Inhibition of the metabolism of brotizolam by erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism

AIMS: To obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam. METHODS: Fourteen healthy male volunteers received erythromycin 1200 mg day(-1) or placebo for 7 days in a double-blind randomized crossover manner. On the 6th day they received a single oral 0.5-mg dose of brotizolam, and blood samplings were performed for 24 h. RESULTS: Erythromycin treatment significantly increased the peak plasma concentration (P < 0.05), total area under the plasma concentration-time curve (P < 0.01), and elimination half-life (P < 0.01) of brotizolam. CONCLUSIONS: The present study provides in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism.     

Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2003 and March 2004

Tendency of isolated bacteria from infections in general surgery during the period from April 2003 to March 2004 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 455 strains including 14 strains of Candida spp. were isolated from 191(75.2%) of 254 patients with surgical infections. Two hundred and thirty-nine strains were isolated from primary infections, and 216 strains were isolated from postoperative infections. From primary infections, anaerobic Gram-positive bacteria and aerobic Gram-negative bacteria were predominant, while aerobic Gram-positive bacteria were predominant from postoperative infections. The isolation rate of aerobic Gram-positive bacteria, such as Enterococcus spp. and Staphylococcus aureus were higher from both types of infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa in this order, and from postoperative infections, E. coli was the most predominantly isolated, followed by P. aeruginosa, E. cloacae, and K. pneumoniae. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. The isolation rate of anaerobic Gram-positive bacteria from primary infections and that of aerobic Gram-positive bacteria from postoperative infections were high in the last several years. In this series, we noticed no vancomycin-resistant Gram-positive cocci, but a few strains of moderately arbekacin-resistant MRSA. Carbapenm-resistant P. aeruginosa was seen in less than 10 per cents. Last year we noticed that there were cefazolin-resistant E. coli producing extended spectrum beta-lactamase, but there was no highly cefazolin-resistant E. coli in this year. In the next series, increase of both anaerobic bacteria and Enterococcus spp. should be carefully followed up.     

Pharmacodynamic evaluation of biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation

This study evaluated the pharmacodynamics of biapenem in peritoneal fluid (PF). Biapenem (300 or 600mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CL(Cr)) as the most significant covariate: CL (L/h)=0.036xCL(Cr)+4.88, V1 (L)=6.95, Q2 (L/h)=2.05, V2 (L)=3.47, Q3 (L/h)=13.7 and V3 (L)=5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration (T>MIC)) in PF were greater than or equal to those in plasma. In the cases of CL(Cr)=90 and 60mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were >/=90%) were 2mug/mL for 300mg every 12h, 4mug/mL for biapenem 300mg every 8h (q8h) and 8mug/mL for 600mg q8h. Thus, these results should support the clinical use of biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.     

Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters,on metabolic index and insulin secretion in spontaneously diabetic GK rats

1. To investigate the pharmacological effects of T-1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T-1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight. 2. T-1095 treatment did not affect 3.3 mmol/L glucose-induced insulin secretion in the isolated perfused pancreas of GK rats. 3. The peak insulin release in T-1095-treated GK rats was significantly higher during the first phase than in untreated GK rats (3-4 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the first phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (35.3 +/- 1.4 vs. 27.3 +/- 2.5 ng in T-1095-treated compared with untreated rats, respectively). 4. During the second phase, insulin release in T-1095-treated GK rats was somewhat higher than in untreated GK rats (7-30 min after beginning 16.7 mmol/L glucose perfusion). The total amount of insulin secreted during the second phase in T-1095-treated GK rats was significantly higher than in untreated GK rats (88.2 +/- 6.1 vs. 68.1 +/- 5.7 ng, respectively). 5. The total amount of insulin secreted during perfusion in T-1095-treated GK rats was significantly higher than in untreated GK rats (123.5 +/- 7.3 vs. 95.4 +/- 7.7 ng, respectively). 6. These data show that the metabolic indices, plasma glucose and HbA1c levels and insulin secretion are significantly improved by T-1095 treatment in GK rats, which are spontaneously diabetic rats, suggesting its usefulness as a novel oral therapeutic antidiabetic agent.     

Evaluation of dextromethorphan N-demethylation activity as a biomarker for cytochrome P450 3A activity in man

The present study evaluates the usefulness of dextromethorphan N-demethylation activity indices to reflect cytochrome P450 (CYP) 3A activity in man. Indices of dextromethorphan N-demethylation activity were categorized as N1=3-methoxymorphinan/dextromethorphan, N2=3-hydroxymorphinan/dextrorphan, N3=(3-methoxymorphinan + 3-hydroxymorphinan)/(dextromethorphan + dextrorphan). Two mg of midazolam were administered orally to 22 Japanese male volunteers, and midazolam clearance determined. Thirty mg of dextromethorphan were also orally administered to these volunteers and N1, N2 and N3 indices determined by 12 hr urine collection. Results showed N2 and N3 were highly correlated (r>0.99, P<0.001), and significantly correlated to oral midazolam clearance (r=0.45, P<0.05); suggesting that N2 and N3 are more suitable than N, when using dextromethorphan as an index of individual CYP3A activity.     

Bacteria isolated from surgical infections and their susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2000 and March 2001

Tendency of isolated bacteria from infections in general surgery and their antimicrobial susceptibilities during the period from April 2000 to March 2001 were investigated in a multicenter study in Japan, and the following results were obtained. The number of cases investigated as objectives was 234 for one year. A total of 388 strains (136 strains from primary infections and 252 strains from postoperative infections) were isolated from 165 cases (70.5% of total cases). In primary infections, anaerobic Gram-positive bacteria were predominant, while from postoperative infections, aerobic Gram-positive bacteria were predominant. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was the highest, followed by that of Staphylococcus aureus from postoperative infections. Among anaerobic Gram-positive bacteria, the isolation rate of Peptostreptococcus spp. was the highest from both types of infections. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae and Pseudomonas aeruginosa in this order, and from postoperative infections, P. aeruginosa was the most predominantly isolated, followed by Enterobacter spp. and Klebsiella spp. Among anaerobic Gram-negative bacteria, the isolation rate of Bacteroides fragilis group was the highest from both types of infections. There was no vancomycin-resistant S. aureus nor Enterococcus spp. Among anaerobic bacteria, there were many resistant strains against penicillins and cephems with MICs higher than 100 micrograms/ml, and the same trend was observed among other Bacteroides spp. and Prevotella spp.     

Characteristics of attenuated endothelium-dependent relaxation seen in rabbit intrapulmonary vein following chronic nitroglycerine administration

1 This study was undertaken to determine whether long-term in vivo administration of nitroglycerine (NTG) downregulates the endothelium-dependent relaxation induced by acetylcholine (ACh) in the rabbit intrapulmonary vein and, if so, whether the type 1 angiotensin II receptor (AT(1)R) blocker valsartan normalizes this downregulated relaxation. 2 In strips treated with the cyclooxygenase inhibitor diclofenac, ACh induced a relaxation only when the endothelium was intact. A small part of this ACh-induced relaxation was inhibited by coapplication of two Ca(2+)-activated K(+)-channel blockers (charybdotoxin (CTX)+apamin) and the greater part of the response was inhibited by the nitric-oxide-synthase inhibitor N(omega)-nitro-L-arginine (L-NNA). 3 The endothelium-dependent relaxation induced by ACh, but not the endothelium-independent relaxation induced by the nitric oxide donor NOC-7, was significantly reduced in NTG-treated rabbits (versus those in NTG-nontreated control rabbits). The attenuated relaxation was normalized by coapplication of valsartan with the NTG. 4 In the vascular wall, both the amount of localized angiotensin II and the production of superoxide anion were increased by in vivo NTG treatment. These variables were normalized by coapplication of valsartan with the NTG. 5 It is suggested that long-term in vivo administration of NTG downregulates the ACh-induced endothelium-dependent relaxation, mainly through an inhibition of endothelial nitric oxide production in the rabbit intrapulmonary vein. A possible role for AT(1)R is proposed in the mechanism underlying this effect.     

Validation of accuracy in image co-registration with computed tomography and magnetic resonance imaging in Gamma Knife radiosurgery

The latest version of Leksell GammaPlan (LGP) is equipped with Digital Imaging and Communication in Medicine (DICOM) image-processing functions including image co-registration. Diagnostic magnetic resonance imaging (MRI) taken prior to Gamma Knife treatment is available for virtual treatment pre-planning. On the treatment day, actual dose planning is completed on stereotactic MRI or computed tomography (CT) (with a frame) after co-registration with the diagnostic MRI and in association with the virtual dose distributions. This study assesses the accuracy of image co-registration in a phantom study and evaluates its usefulness in clinical cases. Images of three kinds of phantoms and 11 patients are evaluated. In the phantom study, co-registration errors of the 3D coordinates were measured in overall stereotactic space and compared between stereotactic CT and diagnostic CT, stereotactic MRI and diagnostic MRI, stereotactic CT and diagnostic MRI, and stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. In the clinical study, target contours were compared between stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. The mean errors of coordinates between images were < 1 mm in all measurement areas in both the phantom and clinical patient studies. The co-registration function implemented in LGP has sufficient geometrical accuracy to assure appropriate dose planning in clinical use.