Xiuhua Zhang

Clearance rate and BP-ANN model in paraquat poisoned patients treated with hemoperfusion.

In order to investigate the effect of hemoperfusion (HP) on the clearance rate of paraquat (PQ) and develop a clearance model, 41 PQ-poisoned patients who acquired acute PQ intoxication received HP treatment. PQ concentrations were determined by high performance liquid chromatography (HPLC). According to initial PQ concentration, study subjects were divided into two groups: Low-PQ group (0.05–1.0 μg/mL) and High-PQ group (1.0–10 μg/mL). After initial HP treatment, PQ concentrations decreased in both groups. However, in the High-PQ group, PQ levels remained in excess of 0.05 μg/mL and increased when the second HP treatment was initiated. Based on the PQ concentrations before and after HP treatment, the mean clearance rate of PQ calculated was 73 ± 15%. We also established a backpropagation artificial neural network (BP-ANN) model, which set PQ concentrations before HP treatment as input data and after HP treatment as output data. When it is used to predict PQ concentration after HP treatment, high prediction accuracy (R = 0.9977) can be obtained in this model. In conclusion, HP is an effective way to clear PQ from the blood, and the PQ concentration after HP treatment can be predicted by BP-ANN model.

Determination of Chlorzoxazone in Rat Plasma by LC-ESI-MS/MS and Its Application to a Pharmacokinetic Study

A sensitive LC-ESI-MS/MS method for determination of chlorzoxazone in rat plasma has been developed. Chromatographic separation was achieved on a Zorbax SB-C18 column, with 45:55 (v/v) acetonitrile–water as the mobile phase. A LC-ESI-MS/MS was performed in a multiple reactions monitoring (MRM) mode using target ions m/z 167.5→131.6 for chlorzoxazone and m/z 230.7→185.6 for phenobarbital (internal standard). The calibration plots were linear over the range of 10.0–2,000 ng/mL. Intra-day and inter-day precisions were better than 5.1% and 6.8%, respectively. The validated method was successfully used to analyze the drug in samples of rat plasma for pharmacokinetic study.

Successful Management of Voriconazole-Associated Hyponatremia with Therapeutic Drug Monitoring

Voriconazole is a broad-spectrum triazole antifungal agent and the first-choice therapy for invasive aspergillosis (IA) (1). Although voriconazole is generally well tolerated, anecdotal case reports have described unexpected severe adverse events related to voriconazole, such as hyponatremia, which potentially could result in death (2–4). We report a case of successful voriconazole treatment of invasive pulmonary aspergillosis (IPA) in a hyponatremia patient. A 72-year-old man with a 10-year history of chronic obstructive pulmonary disease (COPD) was admitted to our respiratory department because of acute exacerbation. Because of his positive aspergillus sputum cultures before admission, he had a higher risk of developing IPA. The patient was treated with intravenous voriconazole (two loading doses of 6 mg/kg of body weight and then 4 mg/kg every 12 h) for 2 weeks and then changed to oral voriconazole tablets at a dose of 200 mg every 12 h. A definite diagnosis of IPA was soon obtained from a computed tomography (CT)guided percutaneous lung biopsy specimen evidencing Aspergillus fumigatus in culture (5). Twenty-six days after commencing voriconazole therapy, the patient showed somnolence and malaise symptoms. Electrolyte levels showed that his sodium level was 104 mmol/liter but that his potassium and creatinine levels were normal. Therapeutic drug monitoring (TDM) was performed, and the voriconazole plasma trough concentration (voriconazole C0) was high (7.10 g/ml). Two days after the discontinuation of voriconazole and infusion of 3% saline, the patient’s mental status and hyponatremia recovered. Our goal voriconazole C0 range was 1.0 to 5.5 g/ml. The voriconazole C0 (0.68 g/ml), obtained 11 days after a half-dose reduction of voriconazole (200 mg/day), was not within the therapeutic range. Since his voriconazole C0 remained subtherapeutic (0.68 g/ml), we increased the dose to 300 mg/day after he was discharged from the hospital. Thirteen days after the treatment, the voriconazole C0 increased to 1.38 g/ml, which mostly achieved the target concentration of 1.0 g/ml. The patient remained asymptomatic, and repeat CT findings showed near resolution of lung lesions upon follow-up in our outpatient department. The CYP2C19 genotype was classified as heterozygous extensive metabolizer (CYP2C19*1/CYP2C19*2). It is well known that CYP2C19 genetic polymorphisms make it particularly difficult to predict exposure to voriconazole and its potential dose-dependent toxicity (6). Indeed, voriconazole C0s of 1.0 g/ml have been associated with improved responses to therapy and survival (7, 8). Increased adverse events have been associated with voriconazole C0s of 5.0 to 6.0 g/ml (9, 10). As a consequence, TDM may be a useful tool to optimize voriconazole therapy. In our case, the voriconazole C0 was 7.10 g/ml, which is considered in the toxic range. Therefore, voriconazole-associated hyponatremia may be concentration dependent. Instead of discontinuing antifungal therapy, it was decided to reduce the voriconazole dose to 200 mg/day, and the voriconazole C0 was subtherapeutic (0.68 g/ml). Finally, TDM revealed an adequate voriconazole C0 (1.38 g/ml) 13 days after dose adjustment to 300 mg/day, suggesting that the dose regimen for this patient was appropriate. So, voriconazole-related hyponatremia suggests that the clinical utility of routine TDM of voriconazole reduces drugrelated adverse events and improves treatment outcome in invasive fungal infections. In conclusion, this case suggests that fatally severe hyponatremia can develop after initiation of voriconazole antifungal therapy. Furthermore, this experience confirms that the appropriateness of voriconazole dose adjustment instead of therapy interruption should be considered according to the voriconazole C0. We believe that TDM is useful to determine the voriconazole dosage in a voriconazole-related hyponatremia patient.

Therapeutic drug monitoring in voriconazole-associated hyponatremia.

Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA). Although voriconazole may be associated with many adverse events, hyponatremia has been rarely reported which potentially could result in death. Therapeutic drug monitoring (TDM) and individualization of therapy by measuring voriconazole plasma concentrations improved the efficacy and safety in patients. We report the effect of TDM to adjust voriconazole dosage in a voriconazole-related hyponatremia patient.

Fisher Discrimination of Metabolic Changes in Rats Treated with Aspirin and Ibuprofen

Background: Aspirin and ibuprofen are the most frequently prescribed non-steroidal anti-inflammatory drugs in the world. However, both are associated with a variety of toxicities. We applied serum metabonomics and Fisher discrimination for the early diagnosis of its toxic reaction in order to help diagnose these toxicities. Methods: A total of 45 rats were randomly divided into Control group, Aspirin group, and Ibuprofen groups. The experiment groups were given intragastric aspirin (15 mg/kg) or ibuprofen (15 mg/kg) for 3 weeks. Liver function tests were performed and blood metabonomics were analyzed by gas chromatography-mass spectrometry. Results: The most important compounds altered were trihydroxybutyric acid and l-alanine in the aspirin group, and acetoacetic acid, l-alanine, and trihydroxybutyric acid in the ibuprofen group. With respect to metabolic profiles, all 3 groups were completely distinct from one another. Fisher discrimination showed that 91.1% of the original grouped cases were correctly classified by the third week. However, only 55.6% of liver function tests were able to classify grouped cases correctly. Conclusion: Trihydroxybutyric acid, l-alanine, and acetoacetic acid were the most significant indicators of altered serum metabolites following intragastric administration of aspirin and ibuprofen in rates. These metabolomic data may be used for classification of aspirin and ibuprofen toxicity.

SIMULTANEOUS DETERMINATION OF TOLBUTAMIDE AND ITS METABOLITE HYDROXYTOLBUTAMIDE IN RAT PLASMA BY LC-MS

A sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method for determination of tolbutamide and its metabolite hydroxytolbutamide in rat plasma was developed and validated. The analytes and internal standard omeprazole were extracted from plasma by liquid-liquid extraction using ethyl acetate, and chromatographically separated on a Zorbax SB-C18 column (2.1 mm × 50 mm, 3.5 µm) using acetonitrile-0.1% formic acid as the mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode, and selected ion monitoring (SIM) mode used to quantify tolbutamide and its metabolite hydroxytolbutamide. The assay was linear over the range 10–20000 ng/mL for tolbutamide and 5–800 ng/mL for hydroxytolbutamide, with a lower limit of quantification (LLOQ) of 10 ng/mL for tolbutamide and 5 ng/mL for hydroxytolbutamide. Intra- and inter-day precision were less than 12% and the accuracy were in the range 88.8–109.7%. This developed method was successfully used for determination of tolbutamide and metabolite hydroxytolbutamide in rat plasma for pharmacokinetic study.