of 1338 pharmacists responded to the survey from November 7, 2020, to December 16, 2020. In terms of the level of preparation for selling EC pills at pharmacies, 1067 (83.9%) respondents cited "lack of preparation of medical questionnaires and explanatory materials", and 975 (76.7%) respondents cited "lack of knowledge of pharmacists" as the most common reasons that were "barriers to EC pill sales at pharmacies". In terms of confidence level, only 289 (22.7%) respondents were confident about conducting the necessary checks while administering medicine. On the other hand, 944 (74.3%) respondents agreed to be able to sell EC pills at their pharmacies. The survey revealed that most of the pharmacists who participated in the survey believe that it is possible to sell EC pills in pharmacies.

Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation.

Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment.

Pharmacokinetic-Pharmacodynamic Analysis of Cisplatin with Hydration and Mannitol Diuresis: The Contribution of Urine Cisplatin Concentration to Nephrotoxicity.

BACKGROUND AND OBJECTIVES: Forced diuresis, high-volume hydration with diuresis, is widely used as a prophylactic treatment against cisplatin nephrotoxicity. However, the details of the underlying mechanisms and the optimal protocol of forced diuresis remain unclear. The present study investigated the alterations in pharmacokinetics and pharmacodynamics (nephrotoxicity) of cisplatin with forced diuresis treatment. METHODS: Cisplatin (5 mg/kg) was intravenously injected to rats (5 rats/group, except for control group in pharmacodynamic study, n = 13) treated with or without forced diuresis 2-h pre- and post-hydration with 10% mannitol at different infusion rates (0.3, 1.0, and 3.0 mL/h). The unbound cisplatin concentrations in plasma and urine, and the platinum amount in the kidney were monitored in the pharmacokinetic studies. The plasma creatinine concentration was evaluated as an index of nephrotoxicity in the pharmacodynamic studies. RESULTS: Forced diuresis treatment did not significantly alter the plasma cisplatin pharmacokinetics but dramatically decreased the urine concentration of unbound cisplatin and its accumulation into the kidneys in a dose-dependent manner, and correspondingly, nephrotoxicity was dose-dependently attenuated by forced diuresis. The pharmacokinetic-pharmacodynamic analysis suggested that the urine cisplatin concentration has a comparable impact on the cisplatin-induced nephrotoxicity to that in plasma, probably owing to the reabsorption of cisplatin from urine, which can be attenuated by forced diuresis. CONCLUSIONS: These results indicated that the nephroprotective effect of forced diuresis is a pharmacokinetic-based drug-drug interaction possibly due to the inhibition of cisplatin reabsorption from urine. Monitoring of urine cisplatin concentration may lead to the optimization of a forced diuresis protocol with mannitol.

Alterations in Cisplatin Pharmacokinetics and Its Acute/Sub-chronic Kidney Injury over Multiple Cycles of Cisplatin Treatment in Rats.

Cisplatin (CDDP)-induced acute kidney injury (AKI) is a major clinical concern. CDDP treatment is generally conducted with multiple cycles; the magnitude of the CDDP-induced AKI may be altered by these cycles. Moreover, sub-chronic kidney injury (sCKI) induced by repeated CDDP treatment is often associated with renal interstitial fibrosis, potentially leading to chronic kidney disease. Therefore, it is suggested that the management of not only AKI but also sCKI induced by CDDP in multiple cycles plays an important role in the outcome of CDDP-based chemotherapy. This study investigated the alteration in pharmacokinetics and toxicodynamics of CDDP that was repeatedly administered for three cycles in rats; a cycle consisted of CDDP (5.0 mg/kg, bolus injection) followed by a 21-d washout period. AKI and sCKI were evaluated by plasma creatinine concentration. In repeated multiple administration of CDDP, renal clearance was decreased and the amounts of accumulated Pt in kidneys increased by the cycle. AKI and sCKI were similarly exacerbated by the cycle, whereas the degree of AKI showed a large inter- and intra-individual variation in each cycle. However, the degree of sCKI constantly increased (creatinine increasing ratio in any cycle is about 150%), suggesting that the degree of sCKI in any given cycle was predictable by monitoring the initial creatinine baseline. In this study, therefore, it is suggested that the evaluation of sCKI by monitoring creatinine concentration at base is important for the estimation of CDDP-induced nephrotoxicity. These results may provide useful information for more effective and safe CDDP-based chemotherapy with evidence-based dose adjustment.

Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center.

PURPOSE: Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). METHODS: A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used. Pre- and postoperative CyA model structure and PPK parameters were separately estimated with a non-linear mixed-effect model, and subsequently, covariate analysis of postoperative data were comprehensively estimated, including preoperative PK parameters. RESULTS: A two-compartment model with first-order absorption and absorption lag time was selected in this study. Aspartate aminotransferase, body surface area (BSA), pretransplant area under the whole blood concentration-time curve/dose, and postoperative days were identified as the covariates on oral clearance. BSA was selected as a covariate of the distribution volume of the central compartment. In addition, diabetes mellitus was selected as a covariate of the first-order absorption rate. CONCLUSIONS: This PPK study used the largest number of blood concentration data among previous reports of living-donor renal transplant patients. Moreover, all patients received the same immunosuppressive regimen in a single center. Therefore, the validity of the selected covariates is reliable with high precision. The developed PPK model and selected covariates provide useful information about factors influencing CyA PK and greatly contributes to the identification of the most suitable dosing regimen for CyA.

Population Semiphysiologic Kinetic Modeling and Simulation of Plasma Triglyceride Levels After Soybean Oil-Based Intravenous Lipid Emulsion Administration in Rats.

BACKGROUND: Soybean oil-based intravenous lipid emulsion (SO-ILE) has clinical utility as an energy source and in lipid rescue therapy. However, an excessive infusion rate of SO-ILE in routine use and in lipid rescue therapy may cause serious side effects. There is little information about plasma triglyceride (TG) kinetics following SO-ILE administration. The present study aimed to develop a population semiphysiologic kinetic model of TG and to predict the TG kinetics even at extremely high concentrations in rats. MATERIALS AND METHODS: TG concentration profiles after intravenous bolus (0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) or infusion (3.0 g/kg/h for 1 hour) of SO-ILE to rats were analyzed by a kinetic model constructed with 4 pathways: apolipoprotein acquisitions, zero-order catabolism, first-order uptake to storage sites, and zero-order secretion from storage sites. The developed model was subjected to internal and external validation. RESULTS: Plasma TG concentrations appeared to decline in a biphasic manner with nonlinear TG kinetics. The developed kinetic model was well validated and found to accurately predict the external validation data. CONCLUSIONS: The proposed kinetic model accurately described TG concentrations after SO-ILE administration at various infusion rates, including a lipid rescue regimen. The maximum acceptable infusion rate of SO-ILE in routine use should correspond to the maximum velocity of the apolipoprotein acquisition: 0.619 g/kg/h in rats. The prediction of TG kinetics at extremely high concentrations will provide useful information for lipid rescue therapy.

Population Pharmacokinetic-Toxicodynamic Modeling and Simulation of Cisplatin-Induced Acute Renal Injury in Rats: Effect of Dosing Rate on Nephrotoxicity.

Nephrotoxicity is the major dose-limiting toxicity of cisplatin (CDDP). The aim of this study was to develop a pharmacokinetic (PK)/toxicodynamic (TD) model of CDDP-induced acute renal injury in rats and to simulate nephrotoxicity at various dosing rates. CDDP was administered to rats by a 30-s bolus or a 2-h infusion (1.0, 2.5, 5.0, and 7.5 mg/kg). Unbound CDDP concentrations in plasma and urine were determined up to 2 h after administration in the PK study, and plasma creatinine (Cr) levels were monitored for up to 7 days as an index of nephrotoxicity in the TD study. The PK was linear and was fitted with a traditional 2-compartment model. The TD was nonlinear and differed between dosing rates. The creatinine concentration profiles were fitted with a signal transduction-indirect response model. Population analysis using a nonlinear mixed-effect model was adapted to the developed PK/TD model and was well-validated. Dosing simulations from the developed population PK/TD model indicated that CDDP-induced nephrotoxicity was due to not only Cmax but also the time above the toxic concentration of CDDP. Prolongation of infusion time will not necessarily attenuate acute nephrotoxicity. This study demonstrated the potential utility of PK/TD modeling for preventing nephrotoxicity.

Preparation and pharmaceutical evaluation of acetaminophen nano-fiber tablets: Application of a solvent-based electrospinning method for tableting.

In this study, we developed nano-fiber-based tablets with acetaminophen (AAP; LogPow=0.51) for controlled-release delivery systems and evaluated in vitro drug dissolution and in vivo pharmacokinetics in rats. Nano-fibers made from methacrylic acid copolymer S (MAC; EUDRAGIT S100) and containing AAP were prepared using a solvent-based electrospinning (ES) method. In vitro dissolution rate profiles of AAP showed tableting pressure-dependent decreases and pH-dependent increases. The results of tablet tracking by X-ray irradiation showed tablets based on MAC nano-fibers did not disintegrate in the upper intestinal lumen and had the properties of a long-term-acting tablet. In addition, the in vitro release profiles of AAP from nano-fiber tablets prepared by dissolving MAC with AAP (NFT), nano-fiber tablets prepared by adsorbing AAP to drug-free MAC nano-fibers (NFTadso), and tablets prepared by adsorbing half the amount of AAP to MAC nano-fibers containing the remaining amount of AAP (NFThalf) showed independent controlled-release aspects of AAP compared with physical mixture tablets (PMT). In vivo pharmacokinetic studies in rats after intraduodenal administration of 14 mg/rat AAP in NFT, NFTadso, and NFThalf demonstrated that all these tablets based on MAC nano-fibers showed sustained-release profiles compared with PMT, and showed ultra-sustained release properties for AAP. These new tablets based on MAC nano-fibers did not disintegrate in the intestine in the lower pH region, and the tablets could regulate the release of AAP in a pH-dependent manner. The ES method is a useful technique to prepare nano-fibers and showed promising results as an oral delivery system for sustained-release regulation.

Pharmacokinetic-pharmacodynamic analyses of antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics of effect and side effects.

To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects.

Enhanced oral bioavailability of vancomycin in rats treated with long-term parenteral nutrition.

Long-term parenteral nutrition (PN) can induce intestinal atrophy, leading to a loss of epithelial integrity in the small intestines. This change may alter the intestinal permeability of vancomycin (VCM), a non-absorbable antibiotic. The aim of the present study was to investigate the effect of PN on the pharmacokinetics of VCM in rats. VCM was intravenously (5 mg/kg) or intraduodenally (20 mg/kg) administered to control and PN rats, which were prepared by administration of PN for 9 days. After intravenous administration, there were no significant differences in any of the VCM pharmacokinetic parameters between the control and PN rats. However, after intraduodenal administration, the maximum concentration and area under the plasma concentration-time curve of VCM in PN rats was approximately 2.4- and 2.6-fold higher, respectively, than in the control rats; the calculated bioavailability was approximately 0.5 and 1.3 % in control and PN rats, respectively. These results indicated that PN administration did not affect VCM disposition, but enhanced VCM absorption; however, the enhanced oral VCM bioavailability was statistically, not clinically, significant. Therefore, while long-term PN administration may play a role in the enhancement of VCM bioavailability, this effect may be negligible without any complications.

Preparation of methacrylic acid copolymer S nano-fibers using a solvent-based electrospinning method and their application in pharmaceutical formulations.

In this study, we applied an electrospinning (ES) method, which is mainly employed in the textile industry, to the field of pharmaceuticals. We developed and modified an ES instrument and then utilized it to produce methacrylic acid copolymer S (MAC) nano-fibers to prepare tablets. By attaching a conductor rod made from stainless steel to the central part of the nano-fiber-collection plate of the ES apparatus, a MAC nano-fiber sheet could be produced effectively. In addition, we studied various operating conditions for this new ES method, including needle gauge, voltage between the electrodes, distance between the needle and nano-fiber-collection plate and the flow rate of MAC polymer solution, but these had no significant effect on the diameter of MAC nano-fibers. On the other hand, the viscosity (concentration) of MAC polymer solution and permittivity of solvent used to dilute MAC were closely related to the mean diameter of the nano-fibers. Tableting of MAC nano-fibers was performed using a tableting machine without lubricants, and addition of Tween 20 to the tablets enabled regulation of the release profile of a water-soluble drug. The modified ES method reported here is a useful technique for the controlled-release of drugs and has wide-ranging potential for pharmaceutical applications.

Effect of intestinal atrophy and hepatic impairment induced by parenteral nutrition on drug absorption and disposition in rats.

BACKGROUND: Long-term parenteral nutrition (PN) has a high risk of hepatic dysfunction and intestinal atrophy. The present study investigated the effect of PN-induced intestinal atrophy and hepatic impairment on drug pharmacokinetics by using 2 contrasting compounds: phenolsulfonphthalein (PSP) and cyclosporin A (CyA). MATERIALS AND METHODS: PSP or CyA was administered to 7-day PN-fed Rats (PN rats) and sham operated rats (control rats) via intravenous (IV) or intraloop administration of the intestine. Pharmacokinetic parameters with 2-compartment analysis including area under the concentration vs time curve (AUC) and the permeability after in situ intraloop administration (P loop) were obtained from both concentration profiles after different administration routes. RESULTS: After IV administration of PSP to control and PN rats, there was no notable difference in any of the pharmacokinetic parameters. In contrast, after intraloop administration, AUC and P loop in PN rats were approximately 2.6- and 2.0-fold higher than that in control rats, respectively. On the other hand, after IV administration of CyA, the terminal half-life and total body clearance were prolonged and decreased in PN rats, respectively, resulting in 2.0-fold increase in AUC. After intraloop administration, the AUC of PN rats was increased to approximately 1.3-fold that of control rats, whereas no notable difference was observed in P loop. CONCLUSION: The intestinal permeability of PSP was enhanced by intestinal atrophy induced by PN, while the metabolism of CyA was diminished by hepatic impairment by PN. These results revealed the physicochemical property-based pharmacokinetic alterations during PN; for a more detailed understanding, however, further studies are needed.

Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats.

1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.

Pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for erythropenia in rats.

INTRODUCTION: The aim of the present study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model in rats that could predict the onset and degree of erythropenia, a severely toxic side effect that severely limits the use of the anticancer agent 5-fluorouracil (5-FU). METHODS: Total erythrocyte counts, hemoglobin (Hb) concentrations, and hematocrit (Hct) levels were measured in rats following the intravenous bolus administration of 5-FU for 4 days in order to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with two compartments for the PD model and nine structural PK-PD model parameters. RESULTS: After the intravenous bolus administration of 5, 10, or 20 mg/kg of 5-FU to rats, absolute erythrocyte counts, Hb concentrations, and Hct levels transiently decreased, reached minimum levels on Days 7-14, and then returned to baseline levels. The nadir values (Cnadir) for rats treated with 5, 10, or 20 mg/kg of 5-FU were significantly decreased to approximately 79.4, 76.3, or 46.5% of the baseline value (Cbaseline) in erythrocyte counts, 86.3, 83.3, or 45.7% of Cbaseline in Hb concentrations, 88.6, 85.5, or 47.1% of Cbaseline in Hct levels, respectively. The PK-PD model effectively captured the features of erythropenia and Cnadir after 5-FU chemotherapy. This PK-PD model was successfully used to characterize the learner relationship between the area under the plasma 5-FU concentration-time curve (AUC0-∞) following the intravenous bolus administration of 5-FU and the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels after the 5-FU treatment. DISCUSSION: The results of the present study suggest that the administration of a pharmacokinetically modified dose of 5-FU could minimize the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels following the administration of 5-FU. The PK-PD model and simulation represent valuable approaches for quantifying and predicting erythropenia as well as determining individual doses and the time at which the subsequent course of the treatment should start.

Semi-physiological pharmacokinetic-pharmacodynamic modeling and simulation of 5-fluorouracil for the whole time course of alterations in leukocyte, neutrophil and lymphocyte counts in rats.

We aimed to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats. Our PK-PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model. The semi-physiological PK-PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK-PD analytical simulation curves against the area under the plasma 5-FU concentration-time curve (AUC0-∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r2=0.989, 0.877 and 0.956, respectively. The semi-physiological PK-PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.

Preparation and pharmaceutical evaluation of nano-fiber matrix supported drug delivery system using the solvent-based electrospinning method.

In this study, utilizing the solvent-based electrospinning (ES) method, which is mainly employed in the textile industry, we prepared nanofiber-based capsules including drugs for controlled-release delivery systems using methacrylic acid copolymer (EUDRAGIT(®) S100, MAC) as a polymer, and evaluated their in vitro drug dissolution profiles and in vivo pharmacokinetics in rats. As the model drugs, uranine (UN) was used as a water-soluble drug and nifedipine (NP) as a water-insoluble drug. The mean diameters of drug free nano-fiber and nano-fiber including NP or UN were 751.5 ± 67.2, 703.3 ± 71.2 and 2477.8 ± 206.1 nm, respectively. X-ray diffraction for the nano-fibrotic sheet showed that UN and/or NP were packed in nano-fiber in an amorphous form. The in vitro release of UN or NP from the nano-fiber packed capsules (NFPC) and milled-powder of nano-fiber packed capsules (MPPC) showed controlled release of UN or NP as compared to capsules of a physical mixture of MAC and each drug. An in vivo pharmacokinetic study in rats after intraduodenal administration of NFPC or MPPC including UN and/or NP clearly demonstrated that application of nano-fibrotic technique as a drug delivery system offers drastic changes in pharmacokinetic profiles for both water-soluble and water-insoluble drugs. The ES method is a useful technique to prepare a nano-fiber like solid dispersion for polar or nonpolar drugs, and has wide potential pharmaceutical applications.

A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer.

The relationship between the plasma ratio of dihydrouracil/uracil (UH2/Ura) and hepatic dihydropyrimidine dehydrogenase (DPD) activity after repeated 5-fluorouracil (5-FU) treatment in rats with colorectal cancer (CRC) was investigated. Repeated intravenous 5-FU bolus injections resulted in a significant decrease in the total clearance (CLtot ) and an increased area under the curve (AUC0-∞ ) in CRC rats. Furthermore, the hepatic DPD levels and the plasma ratio of UH2/Ura decreased significantly and lost their circadian rhythms in CRC rats treated repeatedly with 5-FU, although significant circadian variation in the two parameters was observed in the control CRC rats. Moreover, a significant correlation was found between the plasma ratio of UH2/Ura and hepatic DPD activity in CRC rats untreated and treated with single or repeated 5-FU administration (r(2) = 0.865, p < 0.01). The ratio of UH2/Ura in plasma could be a predictive biomarker of the suppression of hepatic DPD levels during repeated 5-FU-based treatment. Furthermore, by plotting the observed pharmacokinetic parameters of 5-FU against hepatic DPD activity levels predicted by the ratio of UH2/Ura in plasma, AUC0-∞ , CLtot and half-life (t1/2 ) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC0-∞ , CLtot and t1/2 of 5-FU after single or repeated administration of 5-FU is the hepatic DPD activity and it could be assessed by the ratio of UH2/Ura in plasma.

Controlled release of insulin from self-assembling nanofiber hydrogel, PuraMatrix™: application for the subcutaneous injection in rats.

The concept of this research is, using the acetyl-(Arg-Ala-Asp-Ala)4-CONH2 peptide hydrosol (PuraMatrix™, PM), to develop an new injectable formula of controlled insulin delivery for subcutaneous injection. PM has sol-gel phase transition behavior, and was developed as a scaffold in the field of tissue engineering. The aqueous media of the PM including insulin changed from a sol to a gel phase with increasing ion strength of phosphate ion and pH in working environments in vitro and in vivo. In this study, we examined the in vitro insulin dissolution behavior and the in vivo pharmacokinetics and pharmacodynamics after subcutaneous administration of PM-insulin sol (PM-Isol). In the in vitro release study, after PM-Isol was converted to a gel phase (PM-Igel), PM concentration-dependent and controlled release of insulin were observed at the final concentrations of PM between 0.1% and 2.0% (w/v). The PM-Isol is changed to gel form in vivo, and exhibited a sustained-release pharmacokinetics of insulin, where PM concentration-dependent prolongation of efficacy was found. The plasma glucose level markedly decreased, and the lowest plasma glucose level was maintained up to 24h when 2.0% (w/v) PM-Isol was administered subcutaneously to rats. The PM-Isol, we developed here, is applicable for the wild-type of insulin, and increased the bioavailability and hypoglycemic efficacy of insulin after subcutaneous injection. Hence, the PM is a useful inactive ingredient to produce various types of control-released system of insulin by making just a few changes in PM content of the formulation.