Association of the clinical efficacy of vancomycin with the novel pharmacokinetic parameter area under the trough level (AUTL) in elderly patients with hospital-acquired pneumonia.

WHAT IS KNOWN AND OBJECTIVE: The pharmacokinetic-pharmacodynamic parameter that best predicts the efficacy of vancomycin is the ratio of the area under the concentration versus time curve (AUC) to the minimum inhibitory concentration (MIC). A 24-h AUC (AUC24 )/MIC ratio ≥ 400 was recommended in an American consensus review, but vancomycin treatment occasionally fails despite maintenance of AUC24 /MIC ≥ 400. We evaluated the association between clinical efficacy of vancomycin and two novel pharmacokinetic parameters, the 'area under the trough level' (AUTL) and the 'area above the trough level' (AATL), in hospitalized elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. METHODS: The subjects were hospitalized elderly patients who were administered vancomycin for treatment of MRSA pneumonia between 2006 and 2012 at Sasebo Chuo Hospital (Nagasaki, Japan). Pharmacokinetic parameters of vancomycin were estimated for each patient by Bayesian analysis using population pharmacokinetic parameters for Japanese patients. Based on the patient-specific parameters thus obtained, AUC24 values were calculated as the vancomycin dosage divided by vancomycin clearance. AUTL was calculated as the trough serum concentration multiplied by 24 h, whereas AATL was calculated by subtracting AUTL from AUC24 . RESULTS AND DISCUSSION: Logistic regression analysis demonstrated that efficacy of vancomycin was more strongly associated with AUTL than AUC24 . The optimal cut-off value of AUTL was 331 µg∙h/mL, which means that the optimal cut-off value of the trough serum concentration was 13·8 µg/mL. WHAT IS NEW AND CONCLUSION: Efficacy of vancomycin was associated with AUTL, a novel pharmacokinetic parameter. Determining the target AUTL or trough concentration may enhance the efficacy of vancomycin therapy in elderly patients with MRSA pneumonia. Given that nephrotoxicity may increase with a Ctrough in excess of 15 µg/mL, this level should ideally not be exceeded.

[Anesthetic management for neonates with congenital cystic adenomatoid malformation].

We experienced two cases of congenital cystic adenomatoid malformation (CCAM) diagnosed by prenatal ultrasonography. The first case with type I CCAM underwent the resection of the right upper lobe 8 days after birth. Postoperative course was uneventful. The second case with type III CCAM developed non-immune hydrops, severe mediastinal shift, and polyhydroamnios at 29 weeks' gestation. At 30 weeks' gestation, cesarean section was performed. Immediately after birth, the resection of lung tumor for the neonate was performed. However, the neonate died on the 1st postoperative day.

Hemorrhagic necrosis of pheochromocytoma associated with reversible renal artery stenosis.

An unusual case of pheochromocytoma associated with renal artery stenosis is described. Despite the removal of bilateral adrenal pheochromocytoma, laboratory findings suggested the presence of residual pheochromocytoma and abdominal aortography revealed more pronounced stenosis of the right renal artery. Two months later, the undetected residual pheochromocytoma underwent hemorrhagic necrosis with acute cessation of catecholamine release. Thereafter, the patient's blood pressure decreased to a normal level with marked improvement in hypertensive symptoms. No remaining stenosis was demonstrated on follow up renal angiography. Our case suggests that constant local secretion of catecholamines may be responsible for the development of renal artery stenosis.

Detection of aflatoxin B1 in serum samples of male Japanese subjects by radioimmunoassay and high-performance liquid chromatography.

Aflatoxin B1 (AFB1) was detected in serum samples of healthy Japanese males by radioimmunoassay and high-performance liquid chromatography. Blood samples were obtained from 20 subjects after fasting and from 80 subjects after lunch. The subjects ranged in age from 20 to 63 years of age. Measurement of AFB1 in the samples was performed by radioimmunoassay and was confirmed by high-performance liquid chromatography using a mu Porasil column and a C18-mu Bondapak column after the conversion of AFB1 to its water adduct AFB2a. AFB1 was detected in 5 of 20 fasting blood samples [20 to 56 pg/ml of serum; 33.6 +/- 14.6 (S.D.)] and in 29 of 80 serum samples taken after lunch (20 to 1169 pg/ml of serum; 218.1 +/- 268.3). Mass spectral analysis of the material obtained after high-performance liquid chromatography separation from serum samples confirmed the presence of AFB1.

Studies on the cryopreservation of eggs of Angiostrongylus cantonensis.

The possibility of cryopreserving the eggs of Angiostrongylus cantonensis collected from the uterus of female worms was investigated. Eggs were cultured in NCTC 109 medium containing 50% rat serum, and various growth stages, from one-cell eggs to embryonated eggs, were used in this study. As a cryoprotective agent, dimethylsulphoxide (Me2SO) was added to the medium at a final concentration of 1 M. Eggs suspended in 0.2 ml of the medium at 37 degrees C were cooled to 0 degrees C at a rate of 1 degree C min-1, then an equal volume of 2M-Me2SO solution was added. After equilibration for 15 min, the freezing procedures were started. In the freezing procedures, the effectiveness of (i) a seeding process, (ii) different cooling and warming rates and (iii) the relationship between the growth stages of the eggs and their tolerance to freezing at -20 degrees C were investigated. It was found the highest level of survival could be obtained with 32-cell eggs cooled at a rate of 0.3 degrees C min-1 or more slowly with seeding at -4 degrees C and warming at a rate of 5 degrees C min-1. Survival was influenced more by cooling rate than by warming rate. Using these optimum conditions, the survival of eggs was then investigated following cooling to various temperatures. While more than 50% of eggs were found to survive cooling to -30 degrees C, extremely low survival was noted from lower temperatures.

Specific cytosol binding proteins for 25(OH)D3 and 1.25(OH)2D3 in human breast cancers.

Binding proteins for 1.25 (OH) 2D3 were investigated in thirty breast cancers. Human breast cancer was shown to contain specific, high affinity cytosol binding proteins for 1.25 (OH) 2D3 and 25 (OH) D3. The binding protein for 1.25 (OH) 2D3 sedimented at 3.7 S and the binding protein for 25 (OH) D3 at about 6.0 S on sucrose density gradient analysis containing 0.3 M KCl and 1 mM dithiothreitol in buffer. Kd for 1.25 (OH) 2D3 were from 0.1 x 10(-11) M to 7.1 x 10(-11) M measured by Scatchard plots. Competition binding studies indicated that the relative specificity of the binding protein for 1.25 (OH) 2D3 much greater than 25 (OH) D3 greater than 1 alpha (OH) D3, 24,25 (OH)2D3 greater than D3 much greater than Estradiol-17 beta. 1.25 (OH) 2D3 receptor-positive was detected in twenty-eight out of thirty breast cancers.

Afferent pathways of reflex hypotension and bradycardia during coronary occlusion.

Neural afferent pathways mediating reflex hypotension and bradycardia during coronary occlusion (CO) were determined mainly on the right side in anesthetized cats. Brief occlusion of the left anterior descending (LAD) or circumflex coronary artery (Cx) reuslted in significant hypotension and bradycardia, both of which could be attenuated by bilateral (BVB), unilateral right (RVB), or left vagal cold blockade (LVB) in the nec. The degree of attenuation in the responses was greater as follows: BVB greater than RVB greater than LVB for LAD occlusion, and BVB greater than RBV = LBV for Cx occlusion. Randomized section of cardiac nerves, i.e., the pericoronary nerve, vagal cardiac nerve trunk, and caudal vagal cardiac nerves on the right side produced significant attenuations in the circulatory responses to CO. These results indicate that vagal afferent activity transmitted via these cardiac nerves plays an important role in mediating the reflex responses to CO. This conclusion was further substantiated by electrical stimulation of afferent fibers in thee nerves or by recording increased afferent spontaneous activity form them during CO.

Inhomogeneous spread of excitation in canine Purkinje fibers.

Spread of excitation in isolated canine bundle branches was examined by microelectrode technique in order to investigate the possibility of dissociated impulse transmission in normal Purkinje fibers. In all experiments, local excitation of the preparation evoked either by fine bipolar extracellular electrodes or an intracellular microelectrode proceeded much faster along the longitudinal axis of the fibers than along the transverse axis. As a result, the spread of excitation in the vicinity of stimulating site showed significantly inhomogeneous character. The inhomogeneity of excitation spread became more manifest with more eccentric location of the stimulating site in a given preparation. Larger preparation showed greater degree of inhomogeneity. Nevertheless, the inhomogeneous spread of excitation alone appeared unlikely to provide multiply pathways which were functionally dissociated with each other. When premature stimulation was applied, however, different conductivity among fibers within a single false tendon was oberved, suggesting that each conducting element became more independent.

Effect of cardiotonic polypeptide anthopleurin-A on canine Purkinje and ventricular muscle fibers.

Effects of Anthopleurin-A (AP-A, polypeptide from sea anemone) were studied on electrophysiological properties of isolated canine Purkinje and ventricular muscle fibers. Ap-A (in concentrations above 20 micrograms/l) produced a dose-dependent increase in action potential duration (APD) and the refractory period (RFP) in electrically driven Purkinje fibers, but had no effect on other parameters. Similar but less prominent change in APD and RFP was observed in ventricular muscle fibers. AP-A in high concentrations (200 micrograms/l or higher) did alter the spontaneous firing rate of Purkinje fibers. Since AP-A in low concentrations will increase the refractory period of conducting fibers without affecting a conduction velocity, it may abolish some re-entrant arrhythmias.

Effects of beta-adrenergic blocking drug pindolol (LB46) on cardiac fibers in relation to its membrane effects.

Direct membrane effects and beta-adrenergic blocking action of pindolol were studied comparatively on isolated perfused cardiac fibers of dogs. In Purkinje fibers, the duration of transmembrane action potential decreased in concentrations higher than 0.5 mg/L. Maximum rate of depolarization also decreased in higher concentrations (5.0 mg/L or more). The functional refractory period decreased to a lesser degree compared with the decrease of the action potential duration. Nevertheless, slow-rising action potentials could not be abolished in premature responses, probably because of membrane depressant effects of this drug. In ventricular muscle fibers, these changes were minimum in the same range of concentrations. On the other hand, 0.05 mg/L of pindolol which was close to the therapeutic plasma concentrations and had no effect on action potentials of both Purkinje and ventricular muscle fibers, minimized the increase in automaticity of Purkinje fibers induced by 0.2 mg/L of isoproterenol. It is rationally speculated that the mechanism of antiarrhthmic action of pindolol is mainly due to its beta-adrenergic blocking action.

Effects of l-penbutolol (Hoe 893d) on the transmembrane potentials of canine purkinje fibers and ventricular muscle fibers.

Intrinsic membrane effects (non-specific effects) and beta-adrenergic blocking action (specific effects) of l-penbutolol were studied using intracellular microelectrode techniques. l-Penbutolol in concentrations above 0.1 mg/L reduced the maximum rate of depolarization at phase O of both Purkinje fibers and ventricular muscle fibers without affecting their maximum diastolic potential. The action potential duration of Purkinje fibers were also shortened. The shortening of action potential duration and enhancement of automaticity in Purkinje fibers, normally induced by isoproterenol (0.2 mg/L), were antagonized by l-penbutolol in much lower concentraions (0.1--1.0 microgram/L) than those at which nonspecific effects are observed. The difference between these two concentration ranges is sufficient to suggest that l-penbutolol might be a highly specific beta-adrenergic blocking agent.