Risk factors for infliximab-induced infusion reactions based on a retrospective study of medical information.

OBJECTIVE: Infliximab is indicated for a wide range of diseases, and infusion reactions (IRs) have been reported after infliximab administration in 17.6% of patients in clinical practice. This study aimed to identify the risk factors for IRs before the administration of infliximab based on available patient information. MATERIALS AND METHODS: We retrospectively analyzed patients treated with infliximab. Data were compared between patients with and without IRs immediately before initiation of infliximab. RESULTS: Elevated C-reactive protein (CRP) (odds ratio (OR), 2.150; 95% confidence interval (CI), 1.329 - 3.477; p = 0.002) before infliximab administration was a significant risk factor for developing an IR. CONCLUSION: Patients with elevated CRP levels before therapy initiation may require more careful monitoring after infliximab administration.

Risk factors for amiodarone-induced liver injury: A retrospective analysis of medical records.

OBJECTIVE: This study identified risk factors for drug-induced liver injury (DILI) based on patient information before the administration of amiodarone. MATERIALS AND METHODS: A retrospective analysis was performed on patients who had received amiodarone treatment. Data from patients with and without DILI were compared immediately before the start of amiodarone treatment. RESULTS: An elevated C-reactive protein level (odds ratio (OR) 1.119; 95% confidence interval (CI) 1.009 - 1.241; p = 0.033) before amiodarone administration was a significant risk factor for DILI. CONCLUSION: Possible treatment with alternative drugs should be considered in patients with elevated C-reactive protein levels. Moreover, close monitoring of liver function when amiodarone is administered may prevent the onset and exacerbation of DILI.

Non-destructive visualization of internal structural changes in humidified magnesium oxide tablets using X-ray computed tomography.

Detailed examinations of the internal structure of tablets are imperative for comprehending their formulation, physical attributes, and ensuring their safe utilization. While X-ray computed tomography (CT) is valuable for noninvasively analyzing internal structural changes, the influence of humidity on these structural changes remains unexplored. Accordingly, we aimed to assess the viability of X-ray CT in non-destructively evaluating the internal structure of humidified magnesium oxide (MgO) tablets. MgO tablets were subjected to conditions of 40 °C and 75% humidity for 7 days, weighed pre- and post-humidification, and subsequently stored at room temperature (22-27 °C) until day 90. Their internal structure was evaluated using X-ray CT. We observed a substantial increase in the weight of MgO tablets concomitant with moisture absorption, with minimal changes observed upon storage at room temperature. The skewness reduced immediately post-moisture absorption, remained almost the same post-storage at room temperature, and failed to revert to pre-humidification levels during the storage period. These findings highlight the utility of X-ray CT as an effective tool for non-destructive, three-dimensional, and detailed evaluation of internal structural transformations in MgO tablets.

Retrospective analysis of risk factors for levofloxacin-induced liver injury.

Levofloxacin is used as a first-line drug for the treatment of Legionella pneumonia. However, the relatively high incidence of drug-induced liver injury (DILI) remains a clinical problem. Based on the available patient data, this study aimed to identify the risk factors for DILI before levofloxacin administration. Multiple logistic regression analyses suggested that male sex (odds ratio [OR], 6.975; 95% confidence interval [CI], 1.737-28.000; p = 0.006), elevated C-reactive protein level (OR, 1.182; 95% CI, 1.089-1.283; p = 0.0006), and high haemoglobin level (OR, 1.640; 95% CI, 1.226-2.195; p = 0.001) before administration of levofloxacin were risk factors for DILI. Possible treatment with alternative drugs should be considered in male patients with elevated C-reactive protein and haemoglobin levels. Moreover, close monitoring of liver function tests when levofloxacin is administered may prevent the development and severity of DILI.

Role of protein kinase C beta in phorbol ester-induced c-fos gene expression in neurons of normotensive and spontaneously hypertensive rat brains.

We have previously demonstrated that pressure application of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) onto some neurons in the anterior hypothalamic area of rats increases neural activity in vivo and that this PKC activation-induced increase of neural activity is enhanced in spontaneously hypertensive rats (SHR), an animal model for genetic hypertension. Activation of PKC increases expression of the c-fos gene, an important transcription factor and proto-oncogene thought to be a marker of neural activity. To evaluate PKC isoforms responsible for neural activation, we examined which isoforms of PKC are involved in the PKC activation-induced c-fos gene expression in neuronal cultures of Wistar rat and spontaneously hypertensive rat (SHR) brains. PMA increased c-fos gene expression in neuronal cultures of Wistar rat brain and the PMA-induced c-fos gene expression was inhibited by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7). The PKCalpha,beta,gamma activator thymeleatoxin also increased c-fos gene expression, while the PKCdelta,epsilon activator ingenol did not affect it. In addition, the PMA-induced c-fos gene expression was inhibited by PKCbetaantisense oligonucleotides (AON) but not by PKCalpha and PKCgammaAONs. In SHR brain neuronal cultures, the PMA-induced c-fos gene expression was enhanced as compared with that of Wistar Kyoto rats (WKY), while basal c-fos gene expression was almost the same in both neuronal cultures. The enhancement of PMA-induced c-fos gene expression in SHR brain cultures was abolished by PKCbetaAON. These findings suggest that in rat brain neuronal cultures, PMA increases c-fos gene expression via activation of PKC and that PKCbetaisoforms are partly involved in the PMA-induced c-fos gene expression. In neuronal cultures of SHR brain, it appears that the PMA-induced c-fos gene expression is also enhanced via PKCbeta.

Elucidation of the molecular mechanisms underlying adverse reactions associated with a kinase inhibitor using systems toxicology.

BACKGROUND/OBJECTIVES: Targeted kinase inhibitors are an important class of agents in anticancer therapeutics, but their limited tolerability hampers their clinical performance. Identification of the molecular mechanisms underlying the development of adverse reactions will be helpful in establishing a rational method for the management of clinically adverse reactions. Here, we selected sunitinib as a model and demonstrated that the molecular mechanisms underlying the adverse reactions associated with kinase inhibitors can efficiently be identified using a systems toxicological approach. METHODS: First, toxicological target candidates were short-listed by comparing the human kinase occupancy profiles of sunitinib and sorafenib, and the molecular mechanisms underlying adverse reactions were predicted by sequential simulations using publicly available mathematical models. Next, to evaluate the probability of these predictions, a clinical observation study was conducted in six patients treated with sunitinib. Finally, mouse experiments were performed for detailed confirmation of the hypothesized molecular mechanisms and to evaluate the efficacy of a proposed countermeasure against adverse reactions to sunitinib. RESULTS: In silico simulations indicated the possibility that sunitinib-mediated off-target inhibition of phosphorylase kinase leads to the generation of oxidative stress in various tissues. Clinical observations of patients and mouse experiments confirmed the validity of this prediction. The simulation further suggested that concomitant use of an antioxidant may prevent sunitinib-mediated adverse reactions, which was confirmed in mouse experiments. CONCLUSIONS: A systems toxicological approach successfully predicted the molecular mechanisms underlying clinically adverse reactions associated with sunitinib and was used to plan a rational method for the management of these adverse reactions.