Effect of S-1 on pharmacokinetics of irinotecan in a patient with colorectal cancer.
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Antimetabolites, Antineoplastic↗
Biomedical subjects
Akinobu Hamada
Publications and source records attributed to Akinobu Hamada.
Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients.
Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng . h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/- 4.6% (mean +/- SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.
Aged↗
Phase I and pharmacokinetic study of amrubicin, a synthetic 9-aminoanthracycline, in patients with refractory or relapsed lung cancer.
Amrubicin is a novel synthetic 9-aminoanthracycline derivative and is converted enzymatically to its C-13 hydroxy metabolite, amrubicinol, whose cytotoxic activity is 10-100 times that of amrubicin. We aimed to determine the maximum tolerated dose (MTD) of amrubicin and to characterize the pharmacokinetics of amrubicin and amrubicinol in previously treated patients with refractory or relapsed lung cancer. The 15 patients were treated with amrubicin intravenously at doses of 30, 35, or 40 mg/m(2) on three consecutive days every 3 weeks for a total of 43 courses. Neutropenia was the major toxicity (grade 4, 67%). The MTD was 40 mg/m(2), with the specific dose-limiting toxicities being grade 4 neutropenia persisting for >4 days, febrile neutropenia, or grade 3 arrhythmia in the three patients treated at this dose. A patient with non-small-cell lung cancer showed a partial response, and ten individuals experienced a stable disease. The area under the plasma concentration versus time curve (AUC) for amrubicin and that for amrubicinol increased with amrubicin dose. The amrubicin AUC was significantly correlated with the amrubicinol AUC. The recommended phase II dose of amrubicin for patients with lung cancer refractory to standard chemotherapy is thus 35 mg/m(2) once a day for three consecutive days every 3 weeks.
Aged↗
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.
ARNTL Transcription Factors↗
Pharmacokinetic changes of irinotecan by intestinal alkalinization in an advanced colorectal cancer patient.
The prevention of irinotecan (CPT-11)-induced diarrhea, a well-known adverse reaction to the drug, by treatment with intestinal alkalinization has been carried out in patients with colorectal cancer in Japan. Under acidic conditions, CPT-11 and its active metabolite, SN-38, exists preferably as the lactone form, whereas both exist as the carboxylate form under basic conditions. It has been suggested that the lactone forms of both CPT-11 and SN-38 are diffused passively across the intestinal mucosal membranes, whereas the carboxylate forms are actively transported. The intestinal uptake rate of both forms appears to be pH sensitive under physiological conditions, but it remains unclear whether intestinal alkalinization treatment affects the pharmacokinetics of CPT-11 and SN-38. This study was designed to evaluate the pharmacokinetics of CPT-11 and SN-38 in a colorectal cancer patient with or without alkalinization treatment. We found that intestinal alkalinization significantly decreased the plasma levels of CPT-11 and SN-38. In particular, the AUC of SN-38 was markedly decreased to 56 from 107 ng.h/mL. Intestinal alkalinization was effective in preventing CPT-11-induced diarrhea, but this treatment changed the pharmacokinetics of CPT-11 and SN-38 in the body.
Antineoplastic Agents, Phytogenic↗
[Development of an individualized therapy for establishing the optimal dosage by the pharmacokinetics profiles of anticancer agents].
Therapeutic drug monitoring (TDM) is widely applied to a variety of medications, including antibiotics, immunosuppressants, and antidepressants, but the clinical utility of TDM for anticancer agents is currently limited by several factors. The primary reason is the poorly-defined concentration-effect relationships for most anticancer drugs. TDM has the potential to improve the clinical use of anticancer agents. This paper reviews the relations between the pharmacokinetics of a new anticancer agent, amrubicin, and the clinical response and toxic side effects in patients. The plasma concentration of amrubicin peaked immediately after a bolus intravenous injection of the drug and declined in a biexponential manner thereafter, whereas that of C-13 hydroxy metabolite amrubicinol also peaked just after amrubicin injection but decreased more gradually compared with that of amrubicin. The apparent total clearance of amrubicin showed a large interindividual variability, despite adjustment of dosage for body surface area. Leukocytopenia of grades 3 or 4 occurred in most patients, and thrombocytopenia and anemia of grades 3 or 4 were also common. Since the area-under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematological toxicities, it is thought that the plasma concentration of amrubicin and amrubicinol may provide useful information for establishing the optimal dosage of amrubicin in each patient.
Aged↗
Assessment of adverse reactions and pharmacokinetics of ribavirin in combination with interferon alpha-2b in patients with chronic hepatitis C.
Ribavirin has recently been demonstrated to be efficacious in combination with interferon (IFN) alpha-2b for the treatment of relapsed hepatitis C infections. The aim of this study was to evaluate the relationship between the pharmacokinetics and adverse reactions of ribavirin when ribavirin plus IFN alpha-2b were administered to patients affected with chronic hepatitis C. Nineteen patients received intramuscular IFN alpha-2b at a dose of 6 or 10 million units and oral ribavirin at 600 mg or 800 mg daily for 24 weeks. The pharmacokinetic profiles of ribavirin were assessed by the measurement of plasma concentrations. Twelve patients were continuously given both ribavirin and IFN alpha-2b, whereas in 7 patients the therapy was discontinued due to severe adverse drug reactions such as skin eruption, anemia and depression. There were no significant differences in ribavirin dose, Hb, ALT and AST values between the continued and the discontinued therapy groups. In contrast, the pretreatment platelet level and patient age of the discontinued therapy group were significantly different to the continued group. The trough plasma concentration of ribavirin in the discontinued therapy group was significantly higher than that in the continued group at week 1. These results suggest that the monitoring of plasma ribavirin concentrations may be valid for predicting the early phase of adverse drug reactions, thereby providing useful information for the adjustment of the ribavirin dosing for each patient.
Adult↗
Interaction of imatinib mesilate with human P-glycoprotein.
The interaction of imatinib mesilate with P-glycoprotein (P-gp) was examined using pig kidney epithelial LLC-PK1 cells versus L-MDR1 cells, which overexpress human P-gp on the apical membrane. The basal-to-apical transport of imatinib mesilate in L-MDR1 cells significantly exceeded that in the parental LLCPK1 cells. The intracellular accumulation of imatinib mesilate after its basal application to LLC-PK1 and L-MDR1 cells was 35% and 15%, respectively. A P-gp modulator, cyclosporin A, inhibited the basal-to-apical transport in L-MDR1 cells. The intracellular accumulation of imatinib mesilate in L-MDR1 cells was also increased by cyclosporin A. The rhodamine 123 efflux assay showed that the efflux of rhodamine 123 in K562/DXR cells, which overexpress human P-gp, could be blocked markedly by imatinib mesilate in a dose-dependent fashion. The Ki values for the inhibition of P-gp function by cyclosporin A and imatinib mesilate were estimated to be 6.1 and 18.3 muM, respectively, using a calcein-AM efflux assay. These observations demonstrate that imatinib mesilate is a substrate as well as a modulator of human P-gp, suggesting that imatinib mesilate drug interactions may occur via P-gp. It is necessary to consider the pharmacokinetic and pharmacodynamic interactions of imatinib mesilate with other drugs via P-gp.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor.
High expression of the inducible isoform of heme oxygenase (HO-1) is now well known in solid tumors in humans and experimental animal models. We reported previously that HO-1 may be involved in tumor growth (Tanaka et al., Br. J. Cancer, 88: 902-909, 2003), in that inhibition of HO activity in tumors by using zinc protoporphyrin (ZnPP) significantly reduced tumor growth in a rat model. We demonstrate here that poly(ethylene glycol)-conjugated ZnPP (PEG-ZnPP), a water-soluble derivative of ZnPP, exhibited potent HO inhibitory activity and had an antitumor effect in vivo. In vitro studies with cultured SW480 cells, which express HO-1, showed that PEG-ZnPP induced oxidative stress, and consequently apoptotic death, of these cells. Pharmacokinetic analysis revealed that PEG-ZnPP-administered i.v. had a circulation time in blood that was 40 times longer than that for nonpegylated ZnPP. More important, PEG-ZnPP preferentially accumulated in solid tumor tissue in a murine model. In vivo treatment with PEG-ZnPP (equivalent to 1.5 or 5 mg of ZnPP/kg, i.v., injected daily for 6 days) remarkably suppressed the growth of Sarcoma 180 tumors implanted in the dorsal skin of ddY mice without any apparent side effects. In addition, this PEG-ZnPP treatment produced tumor-selective suppression of HO activity as well as induction of apoptosis. The major reason for tumor-selective targeting of PEG-ZnPP is attributed to the enhanced permeability and retention effect that is observed commonly in solid tumors for biocompatible macromolecular drugs. These findings suggest that tumor-targeted inhibition of HO activity could be achieved by using PEG-ZnPP, which induces apoptosis in solid tumors, probably through increased oxidative stress.
Animals↗
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.
Adolescent↗
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.
Adolescent↗
Evaluation of percutaneous absorption of midazolam by terpenes.
Midazolam is a highly lipophilic drug that is widely used in preanesthetic medication. Recently, terpenes have been reported to show an enhancing effect on percutaneous absorption of drugs. The effect of terpenes (l-menthol, d-limonene, RS-(+/-)-beta-citronellol, geraniol) on the in vitro percutaneous absorption of midazolam through rat skin was evaluated using unjacketed Franz diffusion cells. Since midazolam is a lipophilic drug, percutaneous penetration is low and a percutaneous penetration enhancer is necessary for its percutaneous absorption. The terpenes (5%, w/v) in combination with 30% ethanol, and 20% propylene glycol significantly increased the percutaneous absorption of midazolam in comparison to the control. In vitro data suggested that d-limonene is the most effective enhancer among terpenes and other penetration enhancers such as Azone. In in vivo percutaneous absorption assays, the midazolam formulation using d-limonene could penetrate through rat skin, but the other terpenes could not penetrate. In conclusion, d-limonene in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug midazolam.
Journal Article↗
[Trial of intraventricular ribavirin and interferon-alpha combination therapy for subacute sclerosing panencephalitis (SSPE) in Japan].
A survey was made on 10 patients with subacute sclerosing panencephalitis (SSPE) during the last four years from the viewpoint of clinical safety of ribavirin therapy in Japan. Although the age of onset, latent period, and effectiveness were variable among the cases, they were treated safely with intraventricular ribavirin combined with high doses of interferon (IFN). Their clinical stages on admission ranged from the first to fourth of Jabbour's classification, and those on the beginning of ribavirin therapy also ranged from the first to fourth. Seven of them were first treated with intraventricular IFN-alpha monotherapy, however, the combination of intraventricular IFN-alpha and ribavirin was started after clinical worsening. Although 5 patients showed slow progression, seven responded to the therapy with clinical improvement or decreased measles antibody titers in the CSF. Especially, one patient showed improvement to Jabbour's first stage and no further progression during the following 3 years. Ribavirin therapy caused no severe effects. Lip swelling (50%), sleepiness (40%), and headache (30%) were noted. Although we were unable to perform a double-blinded clinical study for ethical reasons, our results suggest that treatment with intraventricular ribavirin and high doses of IFN may be effective for SSPE. Early administration of intraventricular ribavirin and IFN might be considered especially to IFN in non-responders. To establish this combination therapy as a safe and effective treatment of SSPE, further studies are necessary on the role of ribavirin in the pathogenesis as well as its effects in the central nervous system.
Adolescent↗
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.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Clinical pharmacokinetics of cytarabine formulations.
Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukaemia and lymphocytic leukaemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biologically inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivatives of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degradation and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivatives have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clinically in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compounds have been investigated, few cytarabine derivatives are currently available for clinical use. Further research is needed to improve the efficacy of cytarabine against haematological and solid tumours.
Animals↗