Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017.

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Chronic kidney disease stage is a modulator on the association between high-sensitivity C-reactive protein and coronary vasospastic angina.

The prevalence of coronary vasospasm and also the factors associated with coronary vasospasm in CKD is still unclear. In this cross-sectional study of 859 consecutive CKD patients with angina pectoris received coronary catheterization, we evaluated the factors associated with coronary vasospasm. Patients with vasospasm were older and had higher peripheral blood white cell counts, higher peripheral blood monocyte cell counts, higher haemoglobin levels, higher hs-CRP levels, and lower levels of serum creatinine than patients without vasospasm. The results of multivariate logistic regression analysis revealed that peripheral blood monocyte count and hs-CRP level were independently associated with coronary vasospasm in patients with stage 1 CKD. Only peripheral blood monocyte count but not hs-CRP was independently associated with coronary vasospasm in patients with stages 2 and 3 of CKD. In conclusion, peripheral blood monocyte count is independently associated with coronary vasospasm in patients with stage 1-3 CKD, whereas hs-CRP is only independently associated with coronary vasospasm in patients with stage 1 CKD.

St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats.

St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC(0-t) and C(max) of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC(0-t) of MTX by 55%. In addition, diclofenac enhanced the C(max) of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution.

Structure-activity relationships of a peptidic antagonist of Id1 studied by biosensor method, circular dichroism spectroscopy, and bioassay.

Id1 proteins, inhibitors of differentiation or DNA binding, act as dominant negative antagonists of the bHLH family of transcription factors, which play an important role in cellular development, proliferation, and differentiation. The mechanism of Id proteins is to antagonize bHLH proteins by forming high-affinity heterodimers with other bHLH proteins, thereby preventing them from binding to DNA and inhibiting transcription of differentiation-associated genes. Our goal is to study the SARs of a peptidic antagonist of Id1, peptide 3C, which exhibits high affinity for Id1 and inhibitory effect on the proliferation of cancer cells. A series of N-terminal- and C-terminal-deleted analogs of peptide 3C were designed, synthesized, and characterized. Affinity of each peptide for Id1 or Id1-HLH domain was determined by SPR-based biosensor. The secondary structure of each peptide was studied by CD spectroscopy. Biological effect of each peptide in breast cancer cell (MCF-7) was analyzed by the MTT cell viability assay. Results demonstrated that peptide 3C and peptide 3C-CtD4 exhibited higher affinity for Id1-HLH and the equilibrium dissociation constants (K(D) ) were 3.16 and 2.77 µM, respectively. CD results indicated that the percentage of α-helix (%) in the secondary structure of deleted peptides were different, ranging from 7.93 to 10.45%. Although MTT results showed that treatment of MCF-7 with these peptides did not cause antiproliferative effects in cancer cells, SPR results demonstrated that the high-affinity peptides 3C and 3C-CtD4 are promising for further modifications to enhance their affinity for Id1-HLH and antiproliferative effects in cancer cells and for the development of peptidic antagonists as anticancer agents.

Indoxyl sulfate, a uremic toxin, is biotransformed from indoxyl-beta-D-glucoside (indican) in rats.

Indican (Indoxyl-beta-D-glucoside) is present in many Chinese herbs such as Isatis indigotica, Clerodendrum crytophyllum, Glehnia littoralis, Polygonum tinctorium and P. perfoliatum. This study aims to investigate whether indoxyl sulfate, a uremic toxin, would be biotransformed from indican in rats. Indican was administered intravenously and orally to Sprague-Dawley rats. The blood samples were withdrawn via cardiopuncture at specific time points and the serum concentrations of indican and indoxyl sulfate were assayed by HPLC method. The results showed that indican was rapidly and extensively metabolized to indoxyl sulfate either given intravenously or orally. Indoxyl sulfate showed markedly higher systemic exposure than indican. Because indoxyl sulfate is a harmful uremic toxin, we suggest that the content of indican in the aforementioned medicinal plants be quantitated and well controlled to ensure the safety for clinical use.

Encapsulating Peritoneal Sclerosis in Long-Termed Peritoneal Dialysis Patients.

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but serious clinical complication of long-term peritoneal dialysis (PD) patients with high mortality. The purpose of this study was to assess the clinical characteristics of patients with EPS and to search for possible factors useful for EPS prevention and early diagnosis. METHOD: This retrospective study was performed in a single dialysis center in Taiwan between August 1990 and April 2014. Overall, a total of 565 patients were included and the medical records of those patients who had developed EPS (EPS group) and those who had not developed EPS (control group) were collected. We compared several factors between these two groups. RESULT: In the univariate analysis, EPS was significantly associated with a change of transport state (Delta 2) (p = 0.007), duration of PD (p < 0.001), duration of peritonitis treatment (p = 0.001), number of peritonitis episodes (p = 0.002), and fungus related peritonitis (p = 0.031). After multivariate logistic model analysis, we found that only the duration of PD was independently significantly associated with EPS (p = 0.034). In addition, we used the ROC curve and found that a duration of peritoneal dialysis of about 8.4 years is the best cut-off point to predict EPS occurrence. CONCLUSION: In this study, long-termed PD duration is the only strong independent risk factor for EPS development. Total peritonitis times, total peritonitis treatment duration, and marked increased peritoneal D/Pcr ratio were also significantly associated with the duration of PD.

The Complex Relations Between Wisdom and Significant Life Learning.

This study explores the various relations between two important processes in life-span development: wisdom and learning from significant life experience. A diverse sample of 375 individuals from Taiwan, culled from an initial sample of 475, completed a sequence of three questionnaires that asked them to describe their most significant life learning, the wisdom they had displayed, and the relation between the two. The 375 participants specified one of five relations: (a) their most significant life learning led to their display of wisdom (n = 191, 51%); (b) the two were unrelated (n = 91, 24%); (c) their display of wisdom led to their most significant life learning (n = 67, 18%); (d) the wisdom displayed was part of their most significant life learning (n = 20, 5%); (e) their most significant life learning was part of the wisdom they displayed (n = 6, 2%). These results suggest that wisdom and significant life learning are seen as related in various ways. The findings shed light on how wisdom and the learning acquired from significant life experiences foster individual development.

Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies.

Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.

Evaluation of the cultivation age of dried ginseng radix and its commercial products by using (1)H-NMR fingerprint analysis.

The perfect ginseng radix is collected when the ginseng root reaches a cultivation age of six years; this ensures the best mass quality and consistency of the plant's essential bioactive components. Since traditional means of authentication via physical appearance or smell are hardly reliable, an efficient analytical method that can determine the real cultivation age of dried ginseng radix in commercial products, especially ginseng products of various dosage forms, is urgently required. In the present study, chemical fingerprint by (1)H-NMR spectroscopy was used on dried ginseng radix samples with cultivation ages ranging from 1-6 years. The resulting dataset was then analyzed by using principle component analysis and cluster analysis to build up a distributive model that allows the identification of the real cultivation age of the ginseng radix based on a plant metabolomic strategy. This quality surveillance method was able to clearly discriminate the 6 years old ginseng radix from the other ages, and could be applied on the evaluation of the real cultivation age for the various dried white ginseng radix samples and commercial products accurately.

Real-life contextual manifestations of wisdom.

Wisdom pertains to managing human affairs, and it arises in highly contextualized situations. The present study aims to investigate manifestations of wisdom in real-life contexts through semi-structured interviews with 66 individuals nominated as wise persons. All nominees were ethnic Chinese from Taiwan, an East Asian country which has Confucianism, Taoism, and Buddhism as its predominant philosophies. Analysis of these interview transcripts yielded 220 wisdom incidents that fall into five categories of wisdom. Results of the present study suggests that in real life, wisdom most likely is manifested through: 1) striving for common good by helping others and contributing to society; 2) achieving and maintaining a satisfactory state of life; 3) deciding and developing life paths; 4) resolving difficult problems at work; and 5) insisting on doing the right thing when facing adversity.

Recent methodology in the phytochemical analysis of ginseng.

This review summarises the most recent developments in ginseng analysis, in particular the novel approaches in sample pre-treatment and the use of high-performance liquid-chromatography-mass spectrometry. The review also presents novel data on analysing ginseng extracts by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry (Fourier transform mass spectrometry) in the context of metabolomics.

Application of two-dimensional nuclear magnetic resonance spectroscopy to quality control of ginseng commercial products.

Ginseng has been used as a powder or a crude extract of the plant roots. The quality control of commercial ginseng preparations is difficult due to the diverse compounds present. Most previous quality control methods using TLC or HPLC-UV (or -MS) cannot be expected to cover a wide range of compounds in the commercial ginseng preparations. In this study, the metabolic fingerprinting of ginseng preparations was performed by (1)H-NMR spectroscopy. Although (1)H-NMR spectroscopy could provide information about the total profile of the compounds present, low resolution and overlapping signals make it difficult for further identification of each compound. For overcoming the problem two-dimensional J-resolved NMR spectra and multivariate data analysis techniques was applied for the analysis. Principal component analysis (PCA) of projected J-resolved NMR spectra shows a clear discrimination among those samples by principal component 1 and principal component 3. The loading plot of PC values obtained from all NMR signals indicates that alanine, arginine, choline, fumaric acid, inositol, sucrose as well as ginsenosides are important metabolites to differentiate the preparations from each other. This method allows an efficient discrimination of a ginseng preparation in less than 15 minutes without any pre-purification steps.