Pharmacokinetic and pharmacodynamic evaluation of a new sustained-release capsules using starch-sponge matrix (SSM) release system for nifedipine in rats

We conducted a performance assessment study for a new sustained-release capsule including starch-sponge matrix (SSM). The SSM, which is a support medium for drug release, was made from 2.5% cornstarch glue by means of freezing dry method. The SSM capsule was applied for nifedipine (NFP), a calcium channel blocker, and evaluated pharmacokinetic and pharmacodynamic (PK/PD) profiles of NFP after intraduodenal administration of SSM capsules including 2.5 or 5.0 mg of NFP per capsule to rats. Plasma NFP concentrations from the SSM capsules showed dose-dependent increases with a Michaelis-Menten like behavior over 360 minutes after intraduodenal administration. The values of area under the concentration vs. time curve from time zero to 360 min (AUC0-360) of NFP declined in making SSM capsules as compared to control capsules due to a simple physical mixture of NFP and cornstarch, but the values of mean residence time (MRT0-360) extended and abidingness of SSM capsules were admitted with dose-dependent manner. As for a PD parameter, the mean arterial blood pressure (mABP) derived from the SSM capsules showed 15~20% decrease of baseline within 120min after intraduodenal administration, and thereafter the mABP in 2.5 mg SSM capsule was gradually recovered, while a relatively smooth and even change was found in the mABP at 5.0 mg SSM capsule. The relationships between plasma NFP concentration and sampling-time corresponding mABP after intraduodenal administration of SSM capsules showed no rapid change in the mABP, indicating that a sustained-release mechanism due to the SSM functions sufficiently to avoid a fluctuating blood pressure accompanied by going up and down of plasma levels of NFP. The SSM capsules exhibited a sustained-release pharmacokinetics of NFP, and made the fluctuation range with blood pressure small compared to the physical mixture preparations. Thus, it was evidenced that the SSM capsule is useful device to provide a sustained-release systems and optimal therapeutic efficacy of drugs.Keywords: Controlled-release, Cornstarch, Matrix, Nifedipine, Pharmacokinetics, Pharmacodynamics

Optical and radiographical characterization of silica aerogel for Cherenkov radiator

We present optical and X-ray radiographical characterization of silica aerogels with refractive index from 1.05 to 1.07 for a Cherenkov radiator. A novel pin-drying method enables us to produce highly transparent hydrophobic aerogels with high refractive index by shrinking wet-gels. In order to investigate the uniformity in the density (i.e., refractive index) of an individual aerogel monolith, we use the laser Fraunhofer method, an X-ray absorption technique, and Cherenkov imaging by a ring imaging Cherenkov detector in a beam test. We observed an increase in density at the edge of the aerogel tiles, produced by pin-drying.Comment: To be published in IEEE Trans. Nucl. Sci., 7 pages, 9 figures, 1 tabl

Development of SrtA-mediated Peptide-labeled Liposome

Background/Aim: In order to develop an efficient drug-delivery system (DDS), a lipopeptide-loaded liposome that functions as a platform for the transpeptidase reaction mediated by sortase A (SrtA) was constructed and its stability, as well as cell-specific targeting were evaluated in the present study. Materials and Methods: Several lipopeptides possessing an acceptor peptide sequence (oligoglycine ≥ three residues) or donor peptide sequence (LPETG) for the SrtA-mediated reaction were chemically synthesized and then inserted into the liposome membrane composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol (DPPC-Chol-lipo) to obtain the lipopeptide-loaded liposomes. The transpeptidase reaction mediated by recombinant SrtA (His-ΔN59SrtA) was employed to modify the peptide moiety on the liposomal surface using a fluorescently-labeled substrate peptide corresponding to the species of each loaded lipopeptide. Furthermore, lung tumor-binding peptide (LTBP)-labeled liposomes, prepared by this transpeptidase reaction, were investigated for selective targeting to lung cancer cells in vitro. Results and Discussion: The His-ΔN59SrtA-mediated transpeptidation of fluorescently-labeled peptide on the lipopeptide-loaded DPPC-Chol-lipo was confirmed. The selective targeting of LTBP-labeled liposomes to the lung cancer cell line A549 was also observed in vitro. These results suggest that the labeling of acceptor or donor lipopeptide-loaded liposomes with the transpeptidase SrtA could be a useful method for developing a platform applicable to a cancer-targeting DDS

Evaluation of atherosclerotic lesions using dextran- and mannan–dextran-coated USPIO: MRI analysis and pathological findings

Magnetic resonance imaging (MRI) can detect atherosclerotic lesions containing accumulations of ultrasmall superparamagnetic iron oxides (USPIO). Positing that improved USPIO with a higher affinity for atherosclerotic plaques would yield better plaque images, we performed MRI and histologic studies to compare the uptake of dextran- and mannan–dextran-coated USPIO (D-USPIO and DM-USPIO, respectively) by the atherosclerotic walls of rabbits. We intravenously injected atherosclerotic rabbits with DM-USPIO (n = 5) or D-USPIO (n = 5). Two rabbits were the controls. The doses delivered were 0.08 (dose 1) (n = 1), 0.4 (dose 2) (n = 1), or 0.8 (dose 3) (n = 3) mmol iron/Kg. The dose 3 rabbits underwent in vivo contrast-enhanced magnetic resonance angiography (MRA) before and 5 days after USPIO administration. Afterwards, all animals were euthanized, the aortae were removed and subjected to in vitro MRI study. The signal-to-noise ratio (SNR) of the aortic wall in the same region of interest (ROI) was calculated in both in vivo and in vitro studies. Histological assessment through measurement of iron-positive regions in Prussian blue-stained specimens showed that iron-positive regions were significantly larger in rabbits injected with DM- rather than D-USPIO (P < 0.05) for all doses. In vivo MRA showed that the SNR-reducing effect of DM- was greater than that of D-USPIO (P < 0.05). With in vitro MRI scans, SNR was significantly lower in rabbits treated with dose 2 of DM-USPIO compared with D-USPIO treatment (P < 0.05), and it tended to be lower at dose 3 (P < 0.1). In conclusion, we suggest that DM-USPIO is superior to D-USPIO for the study of atherosclerotic lesions in rabbits

Recurring radiation-induced angiosarcoma of the breast that was treated with paclitaxel chemotherapy: a case report

Background Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX). Case presentation A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy. Conclusion Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

がんゲノム医療のさらなる拡大へ向けた一歩 --コンピュータ解析で意義不明変異のなかに治療標的となる新たな遺伝子変異を発見--. 京都大学プレスリリース. 2022-09-29.Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71, 756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca²⁺ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations