Carbamazepine-imatinib interaction in a child with chronic myeloid leukemia.

Imatinib mesylate, a selective tyrosine kinase inhibitor, is the frontline therapeutic agent used for the treatment of chronic myeloid leukemia (CML), and its therapeutic efficacy is associated with trough concentrations. Therefore, monitoring imatinib trough concentrations is strongly recommended for successful treatment of CML patients. It has been recently shown that some drugs altered imatinib plasma levels in adult patients. However, drug interactions with imatinib in children are still unknown. Here, we report a case of a 12-year-old child with epilepsy who was also diagnosed with CML and given imatinib in addition to an enzyme-inducing antiepileptic drug, carbamazepine. Compared to population kinetics data, the data obtained for the patient showed a significant decrease of imatinib plasma concentrations. Our findings suggest that monitoring imatinib plasma concentrations in children receiving enzyme-inducing antiepileptic drugs is needed to optimize the therapeutic efficacy of imatinib.

False tacrolimus concentrations measured by antibody-conjugated magnetic immunoassay in liver transplant patient: 2 case reports and literature review.

Safe use of tacrolimus relies on regular whole-blood drug monitoring. Of the methods used to assess whole-blood tacrolimus concentration, antibody-conjugated magnetic immunoassay is mostly used for therapeutic drug monitoring because it requires only a minimal sample preparation and no pretreatment procedure. However, several cases recently have been reported in which abnormally false elevated tacrolimus concentrations were measured by antibody-conjugated magnetic immunoassay (>15 ng/mL), despite the absence of clinical symptoms. We present 2 cases of falsely detected tacrolimus concentrations that did not show abnormally high values within the therapeutic range. Whole-blood tacrolimus concentrations obtained by antibody-conjugated magnetic immunoassay showed well-controlled concentrations (approximately 2-8 ng/mL), whereas those obtained by another immunoassay and in washed erythrocytes were below the assay range (< 1.2 ng/mL). Thus, antibody-conjugated magnetic immunoassay can elicit falsely positive results of tacrolimus concentrations, even though they are within the therapeutic range.

A reduced linezolid dosage maintains favorable efficacy with minimal hematologic toxicity in a methicillin-resistant Staphylococcus aureus-infected patient with renal insufficiency.

The optimal dosage of linezolid to avoid hematologic toxicity is unknown. We report the case of an 87-y-old woman with renal insufficiency who developed a surgical site infection with refractory methicillin-resistant Staphylococcus aureus. The standard dosage of linezolid (1200 mg daily) was not initially tolerated by the patient due to severe thrombocytopenia, but she was successfully treated when the dose was reduced by half (600 mg daily) based on a population pharmacokinetic-pharmacodynamic model. Appropriate dose adjustments can be made to optimize linezolid therapy especially in cases with preexisting renal dysfunction.

Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure.

PURPOSE: The purpose of the present study was to explore the involvement of indoxyl sulfate (IS) in nephrotoxicity and central nervous system (CNS) toxicity in cisplatin (CDDP)-treated rats. MATERIALS AND METHODS: Renal function was evaluated by serum creatinine and BUN levels. The IS levels in the serum, brain and kidney was monitored by high-performance liquid chromatography method. Body weight and rectal temperature were monitored. Real-time PCR analysis was performed to examine rPer2 mRNA expression. RESULTS: Renal function deteriorated in a time-dependent manner after administration of CDDP. The concentration of IS in the serum, brain and kidney markedly increased 24-84 h after commencement of CDDP treatment. The observed increase in the levels of serum creatinine, BUN and IS was suppressed by concomitant administration of AST-120. Rectal temperature was significantly lowered 72-92 h after CDDP-treatment, which was partially restored by coadministration of AST-120. Moreover, the amplitude of rectal temperature rhythms was disrupted by treatment with CDDP. Circadian rhythm of rPer2 mRNA expression, a clock gene, in suprachiasmatic nucleus (SCN) and kidney was disturbed in CDDP-treated rats. CONCLUSIONS: An increase in the IS level and the associated disturbance to the circadian rhythm are involved in the renal and CNS toxicities in CDDP-treatment.

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.

Case study: differences in human Per2 gene expression, body temperature, cortisol, and melatonin parameters in remission and hypersomnia in a patient with recurrent hypersomnia.

Recurrent hypersomnia is characterized by recurring episodes of hypersomnia of 18 h or more per day lasting from several days to several weeks. We report the case of a 17-year-old male subject with recurrent hypersomnia who displayed change in the 24 h expression of the hPer2 gene in whole red and white blood cells as well as markers [deep body temperature (DBT) and cortisol] of the circadian time structure during an episode of hypersomnia compared to remission. The patient was studied for the temporal characteristics of hPer2 gene, DBT, cortisol, and melatonin expression during a single 24 h span during an episode of hypersomnia and again during a single 24 h span in the following remission. The approximation of a 24 h cosine curve to the time series data revealed circadian rhythmicity (P < 0.05) only in DBT in the two stages of the disease with differences in amplitude and acrophase. Cortisol circadian rhythmicity was detected during remission, but not during hypersomnia. Statistically significant differences were detected by ANOVA between the remission and active disease stages in the 24 h mean level of hPer2 gene expression (P < 0.05), cortisol (P < 0.05), and DBT (P < 0.05). The findings of this case study suggest the expression of hPer2 gene and alterations in circadian time structure might play an important role in the pathogenesis of recurrent hypersomnia, although additional study is required.

Trial of intraventricular ribavirin therapy for subacute sclerosing panencephalitis in Japan.

Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.

Bromocriptine reverses P-glycoprotein-mediated multidrug resistance in tumor cells.

One of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR). The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the MDR1 gene, which encodes a transmembrane glycoprotein named P-glycoprotein (P-gp). This study evaluated whether bromocriptine, a D2 dopaminergic receptor agonist, influenced anticancer drug cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. The K(i) values for P-gp of cyclosporine and verapamil were 1.09 and 540 microM, respectively, and that of bromocriptine was 6.52 microM in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 microM reduced the IC50 of doxorubicin (DXR) in K562-DXR from 9000 to 270 ng/ml and that of vincristine (VCR) in K562-VCR from 700 to 0.30 ng/ml, whereas the IC50 values of DXR and VCR in the K562 subline were only marginally affected by these drugs. Bromocriptine restored the anticancer effect of DXR, VCR, vinblastine, vinorelbine and etoposide on MDR-tumor cells overexpressing P-gp. These observations suggest that bromocriptine has the potential to reverse tumor MDR involving the efflux protein P-gp in the clinical situation.