Quantification of oxaliplatin- and ioversol-related compounds in pharmaceutical formulations using novel HPLC-ICP-MS methods.

PURPOSE: Accurate quantifying of drug-related compounds in medicines is vital for safety. Commonly used structure-dependent methods rely on analytical standards. High-performance liquid chromatography coupled with inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) offers a promising solution, being structure-independent and not requiring standards. In this study, we aim to develop HPLC-ICP-MS methods for the determination of related compounds in oxaliplatin and ioversol injections. RESULTS: The target analytes were eluted on an XSelect HSS T3 column (2.1 ×50 mm, 5 µm). Specifically, oxaliplatin injection was eluted isocracially for 3.5 min, and ioversol injection was eluted gradient with a total chromatographic run time of 12 min. The measurements to determine dihydroxy oxaliplatin-Pt(IV) and two related compounds of ioversol were performed by monitoring at m/z for 195Pt and 127I, respectively. The calibration curves were established over the range of 0.05-1 µM for Pt and 0.3-15 µM for I with the correlation coefficients greater than 0.999. The limits of quantification were 0.004 µM for dihydroxy oxaliplatin-Pt(IV), 0.022 µM for ioversol related compound A and 0.026 µM for ioversol related compound B. The accuracy (recovery between 93-105%) and precision (repeatability ≤ 6.1% RSD) were fit-for-purpose for dihydroxy oxaliplatin-Pt(IV), and the accuracy (recovery between 95-107%) and precision (repeatability ≤ 3.9% RSD) were also fit-for-purpose for both ioversol related compound A and ioversol related compound B. CONCLUSION: The quantitation accuracy of HPLC-ICP-MS closely matched that of the standard HPLC-UV approach. HPLC-ICP-MS can be used as a complementary analytical technique for quantitative determination of drug-related compounds.

Development and validation of a UPLC-PDA method for quantifying ceftazidime in dried blood spots.

Bacterial infection is a leading cause of neonatal death. Ceftazidime, commonly used for neonatal infections, is often used off-label. Blood sampling limits pharmacokinetic (PK) studies in neonatal patients. The dried blood spots (DBS) are a potential matrix for microsampling. Herein, we describe an ultra-performance liquid chromatography with a photodiode array (UPLC-PDA) to determine ceftazidime in DBS from neonatal patients in support of pharmacokinetic studies. The Capitainer® device-based DBS samples containing 10 µL blood were extracted in 70% methanol/water (v/v) with acetaminophen as the internal standard (IS). The extraction process was carried out at 20 °C using a block bath shaker at 1000 rpm for 30 min. The extracted ceftazidime was subsequently eluted through an Acquity UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm). Elution was achieved using a water (containing 0.1% trifluoroacetic acid)/acetonitrile linear gradient at a flow rate of 0.5 mL/min, and the analytical time was 3.2 min. The PDA detection wavelength was set at 259 nm. The method underwent thorough validation following the recommendation of the European Bioanalysis Forum (EBF) and the bioanalytical guideline established by the European Medicines Agency (EMA). No interfering peaks were detected at the retention times of ceftazidime and IS. The ceftazidime exhibited a quantification range spanning from 0.5 to 200 µg/mL, and the assay demonstrated good accuracy (intra/inter-assay ranging from 90.1% to 104.8%) and precision (intra/inter-assay coefficient of variations ranging from 4.8% to 11.7%). The method's applicability was demonstrated by analyzing clinical DBS samples collected from neonatal patients.

Acute gout attacks during the perioperative period and risk factors of recurrence after orthopedic surgery among untreated gout patients.

BACKGROUND: This study aimed to explore the clinical characteristics of perioperative acute gout attacks in patients with varying uric acid levels undergoing orthopedic surgery, identify the risk factors for gout recurrence within the first postoperative year, and provide a disease prevention and diagnostic reference. METHODS: This hospital-based retrospective study was conducted between January 2018 and December 2020. According to the blood uric acid levels at admission, the patients were grouped into either the normal uric acid level group or the hyperuricemia group. Patient comorbidities, serum uric acid levels, inflammatory indicators, follow-up recurrence rates, and other indicators were compared. RESULT: The uric acid decline ratio and the inflammatory indexes (white blood cell count and C-reactive protein level) at the time of the attack were significantly higher in the normal uric acid level group than in the hyperuricemia group (P < 0.05). Patients in the hyperuricemia group with diabetes and tophi and those administered diuretics were more prone to acute gout attacks than those in the normal uric acid level group (P < 0.05). In the normal uric acid level group, 22 patients (84.6%) exhibited single joint involvement, whereas only 18 patients (47.4%) in the hyperuricemia group demonstrated single joint involvement (P < 0.05). After 1 year of follow-up, the gout recurrence rate in the hyperuricemia group was 44.7%, which was significantly higher that the recurrence rate in the normoglycemic group (11.5%; P < 0.05). Presenting tophi in perioperative orthopedic surgery patients was found to be an independent risk factor for gout recurrence within 1 year (RR = 4.80; P = 0.029). CONCLUSION: The recurrence rate of gout in patients with hyperuricemia during perioperative period increased 1 year after operation. Therefore, it is crucial to monitor the uric acid level to prevent acute gout attacks during the perioperative period and recurrence during the 1-year follow-up period. Moreover, the risk of an acute gout recurrence 1 year after operation increased in patients who presented tophi; therefore, it is necessary to maintain appropriate blood uric acid level during perioperative period among patients undergoing orthopedic surgery.

Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model.

Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients. Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1−10 × 107 CFU) of Pseudomonas aeruginosa ATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics of the model drug meropenem in the developed sepsis rat model was then evaluated, and PK modeling and simulation was applied to design meropenem dosing regimens attaining various PD targets (40%fT > MIC, 100%fT > MIC, and 100%fT > 4 × MIC). The microbiological response and survival outcomes for different meropenem treatment regimens were investigated in the rat sepsis model (n = 12 for each group). Results: The optimal inoculum for the rat sepsis model was 1 × 107 CFU of Pseudomonas aeruginosa ATCC9027. A one-compartment model with first-order absorption best described the PK of meropenem in sepsis rats. Pronounced survival prolongation and lower hazard risk were observed in the treatment groups of 50 or 75 mg/kg/q2.4h (100%fT > MIC) and 75 mg/kg/q2h (100%fT > 4 × MIC) compared to the 75 mg/kg/q6h (40%fT > MIC) group, while meropenem groups with PD targets of 100%fT > MIC and 100%fT > 4 × MIC showed comparable survival curves. Microbiological response for different PD targets is inconclusive due to irregular bacterial counts in blood samples. Conclusions: The PD target of 40%fT > MIC is suboptimal for sepsis rats, and the aggressive 100%fT > 4 × MIC target does not provide a survival benefit against the target of 100%fT > MIC.

Study on Characteristics of Triterpenoids and Hepatoprotective Effects of Fruit Body of Stout Camphor Mushroom, Taiwanofungus camphoratus (Agaricomycetes), Cultivated with Apple-Wood.

Taiwanofungus camphoratus is a parasite medicinal fungus with significant hepatoprotective activity that grows in Cinnamomum camphora, a class II protected tree species in Taiwan. Currently, commercial cultivation of T. camphoratus is limited by the resources of C. camphora. To broaden the range of substrates, this study investigated the feasibility of using apple-wood as a substrate for T. camphoratus cultivation and examined the content of fruit body triterpenoids and liver-protective activity as quality indicators. The triterpenoids were determined by ultra-performance liquid chromatography-mass spectrometry and compared with T. camphoratus cultivated in C. camphora. The ICR mouse acute alcoholic liver injury model was used to explore the hepatoprotective effects of the apple-wood cultivated fungus. T. camphoratus grew on apple-wood medium within 7 months; a total of 62 fungal triterpenoid components were detected, including the seven characteristic triterpenoids. Only three were higher in T. camphoratus cultured on C. camphora. The medium-dose fungal extracts (150 mg/kg) produced significant protective effects against acute alcoholic liver injury in mice. These results indicate that apple-wood cultivation is a feasible method compared to C. camphora for commercial cultivation of T. camphoratus.