Augmentation of the antitumor effects of PARP inhibitors in triple-negative breast cancer via degradation by hydrophobic tagging modulation.

Triple-negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis due to the lack of specific targeted treatments. The development of an effective therapeutic strategy with a novel mechanism is essential for TNBC management. Olaparib, a PARP inhibitor, has been approved for the treatment of breast or ovarian cancer patients with breast cancer gene 1/2 (BRCA1/2) mutations. Here, we report the development of a small molecule targeting PARP1 based on the hydrophobic tagging (HyT) method. Targeted protein misfolding and consequent degradation are caused by HyT. Hydrophobic-tagged olaparib induces the proteasome-dependent degradation of PARP1 and shows enhanced antitumor effects compared to olaparib in TNBC cells. In addition, hydrophobic-tagged olaparib causes ER stress-related unfolded protein response (UPR), autophagy, and apoptosis. These results point towards encouraging prospects for chemically modifying approved drugs that not only exhibit superior effects compared to those of the original drugs by triggering novel mechanisms but also provide great feasibility in the translational scenario.

Comparison of the Pharmacokinetics, Safety, and Tolerability of the Autoinjector (AI) and Pre-Filled Syringe (PFS) of SB4 in Healthy Subjects.

PURPOSE: SB4 is an etanercept biosimilar, approved by the European Commission (EC) and the US Food and Drug Administration (FDA) following a demonstration of equivalent efficacy and safety and comparable quality data to the reference product. This study aimed to demonstrate equivalent pharmacokinetic (PK) profiles, safety, and tolerability between SB4 autoinjector (AI) and SB4 pre-filled syringe (PFS). PATIENTS AND METHODS: This was an open-label, two-period, two-sequence, single-dose, cross-over study to evaluate bioequivalence of PK profiles, safety, and tolerability between SB4 AI and PFS in healthy adults. Treatment periods were separated by 14 days resulting in a 35-day washout between investigational product (IP) administration in Periods 1 and 2. RESULTS: A total of 50 subjects were randomized: 24 subjects in Sequence I and 26 in Sequence II, and 6 subjects discontinued from the study. The primary PK endpoints including area under the concentration-time curve from time zero to infinity (AUCinf) and to the last quantifiable concentration (AUClast), and maximum serum concentration (Cmax) were all within the equivalence margin of 80.00-125.00%. Safety and tolerability were comparable between the two treatments. CONCLUSION: PK profiles showed that SB4 AI and PFS were bioequivalent in healthy subjects. Safety assessment was also comparable between the two treatments.

Correction to: Differentiation of endogenous and exogenous γ-Hydroxybutyrate in rat and human urine by GC/C/IRMS.

The above article was published online with incorrect author names. The right spelling should be Dong-Hun Lee instead of Donghun Lee, Sanggil Choe instead of Sanggil Choi. The correct names are presented here. The original article has been corrected.

Differentiation of endogenous and exogenous γ-Hydroxybutyrate in rat and human urine by GC/C/IRMS.

Gamma (γ)-hydroxybutyric acid (GHB) has been reported to be an endogenous compound in the mammalian brain. It used to treat symptoms of alcohol, opioid, and drug withdrawal and cataplexy of narcolepsy. However, it is often used for criminal purposes because it is colorless, tasteless, and has short half-life. For this reason, there is a need for a method of distinguishing between endogenous and exogenous GHB administration. Therefore, urine from rat before administration of GHB and GHB urine after the single intraperitoneal injection of GHB as 30 mg/100 g were collected from Sprague-Dawley rats (7 weeks old, 10 males and females). Negative control urine, urine from individuals suspected of taking GHB, and urine from victims who were GHB-involved crime were collected. In urine samples, GHB was extracted with two-step SPE and collected fraction was derivatized and analyzed by GC/MS and GC/C/IRMS. In GC/MS and GC/C/IRMS analysis of rat urine, there was a statistically significant difference between urine from rat before administration of GHB and GHB rat urine (p < 0.05). In GC/MS analysis of human urine samples, there was no significant difference among human urine groups (negative control, suspects' urine, and victims' urine), but in GC/C/IRMS analysis of human urine samples, there was a statistically significant difference among human urine groups (p = 0.0001). Through these results, GC/C/IRMS can be more effective tool to identify endogenous and exogenous GHB in urine than GC/MS. This study can build a drug management system in forensic investigation agency and offer interpretation method to forensic science and court.

Analysis of hypoxanthine and lactic acid levels in vitreous humor for the estimation of post-mortem interval (PMI) using LC-MS/MS.

Hypoxanthine (Hx) is produced during terminal stages of purine catabolism in humans. The concentrations of Hx and l-lactic acid in vitreous humor highly correlate with post-mortem interval (PMI). In this study, we measured the concentrations of Hx and l-lactic acid in uncontrolled authentic vitreous humor from cadavers, and investigated the correlation between these molecules and PMI. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for the quantitative analysis of Hx and l-lactic acid in vitreous humor. These concentrations were also corrected by four seasons such as spring, summer, autumn, and winter and temperatures on the day of death such as -10 to 5 °C, 6-15 °C, 16-25 °C, and 26-32 °C that may affect the biomarker concentrations. Vitreous humors were collected from cadavers with known time of death at the National Forensic Service (NFS), Republic of Korea. The correlation between the concentrations of Hx and l-lactic acid in vitreous humors and PMI was evaluated using 79 corpses (53 males and 26 females), with sampling time ranging from 13 to 103 h after death. The average daily ambient temperature at the time of death of each sample was investigated to calibrate the correlation with PMI. Following correction of the concentrations of Hx and l-lactic acid with temperature, the correlation of Hx and l-lactic acid with PMI increased from 0.53 to 0.59 for Hx and 0.38 to 0.42 for l-lactic acid. The highest correlation of Hx and l-lactic acid concentrations with PMI was observed in the winter season, with an R2 value of 0.80 and 0.71 for Hx and l-lactic acid, respectively. The correlation of Hx and l-lactic acid with PMI was corrected by ambient temperature for each season, resulting in an increase in the R2 value to 0.88 for Hx and 0.72 for l-lactic acid. The best correlation was observed when the temperature was corrected after dividing by season.

Urine Multi-drug Screening with GC-MS or LC-MS-MS Using SALLE-hybrid PPT/SPE.

To intoxicated patients in the emergency room, toxicological analysis can be considerably helpful for identifying the involved toxicants. In order to develop a urine multi-drug screening (UmDS) method, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to determine targeted and unknown toxicants in urine. A GC-MS method in scan mode was validated for selectivity, limit of detection (LOD) and recovery. An LC-MS-MS multiple reaction monitoring (MRM) method was validated for lower LOD, recovery and matrix effect. The results of the screening analysis were compared with patient medical records to check the reliability of the screen. Urine samples collected from an emergency room were extracted through a combination of salting-out assisted liquid-liquid extraction (SALLE) and hybrid protein precipitation/solid phase extraction (hybrid PPT/SPE) plates and examined by GC-MS and LC-MS-MS. GC-MS analysis was performed as unknown drug screen and LC-MS-MS analysis was conducted as targeted drug screen. After analysis by GC-MS, a library search was conducted using an in-house library established with the automated mass spectral deconvolution and identification system (AMDISTM). LC-MS-MS used Cliquid®2.0 software for data processing and acquisition in MRM mode. An UmDS method by GC-MS and LC-MS-MS was developed by using a SALLE-hybrid PPT/SPE and in-house library. The results of UmDS by GC-MS and LC-MS-MS showed that toxicants could be identified from 185 emergency room patient samples containing unknown toxicants. Zolpidem, acetaminophen and citalopram were the most frequently encountered drugs in emergency room patients. The UmDS analysis developed in this study can be used effectively to detect toxic substances in a short time. Hence, it could be utilized in clinical and forensic toxicology practices.

Synthesis of two distinct pyrrole moiety-containing arenes from nitroanilines using Paal-Knorr followed by an indium-mediated reaction.

Synthesis of arenes substituted with two differently substituted-pyrrole moieties was investigated. A Paal-Knorr condensation reaction of nitroanilines with 1,4-diketone to nitrophenyl-1H-pyrroles followed by an indium-mediated reduction-triggered coupling reaction with another kind of 1,4-diketone resulted in two distinct pyrrole-containing arenes, variously substituted 1-((1H-pyrrol-1-yl)phenyl)-1H-pyrroles, in reasonable yield.