Discontinued cardiovascular drugs in 2015.

INTRODUCTION: About 10,000 compounds will be tested for an individual drug to eventually reach the market. It might be helpful recapitulating previous failures and identifying the main factors of the disappointments. AREAS COVERED: In this review, the author(s) detailed the 7 cardiovascular compounds discontinued after reaching animal studies or Phase I-III clinical trials during 2015. Meanwhile, the reasons for these discontinuations were reported. Among these drugs, most discontinuations (6 drugs) were attributed to lack of efficacy. In general, failures due to lack of efficacy and safety demonstrate the need for the development of more predictive animal models. However, recent related studies showed that the absence of toxicity in animals provided little or virtually no evidential weight that adverse drug reactions would also be absent in humans. In this case, microdosing and collaborating more closely with biotech companies may be the better choices to improve the success ratio. EXPERT OPINION: Future researches may benefit from the seven developments and investigators conducting similar studies may learn from these failures.

Discontinued cardiovascular drugs in 2013 and 2014.

INTRODUCTION: Cardiovascular diseases (CVDs) are the number one cause of death globally. The dramatically high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention within the pharmaceutical industry. However, ∼ 10,000 compounds are tested for every one drug that reaches the market. For this reason, it is helpful to recapitulate previous failures and learn from these experiences. AREAS COVERED: This paper focuses on the 10 cardiovascular drugs discontinued after reaching animal studies or Phase I - II clinical trials between 1 January 2013 and 31 December 2014. EXPERT OPINION: The trend of increasing numbers of cardiovascular drug development terminations seen in recent years has changed. Only 10 cardiovascular drugs were discontinued after reaching animal studies or Phase I - II clinical trials between 2013 and 2014. Only two candidates were discontinued in the Phase I clinical evaluation, and eight were discontinued during Phase II development. Most discontinuations were attributed to lack of efficacy and safety. One orphan drug (RTA-402) appeared in the list of discontinued cardiovascular drugs. The most eye-catching one of the 10 discontinued drugs is RG-7652, a monoclonal antibody against PCSK9, which is predicted as the next statin.

Bioequivalence evaluation of menthol after oral administration of peppermint oil soft capsules in dogs.

A randomized, two-way, crossover, bioequivalence study in 6 beagle dogs was conducted to compare the bioavailability of two peppermint oil formulations, soft capsule and hard capsule. The drug was given in a single dose of two capsules (total, 200 mg), and blood samples were withdrawn during the 12 h after drug administration. Menthol (CAS 2216-51-5) as the main component of peppermint oil was determined by a gas chromatography-tandem mass spectrometry (GC-MS/I MS) method after cleavage with beta-glucuronidase. The following pharmacokinetic variables were computed for the two formulations: maximum concentration (Cmax), time to maximum concentration (Tmax), half-life of elimination (t1/2), mean residence time (MRT), and areas under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)). For calculation of the 90% confidence interval (CI), an analysis of variance (ANOVA) was carried out. The results indicated that treatment and subject had statistically significant effect on AUC(0-t), AUC(0-infinity), and Cmax, and the 90% CIs for AUC(0-t), AUC(0-infinity), and Cmax were outside the acceptable bioequivalence range. The relative bioavailability was 121.4 +/- 10.6% for AUC(0-infinity). Therefore, it can be concluded that the two formulations are not bioequivalent and the bioavailability of soft capsules is significantly higher than that of hard capsules.

[Studies on characteristic fingerprints of fat-soluble components of Marsdenia tenacissima by GC].

OBJECTIVE: To study characteristic fingerprints of the fat-soluble components of different Marsdenia tenacissima samples by GC and GC-MS. METHOD: The sample was split in the 280 degrees C injection port, with 10:1 split ratio, and separated on a fused silica capillary column (DB-5, 30 m x 0.25 mm I. D., 0.25 microm film). The temperature program was 70 degrees C for 5 min, 8 degrees C x min(-1) to 200 degrees C, then 5 degrees C x min-1 to 260 degrees C, 260 degrees C for 10 min. The high pure nitrogen was used as a carrier gas, The FID temperature was 300 degrees C. RESULT: There are 15 common peaks in the GC fingerprints of M. tenacissima and they are identified by GC-MS. The analyses on cluster and similarity degree of the finger the crude drugs from various habitats have been performed. CONCLUSION: The method has good repeatability. The GC fingerprint combined with the HPLC fingerprint of M. tenacissim can be used to evaluate its quality integrally.

[Determination of ursolic acid of Liuwei Dihuangwan simulation samples by NIR].

OBJECTIVE: Determine the content of ursolic acid of Liuwei Dihuangwan. METHOD: Using NIR with PLS, PCA-BPANN and WT-BPANN. RESULT: The predication recovery were 100.7%, 100.6%, 100.1%, and the RSD were 5.42%, 6.49%, 6.52% respectively. CONCLUSION: NIR can be used in the determination of ursolic acid, which set up the foundation of on-line control of traditional Chinese medicine.

[A quantum chemistry investigation on antimalarial mechanism of Qinghaosu based on cleavage of the peroxide bridge].

AIM: To investigate antimalarial mechanism of Qinghaosu ( QHS) and its derivatives. METHODS: The electronic structure of QHS and its derivatives were completely optimized and calculated at B3LYP/6-31G * level, while the route was at HF/STO-3G level. RESULTS: The peroxide bridge is the active center of QHS and induced by ferrous iron to produce cyclic product. CONCLUSION: Heme can link with QHS derivatives.

Analysis of Psoralea corylifolia L. fruits in different regions.

Application of multivariate data analysis has become a popular method in the last decades, mainly because it can provide information not otherwise accessible. The information includes classification, searching similarities, finding relationships, finding physical significance to principal components, etc. Twenty-two Chinese medicinal herbs containing twelve constituents were collected and determined by HPLC. The results were studied by hierarchical cluster analysis (HCA) and principal components analysis (PCA). It was shown that the samples could be clustered reasonably into three groups, hence corresponding with the typical habitats of Psoralea corylifolia L.

Determination of five coumarins in Cnidii Fructus by micellar electrokinetic capillary chromatography.

A micellar electrokinetic capillary chromatography (MEKC) method for the separation and quantification of the coumarins in Cnidii Fructus was developed for the first time. Within 25 minutes, 5 major coumarins were separated using 18 mM borate, 12 mM phosphate and 50 mM SDS (pH 9.2) containing 20 % methanol. The relative standard deviations of migration times and peak areas were less than 5 %. The total contents of the five coumarins in plants from different habitats ranged from 13.6 to 44.6 mg/g, and recoveries ranged from 96.0 to 102.8 %. The effects of buffer concentration, SDS, pH value and organic modifier on the separation were investigated.