International journal of clinical pharmacology and therapeutics最新文献

Background: Obesity is a complex disease for which pharmacotherapy is often used. Anti-obesity drugs (AODs) are characterized by inducing a variable inter-subject body weight reduction (BWR), the attainment of a plateau after their maximal effect is achieved, and weight regain after drug discontinuation, which complicate individualized treatment of obesity.

Objective: This exploratory analysis aimed to compare the first-month body weight reduction in kg (1mo-BWRkg) and tolerance development (moT) of four known interventions with low (placebo), intermediate (phentermine or mazindol monotherapy), and high (5 active ingredients fixed-dose combination) efficacy, as predictors of their 6-month body weight reduction efficacy in percent (6mo-BWR%). In addition, a detailed analysis of the 6-to-12-month BWR follow-up in subjects under orlistat or diet and exercise regimens was performed.

Materials and methods: The analysis included 662 adult subjects with obesity. After the construction of average efficacy and weight rebound curves, subjects were grouped into various 1mo-BWRkg, moT, and 6mo-BWR% intervals, or 6-month body weight rebound parameters for further evaluation.

Results: The 6mo-BWR% efficacy level of interventions was confirmed, although a general high intersubject variation was observed. 1mo-BWRkg + moT was found as an acceptable predictor of 6mo-BWR%. Between 50 and 80% of the 6-to-12-month follow-up completers maintained at least 5% BWR%.

Conclusion: Short-term AODs are useful adjuvants for the 1-year rational treatment of obesity. 1mo-BWRkg + moT is an acceptable parameter to predict the 6mo-BWR% efficacy of these interventions.

Objective: To assess the safety, tolerability, and effectiveness of the intravenous immunoglobulin (IVIG) Intratect 50 g/L in immunoglobulin replacement therapy (IgRT) in a prospective, large-scale non-interventional study (NIS). The analysis focused upon patients with secondary immunodeficiency (SID), the most frequent indication for IgRT in this NIS.

Materials and methods: Patients were enrolled at 123 centers in Germany. Each patient received IVIG as prescribed by the physician, guided by the Summary of Product Characteristics. Data were acquired from medical records and patients' questionnaires.

Results: In the NIS, 3,563 patients were documented. The main indication for IgRT was SID (73.2%), followed by primary immunodeficiency (14.7%), immune thrombocytopenia (5.8%), and other indications (6.2%). Among the SID patients, 52.9% were male, mean age was 66.5 years, and most (63.8%) were IVIG-naïve. Their annual infection rate improved from 3.7 before documentation in the NIS to 1.1 during the first year of the study. IgG trough plasma levels increased during treatment (> 6 g/L: 44.5% of SID patients at study entry and 64.8% in long-term treatment) and were associated with a trend toward reduced infection rate (p = 0.08). A 1-year infection analysis showed a significantly lower infection risk in the medium- and high-dose groups than in the low-dose group (p = 0.028 and p = 0.017, respectively). Patients' treatment satisfaction and quality of life improved from baseline. Adverse drug reactions (ADRs) in SID occurred at a low frequency with 0.8% at infusion level. On the patient level, ADRs occurred in 251 (15.3%) SID patients, with chills (7.4%) and pyrexia (0.9%) reported most frequently.

Conclusion: Effectiveness, safety, and quality of life confirmed the positive benefit-risk profile of IgRT. Higher IVIG dosages per body weight led to higher IgG plasma trough levels, in turn leading to reduced infection rates. Obese patients may need body-weight-adjusted treatment to reduce the risk of infection.

Objective: This study aimed to analyze the pharmacokinetic (PK) characteristics, safety, and bioequivalence (BE) of a test (T) preparation of a nifedipine controlled-release tablet and the reference (R) drug (Adalat GTIS) in Chinese study participants in the context of fasting and postprandial states.

Materials and methods: An open-label, single-center, randomized, single-dose, two-period study was designed including two separate arms, one with administration under fasting conditions and one with administration under postprandial conditions (high-fat, high-calorie breakfast). After oral administration, the nifedipine concentrations in plasma were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) at regular intervals. Primary PK parameters, including the area under the concentration curve from 0 to infinity (AUC_0-∞), the area under the concentration profile from 0 to the last measurable concentration time (AUC_0-t), and maximal measured plasma concentration (C_max) were log-transformed with BE limits of 80 - 125% to evaluate BE. All adverse events (AEs) were wholly supervised.

Results: The PK profiles of the T and R formulations were comparable to each other under both fasting and postprandial conditions. The 90% confidence intervals (CIs) of the AUC_0-∞, AUC_0-t, and C_max were 92.69 - 106.06%, 93.32 - 107.05%, and 99.53 - 116.71%, respectively, under the fasting state. The 90% CIs of the AUC_0-∞, AUC_0-t, and C_max were 105.05 - 117.40%, 105.43 - 117.82%, and 102.66 - 116.30%, respectively, in the postprandial arm. 47 cases of drug-associated AEs were noted in the entire research.

Conclusion: Under both the fasting and postprandial states, the two nifedipine controlled-release formulations were bioequivalent and safe in healthy Chinese subjects.

A variety of drugs have been known to induce disulfiram-like reactions in individuals exposed to ethanol, including certain cephalosporin antibiotics with methylthiotetrazole (MTT) substituents or methylthiodioxotriazine (MTDT) rings. Among cephalosporins, cefixime is known to cause fewer disulfiram-like reactions. This case report, the first involving a pediatric patient, presents the scenario of a 14-year-old female who exhibited drowsiness, loss of consciousness, and cold extremities within an hour after ingesting 9 cefixime capsules. Upon admission, drug intoxication was considered, prompting immediate gastric lavage and toxicology tests, which revealed the presence of both cefixime and alcohol. Subsequent monitoring of vital signs, rehydration, and symptomatic treatments aimed at facilitating toxic excretion were administered during hospitalization. Following initial assessment by a clinical pharmacist, drug intoxication was deemed improbable, though an atypical disulfiram-like reaction or alcohol intoxication could not be ruled out. Further evaluation, coupled with the child's cefixime overdose, suggested an atypical disulfiram-like reaction. This case underscores the potential for disulfiram reactions even with cephalosporins lacking MTT substituents or MTDT rings. Notably, it is the first report of an atypical disulfiram-like reaction triggered by alcohol consumption following cefixime overdose, emphasizing the importance of caution in cefixime usage and avoidance of alcohol or alcohol-containing substances.

Objectives: This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization.

Materials and methods: Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology.

Results: The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased.

Conclusion: The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.

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.