Patient resuscitated after cardiopulmonary arrest exhibits abnormally increased phenytoin metabolic rate due to unknown factors: a case report.

BACKGROUND: Fosphenytoin (FOS) is a prodrug of phenytoin (PHT) with a metabolism that exhibits Michaelis-Menten-type kinetics. Genetic polymorphisms of the metabolic enzymes of PHT make it challenging to predict its plasma concentrations. High plasma PHT concentrations are typically problematic, and several causes have been elucidated. In contrast, cases of patients with low PHT plasma concentrations that did not increase despite the administration of appropriate PHT doses have been reported, and the causes may include changes in plasma protein-binding rates, genetic mutations, and concomitant use of drugs that induce liver enzymes; however, even these factors do not explain the low PHT plasma concentrations in some cases. CASE PRESENTATION: We encountered the case of a patient with plasma PHT concentrations that were continuously < 0.7 µg/mL after daily use of FOS for seizures that occurred after cardiopulmonary arrest. We analyzed the protein-unbound fraction, urinary metabolites, and related genes to investigate the cause. False negatives due to the measurement method, errors in dosage and administration method, and increased excretion of PHT were excluded. Hepatic metabolic activity of PHT increased to 4.6-6.1 times the normal level. The S/R ratio of 5-(p-hydroxyphenyl)-5-phenylhydantoin-glucuronide, a major PHT metabolite, was normal at 15.2, suggesting increased activities of CYP2C9 and CYP2C19. Furthermore, the protein-unbound fraction of PHT was 5.2-6.9%, CYP2C19*17 was wild type, and there was no concomitant drug use to induce both enzymes. CONCLUSIONS: The low PHT plasma concentration in this patient was found to be caused by increased hepatic metabolic activity that could not be explained by known factors. Careful monitoring is necessary to consider the possibility of increased hepatic metabolic activity in similar cases.

Increased c­SRC expression is involved in acquired resistance to lenvatinib in hepatocellular carcinoma.

Lenvatinib, a multi-kinase inhibitor, serves a crucial role in the treatment of unresectable hepatocellular carcinoma (HCC). However, >50% of patients receiving lenvatinib therapy experience tumor growth or metastasis within 1 year, highlighting the need to address acquired resistance as a critical clinical challenge. To elucidate the factors associated with acquired resistance to lenvatinib, a lenvatinib-resistant HCC cell line (JHH-7_LR) was established by exposing a lenvatinib-sensitive HCC cell line, JHH-7, to lenvatinib. The changes in protein expression associated with the development of resistance were analyzed using a proteomic approach, detecting 1,321 proteins and significant changes in the expression of 267 proteins. Using Ingenuity Pathway Analysis bioinformatics software, it was revealed that the activity of multiple signaling pathways varied alongside the changes in expression of these proteins, and c-SRC was identified as a protein involved in a number of these signaling pathways, with its activity varying markedly upon the acquisition of resistance. When co-administering dasatinib, a c-SRC inhibitor, the partial restoration of lenvatinib sensitivity in the JHH-7_LR cell line was observed. The present study demonstrated that increased c-SRC expression was partially associated with HCC resistance to lenvatinib, suggesting that c-SRC inhibition could reduce the resistance of HCC to lenvatinib.

Target concentration achievement for efficacy and safety of patients with osteosarcoma treated with high-dose methotrexate based on individual pharmacokinetics: A retrospective study.

In the high-dose methotrexate (HD-MTX) treatment of patients with osteosarcoma, a dose-adjustment method using individual pharmacokinetic parameters (PK method) to optimize the concentration was developed in 2010. However, to the best of our knowledge, the clinical usefulness of the PK method has not been verified until now. In the present retrospective study, to assess the usefulness of the PK method, the achievement rate of an effective and safe concentration range was evaluated. A total of 43 patients with osteosarcoma who were administered HD-MTX therapy (43 first courses and 200 subsequent courses) were enrolled. The MTX dose in the first course was determined using a common method based on body surface area (BSA method); a total of 8-12 g/m2 was administered as an initial dose for 1 h and a maintenance dose for 5 h. In the subsequent courses, loading and maintenance doses were calculated by the PK method based on the serum MTX concentration profile of the previous course. The effective target concentration during 1-6 h after the start of MTX administration was 700-1,000 µmol/l, whereas the target safe MTX level was less than 10, 1 and 0.1 µmol/l at 24, 48 and 72 h, respectively. Notably, the rate of achieving the effective target concentration was significantly higher when using the PK method as compared to that when using the BSA method. The achievement rate of the safe target concentration at 24, 48 and 72 h when using the PK method was significantly higher. Additionally, the incidence of abnormal laboratory values of aspartate aminotransferase and alanine aminotransferase was significantly lower when using the PK method. Therefore, the PK method was suggested to be very useful in HD-MTX therapy for patients with osteosarcoma.

Risk of exposure of patients' family members to lenalidomide at home.

OBJECTIVES: Lenalidomide, a hazardous drug, has strict distribution controls. However, the risk of contamination with lenalidomide when patients take the drug has not been studied and the risk of drug exposure to people in the patient's living environment is unknown. Thus, we investigated the amount of lenalidomide that could be dispersed during the period between removal of the capsule and returning the used blister packages, and we considered the conditions under which lenalidomide could be dispersed and countermeasures. METHODS: The amount of lenalidomide contamination was measured on the outside of the unused blister packages returned by the patients, on the surface of the capsule, and on the inside of the package immediately after removal of the capsule. In addition, the amount of contamination was measured on the blister packages used by the patients and on the gloves worn by the pharmacists on receipt of the packages. Lenalidomide was analysed by liquid chromatography-tandem mass spectrometry. RESULTS: Lenalidomide amounts on the outside of the unused blister packages returned by the three patients were <10, <10, and 26.8 ng/pack, those on the capsule surface immediately after removal from the packages were 297, 388, and 297 ng/capsule, and those on the inside of packages immediately after removal of all capsules were 143, 184, and 554 ng/pack, respectively. A median of 15.6 ng/pack lenalidomide was detected on the surface of packages used by the patients (n=18). The lenalidomide remaining in the packages immediately after capsule removal (~200 ng/pack), except for the 15.6 ng/pack detected in the packages used by the patients, may have been dispersed in the patient's living environment (~90% or more). The maximum amount of lenalidomide on the surface of the packages used by the patients was over 2500 ng/pack. CONCLUSIONS: The amount of lenalidomide contamination per package was found to be at least 100 ng less after collection by the pharmacist than immediately after removal of the capsules. Therefore, it is recommended to clean the surrounding area and wash one's hands after taking the capsules.

MAOA, MTHFR, and TNF-ß genes polymorphisms and personality traits in the pathogenesis of migraine.

Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-ß) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-ß), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-ß G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.

Association of the A-1438G polymorphism in serotonin 2A receptor in migraine with aura among Japanese patients.

We investigated the possible association of serotonin (5-HT) 2A receptor gene A-1438G polymorphism in Japanese patients with migraine. Genotyping of 5-HT(2A) A-1438G polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism in patients with migraine (male 17 : 3 with aura and 14 without aura, female 65 : 17 with aura and 48 without aura) and controls (male 31, female 84). The distribution of 5-HT(2A) A-1438G genotype frequency between migraine patients and controls did not differ. These results suggest that the A-1438G polymorphism of the 5-HT(2A) receptor gene is not a direct risk factor for migraine; however, the incidence of the A/A genotype between migraine with aura (MA) and without aura (MO) was significantly different. The 5-HT(2A) A-1438G polymorphism may be involved in determining the subtypes of migraine in Japanese.

[Is a migraine screener useful for pharmacists in community pharmacy to distinguish patients with migraine?].

In this study, to clarify the characteristics of a migraine screener that would be useful to pharmacists in community pharmacies, we used the migraine screener to investigate patients with migraine. Diagnosis of migraine was made according to the internal classification of headache disorders 2nd edition (ICHD-II). Eighty patients with migraine (with aura: n=21, without aura: n=59) were divided into a positive group (n=51, 64%) and a negative group (n=29, 36%) based on the results of the migraine screener, which included a 4-item (headache exacerbation in daily performance, nausea, light-sensitivity and hypersensitivity to odors). The positive rate of the migraine screener was 64%. In the positive group, patients had moderate-to-severe migraine attacks in the past 3 months. Moreover, 82% of patients in the positive group reported disturbances in their daily of life due to headache. In the negative group, 41% of patients also reported disturbances in their daily of life. Therefore, pharmacists have to check the influence of headache on daily of life not only in the positive group but also in the negative group. These findings provide useful information to guide pharmacists in community pharmacies when using the screener for migraine to distinguish patients with headache from those with migraine.

L-Lactate dehydrogenase B may be a predictive marker for sensitivity to anti-EGFR monoclonal antibodies in colorectal cancer cell lines.

Recently, proteins derived from cancer cells have been widely investigated as biomarkers for predicting the efficacy of chemotherapy. In this study, to identify a sensitive biomarker for the efficacy of anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), proteins derived from 6 colorectal cancer (CRC) cell lines with different sensitivities to cetuximab, an anti-EGFR mAb, were analyzed. Cytoplasmic and membrane proteins extracted from each CRC cell line were digested using trypsin and analyzed comprehensively using mass spectrometry. As a result, 148 and 146 peaks from cytoplasmic proteins and 363 and 267 peaks from membrane proteins were extracted as specific peaks for cetuximab-resistant and -sensitive CRC cell lines, respectively. By analyzing the proteins identified from the peptide peaks, cytoplasmic L-lactate dehydrogenase B (LDHB) was detected as a marker of cetuximab sensitivity, and it was confirmed that LDHB expression was increased in cetuximab-resistant CRC cell lines. Furthermore, LDHB expression levels were significantly upregulated with the acquisition of resistance to cetuximab in cetuximab-sensitive CRC cell lines. In conclusion, LDHB was identified as an important factor affecting cetuximab sensitivity using comprehensive proteome analysis for the first time.

Effect of genetic polymorphisms on effectiveness of low-dose azathioprine in Japanese patients with systemic lupus erythematosus.

PURPOSE: The effect of genetic polymorphisms on the effectiveness of low-dose azathioprine in Japanese patients with systemic lupus erythematosus (SLE) was studied. METHODS: Sixty-one unrelated Japanese patients with SLE treated with azathioprine were included in the study. The selected genetic polymorphisms evaluated in the analysis were ITPA 138G>A, ITPA 563G>A, IMPDH 1575A>G, XO 837C>T, XO 2211C>T, XO 3030C>T, and MRP4 2269G>A. The DNA isolation and genotyping procedures for ITPA 94C>A and TPMT*3C were the same as those in a previous study. Genotyping of ITPA 138G>A, ITPA 563G>A, IMPDH 1575A>G, MRP4 2269G>A, XO 837C>T, XO 2211C>T, and XO 3030C>T was performed using a validated genotyping assay. The SLE disease activity index (SLEDAI) score was used as a marker for the efficacy of azathioprine treatment, and the correlations between the changes in the SLEDAI score and the considered polymorphisms were evaluated. RESULTS: The mean SLE duration, SLEDAI score, and azathioprine dosage prescribed were 5.6 years, 6.0, and 1 mg/kg/day, respectively. Small (but not significant) p values suggested a tendency for the reduction in the SLEDAI score to be greater in patients with the ITPA 94A allele. Further, the ITPA 94C>A polymorphism correlated highly with the change in the SLEDAI score. However, there were no significant associations among TPMT*3C, ITPA 138G>A, ITPA 563G>A, IMPDH 1575A>G, XO 837C>T, XO 2211C>T, and XO 3030C>T and the mean changes in the SLEDAI score over the one-year investigation period. CONCLUSION: The ITPA 94C>A polymorphism was found to possibly influence the clinical response to low-dose azathioprine in Japanese patients with SLE. The other studied single-nucleotide polymorphisms appeared to have little influence on the effectiveness of azathioprine.