Vancomycin (VCM), a glycopeptide antibiotic, was developed and released in the 1950's for the treatment of aerobic gram-positive infections and has been widely used mainly in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Early reports regarding the possibility of nephrotoxicity and ototoxicity led to concern about the use of VCM and monitor serum VCM concentrations.In general, the purposes of therapeutic drug monitoring (TDM) are to improve clinical effects, to avoid side effects, and to reduce drug costs. In the case of VCM, however, an exhaustive review of the literature revealed that there are no studies analyzing a direct effect of serum VCM concentrations and clinical outcome.1-3) There have been a few studies examining the minimum inhibitory concentration (MIC)/ minimum bactericidal concentration (MBC) ratios and cure rates, 4-6) these studies are not efficient to answer the question what concentration of VCM was required for the successful treatment of infections. Recently, some clinical reports evaluating the TDM of VCM have proposed the following conclusions: 1) TDM is associated with a decreased incidence of VCM-induced nephrotoxicity, indicating that TDM is a cost-effective procedure, 1,[7][8][9] and 2) VCM works most effectively if the concentration at the site of infection is maintained above MIC values throughout the dose interval. So, the clinical efficacy of VCM can usually be obtained if the trough concentration is sufficiently above the MIC at the site of infected organisms. 10,11) Since the MIC values for susceptible organisms were below 5 mg/ml and reported toxicities had occurred most often at drug serum concentrations above 40 mg/ml, clinicians and researchers designated therapeutic trough concentrations at 5-15 mg/ml and peak concentrations at 25-40 mg/ml. 1,[12][13][14] In practice, however, the peak concentration hardly exceeds 40 mg/ml, as long as the trough concentration is kept below 15 mg/ml. 15) For this reason, the policy of monitoring the trough concentration alone for VCM has recently spread worldwide. In Japan, however, both the trough and peak concentrations of VCM are monitored in most of hospitals. Therefore, it would be worthwhile to investigate whether monitoring peak concentration is essential or not.The purpose of the present study was to investigate the clinical utility of the TDM VCM and the relationship between its peak concentrations and clinical effects in MRSAinfected patients. MATERIALS AND METHODS Subjects and Study DesignSubjects (0-86 years of age) in this retrospective study were MRSA-infected patients who received intravenous infusion of VCM (Shionogi & Co., Ltd., Osaka, Japan) from January 1996 to March 2002 and also had confirmed the disappearance of the bacteria thereafter.The incidence of nephrotoxicity, including VCM-induced or MRSA-related nephrotoxicity, was compared between the TDM group (nϭ73) and the non-TDM group (nϭ111). Serum VCM concentrations in the TDM group were monitored within 10 d from the start of VCM ther...
A close relationship among postprandial hyperglycemia, advanced age, and hypercholesterolemia is a characteristic of SDM in patients with neurologic diseases. Therefore, monitoring the plasma glucose concentration 2 hours after lunch may be useful to detect SDM in these patients.
SUMMARYPurpose: To identify risk factors for hyperammonemia in pediatric patients with epilepsy. Methods: A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 lg/dl with reference to the standard range and previous reports. Key Findings: The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 lg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide. Significance: A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia. KEY WORDS: Hyperammonemia, Epilepsy, Children, Risk factor, Valproic acid, Phenytoin.Hyperammonemia is a frequent problem associated with antiepileptic drugs (AEDs) that can lead to vomiting, aggression, ataxia, and exacerbation of seizures. Acute hyperammonemia can also cause cerebral edema and severe brain damage (encephalopathy), whereas chronic hyperammonemia due to metabolic disorders is associated with developmental delay and intellectual disability (Cagnon & Braissant, 2007;Lichter-Konecki, 2008). Among the AEDs, valproic acid (VPA) is recommended as a first-line treatment for generalized epilepsy. Although VPA can cause an increase of the blood ammonia level, VPA therapy is rarely associated with hyperammonemic encephalopathy.The exact relationship between symptoms and the ammonia level remains unclear. Murphy and Marquardt (1982) reported that patients with hyperammonemia not exceeding 240 lg/dl were asymptomatic. In contrast, Coulter and Allen (1981) recommended reducing the VPA dose when the ammonia level exceeded 100 lg/dl. Our data (see later) indicate that hyperammo...
There is a large interindividual variation in CD ratio of perampanel because its metabolism is highly susceptible to interactions with enzyme-inducing AEDs. Therapeutic drug monitoring could be clinically useful for determining the influence of AED CYP3A4 inducers on perampanel concentrations.
Hyperglycemia is a persistent symptom of diabetes mellitus. The complex pathogenesis of type 2 diabetes involves the progressive development of insulin resistance and defective insulin secretion, which leads to overt hyperglycemia. 1)These pathological states are mostly attributable to life styles and genetic background, 2) and various animal models of diabetes have been developed and investigated to clarify the mechanisms by which hyperglycemia is induced. [3][4][5][6][7][8] We previously showed that sustained hyperglycemia could be induced in ddY mice by refeeding with standard chow pellets after fasting for 48 h. 9) We proposed that, in this case, hyperglycemia was induced by defects in insulin secretion and action, and maintained by the resulting insulin resistance. However glucose levels and the duration of hyperglycemia were variable in individual mice. Since then, we have attempted to select those mice with induced serious hyperglycemia by selective breeding based on serum glucose levels after refeeding. Two strains, namely, spontaneous insulin resistant mice (ddY-H) and none insulin resistant mice (ddY-L), have been isolated from ddY mice by inbreeding. In this study, we investigated the characteristics of these mice. MATERIALS AND METHODSAnimal Care Four-week-old male ddY mice were purchased from SLC Inc. (Hamamatsu, Japan), and ddY-H and ddY-L mice from our own colony were used. Mice were maintained on 12 h light/dark cycles with free access to standard chow pellets (MF diet, Oriental Yeast Co., Ltd., Tokyo, Japan) and water ad libitum until the experiments were carried out. Animal care and experiments were performed in accordance with the guidelines for the care and use of laboratory animals of the University of Shizuoka, Japan.Fasting and Refeeding Fasting commenced by removing the chow pellets from mouse home cages at 21:00. After 48 h, mice were refed standard chow pellets for 12 h and blood was obtained from the caudal vein for the determination of serum glucose level. In some experiments, mice were fasted for 12 h and refed for 1 h as described above.Oral Glucose Tolerance Oral glucose tolerance test was carried out as described previously.9) Briefly, mice were orally administered with glucose (3 g/kg) and blood was withdrawn from caudal veins 0, 30, 60 and 120 min later to measure serum glucose level.Measurement of Serum Glucose and Insulin Levels Serum glucose and insulin levels were determined using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd., Osaka, Japan) and the Insulin ELISA kit (Morinaga Institute of Biological Sciences, Inc., Kanagawa, Japan), respectively, according to manufacturer's instructions.Insulin Sensitivity and Insulin Resistance Insulin sensitivity and insulin resistance were calculated from glucose and insulin levels in the serum of mice fasted for 12 h (21:00-9:00) as follows: glucose (mg/dl)/insulin (ng/dl) and glucose (mg/dl)ϫinsulin (ng/dl)/100, respectively. 10,11)Cross-Mating between ddY-H Mice and ddY-L Mice ddY-H mice and ddY-L mice at 10 weeks of age w...
Romidepsin (FK228) is a potent histone deacetylase (HDAC) inhibitor, which has a potent anticancer activity, but its molecular mechanism is unknown. We investigated the mechanism of FK228-induced apoptosis in the human leukemia cell line HL-60 and its hydrogen peroxide (H 2 O 2 )-resistant sub-clone, HP100, and the human colon cancer cell line Caco-2. Cytotoxicity and DNA ladder formation induced by FK228 could be detected in HL-60 cells after a 24-h incubation, whereas they could not be detected in HP100 cells. Trichostatin A (TSA), an HDAC inhibitor, induced DNA ladder formation in both HL-60 and HP100 cells. In contrast, FK228 inhibited HDAC activity in both HL-60 and HP100 cells to a similar extent. These findings suggest that FK228-induced apoptosis involves H 2 O 2 -mediated pathways and that TSA-induced apoptosis does not. Flow cytometry revealed H 2 O 2 formation and a change in mitochondrial membrane potential (Dwm) in FK228-treated cells. FK228 also induced apoptosis in Caco-2 cells, which was prevented by N-acetyl-cysteine, suggesting that reactive oxygen species participate in apoptosis in various types of tumor cells. Interestingly, in a cell-free system, FK228 generated superoxide (O 2 ) ) in the presence of glutathione, suggesting that H 2 O 2 is derived from dismutation of O 2 ) produced through redox-cycle of FK228. Therefore, in addition to HDAC inhibition, H 2 O 2 generated from FK228 may participate in its apoptotic
Cachexia had an effect on oxycodone metabolism and the clinical responses to oxycodone. The observed reduction in serum albumin concentration was associated with dose escalation. These findings suggest that cachexia affects the clinical responses to oxycodone through metabolic and nutritional disorders in cancer patients.
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