Prevention of Postoperative Cognitive Dysfunction by Minocycline in Elderly Patients after Total Knee Arthroplasty: A Randomized, Double-blind, Placebo-controlled Clinical Trial.

BACKGROUND: There are no effective pharmacologic interventions for preventing postoperative cognitive dysfunction in daily practice. Since the antibiotic minocycline is known to suppress postoperative neuroinflammation, this study hypothesized and investigated whether minocycline might have a preventive effect on postoperative cognitive dysfunction after noncardiac surgery. METHODS: This study included patients aged more than 60 yr undergoing total knee arthroplasty under general anesthesia. They were randomly assigned to minocycline and placebo groups, to orally receive 100 mg of minocycline or placebo twice daily from the day before surgery until the seventh day after surgery. Cognitive function was evaluated before surgery, and 1 week and 3 months after surgery, using a battery of four cognitive function tests, including Visual Verbal Learning Test, Trail Making Test, Stroop Color and Word Test, and Letter-Digit Coding Task. Additionally, 30 healthy volunteers were subjected to the same tests as the patients to examine the learning effect of repeated tests. The occurrence of postoperative cognitive dysfunction was judged from the results of the neurocognitive test battery, with consideration of the learning effect. The secondary endpoints were the effects of minocycline on postoperative delirium and postoperative pain. RESULTS: A total of 100 patients were randomized to the minocycline group, and 102 were randomized to the placebo group. The average age of patients was 75 yr. Evaluation showed no significant difference in the incidence of postoperative cognitive dysfunction between the minocycline and placebo groups at both 1 week (8 of 90 [8.9%] vs. 4 of 95 [4.2%]; odds ratio, 2.22 [95% CI, 0.64 to 7.65]; P = 0.240) and 3 months (15.3 of 90 [17.0%] vs. 15.3 of 95 [16.1%]; odds ratio, 1.07 [95% CI, 0.49 to 2.32]; P = 0.889) postoperatively. Missing data 3 months after surgery were corrected by the multiple imputation method. There were no differences between the two groups in postoperative delirium and postoperative pain. CONCLUSIONS: Minocycline is likely to have no preventive effect on postoperative cognitive dysfunction.

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.

Prediction and structural equation model of sertraline treatment response in Japanese patients with major depressive disorder.

OBJECTIVE: The aim of this study was to extract the factors possibly associated with sertraline treatment response and elucidate their interactions and extent of influence. METHODS: Demographic state, stress state, personality, and eight genetic polymorphisms at baseline and clinical symptoms at baseline and 8 weeks were analyzed and examined by logistic regression and a structural equation model in sertraline treatment study of 96 Japanese patients with major depressive disorder. RESULTS: Non-responders were associated with higher scores of harm avoidance in Temperament and Character Inventory, higher scores (≥24) of 17-item Hamilton Rating Scale for Depression at baseline, recurrence, and 12/12 genotype of the serotonin transporter variable number of tandem repeat polymorphism in intron 2 (5HTTSTin2). When we calculated the response index using four factors extracted, the mean response index value of non-responders was significantly higher than that of responders. The symptoms at baseline, personality, recurrence, and polymorphism of 5HTTSTin2 showed significantly direct and positive influences on the symptoms at 8 weeks in our final structural equation model with a good model fit. CONCLUSION: Considering the combination of four factors extracted may be useful for predicting a worse response to sertraline treatment and selecting different treatment other than sertraline.

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.

Blood Concentration of Cabazitaxel in a Patient Whose General Condition Worsened with Concomitant Use of Clarithromycin.

We encountered a case in which the general condition of a patient receiving cabazitaxel worsened with concomitant use of clarithromycin. Cabazitaxel is metabolized mainly by CYP3A4, and the frequency of adverse events is known to increase with increasing exposure. Although these drugs are not often quantified in daily practice, we quantified them because we considered it possible that the blood concentration of cabazitaxel had increased due to CYP3A4 inhibition of clarithromycin and that cabazitaxel-related adverse events had occurred. However, the concentration of cabazitaxel was not increased and we attributed the patient's deterioration to decreased tolerability of cabazitaxel. At least at a trough concentration of 70 ng/mL, which is the trough concentration when a normal dose of clarithromycin is administered, clarithromycin does not appear to have a significant effect on the blood concentration of cabazitaxel. This case suggests that the administration of the normal dose of clarithromycin might be relatively safe in patients receiving cabazitaxel.

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.

Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma.

The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07-4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients.

Assessment of DDR2, BRAF, EGFR and KRAS mutations as therapeutic targets in non-adenocarcinoma lung cancer patients.

Molecular-targeted therapy has not been established in non-adenocarcinoma lung cancer (non-AdLC), as no targets that affect the clinical efficacy of molecular-targeted drugs have yet been identified. In this study, we investigated the frequency of genetic variations in discoidin domain receptor 2 (DDR2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-AdLC patients, in order to evaluate the possibility of genetic mutations in these genes being used as therapeutic targets for the treatment of patients with non-AdLC. For this purpose, we enrolled 150 non-AdLC patients who had undergone surgery at the Gunma University Hospital between December, 2003 and December, 2012. Genetic mutations in the EGFR, KRAS, DDR2 and BRAF genes were detected by a sequencing method or probe assay using DNA derived from cancer tissues. No somatic mutations in DDR2 or BRAF were detected in non-AdLC patients. Conversely, genetic mutations in EGFR exon 19 were found in 3 squamous cell carcinoma (SCC) and 3 adenosquamous carcinoma patients, whereas KRAS codon 12 mutations were also found in 3 SCC patients and 1 large-cell neuroendocrine carcinoma patient. EGFR and KRAS mutations were mutually exclusive. This study indicated that, although DDR2 and BRAF mutations may only rarely be used as therapeutic targets, EGFR and KRAS mutations may represent candidate therapeutic targets, at least in the non-AdLC patients investigated.

Review of the treatment of non-small cell lung cancer with gefitinib.

In the past decade, molecular-targeted drugs have been focused upon for the treatment of cancer. In 2002, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor became available in Japan for the treatment of non-small cell lung cancer (NSCLC). Over 80% of selected patients, such as EGFR mutation-positive patients, respond to gefitinib treatment; however, most patients develop acquired resistance to gefitinib within a few years. Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects. This article reviews the use of gefitinib for the treatment of NSCLC from a pharmaceutical viewpoint.