International journal of clinical pharmacology and therapeutics最新文献

Objective: High plasma levels of mono-N-desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations.

Materials and methods: A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ² automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥ 0.6 μg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis.

Results: The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008 - 1.021, p < 0.001) and 0.91 (95% confidence interval: 0.834 - 0.988, p = 0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥ 0.6 μg/mL was relatively high, combined with a daily dose of amiodarone > 100 mg and body mass index ≤ 22.3 kg/m² at 69.0% (20/29), and its trend was also detected in the sensitivity analysis.

Conclusion: Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤ 22.3 kg/m² warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease usually treated by azathioprine. It is a well-established risk factor for colorectal cancers and extraintestinal malignancies. Nevertheless, the risk of myeloid leukemia in patients with UC is less known. We report a case of a 51-year-old patient, with a history of extensive ulcerative colitis, who was treated with azathioprine at a dose of 2.5 mg/kg/day. Seven years later, he presented an increased count of white blood cells at 25,400/μL and of platelets at 1,382,000/μL. Peripheral blood smear showed 1% blasts and 20% myelemia. The karyotype showed the Philadelphia chromosome and the RT-PCR revealed the BCR-ABL transcript. Thus, chronic myeloid leukemia (CML) was confirmed and imatinib was prescribed. This case reported a rare and serious event in a UC patient and illustrates the importance of closely monitoring this population.

Background: Treatment of arthritis is carried out using corticosteroids, methotrexate, sulfasalazine-like agents, and TNF-α-blocking agents such as infliximab and adalimumab. The disadvantages of these agents are high-cost, severe side effects including leucopenia, and in some cases the necessity of administration by injection. Polyvalent immunoglobulin formulations derived from bovine colostrum and marketed as a standardized formulation for oral application, are reported to be efficacious in chronic pain syndromes but are rarely, if ever, used as an alternative medication in such patients.

Aims: To treat arthritis in a real-world setting using polyvalent immunoglobulins in 2 patients, in one case where no alternative treatment modality was available and in another patient in whom the use of polyvalent immunoglobulins appeared to be a suitable option.

Materials and methods: Two male subjects aged 46 and 82 years with confirmed diagnosis but not well-controlled arthritis/polyarthritis receiving either high-dose NSAIDS, corticosteroids, methotrexate injections, with previous use of, or recommendations for treatment with monoclonal antibodies (etanercept and adalimumab) were treated with oral polyvalent immunoglobulins (KMP01; dose range 10 - 20 g daily) in real-world settings, in one case during a field excursion in Peru.

Results: The treatment produced a rapid alleviation of pain in both patients, in one patient where the symptoms were severe and debilitating. In the second patient methotrexate SC injections could be discontinued, and there was a progressive reversal of leucopenia (leucocyte count 3.9 × 10³/µL) over a period of ~ 3 months.

Discussion: Polyvalent immunoglobulins have been shown previously to reduce the expression of interleukin-6 and C-reactive protein in peripheral blood monocytes, events attributed to the neutralization of gut-derived endotoxin ligands lipopolysaccharides (LPS) driving the basal immune response. The mode of action of KMP01 on cytokine expression is therefore similar to the TNF-α-blocking agents etanercept and adalimumab.

Conclusion: Findings from two case reports support the rationale for using polyvalent immunoglobulins as an effective and safe alternative in arthritis patients receiving standard treatments, in particular, methotrexate and TNF-α-blocking agents.

Objective: We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment.

Materials and methods: 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20 mg/d), ezetimibe (10 mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters.

Results: ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p < 0.0001), simvastatin (p < 0.0001), and combination treatment (p < 0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p = 0.0106) and combination treatment (p = 0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers.

Conclusion: Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

The direct-acting oral anticoagulant dabigatran etexilate (DE) targets thrombin and is used widely to prevent thromboembolism. A 79-year-old man was admitted to the Emergency Department due to anuria for 2 days. An urgent laboratory examination revealed a serum creatinine concentration of 888 µmol/L. He was diagnosed with acute exacerbation of chronic renal insufficiency. During continuous renal replacement therapy (CRRT), the coagulation test showed a severe reduction in the fibrinogen level as well as a significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). The patient had been taking DE (110 mg twice daily) for a long time and had not suspended the medication or reduced the dose during the worsening of anuria. Therefore, it should be evaluated before considering plasma replacement therapy for the patient, whether the abnormal coagulation parameters were induced by interference of excessive DE. Tentatively, we used activated charcoal to treat the plasma and then retested the fibrinogen, PT, and APTT. Results showed that the coagulation indices nearly returned to normal. The present case indicated that activated charcoal could adsorb DE in plasma effectively and eliminate its interference with coagulation test results, thereby providing support for clinical diagnosis and treatment.

Objectives: Although the clinical role of protein convertase subtilisin kexin type 9 (PCSK9) inhibitors for cholesterol management is increasing, the post-marketing period of use is short compared to other lipid-lowering drugs, so there is still insufficient evidence for their efficacy and safety. In this meta-analysis, we evaluated preventive effects of stroke and cardiovascular (CV) events using evolocumab and alirocumab.

Materials and methods: We assessed the relative risk of stroke and CV events after alirocumab or evolocumab treatment in individuals with or without clinical CV diseases compared with that in controls. In addition, we evaluated the relative risk of hemorrhagic stroke.

Results: A total of 25 articles were included (median of study duration = 52 weeks). The risk of stroke was significantly decreased after treatment with alirocumab or evolocumab (primary prevention in patients without CV diseases: RR = 0.733; 95% CI, 0.618 - 0.870; secondary prevention in patients with CV diseases: RR = 0.703; 95% CI, 0.562 - 0.880). The risk of CV events also significantly decreased in patients treated with alirocumab or evolocumab (primary prevention: RR = 0.818; 95% CI, 0.777 - 0.861; secondary prevention: RR = 0.725; 95% CI, 0.578 - 0.910). The relative risk of hemorrhagic stroke was not significantly different between PCSK9 inhibitor-treated patients and controls (RR = 1.041; 95% CI, 0.690 - 1.573).

Conclusion: Our findings indicate that evolocumab and alirocumab are significantly effective without increasing the risk of hemorrhagic stroke. Based on this, the PCSK9 inhibitors can be highly recommended for cholesterol management.

Introduction: Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression.

Case presentation: We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression.

Conclusion: Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.

Background: COVID-19 induces a pro-coagulant state with thrombotic events. This meta-analysis explores the efficacy and safety of antiplatelet-based therapy in COVID-19 patients through randomized controlled trials (RCTs).

Materials and methods: A systematic literature search until March 10, 2023, identified 7 RCTs involving 23,415 inpatients. Of these, 11,891 received antiplatelet-based treatment, and 11,524 received placebo/other drugs. Statistical analysis was performed using Review Manager 5.4.

Results: The included trials involved patients with a mean age ranging from 54.3 to 62.0 years and a prevalence of hypertension ranging from 10.9 to 65.0% and coronary artery disease ranging from 3.2 to 32.7%. The pooled analysis showed no significant difference in overall mortality between groups (RR 1.0, 95% CI 0.99 - 1.01, p = 0.76). However, antiplatelet therapy significantly reduced major thrombotic events (RR 0.86, 95% CI 0.75 - 0.99, p = 0.04). Conversely, it increased major bleeding risks (RR 1.62, 95% CI 1.24 - 2.12, p = 0.0005). There was no significant difference in the incidence of invasive mechanical ventilation and respiratory death.

Conclusion: Antiplatelet therapy does not confer mortality benefit in COVID-19 patients but lowers major thrombotic events while increasing major bleeding risks. Ongoing large RCTs will provide more information on the therapeutic value of this therapy.

Objective: Azvudine is an effective treatment for patients infected with common COVID-19. However, physicians have reported a series of adverse reactions, including multiple cases of liver injury, caused by azvudine in clinical practice. This study assessed the incidence, clinical features, and associated risk factors of liver injury induced by azvudine in real-world settings, offering guidance for safe clinical use.

Materials and methods: This study utilized the Chinese Hospital Pharmacovigilance System (CHPS) to retrospectively analyze the treatment of COVID-19 patients with azvudine at Changsha Central Hospital from December 19, 2022, to June 6, 2023. A case-control study was conducted to analyze the occurrence of azvudine-induced liver injury in COVID-19 patients who triggered a CHPS alert compared to normal COVID-19 patients.

Results: Among the total of 2,141 COVID-19 patients, 31 (1.45%) developed azvudine-induced liver injury, which is classified as an occasional adverse reaction. Liver injury was observed in 93.55% of patients between days 4 and 12 of the azvudine treatment, with elevated transaminases as the primary clinical manifestation. Univariate and binary logistic regression analyses indicated that low albumin levels and co-administration of low-molecular-weight heparin were statistically significant risk factors (p < 0.05).

Conclusion: This study represents the first investigation of azvudine-induced liver injury and high-risk patients using the CHPS. The findings provide valuable insights to promote the safety of anti-COVID-19 drugs, serving as an important reference for future drug safety measures.

Objective: Area under the curve (AUC)-based vancomycin dose adjustment is recommended to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. AUC estimation methods include Bayesian software programs and simple analytical equations. This study compared the AUC obtained using the Bayesian approach with that obtained using an equation-based approach.

Materials and methods: Patients receiving intravenous vancomycin for MRSA infection were included. Peak and trough levels were measured for each patient on days 3, 7, and 10 post vancomycin dosing (day 1). AUC was calculated using software based on the Bayesian method (MwPharm Online) and an equation-based calculator, Stanford Health Care (SHC) calculator.

Results: The AUC estimated using MwPharm Online was similar to that estimated using the SHC calculator. The geometric mean ratio (GMR) and their 90% confidence intervals (90% CI) were 1.08 (1.05 - 1.11), 1.03 (0.99 - 1.07), and 0.99 (0.94 - 1.05) at days 3, 7, and 10, respectively. Furthermore, according to the software used, there were no significant differences in the proportions of patients in the categories "within" and "below or above" the AUC target range. Additionally, trough levels predicted by both software programs were lower than the observed ones. Still, there was no significant difference between the predicted and observed peak levels for both software programs on day 10.

Conclusion: AUC calculated using the Bayesian software allows for calculation with samples at a non-steady state, can integrate covariates, and is interconvertible with that estimated using an equation-based calculator, which is simpler and relies on fewer assumptions. Therefore, either method can be used, considering each method's strengths and limitations.