Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022).

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

OBJECTIVES: To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. METHODS: Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. RESULTS: A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. CONCLUSIONS: A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

Bladder paraganglioma, gastrointestinal stromal tumor, and SDHB germline mutation in a patient with Carney-Stratakis syndrome: A case report and literature review.

Background: Carney-Stratakis syndrome (CSS) is a rare dyad of paraganglioma (PGL)/pheochromocytoma (PHEO) and gastrointestinal stromal tumor (GIST). PGLs are neuroendocrine tumors of neural crest origin which are mostly found in the head, neck, and retroperitoneal space. GISTs are the most common mesenchymal tumors of the digestive tract, usually caused by KIT/PDGFRA mutations. Here, we reported a case of CSS with unusual bladder PGL and succinate dehydrogenase (SDH) deficient GIST due to a germline mutation in SDH-subunit B (SDHB) gene. Case presentation: A 39-year-old female patient initially diagnosed with gastric GIST and isolated pelvic metastasis was eventually found to be CSS with bladder PGL and SDH-deficient GIST after surgery. This patient underwent resection of gastric and bladder tumors, and postoperative pathology confirmed the diagnosis of CSS. According to the next-generation sequencing (NGS), the patient carried a germline mutation in the SDHB gene, which was the cause of the disorder. The patient had no tumor recurrence with regular follow-up in 10 months. Conclusions: CSS is an autosomal genetic disorder with no gender difference in incidence, and PGLs are more frequent than GISTs. SDH germline mutation is the molecular biological mechanism of CSS while the most common type is SDHB mutation. The unique mechanism of tumorigenesis including hypoxia and hypermethylation caused by SDH deficiency renders target therapy with tyrosine kinase inhibitors ineffective, therefore complete surgical resection is the optimal treatment in the absence of tumor metastases.

Combination of Type I and II tyrosine kinase inhibitors-avapritinib and sunitinib-in refractory gastrointestinal stromal tumor after failure to multi-line therapy: a case report.

Background: Tyrosine kinase inhibitors (TKIs) are currently the main treatment choice for gastrointestinal stromal tumors (GISTs). However, the long-term use of TKIs can lead to drug resistance. There is no study or clinical report of combination therapies of TKIs that have been approved for marketing. Combination pharmacotherapy is a new approach for patients who do not respond to monotherapy. This case provides a reference value for selective combination of TKIs in treating advanced GIST. Case Description: In this article, we report the case of a 55-year-old female who was diagnosed with duodenal GIST in April 2018 and underwent R0 resection. KIT exon 9 mutation was detected. The patient had disease recurrence with multiple abdominal metastases during imatinib adjuvant therapy after 27 months, and failure to 2nd-line sunitinib treatment after 6 months. She underwent a cytoreductive surgery (R1), and the postoperative mutation analysis suggested KIT exon 9 mutation, with newly found secondary KIT_exon16_p. L783V mutation and other mutations on TP53, POT1, and SETD2, etc. The patient experienced short-term tumor control of standard 3rd-line therapy of regorafenib and the rapid progression of the 4th-line of ripretinib afterwards. Different TKI combination therapies (i.e., ripretinib plus sunitinib, ripretinib plus avapritinib and avapritinib plus sunitinib) were administered to the patient sequentially. Ripretinib plus sunitinib led to stable disease but was discontinued due to intolerable adverse effects. Finally, the patient received a combination regimen of avapritinib plus sunitinib. The patient's tumor showed continuous shrinking in 2 consecutive computed tomography scan evaluations within 4 months with acceptable side effects. Conclusions: Combined type I and type II TKIs of avapritinib combined with sunitinib therapy achieved tumor regression for a heavily multi-line treated patient. Our case provides a reference for a savage treatment choice in refractory GISTs after failure to all standard treatment.

[18F]FAPI-42 PET/CT versus [18F]FDG PET/CT for imaging of recurrent or metastatic gastrointestinal stromal tumors.

PURPOSE: PET has been important for monitoring recurrence and metastasis of Gastrointestinal Stromal Tumors (GISTs) and the selection of therapeutic strategies. A significant portion of GISTs lesions show negative FDG uptake and therefore calls for more tumor-specific imaging biomarkers. This study compared the imaging performance of [18F]FAPI-42 PET/CT and [18F]FDG PET/CT in recurrent or metastatic gastrointestinal stromal tumors (R/M GISTs). METHODS: This study retrospectively included 35 patients with R/M GISTs who underwent both FAPI PET/CT and FDG PET/CT. The definite diagnosis was confirmed by pathology or follow-up drug treatment effects. The differences in detection rates and tumor-to-background SUVmax ratio (SUVTBR) of different locations between dual-tracer PET/CT were compared. Factors including tumor size, degree of enhancement, type of gene mutation, and targeted treatment potentially influencing the uptake of both tracers were assessed. The excised lesions (n = 3) underwent immunohistochemical staining to verify FAP expression in the tissue. RESULTS: A total of 106 lesions in 35 patients were identified, out of which 38/106 (35.8%) lesions (FAPI + /FDG -) were additionally detected by FAPI PET/CT as compared to that by FDG, including 26 liver metastases, ten peritoneal metastases, one gastrointestinal recurrence, and one bone metastasis. The positive detection rate of FAPI PET/CT for recurrent or metastatic GISTs was higher than that of FDG (80.2% vs. 53.8%, P< 0.001), especially in liver metastases (87.5% vs. 33.3%, P< 0.001). Moreover, the SUVTBR of liver metastases of GISTs in FAPI PET/CT was higher than that in FDG [2.4 (0.3 to 11.2) vs. 0.9 (0.3 to 6.5), P< 0.001]. The longest diameter of tumors in the FDG-positive group was higher than that of the FDG-negative group (P= 0.005); still, it did not differ between the FAPI-positive group and the FAPI-negative group. No difference in the degree of enhancement was observed between both tracers' positive and negative groups. Besides, the SUVTBR of FDG but not FAPI differed significantly among various gene mutations (P< 0.001) as well as the targeted therapy and no targeted therapy groups (P= 0.001). FAP was expressed in R/M GISTs, and the uptake of FAPI corresponded to the level of FAP expression. CONCLUSION: In conclusion, FAPI for imaging of R/M GISTs could be superior to FDG, specifically for liver metastases. The uptake of FAPI could reflect the level of FAP expression, and it was independent of tumor size, degree of enhancement, type of gene mutation, and targeted therapy as compared to FDG.

Genotyping guided ripretinib directly after the progression of first-line imatinib therapy in advanced gastrointestinal stromal tumor: a case report.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery and tyrosine kinase inhibitor (TKI) therapy are the main choices of treatment. However, the long-term use of TKIs is prone to drug resistance. Herein, we report the case of a 47-year-old female with primary gastric GIST with liver metastases since June 2015. The patient achieved disease control under imatinib therapy and underwent primary lesion resection. She took postoperative imatinib maintenance therapy, but discontinued imatinib for 10 months about 2 years after surgery. The patient suffered from disease progression in May 2019, with recurrence of liver metastases and new abdominal metastases. From then on, imatinib was resumed and partial response (PR) persisted for another 2 years. The patient subsequently experienced tumor progression due to secondary KIT exon 17 mutation confirmed by tissue biopsy and circulating tumor DNA (ctDNA) detection. After multidisciplinary team discussion, the patient received ripretinib as a second-line therapy, and ctDNA monitoring demonstrated that the KIT mutations turned negative. After disease control from ripretinib for 2+ months, she underwent cytoreductive surgery (R0/1) and received ripretinib maintenance treatment postoperatively. We believe that this case provides a reference value for individualized ripretinib precise therapy according to mutational analysis after the progression of first-line GIST treatment, and ctDNA can predict effectiveness to guide treatment.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

STUDY OBJECTIVES: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Voriconazole pharmacokinetics in a critically ill patient during extracorporeal membrane oxygenation.

The pharmacokinetics (PK) of several drugs including antimicrobials might be highly altered during extracorporeal membrane oxygenation (ECMO) therapy. We present the change of voriconazole (VRC) PK during ECMO in a critically ill patient who received intravenous VRC at a maintenance dose of 200 mg every 12 h for empirical antifungal therapy. Two PK profiles were drawn before and after the initiation of ECMO therapy. Though the trough levels (both C0 and C12) with ECMO were slightly lower than that without ECMO (12.58 and 12.84 vs. 14.02 µg/mL), the peak levels and the area under the concentration-time curve from 0 h to 6 h (AUC0-6) were comparable (16.36 vs. 16.06 µg/mL and 90.78 vs. 91.45 µg·h/mL, respectively), indicating that VRC plasma exposure during ECMO therapy did not greatly decrease in our patient. The circuit factors including the type of membrane should be taken into account to further identify the effects of ECMO on the PK of VRC.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy.

Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review: flucloxacillin, piperacillin/tazobactam, ceftriaxone, ceftazidime/avibactam, cefepime, ceftolozane/tazobactam, sulbactam, meropenem, imipenem, panipenem, biapenem, ertapenem, doripenem, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, azithromycin, tigecycline, polymyxin B, colistin, vancomycin, teicoplanin, linezolid, daptomycin, sulfamethoxazole/trimethoprim, fluconazole, voriconazole, posaconzole, caspofungin, micafungin, amphotericin B, acyclovir, ganciclovir, oseltamivir, and peramivir.

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors.

BACKGROUND: Imatinib is the standard treatment for patients with gastrointestinal stromal tumors (GISTs), but there is significant variation in imatinib plasma trough concentrations (Cmin ) among patients. The imatinib Cmin distribution at different doses and the correlation of adverse reactions with Cmin in Chinese patients with GIST from a high-volume center were evaluated. METHODS: From July 1, 2017 to December 31, 2018, patients who were receiving imatinib treatment for GIST were prospectively enrolled. Steady-state blood samples were obtained from patients who had received same-dose imatinib treatment for ≥1 month with good compliance. Adverse reactions were recorded during regular follow-up, and blood samples were collected 24 ± 2 hours after dosing. Liquid chromatography-tandem mass spectrometry was used to measure drug concentrations. RESULTS: In total, 307 patients who received 367 dose levels were investigated. The imatinib Cmin was 1315 ± 716 ng/mL, 2117 ± 597 ng/mL, and 3844 ± 987 ng/mL in patients who were receiving imatinib 400 mg, 600 mg, and 800 mg daily, respectively. The Cmin was significantly correlated with periorbital and limb edema (P < .001), anemia (P < .001), and rash (P = .037). Nausea and vomiting, diarrhea, and conjunctival hemorrhage also were correlated, but not significantly. A much higher Cmin was observed with severe adverse reactions. There was no correlation between the imatinib Cmin and leukopenia, muscle cramps, or hepatobiliary dysfunction. CONCLUSIONS: In Chinese patients with GIST, the imatinib Cmin was higher than that reported for Western populations, especially at higher doses. The Cmin was correlated with periorbital and limb edema, anemia, and rash, suggesting that monitoring the imatinib Cmin should be considered when patients develop severe adverse reactions caused by excessive imatinib plasma concentrations.

Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit.

OBJECTIVES: To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. METHODS: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. RESULTS: There were good correlations between the area under the curve (AUC0-12) of PK curve 2 and the corresponding trough concentration (C0) and peak concentration (Cmax) (r2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t1/2) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (Vss) of PK curve 1 was positively correlated with actual body weight (r2 = 0.450, p = 0.004). The median first C0 of 17 patients determined on day 5 was 5.27 (2.61) µg/ml, and 29.4% of C0 exceeded the upper limit of the therapeutic window (2-6 µg/ml). CONCLUSIONS: The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t1/2, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.

Effect of phorbol 12-myristate 13-acetate on function and gene expression of P-glycoprotein in adriamycin-resistant K562/ADM cells.

BACKGROUND/AIMS: Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Phorbol 12-myristate 13-acetate (PMA), a diester of phorbol, is a typical activator of protein kinase C (PKC). In the present study, we investigated the effect of PMA on MDR and P-glycoprotein (P-gp) gene expression in K562/ADM cells. METHODS: 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay was used to assess adriamycin (Adr)-induced cytotoxicity towards K562/ADM cells in the absence or presence of PMA. The intracellular accumulation of Adr was measured by determining the mean fluorescence intensity. The effect of PMA on P-gp activity was investigated by rhodamine-123 accumulation and efflux experiment. Protein expression and mRNA expression of P-gp in K562/ADM cells were determined by Western blot analysis and real-time qPCR, respectively. RESULTS: Adr-induced cytotoxicity towards K562/ADM cells was significantly decreased by PMA at 5 µmol/l. Furthermore, intracellular Adr-associated mean fluorescence intensity was attenuated by 53.8% 1 h after exposure to PMA at 5 µmol/l compared with the control group (p < 0.05). A dose-dependent decrease of intracellular rhodamine-123 and increase of efflux activity of P-gp were also observed in K562/ADM cells incubation with PMA. In addition, P-gp mRNA and protein expression were significantly induced by PMA. CONCLUSION: Activation of PKC pathway by PMA can significantly induce expression and activity of P-gp, and thus decrease intracellular Adr level and strengthen MDR in K562/ADM cells.

Wedelolactone exhibits anti-fibrotic effects on human hepatic stellate cell line LX-2.

Wedelolactone is a major coumarin of Eclipta prostrata, which is used for preventing liver damage. However the effects of wedelolactone on hepatic fibrosis remained unexplored. The purpose of this study was to demonstrate the anti-fibrotic effects of wedelolactone on activated human hepatic stellate cell (HSC) line LX-2 and the possible underlying mechanisms by means of MTT assay, Hoechst staining, as well as real-time quantitative PCR and western blot. The results showed that wedelolactone reduced the cellular viability of LX-2 in a time and dose-dependent manner. After treatment of wedelolactone, the expressions of collagen I and α-smooth muscle actin, two biomarkers of LX-2 activation, were remarkably decreased. The apoptosis of LX-2 cells was induced by wedelolactone accompanied with the decreasing expression of anti-apoptotic Bcl-2 and increasing expression of pro-apoptotic Bax. In addition, phosphorylated status of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was up-regulated, but not in p38. Moreover, wedelolactone significantly repressed the level of phosphorylated inhibitor of nuclear factor κB (IκB) and p65 in nucleus in spite of tumor necrosis factor-α stimulation. In conclusion, wedelolactone could significantly inhibit the activation of LX-2 cells, the underlying mechanisms of which included inducing Bcl-2 family involved apoptosis, up-regulating phosphorylated status of ERK and JNK expressions, and inhibiting nuclear factor-κB (NF-κB) mediated activity. Wedelolactone might present as a useful tool for the prevention and treatment of hepatic fibrosis.