External Evaluation of Population Pharmacokinetics and Pharmacodynamics in Linezolid-Induced Thrombocytopenia: The Transferability of Published Models to Different Hospitalized Patients.

BACKGROUND: The objective of this study was to perform an external evaluation of published linezolid population pharmacokinetic and pharmacodynamic models, to evaluate the predictive performance using an independent data set. Another aim was to offer an elegant environment for display and simulation of both the concentration and platelet count after linezolid administration. METHODS: We performed a systematic literature search in PubMed for all studies evaluating the population pharmacokinetic and pharmacodynamic parameters of linezolid in patients and selected the models to be used for the external validation. The bias of predictions was visually evaluated by plotting prediction errors (PEs) and relative PEs. The precision of prediction was evaluated by calculating the mean absolute error (MAE), root mean squared error (RMSE), and mean relative error (MRE). RESULTS: Three articles (models A, B, and C) provided linezolid-induced platelet dynamic models using population pharmacokinetic and pharmacodynamic modeling approaches. The PE and relative PE of both linezolid concentrations and platelet counts for models A and C showed similar predictive distributions. With respect to the prediction accuracy of total linezolid concentration, the MAE, RMSE, and MRE of population prediction values for model C was the smallest. The comparison of the MAE, RMSE, and MRE of patient-individual prediction values for the 3 pharmacodynamic models revealed no large differences. CONCLUSIONS: We confirmed the transferability of published population pharmacokinetic and pharmacodynamic models and showed that they were suitable for extrapolation to other hospitals and/or patients. This study also introduced application software based on model C for the therapeutic drug monitoring of linezolid.

Evaluation of the relationship between linezolid exposure and hyponatremia.

INTRODUCTION: Aims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background. METHOD: Clinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia. Mann-Whitney's U test was used to evaluate the effects of the area under the time-concentration curve (AUC) of linezolid at the nadir sodium level, clinical characteristics (e.g. laboratory data), and baseline serum sodium levels on the development of hyponatremia. RESULTS: The hyponatremia was occurred in 21 of 89 patients (23.6%). Data are compared for baseline and nadir serum sodium levels of patients with and without hyponatremia. In both groups, nadir serum sodium levels were significantly different from those of the baseline values (P < 0.05). The values of AUC0-12, accumulated AUC, baseline serum sodium levels and age were significantly different between patients with and without hyponatremia (P < 0.05). CONCLUSIONS: Linezolid exposure, age, and baseline sodium levels were detected as the risk factors for linezolid-related hyponatremia. Our findings suggest that regular monitoring of serum sodium levels is desirable during treatment with linezolid, especially for the elderly and patients with low serum sodium levels before the start of linezolid administration.

Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold.

A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.

Effects of Morinda citrifolia on Rheumatoid Arthritis in SKG Mice.

Morinda citrifolia L., known as noni, originated from Indonesia exhibits various pharmacological activities including anti-inflammatory properties. However, the validity of noni fruit juice as a treatment for rheumatoid arthritis (RA), an autoimmune disorder, has not been confirmed yet. Therefore, the main purpose of this research was to evaluate the efficacy of noni fruit juice (INFJ) made in Indonesia using SKG mice as an animal model of RA, which shows the resembling characteristics of human RA patients. Furthermore, the safety of INFJ was examined by repeated dose experiments in mice. INFJ was mixed with water at 50% and administered to SKG mice sensitized with mannan, free access for 4 weeks. Arthritis scores of fore- and hind-leg joints were measured and the joints were histopathologically examined. The sub-acute and sub-chronic toxicities of INFJ were evaluated using BALB/c mice. The arthritic scores were significantly lower from the 7 d after sensitization in the INFJ group than the control group. Histopathological examinations of the joints revealed inhibition of severity of RA. In both toxicity studies, INFJ did not show any toxicities. INFJ exhibited anti-arthritic activity in arthritic and histopathological examinations of the joints in SKG mice. Present study was the first report where noni juice may be effective against RA. The dose of noni juice showing efficacy against RA was confirmed safe from repeated dose studies in mice.

Pharmacokinetics, toxicity and clinical efficacy of linezolid in Japanese pediatric patients.

OBJECTIVES: The aims of the present study were (a) to evaluate the pharmacokinetics of linezolid, and (b) to assess the toxicity and clinical efficacy of linezolid in Japanese pediatric patients. PATIENTS AND METHODS: Routine clinical data including serum linezolid total and unbound concentrations were collected from 15 pediatric patients (0-13 years old). Pharmacokinetics of linezolid was assumed to follow one-compartment with the first-order absorption model. The relationship between risk for thrombocytopenia and linezolid concentrations, and the variations in C-reactive protein (CRP) concentrations and body temperatures were evaluated as clinical efficacy assessment. RESULTS: Body weight (WT) and maturation of body function were significant covariates for pharmacokinetics of linezolid in pediatric patients. The elimination half-life of linezolid in a pediatric patient with a WT of 9.9 kg and age of 24 months (median of this study) was 3.0 h. Thrombocytopenia was detected in three patients (21.4%), and the minimum concentrations (Cmin) in these patients were significantly higher than those in patients without thrombocytopenia (P < 0.05). The CRP concentrations decreased more than 50% in all pediatric patients after the treatment with linezolid, however body temperatures at the end of treatment were higher than 37.5 °C in 6 patients (42.9%). CONCLUSIONS: Although dose adjustment based on body size was performed for pediatric patients, thrombocytopenia was detected in 21.4% of pediatric patients, and higher Cmin was associated with the risk of thrombocytopenia. These results encourage the implementation of individual dose adjustment based on linezolid serum concentrations for safe and appropriate treatment with linezolid.

Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function.

OBJECTIVE: Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. METHODS: Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. RESULTS: The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4)-0.68 × Total body weight/600.81, omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. CONCLUSION: The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed.

Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression.

Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found thatIrp2mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCK(Δ19)) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCK(Δ19)expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor.

Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

AIMS: Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. METHODS: The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. RESULTS: About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. CONCLUSION: We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.

Pregabalin reduces cisplatin-induced mechanical allodynia in rats.

Although cisplatin (CDDP) is a key drug in cancer chemotherapy, CDDP-induced peripheral neuropathy is a dose-limiting factor. We previously reported that CDDP-induced peripheral neuropathy, which progressed from allodynia to hypoalgesia, was ameliorated by the administration of CDDP to rats at a specific time. However, mechanical allodynia cannot be prevented therapeutically. Pregabalin (PGN) is used to suppress neuropathic pain from herpes zoster and diabetes. Therefore, we investigated the effects of PGN on CDDP-induced mechanical allodynia in rats. CDDP (4 mg/kg) was administered intravenously to male Sprague-Dawley rats at 5:00 once a week for 2 weeks, while saline was given to the control group. PGN (10 mg/kg/day) was administered orally twice a day at 8:00 and 20:00, and distilled water was given to the control group. The von Frey and hot-plate tests were performed to assess CDDP-induced peripheral neuropathy. Withdrawal thresholds were significantly greater than those in with the CDDP alone group when PGN was administered before and after the onset of CDDP-induced mechanical allodynia. Furthermore, CDDP-induced mechanical allodynia was suppressed by the administration of PGN only. These results demonstrate that PGN effectively ameliorates CDDP-induced mechanical allodynia during the administration of PGN.

Influence of dosing times on cisplatin-induced peripheral neuropathy in rats.

BACKGROUND: Although cis-diamminedichloro-platinum (CDDP) exhibits strong therapeutic effects in cancer chemotherapy, its adverse effects such as peripheral neuropathy, nephropathy, and vomiting are dose-limiting factors. Previous studies reported that chronotherapy decreased CDDP-induced nephropathy and vomiting. In the present study, we investigated the influence of dosing times on CDDP-induced peripheral neuropathy in rats. METHODS: CDDP (4 mg/kg) was administered intravenously at 5:00 or 17:00 every 7 days for 4 weeks to male Sprague-Dawley rats, and saline was given to the control group. To assess the dosing time dependency of peripheral neuropathy, von-Frey test and hot-plate test were performed. RESULTS: In order to estimate hypoalgesia, the hot-plate test was performed in rats administered CDDP weekly for 4 weeks. On day 28, the withdrawal latency to thermal stimulation was significantly prolonged in the 17:00-treated group than in the control and 5:00-treated groups. When the von-Frey test was performed to assess mechanical allodynia, the withdrawal threshold was significantly lower in the 5:00 and 17:00-treated groups than in the control group on day 6 after the first CDDP dose. The 5:00-treated group maintained allodynia throughout the experiment with the repeated administration of CDDP, whereas the 17:00-treated group deteriorated from allodynia to hypoalgesia. CONCLUSIONS: It was revealed that the severe of CDDP-induced peripheral neuropathy was inhibited in the 5:00-treated group, whereas CDDP-treated groups exhibited mechanical allodynia. These results suggested that the selection of an optimal dosing time ameliorated CDDP-induced peripheral neuropathy.

Population Pharmacokinetic Approach to the Use of Low Dose Cyclosporine in Patients with Connective Tissue Diseases.

This study describes the population pharmacokinetics and dose personalization of cyclosporine in 36 patients with connective tissue diseases. A one-compartment open model with absorption was adopted as a pharmacokinetic model, and a nonlinear mixed effects model was used to analyze the population pharmacokinetic models. In the final model, age (AGE) and total body weight (TBW) were influential covariates on clearance (CL/F), which was expressed as CL/F (L/h)=17.8×(AGE/60)(-0.269)×(TBW/46.9)(0.408), in addition to the volume of distribution (Vd/F), (L)=98.0 and absorption rate constant (Ka) (h(-1))=0.67 (fixed). The results of the present study provide novel insights into factors involved in determining the most suitable dose and dosing strategy for individual patients with connective tissue disease.

[Rheumatoid arthritis].

Although many requirements must be met to establish a diagnosis of rheumatoid arthritis (RA), morning stiffness is a characteristic feature of RA. Inflammatory cytokines show high concentrations in human blood and synovial fluid of RA, and excess production of these cytokines plays a central role in the pathogenesis of RA. The inflammatory cytokines in blood also show circadian rhythms peaking from midnight to early morning, which mirrors the timing of morning stiffness. In the treatment of RA, steroids are used to reduce pain and inflammation, and methotrexate are used prior to the development of destructive changes in bones, joints, and organ tissues. In this chapter, I would like to introduce the circadian rhythm of RA and the chronotherapies.

Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress.

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin. Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR. We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia. Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans.

Comparison of the efficacy of anti-diabetic medications as add-on to metformin in type 2 diabetes mellitus from a real-world database.

BACKGROUND: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. METHODS: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. RESULTS: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). CONCLUSIONS: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c.

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVE: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. METHODS: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. RESULTS: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. CONCLUSIONS: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

Chronopharmacology of mizoribine in collagen-induced arthritis rats.

We previously reported that higher therapeutic effects were obtained in rheumatoid arthritis (RA) patients and RA model animals when the dosing-times of methotrexate and tacrolimus were chosen according to the 24-h rhythms of the inflammatory response. Mizoribine (MZR) is an immunosuppressive agent and is used against RA in the same manner as methotrexate and tacrolimus. In this study, we examined whether a dosing-time dependency of the therapeutic effect of MZR could be detected in collagen-induced arthritis (CIA) rats. To measure C-reactive protein (CRP) and tumor necrosis factor (TNF)-α levels, blood was collected from CIA rats at different times. MZR was administered at two different dosing-times based on these findings and its effects and toxicity were examined. CRP and TNF-α concentrations in blood showed significant 24-h rhythms. The exacerbation of arthritis and excessive increase in leukocytes in CIA rats were markedly lower in the group treated with MZR at the dark phase than those of the group treated with MZR at the light phase. These findings suggest that the therapeutic index of RA therapy may be improved by administering MZR at a time in the day when the inflammatory reaction begins to activate.

Formulation and In Vitro Characterization of a Vacuum-Dried Drug-Polymer Thin Film for Intranasal Application.

Intranasal drug applications show significant therapeutic potential for diverse pharmaceutical modalities. Because the formulation applied to the nasal cavity is discharged to the pharyngeal side by mucociliary clearance, the formulation should be dissolved effectively in a limited amount of mucus within its retention time in the nasal cavity. In this study, to develop novel formulations with improved dissolution behavior and compatibility with the intranasal environment, a thin-film formulation including drug and polymer was prepared using a vacuum-drying method. The poorly water-soluble drugs ketoprofen, flurbiprofen, ibuprofen, and loxoprofen were dissolved in a solvent comprising water and methanol, and evaporated to obtain a thin film. Physical analyses using differential scanning calorimetry (DSC), powder X-ray diffraction analysis (PXRD), and scanning electron microscopy SEM revealed that the formulations were amorphized in the film. The dissolution behavior of the drugs was investigated using an in vitro evaluation system that mimicked the intranasal physiological environment. The amorphization of drugs formulated with polymers into thin films using the vacuum-drying method improved the dissolution rate in artificial nasal fluid. Therefore, the thin film developed in this study can be safely and effectively used for intranasal drug application.

Development of In Vitro Evaluation System for Assessing Drug Dissolution Considering Physiological Environment in Nasal Cavity.

Estimating the dissolution behavior of a solid in the nasal mucus is challenging for solid dosage forms designed for the nasal application as the solid dissolves into nasal mucus and permeates through the mucosa. In the current study, the dissolution behavior of powders in the artificial nasal fluid was investigated using a 3D-printed chamber system to establish in vitro evaluation system for the dissolution of solid formulations that can simulate the intranasal environment in vivo. The dissolution rates of the five model drugs correlated with their solubility (r2 = 0.956, p < 0.01). The permeation rate of drugs across the Calu-3 cell layers after powder application depends on the membrane permeability of the drug. An analysis of membrane permeability considering the dissolution of powders showed the possibility of characterizing whether the drug in the powder was dissolution-limited or permeation-limited. This suggests that critical information can be obtained to understand which mechanism is more effective for the improvement of drug absorption from powders. This study indicates that the elucidation of drug dissolution behavior into nasal mucus is an important factor for the formulation of nasal powders and that the in vitro system developed could be a useful tool.

Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity.

We revealed that pre-treatment with docetaxel (DOC) 12 h before adriamycin (ADR) administration significantly reduced ADR-induced toxic death compared with the simultaneous dosing schedule that was commonly used in previous studies. We considered that pre-treatment with DOC relieves ADR-induced cardiotoxicity. In this study, we investigated the influence of DOC on the pharmacokinetics and pharmacodynamics of ADR in order to clarify the mechanism by which DOC pre-treatment relieves ADR-induced cardiotoxicity. When ADR and/or DOC was intravenously administered, the DOC pre-treatment (DOC-ADR) group showed significantly less toxic death than the ADR-alone group. We examined hepatopathy, nephropathy, leukopenia, and cardiotoxicity, all of which can cause toxic death. Of these toxicities, ADR-induced cardiotoxicity was significantly relieved in the DOC-ADR group. To elucidate the mechanism by which DOC pre-treatment relieved ADR-induced cardiotoxicity, lipid peroxidation as a proxy for the free radical level and the pharmacokinetics of ADR were measured. There was no difference in the pharmacokinetics of ADR between the ADR and DOC-ADR groups. On the other hand, the DOC-ADR group showed significantly inhibited lipid peroxidation in the heart compared with the ADR group. It was considered that DOC pre-administration inhibited ADR-induced free radicals and decreased cardiotoxicity.

Dosing time-dependency of the arthritis-inhibiting effect of tacrolimus in mice.

Stiffness and cytokine in blood levels show 24-h rhythms in rheumatoid arthritis (RA) patients. We previously revealed that higher therapeutic effects were obtained in RA patients and RA model animals when the dosing time of methotrexate was chosen according to the 24-h rhythms to cytokine. In this study, we examined whether a dosing time-dependency of the therapeutic effect of tacrolimus (TAC) could be detected in collagen-induced arthritis (CIA) and MRL/lpr mice. To measure the levels of cytokines and serum amyloid A (SAA), blood was collected from CIA mice at different times. TAC was administered at two different dosing times based on these findings and its effects on arthritis and toxicity were examined. Plasma tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and SAA concentrations showed obvious 24-h rhythms with higher levels during the light phase and lower levels during the dark phase after RA crisis. The arthritis score and leukocyte counts were significantly lower in the group treated at 2 h after the light was turned on (HALO) than in the control and 14 HALO-treated groups. Our findings suggest that choosing an optimal dosing time could lead to the effective treatment of RA by TAC.