Soft-x-ray harmonic comb from relativistic electron spikes.

We demonstrate a new high-order harmonic generation mechanism reaching the "water window" spectral region in experiments with multiterawatt femtosecond lasers irradiating gas jets. A few hundred harmonic orders are resolved, giving µJ/sr pulses. Harmonics are collectively emitted by an oscillating electron spike formed at the joint of the boundaries of a cavity and bow wave created by a relativistically self-focusing laser in underdense plasma. The spike sharpness and stability are explained by catastrophe theory. The mechanism is corroborated by particle-in-cell simulations.

Enhancement of photon number reflected by the relativistic flying mirror.

Laser light reflection by a relativistically moving electron density modulation (flying mirror) in a wake wave generated in a plasma by a high intensity laser pulse is investigated experimentally. A counterpropagating laser pulse is reflected and upshifted in frequency with a multiplication factor of 37-66, corresponding to the extreme ultraviolet wavelength. The demonstrated flying mirror reflectivity (from 3 x 10(-6) to 2 x 10(-5), and from 1.3 x 10(-4) to 0.6 x 10(-3), for the photon number and pulse energy, respectively) is close to the theoretical estimate for the parameters of the experiment.

Electron optical injection with head-on and countercrossing colliding laser pulses.

A high stability electron bunch is generated by laser wakefield acceleration with the help of a colliding laser pulse. The wakefield is generated by a laser pulse; the second laser pulse collides with the first pulse at 180 degrees and at 135 degrees realizing optical injection of an electron bunch. The electron bunch has high stability and high reproducibility compared with single pulse electron generation. In the case of 180 degrees collision, special measures have been taken to prevent damage. In the case of 135 degrees collision, since the second pulse is countercrossing, it cannot damage the laser system.

Sub-MeV tunably polarized X-ray production with laser Thomson backscattering.

Reported in this article is the generation of unique polarized x-rays in the sub-MeV region by means of the Thomson backscattering of the Nd:YAG laser photon with a wavelength of 1064 nm on the 150 MeV electron from the microtron accelerator. The maximum energy of the x-ray photons is estimated to be about 400 keV. The total energy of the backscattered x-ray pulse is measured with an imaging plate and a LYSO scintillator. The angular divergence of the x-rays is also measured by using the imaging plate. We confirm that the x-ray beam is polarized according to the laser polarization direction with the Compton scattering method. In addition, we demonstrate the imaging of the object shielded by lead with the generated x-rays.

Electro-optic spatial decoding on the spherical-wavefront Coulomb fields of plasma electron sources.

Detections of the pulse durations and arrival timings of relativistic electron beams are important issues in accelerator physics. Electro-optic diagnostics on the Coulomb fields of electron beams have the advantages of single shot and non-destructive characteristics. We present a study of introducing the electro-optic spatial decoding technique to laser wakefield acceleration. By placing an electro-optic crystal very close to a gas target, we discovered that the Coulomb field of the electron beam possessed a spherical wavefront and was inconsistent with the previously widely used model. The field structure was demonstrated by experimental measurement, analytic calculations and simulations. A temporal mapping relationship with generality was derived in a geometry where the signals had spherical wavefronts. This study could be helpful for the applications of electro-optic diagnostics in laser plasma acceleration experiments.

Burst intensification by singularity emitting radiation in multi-stream flows.

Burst Intensification by Singularity Emitting Radiation (BISER) is proposed. Singularities in multi-stream flows of emitting media cause constructive interference of emitted travelling waves, forming extremely localized sources of bright coherent emission. Here we for the first time demonstrate this extreme localization of BISER by direct observation of nano-scale coherent x-ray sources in a laser plasma. The energy emitted into the spectral range from 60 to 100 eV is up to ~100 nJ, corresponding to ~1010 photons. Simulations reveal that these sources emit trains of attosecond x-ray pulses. Our findings establish a new class of bright laboratory sources of electromagnetic radiation. Furthermore, being applicable to travelling waves of any nature (e.g. electromagnetic, gravitational or acoustic), BISER provides a novel framework for creating new emitters and for interpreting observations in many fields of science.

Estimation of photon dose generated by a short pulse high power laser.

The authors obtain a new equation to estimate the forward component of a photon dose generated through the interaction between a target and a short pulse high power laser. As the equation is quite simple, it is useful for calculating the photon dose. The equation shows that the photon dose is proportional to the electron temperature in the range>3 MeV and proportional to the square of the electron temperature in the range<3 MeV. The dose estimated with this method is roughly consistent with the result of Monte Carlo simulation. With some assumptions and corrections, it can reproduce experimental results obtained and the dose result calculated at other laboratories.

Electron acceleration by a nonlinear wakefield generated by ultrashort (23-fs) high-peak-power laser pulses in plasma.

We study experimentally the interaction of the shortest at present (23-fs) , relativistically intense (20-TW), tightly focused laser pulses with underdense plasma. MeV electrons constitute a two-temperature distribution due to different plasma wave-breaking processes at a plasma density of 10(20) cm(-3). These two groups of electrons are shown numerically to constitute bunches with very distinctive time durations.

Pharmacokinetics and pharmacodynamics of (+)-threo-methylphenidate enantiomer in patients with hypersomnia.

The pharmacokinetics of (+)-methylphenidate after oral administration of 20 mg racemic methylphenidate hydrochloride and the relationship between clinical effects of plasma (+)-methylphenidate concentration were investigated in 15 patients with hypersomnia and four healthy volunteers. The elimination half-life of (+)-methylphenidate in patients was within the range of 2.6 to 3 hours, and the time to reach the peak concentration ranged from 1 to 3 hours. The values of half-life and time to reach the peak concentration in the patients were almost the same as the values in healthy subjects. The plasma (+)-methylphenidate concentration profiles after repeated administration of racemic methylphenidate were similar to those after single administration. No correlation was observed between the plasma (+)-methylphenidate concentration and the subjective sleepiness as measured by Stanford Sleepiness Scale. On the other hand, a significant correlation was found between the sleep latency as measured by the multiple sleep latency test and the plasma concentrations of (+)-methylphenidate (r = 0.850). The time course of the sleep latency after repeated administration was similar to that after single administration. The sleep latency of more than 10 minutes was achieved by maintaining the plasma (+)-methylphenidate concentrations above 3 ng/ml.

Safe and effective topical application dose of lidocaine for surgery with laryngomicroscopy.

A clinical case of a patient in whom seizure developed after topical application of lidocaine to the oropharyngeal region was described. The exploratory studies on the optimal dosage of lidocaine in the surgery under laryngomicroscope was performed in 22 patients. During the application of 2% lidocaine viscous and 4% lidocaine solution to the oropharyngeal region, the patient was instructed to expectorate the excess intermittently to avoid absorption. In addition, the oropharyngeal region was swabbed with gauze. The serum lidocaine concentrations after application were less than 1.8 micrograms/ml. The total application dose of the drug was within the range of 324 to 640 mg, and the total recovery rate from the saliva and gauze was 52% to 81%. We found a good correlation between net application dose (total application dose minus excessive lidocaine dose) and serum lidocaine concentration. In this study, it was shown that the safe and effective net application dose of lidocaine for the surgery may be within the range of 127 to 260 mg.

Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats.

We investigated the relationships between methylphenidate (MPD) enantiomers and endogenous dopamine (DA) levels in striatal extracellular fluid, and that between DA level and locomotor activity, after intravenous administration of racemic MPD (2, 5 or 10 mg/kg dose) or the individual enantiomers (2.5 mg/kg dose) to rats. MPD and DA levels in the extracellular fluid were measured by in vivo brain microdialysis. The maximum levels of MPD enantiomers in the striatal extracellular fluid were obtained within 15 min after administration. On the other hand, the mean maximum DA levels after administration of 2-10 mg/kg dose of racemic MPD were obtained within 10 min with values in the range of 3.0- to 8.6-fold higher than the basal DA level. The maximum DA level (4.2-fold of the basal level) after administration of (+/-)-MPD was greater than that (2.2-fold) of the same dose of (-)-MPD. A clockwise hysteresis was observed between MPD concentration and DA level in the extracellular fluid after MPD administration. Locomotor activity after administration of (+)-MPD was also greater than (-)-MPD. From these results, it was shown that the locomotor activity induced by MPD may be related to the increase of DA level in the extracellular fluid, and the degree of increase of the DA level by (+)-MPD was greater than that of the (-)-isomer.

Effect of anti-inflammatory bowel disease drug, E3040, on urate transport in rat renal brush border membrane vesicles.

To confirm the assumption that 6-hydroxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole (E3040) acts on urate reabsorption by inhibiting urate-anion exchange at the luminal membrane of renal tubules, we investigated the inhibitory effect of E3040 and its two conjugated metabolites on hydroxyl ion (OH(-)) gradient-dependent urate uptake into brush border membrane vesicles from rat renal cortex and compared it with other uricosuric agents. The order of potency was AA193 (5-chloro-7, 8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid)>benzbromarone>E3040>probenecid>E3040 sulfate>E3040 glucuronide. Furthermore, kinetic analysis revealed that E3040 may be a competitive inhibitor of the OH(-) gradient-dependent uptake of urate into brush border membrane vesicles.

Saltatory conduction of peripheral nerve impulse in clioquinol-treated rats.

By using a new method, unidimensional latency-topography, which shows the saltatory conduction pattern of an impulse along peripheral nerve fibers, the internodal length, internodal conduction time and conduction velocity were determined from the L5 ventral and/or dorsal root filaments of clioquinol-treated rats (CTR). The saltatory conduction pattern was preserved in most of the CTR fibers tested, but was not seen in some fibers. A positive correlation was seen between the conduction velocity and the internodal length in the nerve fibers of both the normal rats and CTR. Although there was no difference in the internodal length between normal rats and CTR, conduction velocities determined in CTR fibers were lower than those in normal rat fibers. Myelin length was calculated from the saltatory conduction pattern in the topography to represent the functional length of the saltatory conduction. The functional myelin length of the CTR fiber was shorter than that of normal rats. Shortening of the functional myelin length in CTR is due to the widening of the Ranvier node, which corresponds to the exposure of the Ranvier node, i.e. demyelination. It was concluded that the decrease in conduction velocity in CTR fibers was due to exposure which caused delayed excitation at the Ranvier nodes.

Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats.

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 microg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 +/- 1.40 vs 56.60 +/- 0.748 msec, mean +/- SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

Kinetic analysis of enantiomers of threo-methylphenidate and its metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method.

A gas chromatographic-mass spectrometric method was developed for the stereoselective quantification of threo-methylphenidate (MPD) and its metabolite, ritalinic acid (RA), in plasma or urine. The plasma concentrations of (+)-MPD after oral administration of two 10-mg conventional tablets containing racemic MPD.HCl or of 20-mg of racemic MPD.HCl crystals to two healthy subjects were much higher than those of the (-)-isomer. The plasma concentrations of the metabolite, (-)-RA, were higher than that of the (+)-isomer during the first 4 h after administration of racemic MPD.HCl in both tablet and crystal forms. Although in urine both (+)- and (-)-RA were largely excreted in 48 h (37 and 40% of the dose, respectively), the percentage excretion of (-)-RA during the first 3-4 h was approximately twice that of the (+)-isomer. These results suggest that one reason for the difference in the plasma levels between (+)- and (-)-MPD may be due to differences in their rates of metabolism. Pharmacokinetic parameters of (+)-MPD after administration of 10 mg of (+)-MPD.HCl crystals were almost the same as those after administration of racemic MPD.HCl crystals. The AUC infinity 0 of (-)-MPD after administration of 10 mg of (-)-MPD.HCl crystals was smaller than that after administration of racemic MPD.HCl crystals.

Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method.

An improved high-performance liquid chromatographic method was developed for the quantification of glycyrrhizin and its metabolites in human plasma. The improved method was selective and made it possible to determine precisely glycyrrhizin at levels as low as 500 ng/mL. The pharmacokinetic behavior of glycyrrhizin and its metabolites after oral and intravenous administration of glycyrrhizin to normal subjects was investigated. After oral administration of glycyrrhizin (100 mg) to three normal subjects, the major metabolite of glycyrrhizin (glycyrrhetic acid) appeared in plasma (less than 200 ng/mL), but glycyrrhizin was not found. On the other hand, glycyrrhizin was found in urine, and the amount excreted was 1.1-2.5% of the dose. This finding suggests that glycyrrhizin is partly absorbed in the intact form from the gastrointestinal tract. The concentration of glycyrrhizin in plasma after intravenous administration of glycyrrhizin (40, 80, and 120 mg) showed biexponential profiles during the 24-h period after administration of each dose. The glycyrrhizin metabolites, glycyrrhetic acid and glycyrrhetic acid-3-O-glucuronide, were not detected in either plasma or urine. The terminal half-life of glycyrrhizin, the apparent volume of the central compartment, the steady-state distribution volume, and the total body clearance in three dosing experiments were 2.7-4.8 h, 37-64 mL/kg, 59-98 mL/kg, and 16-25 mL/kg/h, respectively. Glycyrrhizin was not detected in plasma after oral administration of the usual therapeutic dose of glycyrrhizin, and no dose dependency of the drug was observed in the dose range of 40-120 mg.

Effect of cilastatin on renal handling of vancomycin in rats.

To provide insights into the possibility of reducing the nephrotoxicity of vancomycin (VCM) by cilastatin, the effect of cilastatin on the renal handling of VCM, as well as on glomerular filtration rate (GFR) and plasma protein binding of VCM, were studied using rats. After a bolus intravenous (iv) dose of VCM (100 mg/kg), concomitant cilastatin administration (100 mg/kg, iv) resulted in a significant increase in the total VCM clearance and significant decrease in the kidney uptake clearance of VCM, defined as kidney VCM concentration vs AUC ratio. Moreover, after a 3-h continuous iv infusion of VCM (18 or 90 mg/h/kg), significant decrease in the kidney uptake clearance of VCM was observed with concomitant cilastatin iv infusion (300 mg/h/kg). On the other hand, GFR and VCM plasma protein binding did not show any significant change with cilastatin. From the observation that cilastatin decreased the kidney uptake clearance of VCM and enhanced its urinary excretion, it was suggested that cilastatin inhibited the reabsorption of VCM in the renal proximal tubular cells. Thus, it may be possible that cilastatin alleviates the nephrotoxicity of VCM due to reduced accumulation and accelerated renal excretion of VCM.

Kinetic analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats: role of enterohepatic circulation.

The role of enterohepatic circulation of glycyrrhetic acid (GA) in rats was determined by kinetic analysis of GA. The concentrations of GA in the plasma of the control rat (without bile duct cannulation) during the first 5 h after intravenous (iv) administration of GA (2, 5, 10, and 20 mg/kg) were similar to those in the bile duct-cannulated rat at each dose. No significant difference was observed in the values of the terminal half-life, the total body clearance, the distribution volume at steady state, the area under the curve of concentration in plasma versus time, and the mean residence time in each dose between both groups. When GA (2, 5, 10, and 20 mg/kg) was administered i.v. to the bile duct-cannulated rat, excretion of unchanged GA in bile was < 1% of each dose, that of the acid-hydrolyzed products was 14-16%, and that of GA-3-O-glucuronide was only 1-2%. In the control rat, a secondary peak of GA concentration was observed 12 h after i.v. administration of GA (20 mg/kg). The enterohepatic circulation of GA was confirmed by the linked-rat method in which bile of the donor rat after i.v. administration of GA (20 mg/kg) was allowed to flow directly into the duodenum of the recipient rat. GA was found in the plasma of the recipient rat after 6 h, and its concentration reached the maximum (approximately 0.5 microgram/mL) 8-12 h after dosing the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats.

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an "effect compartment" could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadministration of DP and EM in rats.