Journal of clinical pharmacology最新文献

We investigated whether effervescent paracetamol, as an important source of nondietary sodium and fluid load, is associated with a transient increase in the risk of hospitalization for acute heart failure (AHF). We conducted a unidirectional case-crossover study using data from the 1 in 97th representative sample from the French health care database. Subjects aged ≥18 years, hospitalized for AHF during the 2014-2016 period, were included. Exposure to effervescent paracetamol was compared between a risk period (ie, 15 days immediately before admission for AHF) and 3 earlier 15-day control periods, to test a possible trigger effect of effervescent paracetamol intake on AHF. Adjusted odds ratios (aORs) were estimated with a conditional logistic regression. We identified 4301 patients hospitalized for AHF. We found that 5.7% of AHF subjects were exposed to effervescent paracetamol during the risk period, as compared with 4.1% during the control periods (aOR, 1.56 [95% confidence interval [CI], 1.27-1.90]; P < .001). This association was also found in the subgroup of subjects with hypertension (aOR, 1.45 [95%CI, 1.13-1.87]; P = .004, n = 2648) and in the subgroup of subjects aged ≥83 years (aOR, 1.70 [95%CI: 1.28-2.24], P < .001, n = 2238). A similar analysis, considering exposure to noneffervescent paracetamol, did not support the existence of an indication bias likely to explain the association observed for effervescent paracetamol. This study suggests an association between effervescent paracetamol and admission for AHF and should be confirmed with other complementary study designs.

The aim of this study was to investigate the pharmacokinetic/pharmacodynamic parameters of linezolid in both the plasma and epithelial lining fluid (ELF) of patients with pneumonia-induced sepsis. Blood specimens and bronchoalveolar lavage samples were collected at defined time points after administration of linezolid. The concentration in the ELF was calculated by urea dilution method. PK parameters were calculated, and probability of target attainment was evaluated by Monte Carlo simulations. Twenty-three patients were enrolled, 8 of whom had septic shock. The maximum concentration of linezolid was higher in the ELF than in the plasma (36.02 ± 13.17 vs 19.51±4.83 mg/L, P < .001) in all of the patients. In patients with septic shock, the maximum concentration in the ELF was significantly higher than that in the non-septic shock group (45.25 ± 11.70 vs 31.10 ± 11.38 mg/L, P = .01), while there was no significant difference in the plasma. The corresponding probability of target attainment values were 90.5% and 65.1% in ELF and plasma, respectively, with a minimum inhibitory concentration of 2 mg/L, which were 99.9% in the ELF in the patients with septic shock. Linezolid possesses an efficient penetration into the ELF of patients with pneumonia-induced sepsis with mechanical ventilation. When minimum inhibitory concentration ≤ 2 mg/L, 600 mg of linezolid every 12 hours could achieve the optimal therapeutic targets in the ELF rather than in the plasma of patients with pneumonia-induced sepsis.

Numerous drugs are being investigated for the treatment of COVID-19, including antivirals and therapies targeting complications related to COVID-19. The clinical presentation of COVID-19 varies from mild fever, cough, and dyspnea in the early stages of disease to severe complications such as acute respiratory distress syndrome, systemic hyperinflammation, and sepsis. A thorough understanding of the disease pathogenesis and the disease complications is essential to developing effective therapies to treat this potentially life-threatening disease. This review offers key clinical pharmacology considerations involved in the development of small molecules for the treatment of COVID-19. They are based on the major observed disease complications that impact drug absorption, distribution, metabolism, and elimination. We also address considerations regarding potential drug interactions, alternative routes and methods of administration, and dosing in patients on hemodialysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) or drug-induced liver injury (DILI) are severe drug-induced reactions, known as idiosyncratic drug reactions. It is believed that immune response can lead to these severe adverse drug reactions. Our previous analysis of the Japanese Spontaneous Drug Reaction database suggested that the onset of SJS/TEN and DILI was strongly associated with infection. Hence, we conducted a matched, nested case-control study to elucidate the association between concurrent infection and the onset of SJS/TEN or liver injury in patients prescribed antipyretic analgesics. We extracted 4 112 055 patients who were prescribed antipyretic analgesics between January 2014 and December 2015. Amongst them, 553 (0.01%) were diagnosed with SJS/TEN and 12 606 (0.3%) with liver injury. In a matched, nested case-control study, 131 and 2847 cases matched for SJS/TEN or liver injury, respectively. For each case, 3 controls were randomly matched with the case for age at index date and sex. In the conditional logistic regression analysis, there was a significant association between the combination of infection and antipyretic analgesics and the onset of SJS/TEN or liver injury (SJS/TEN: adjusted OR, 5.59; 95%CI, 2.01-15.51; liver injury: adjusted OR, 2.79; 95%CI, 2.24-3.46). Although it was not possible to distinguish whether the associations were caused by the infection or were a direct consequence of the antibiotic agents, our findings may help to increase awareness of the possibility of the increased onset of idiosyncratic drug reactions (SJS/TEN and liver injury) in antipyretic analgesic users because of infections.

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 μg/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene-related peptide receptor-in development for migraine prevention-is thus likely to be used by women taking oral contraceptives. This phase 1, open-label, single-center, 2-period, fixed-sequence study examined the effect of multiple-dose atogepant 60 mg once daily on the single-dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7-day washout. In period 2, atogepant was given once daily on days 1-17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty-six participants aged 45-64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration-time curve extrapolated to infinity (AUC_0-∞ ) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC_0-∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified.

Currently, the world is facing the pandemic of a novel strain of beta-coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS) is the most devastating complication of SARS-CoV-2. It was indicated that cytokine-release syndrome and dominantly interleukin (IL)-6 play a central role in the pathophysiology of ARDS related to the novel 2019 coronavirus disease (COVID-19). Despite the global emergency of the disease, at this time, there are no proven therapies for the management of the disease. Tocilizumab is a potential recombinant monoclonal antibody against IL-6 and currently is under investigation for the management of ARDS in patients with COVID-19. Given these points, we reviewed the current evidence regarding the potential therapeutic role of tocilizumab and its important clinical issues in the treatment of ARDS related to COVID-19.