Yoshiharu Karube

Vitamin E isoforms α-tocotrienol and γ-tocopherol prevent cerebral infarction in mice

Abstract α-tocopherol and its derivatives have been shown to be effective in reducing cerebral ischemia-induced brain damage. However, the effects of other vitamin E isoforms have not been characterized. In the present study, we investigated the effects of six different isoforms of vitamin E on the ischemic brain damage in the mice middle cerebral artery (MCA) occlusion model. All vitamin E isoforms were injected i.v., twice, immediately before and 3 h after the occlusion. α-tocopherol (2 mM), α-tocotrienol (0.2 and 2 mM) and γ-tocopherol (0.2 and 2 mM) significantly decreased the size of the cerebral infarcts 1 day after the MCA occlusion, while γ-tocotrienol, δ-tocopherol and δ-tocotrienol showed no effect on the cerebral infarcts. These results suggest that α-tocotrienol and γ-tocopherol are potent and effective agents for preventing cerebral infarction induced by MCA occlusion.

Correlation between serum linezolid concentration and the development of thrombocytopenia

Abstract We evaluated the possible association between trough linezolid (LZD) concentrations and platelet counts using a dose–response curve with a logit model equation. We demonstrated that trough LZD concentrations correlated with platelet counts. A significant decrease in platelet count was observed in patients with trough LZD concentrations higher than 22.1 μg/ml.

Pharmacokinetics of repeated dosing of linezolid in a hemodialysis patient with chronic renal failure.

Linezolid (LZD) is thought not to require dose adjustment in patients with renal dysfunction, making it a drug of choice for these patients. However, in the current study we show LZD accumulation occurring with repeated dosing during hemodialysis in a 64-year-old man receiving hemodialysis treatment. In this patient, methicillin-resistant Staphylococcus aureus (MRSA) caused an abscess under the abdominal wall due to wound infection after colon cancer surgery. Treatment was initiated with intravenous LZD (600 mg) every 12 h. However, pancytopenia and liver dysfunction occurred during the LZD administration period. A high trough level, of 15–20 μg/ml, during LZD administration was determined from stored blood biochemistry samples, and pharmacokinetic parameters, estimated by the Bayesian nonlinear least squares method, were as follows: clearance (CL), 1.56 l/h; clearance during hemodialysis (CLHD), 2.23 l/h; volume of distribution (Vd), 18.69 l; and area under the curve (AUC), 384.07 μg/ml · h. Simulation of the serum concentration-time profile from the estimated pharmacokinetic parameters gave a trough level about four to five times higher than that in healthy individuals in the early administration period, indicating LZD accumulation in blood. These findings suggest a causal relationship between the high LZD level and the adverse effects. The cause of the high LZD level is unclear, but the findings indicate that careful monitoring and dose adjustment of LZD is necessary in hemodialysis patients.

Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient

Abstract We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m2). Linezolid was administered at a dose of 600 mg by intravenous drip infusion for 60–90 min at 12-h intervals. The results showed increased clearance of linezolid and a reduced serum concentration compared to population pharmacokinetic parameters, with trough levels below the 90% minimum inhibitory concentration. However, linezolid was effective for improving lung infection and inflammation in our patient, which may be due to its particularly effective transfer into lung tissues. Linezolid undergoes slow non-enzymatic oxidation in vivo that may be increased in obese patients, and this may account for the greater clearance. Our findings are useful for the planning of linezolid therapy in obese patients.

Population Pharmacokinetic Analysis of Linezolid in Low Body Weight Patients with Renal Dysfunction

Linezolid has antibacterial activity against aerobic Gram‐positive cocci, including methicillin‐resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high‐performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR0.428 × HB0.502 × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR0.428 × HB0.502 (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.

Inhibition of nerve growth factor-induced neurite outgrowth from PC12 cells by dexamethasone: signaling pathways through the glucocorticoid receptor and phosphorylated Akt and ERK1/2.

Glucocorticoids are important mediators of the stress response and are commonly employed as drugs for the suppression of immune rejection after organ transplantation. Previous investigations uncovered the possibility of mood depression in patients undergoing long-term treatment with synthetic glucocorticoids, including dexamethasone (DEX). Exogenous glucocorticoids and their synthetic derivatives can also adversely affect the development of the central nervous system. Although neurite extension from rat pheochromocytoma-derived PC12 cells and a variety of primary neurons is stimulated by nerve growth factor (NGF), and signaling pathways triggered by the binding of NGF to tyrosine kinase receptor type 1 (TrkA) function in both neurite outgrowth and neuronal survival, the effect of DEX on the activation of regulatory proteins and pathways downstream of TrkA has not been well characterized. To analyze the influence of DEX on NGF-induced neurite outgrowth and signaling, PC12 cells, a widely utilized model of neuronal differentiation, were pretreated with the glucocorticoid prior to NGF induction. NGF-induced neurite outgrowth was attenuated by pretreatment with DEX, even in the absence of DEX after the addition of NGF. Moreover, DEX suppressed the phosphorylation of Akt and extracellular-regulated kinase 1/2 (ERK1/2) in the neurite outgrowth signaling cascade initiated by NGF. Finally, the glucocorticoid receptor (GR) antagonist, RU38486, counteracted the inhibitory effect of DEX pretreatment, not only on the phosphorylation of Akt and ERK1/2, but also on neurite extension from PC12 cells. These results suggest that DEX binding to the GR impairs NGF-promoted neurite outgrowth by interfering with the activation/phosphorylation of Akt and ERK1/2. These novel findings are likely to be useful for elucidating the central nervous system depressive mechanism(s) of action of DEX and other glucocorticoids.

Influence of Linezolid Clearance on the Induction of Thrombocytopenia and Reduction of Hemoglobin

Introduction:Although linezolid (LZD) has proven effective for the treatment of infections caused by multidrug-resistant Gram-positive cocci, thrombocytopenia and anemia associated with reduced hemoglobin (Hb) levels are common side effects. To study the association between the development of these adverse effects and blood LZD levels, the authors evaluated the correlation between LZD clearance (LZD-CL), platelet (PLT) counts and Hb levels. Methods:Sixteen patients with methicillin-resistant Staphylococcus aureus infection were administered LZD over a period of 4 to 41 days, and blood was collected at variable time points beginning on day 4 (n = 31). Blood LZD levels were measured by high-performance liquid chromatography, and LZD-CL was estimated by the population pharmacokinetics mean parameter and Bayesian methods. The relationship between the estimated LZD-CL and reductions in PLT counts and Hb levels was then evaluated by regression analysis. Results:During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r2 = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r2 = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. Conclusions:In patients undergoing treatment with LZD, low LZD-CL rates correlated with reductions of both PLT counts and Hb levels, suggesting that increase of blood LZD levels influences hematopoietic function. Because a strong correlation was noted between LZD-CL and Hb levels, closely monitoring changes in Hb levels during treatment with LZD may detect the development of adverse effects such as thrombocytopenia and anemia.

Successful treatment of skin and soft tissue infection due to carbapenem-resistant Acinetobacter baumannii by ampicillin–sulbactam and meropenem combination therapy

In recent years, carbapenem-resistant Acinetobacter baumannii infections have been responsible for outbreaks in medical facilities. A 35-year-old Japanese woman developed a skin and soft tissue infection due to carbapenem-resistant A. baumannii. The isolate was resistant to antibiotics other than ampicillin-sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23. We selected a combination therapy consisting of intravenous ampicillin-sulbactam and meropenem. No changes were observed in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, or serum creatinine during therapy, and carbapenem-resistant A. baumannii was not detected in wound exudates 3 days after therapy initiation. In our patients case, combination therapy with ampicillin-sulbactam and meropenem was successful. Thus, combination therapy with ampicillin-sulbactam and meropenem is effective against skin and soft tissue infection due to carbapenem-resistant A. baumannii. Combination therapy with intravenous ampicillin-sulbactam and meropenem may be an option for skin and soft tissue infections due to carbapenem-resistant A. baumannii.

Preparation and In Vivo Evaluation of a Water-Soluble Prodrug for 2R-γ-Tocotrienol and as a Two-Step Prodrug for 2,7,8-Trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC) in Rat

2R-γ-Tocotrienol (γ-T3) is currently receiving attention because it has beneficial effects not observed with α-tocopherol. To achieve the effective delivery of γ-T3, we synthesized three kinds of ester derivatives of γ-T3 and evaluated their use as hydrophilic prodrugs for γ-T3 in vitro and in vivo. 2R-γ-Tocotrienyl N,N-dimethylamino-acetate hydrochloride (compound 3) was a solid compound, with high solubility and stability in water, and was converted to γ-T3 by esterases in rat and human liver. Intravenous administration of 3 in rats led to a rapid increase in the plasma, liver, heart, and kidney levels of γ-T3. The bioavailability (plasma level) after intravenous administration was 82.5 ± 13.4% and 100 ± 11.3% for 3 and γ-T3 in surfactant, respectively, and the availability in liver was 213 ± 47.6% and 100 ± 4.8% for 3 and γ-T3 in surfactant, respectively. Furthermore, the systemic availability of 2,7,8-trimethyl-2S-(β-carboxyethyl)-6-hydroxychroman (S-γ-CEHC), a metabolite of γ-T3, was 78.6% for compound 3, 47.1% for γ-T3 in surfactant, and 100% for racemic γ-CEHC. Based on these results, we identified compound 3 as the most promising water-soluble prodrug of γ-T3 and two-step prodrug of S-γ-CEHC.

Delivery systems for antioxidant nutrients

The novel role of oxidants and antioxidants as part of cell signaling cascades has opened new areas of research in several disease states and their therapeutic strategies. For successful therapeutic manipulation of reactive oxygen species (ROS)-mediated cellular signaling pathways, it would necessitate control of the critical balance of oxidants/antioxidants in the target site by the antioxidant. Another way of controlling the critical balance is to avoid excessive generation of ROS from nutrients and/or drugs. From the viewpoint of controlling the balance between the oxidant and antioxidant status, this review focuses on the prodrug approach for delivery systems of vitamin E, a major antioxidant nutrient in the membrane, and on the reductive activation-independent delivery system of vitamin K hydroquinone by a prodrug approach, which can avoid excessive generation of ROS synchronized with the activation process of vitamin K.