Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Poplar leaf abscission through induced chlorophyll breakdown by Mg-dechelatase.

Chlorophyll breakdown is observed during senescence. The first step in chlorophyll breakdown is the removal of central Mg by Mg-dechelatase. This reaction is the rate-limiting step in the chlorophyll breakdown pathway. We evaluated the effect of induced chlorophyll breakdown on abscission through the removal of Mg by Mg-dechelatase. Poplar transformants carrying the dexamethasone-inducible Mg-dechelatase gene were prepared using the Arabidopsis Stay-Green1 cDNA. When leaves were treated with dexamethasone, chlorophyll was degraded, photosynthetic capacity was reduced, and an abscission zone was formed, resulting in leaf abscission. In addition, ethylene, which plays an important role during senescence, was produced in this process. Thus, chlorophyll breakdown induces the phenotype in the same way as commonly observed during leaf senescence. This study suggests a physiological role of chlorophyll breakdown in the leaf abscission of deciduous trees. Furthermore, this study shows that the dexamethasone-inducible gene expression system is an available option for deciduous tree studies.

Reduced nephrotoxicity with vancomycin therapeutic drug monitoring guided by area under the concentration-time curve against a trough 15-20 µg/mL concentration.

Vancomycin is often employed as an antibacterial agent against Gram-positive bacteria, although dose-dependent nephrotoxicity is a concern. Although the risk may be reduced by therapeutic drug monitoring (TDM) guided by area under the concentration-time curve (an attempt to target an AUC > 400 µg•h/mL by Bayesian prediction: AUC400-guided TDM), the clinical efficacy of AUC400-guided TDM compared with trough concentration-guided TDM within 15-20 µg/mL (Trough15-20-guided TDM) has yet to be determined. We aimed to retrospectively evaluate the difference in the incidence rate of acute kidney injury (AKI), classified according to the Acute Kidney Injury Network, between these TDM groups. Individual AUC in the AUC400-guided TDM group was calculated by Bayesian prediction using trough and peak concentrations (within 3 h after the end of infusion). The AKI incidence in the Trough15-20-guided TDM group was 28.8% (15/52 patients) compared with an AKI incidence in the AUC400-guided TDM group of 9.1% (2/22 patients). Application of AUC400-guided TDM was identified as an independent factor for avoiding the incidence of AKI by Cox hazard regression analysis [hazard ratio = 0.168, 95% confidence interval (CI) 0.034-0.839] and logistic regression analysis (odds ratio = 0.037, 95% CI 0.003-0.285). As the estimated glomerular filtration rate (eGFR) improved, the surrogate target trough concentration for an AUC > 400 µg•h/mL was lowered (intercept 15.0074, slope -0.0598). In conclusion, AUC400-guided TDM may be superior to Trough15-20-guided TDM for the reduction of nephrotoxicity during vancomycin therapy.

Post-esophagectomy Adjuvant Chemotherapy Benefits Esophageal Cancer Patients.

BACKGROUND/AIM: Postoperative chemotherapy is an absolutely imperative treatment for advanced esophageal cancer patients, while preoperative chemotherapy is the standard therapy for clinical stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. The aim of this study was to report the effect of postoperative chemotherapy on survival after esophagectomy due to thoracic esophageal squamous cell carcinoma. PATIENTS AND METHODS: One hundred thirteen consecutive patients with esophageal carcinoma who underwent esophagectomy were included. Several regiments were performed at various times. RESULTS: Adjuvant chemotherapy brought a significantly superior overall survival (p=0.002), although there was no significant difference in cancer-specific survival (p=0.054) for clinical stage II or stage III esophageal cancer patients. Depth of invasion (p=0.003), number of lymph node metastases (p=0.048), and venous invasion (p<0.001) were risk factors for recurrence in the adjuvant-chemotherapy group with positive lymph nodes. Additionally, a not well-differentiated type, lymphatic and venous invasions were risk factors for recurrence in the surgery-alone group without positive lymph nodes. CONCLUSION: Postoperative adjuvant chemotherapy contributes to the prognosis of clinical stage II or III esophageal cancer patients.

Effects of tinnitus treatments on sleep disorders in patients with tinnitus.

OBJECTIVE: To assess the effects of tinnitus treatments on sleep disorders in patients with tinnitus. DESIGN: Subjects completed the Pittsburg Sleep Quality Index (PSQI), Tinnitus Handicap Inventory (THI), Self-rating Depression Scale (SDS), and State Trait Anxiety Inventory (STAI). The questionnaire results and the patients' sex, age, time since the onset of tinnitus, and mean hearing level were examined, and differences between a sleep disorder group and a normal sleep group were examined. Patients completed the questionnaires again after initiating tinnitus treatments (counselling and use of sound generators), and the change in questionnaire scores at follow-up was evaluated. STUDY SAMPLE: Patients (N = 100) with tinnitus who visited Keio University Hospital and started treatment without medication between 2005 and 2008. RESULTS: Sixty-six percent of the patients had sleep disorders. Compared with patients without sleep disorders, patients with sleep disorders had significantly higher SDS and STAI scores at the first visit. The mean PSQI scores showed significant improvement at follow-up. CONCLUSIONS: Sleep disorders in patients with tinnitus improved after tinnitus treatments. Complex interactions between depressive symptoms and anxiety may occur in these patients. The improvement in sleep disorders at follow-up was correlated with improvements in tinnitus severity and state anxiety.

Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder.

In recent years, circadian rhythm sleep disorders in humans have been increasing. Clinical features characteristic of this disorder are well known, but the specific causes remain unknown. However, various derangements of circadian expression of the clock gene are a probable cause of this disease. We have attempted to elucidate the relationship between the expression of the clock genes in whole blood cells and the clinical features characteristic of this disorder. In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects. The peak phase of Per1, Per2, and Per3 appeared in the early morning, whereas that of Bmal1 and Clock appeared in the midnight hours. Furthermore, in one patient case with circadian rhythm sleep disorder, we observed variations of the peak phase in clock genes by treatments such as light therapy, exercise therapy, and medicinal therapy. This study suggested that the monitoring of human clock genes in whole blood cells, which may be functionally important for the molecular control of the circadian pacemaker as well as in suprachiasmatic nucleus, might be useful to evaluate internal synchronization.

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats.

PURPOSE: The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. METHODS: The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. RESULTS: The area under the blood concentration-time curve (AUC) after the administration of Sandimmun (corn oil) and Neoral (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. CONCLUSION: The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.

cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney.

A cDNA coding a novel organic cation transporter, hOCT2-A, was isolated from human kidney. The hOCT2-A cDNA is an alternatively spliced variant of hOCT2 with an insertion of 1169 bp. The open reading frame encodes a 483-amino acid protein that has 81% amino acid identity with hOCT2. From hydropathy analysis, hOCT2-A is predicted to have nine transmembrane domains. hOCT2-A mRNA is expressed mainly in kidney and weakly in brain, liver, colon, skeletal muscle, bone marrow, spinal cord, testis, and placenta. When expressed in HEK293 cells, hOCT2-A stimulated the uptake of tetraethylammonium (TEA) in an electrogenic manner. The transport of TEA by hOCT2-A-transfected cells was saturable with the apparent Km value of 63 microM. hOCT2-A stimulated the uptake of TEA, 1-methyl-4-phenylpyridinium, and cimetidine as well as did hOCT2. The uptake of guanidine and choline by hOCT2-transfected cells also increased markedly but not that by hOCT2-A-transfected cells. The uptake of TEA mediated by hOCT2-A but not by hOCT2 was inhibited significantly by organic cations such as procainamide, N-acetylprocainamide, and levofloxacin, indicating that hOCT2-A differs from hOCT2 in its affinity for several compounds. These findings suggested that hOCT2-A contributes to the renal clearance of endogenous and exogenous organic cations.