Clinical Pharmacology : Advances and Applications最新文献

Purpose: Patients admitted with neurocritical illness are presumed to be at high risk for venous thromboembolism (VTE). The administration of chemical and/or mechanical VTE prophylaxis is a common practice in critically ill patients. Recent data did not show a significant difference in the incidence of VTE between chemical compared to a combined chemical and mechanical VTE prophylaxis in critically ill patients with limited data in neurocritically ill population. The objective of this study is to investigate the incidence of VTE between chemical alone compared to chemical and mechanical VTE prophylaxis in neurocritically ill patients.

Patients and methods: This was a retrospective cohort study at a tertiary teaching hospital. Data were obtained from electronic medical records for all patients admitted with neurocritical illness from January 1, 2016, to December 31, 2020. Patients were excluded if they did not receive VTE prophylaxis during admission or were younger than 18 YO. Major outcomes were symptomatic VTE based on clinical and radiological findings, intensive care unit (ICU) length of stay (LOS), and hospital LOS. Minor outcomes included severe or life-threatening bleeding based on GUSTO criteria, and mortality at 28-days.

Results: Two hundred and twelve patients were included in this study. Patients did not have any significant differences in their baseline characteristics. The incidence of VTE was similar in the chemical only group compared to the combined VTE prophylaxis group (19/166 (11.3%) vs 7/46 (15.2%)); P = 0.49. No difference between groups in their ICU LOS 6 [3-16.2] vs 6.5 [3-19]; P = 0.52, nor their mortality (18/166 (10.7%) vs 3/46 (6.5%)); P = 0.38, respectively. Less bleeding events were seen in the chemical prophylaxis group compared to the combined VTE prophylaxis group (19/166 (11.3%) vs 12/46 (26.1%); P = 0.01).

Conclusion: Our findings observed no difference between the administration of chemical VTE prophylaxis alone compared to the combined VTE prophylaxis strategy. More data are needed to confirm this finding with more robust methodology.

Background: In addition to the maximum plasma concentration (C_max) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC_24h) to MIC has recently been suggested as pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy and safety in once-daily dosing of gentamicin (ODDG) in critically ill patients.

Purpose: This study aimed to predict the optimal effective dose and risk of nephrotoxicity for gentamicin in critically ill patients for two different PK/PD targets within the first 3 days of infection.

Methods: The gathered pharmacokinetic and demographic data in critically ill patients from 21 previously published studies were used to build a one-compartment pharmacokinetic model. The Monte Carlo Simulation (MCS) method was conducted with the use of gentamicin once-daily dosing ranging from 5-10 mg/kg. The percentage target attainment (PTA) for efficacy, C_max/MIC ~8-10 and AUC_24h/MIC ≥110 targets, were studied. The AUC_24h >700 mg⋅h/L and C_min >2 mg/L were used to predict the risk of nephrotoxicity.

Results: Gentamicin 7 mg/kg/day could achieve both efficacy targets for more than 90% when the MIC was <0.5 mg/L. When the MIC increased to 1 mg/L, gentamicin 8 mg/kg/day could reach the PK/PD and safety targets. However, for pathogens with MIC ≥2 mg/L, no studied gentamicin doses were sufficient to reach the efficacy target. The risk of nephrotoxicity using AUC_24h >700 mg⋅h/L was small, but the risk was greater when applying a C_min target >2 mg/L.

Conclusion: Considering both targets of Cmax/MIC ~8-10 and AUC_24h/MIC ≥110, an initial gentamicin dose of 8 mg/kg/day should be recommended in critically ill patients for pathogens with MIC of ≤1 mg/L. Clinical validation of our results is essential.

Purpose: In people with type 2 diabetes mellitus (T2DM), both glucose metabolism abnormalities and atherosclerosis risk are significant concerns. This study aims to investigate the effects of the sodium-glucose cotransporter 2 inhibitor tofogliflozin (TOFO) and the dipeptidyl peptidase-4 inhibitor anagliptin (ANA) on markers of glucose metabolism and atherosclerosis when administered individually or in combination.

Methods: Fifty T2DM patients were divided into two groups (receiving either TOFO or ANA monotherapy) and observed for 12 weeks (observation points: 0 and 12 weeks). The TOFO and ANA groups were then further treated with ANA and TOFO, respectively, and the patients were observed for an additional 36 weeks (observation points: 24 and 48 weeks). Therapeutic effects and various biomarkers were compared between the two groups at the observation points.

Results: Combination therapy led to significant improvements in HbA1c levels and atherosclerosis markers. Additionally, the TOFO pretreatment group exhibited significant reductions in sLOX-1 and IL-6 levels.

Conclusion: The increase in sLOX-1 and IL-6 levels, which indicates the response of scavenger receptors to oxidized low-density lipoproteins in people with T2DM, is mitigated following TOFO and ANA combination therapy. TOFO alone or in combination with ANA may be beneficial for preventing atherosclerosis development in people with T2DM, in addition to its effect on improving HbA1c levels.

Cefepime is a fourth-generation cephalosporin utilized in treatment of multiple Gram-negative and -positive infections. The current report presents a case of 50-year-old man admitted with epidural abscess who developed neutropenia after prolonged use of cefepime. The neutropenia developed after 24 days of cefepime treatment and resolved 4 days after cessation of cefepime. Assessment of the patient's profile indicated no other possible cause for neutropenia. A literature review was done, and is presented herein to compare and identify the pattern of cefepime-induced neutropenia in 15 patients. The data presented in this article highlight that despite its rarity, cefepime-induced neutropenia should be considered by clinicians when planning a prolonged course of cefepime.

Introduction: Iberdomide, a novel cereblon modulator (CELMoD^®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.

Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12.

Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful.

Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.

[This corrects the article DOI: 10.2147/CPAA.S307464.].

Messenger ribonucleic acid (mRNA) was found as the intermediary that transfers genetic information from DNA to ribosomes for protein synthesis in 1961. The emergency use authorization of the two covid-19 mRNA vaccines, BNT162b2 and mRNA-1273, is a significant achievement in the history of vaccine development. Because they are generated in a cell-free environment using the in vitro transcription (IVT) process, mRNA vaccines are risk-free. Moreover, chemical modifications to the mRNA molecule, such as cap structures and changed nucleosides, have proved critical in overcoming immunogenicity concerns, achieving sustained stability, and achieving effective, accurate protein production in vivo. Several vaccine delivery strategies (including protamine, lipid nanoparticles (LNPs), polymers, nanoemulsions, and cell-based administration) were also optimized to load and transport RNA into the cytosol. LNPs, which are composed of a cationic or a pH-dependent ionizable lipid layer, a polyethylene glycol (PEG) component, phospholipids, and cholesterol, are the most advanced systems for delivering mRNA vaccines. Moreover, modifications of the four components that make up the LNPs showed to increase vaccine effectiveness and reduce side effects. Furthermore, the introduction of biodegradable lipids improved LNP biocompatibility. Furthermore, mRNA-based therapies are expected to be effective treatments for a variety of refractory conditions, including infectious diseases, metabolic genetic diseases, cancer, cardiovascular and cerebrovascular diseases. Therefore, the present review aims to provide the scientific community with up-to-date information on mRNA vaccines and their delivery systems.

Hypotension during kidney transplantation can be common. Vasopressor use during these procedures is often avoided, with a fear of decreasing renal perfusion in the transplanted kidney. However, adequate perfusion for the rest of the body is also necessary, and given that these patients often have underlying hypertension or other comorbid conditions, an appropriate mean arterial pressure (MAP) has to be maintained. Intramuscular injections of ephedrine have been studied in the anesthesiology literature in a variety of case types, and it is seen as a safe and effective method to boost MAP. We present a case series of three patients who underwent renal transplantation and who received an intramuscular injection of ephedrine for hypotension control. The medication worked well for increasing blood pressures without apparent side effects. All three patients were followed for more than one year, and all patients had good graft function at the end of that time period. This series shows that while further research is necessary in this arena, intramuscular ephedrine may have a place in the management of persistent hypotension in the operating room during kidney transplantation.

Background: Traditionally, the root of Acacia seyal is used for the treatment of diarrhea. However, its efficacy has not been scientifically evaluated. Thus, this study aimed to validate the antidiarrheal activities using hydromethanolic crude extract and solvent fractions of Acacia seyal roots in mice.

Methods: In each model, mice were divided into five groups of six mice at random. Group I mice (negative controls) were given 1mL/100 g distilled water for hydromethanolic crude extract tests as well as n-hexane, ethyl acetate and aqueous fractions, while groups II, III, and IV were given 100 mg/kg, 200 mg/kg, and 400 mg/kg of hydromethanolic crude extract or solvent fractions. Group V mice (positive control) were given 3 mg/kg Loperamide for the castor oil-induced diarrhea and enteropooling test. All of the doses were taken orally. However, Atropine sulfate, 5 mg/kg, was given intraperitoneally for the gastrointestinal motility test. Statistical Package for the Social Sciences (SPSS) version 26 was used to examine the statistical significance of differences in the number and weight of wet and total feces, distance traveled by a charcoal meal, and intestinal fluid accumulation across groups.

Results: When compared to the vehicle-treated group, the crude extract and n-hexane fraction notably delayed the onset of diarrhea, reduced the weight and volume of intestinal contents, and hindered the intestinal transit at all tested doses (P < 0.001). The ethyl acetate fraction also significantly (P < 0.001) decreased the weight of intestinal content at all doses examined. Only at 400 mg/kg did the aqueous fraction statistically (P < 0.01) prolonged the onset of diarrhea and impeded gastrointestinal motility.

Conclusion: According to this study, the hydromethanolic crude extract and solvent fractions of Acacia seyal roots have promising antidiarrheal effects.

Clostridioides difficile infection (CDI) remains a devastating infection both in hospital settings and in the community. While a number of antibiotics have anti-C. difficile activity, fidaxomicin is unique as a minimally absorbed antibiotic with narrow spectrum of activity. These features make it an appealing option for pediatric CDI to balance safety and efficacy. The purpose of this structured review was to outline the clinical evidence for safety and efficacy of fidaxomicin for pediatric CDI. A structured literature search was performed to identify relevant clinical data. Fidaxomicin is similarly effective to oral vancomycin with a lower rate of recurrent CDI. There were no serious safety signals reported with fidaxomicin. In conclusion, fidaxomicin is a safe and effective treatment option for pediatric CDI.