Femtosecond Laser-Induced Surface Modification and its Application

In this chapter, we present femtosecond laser micromachining to fiber optics, focusing on surface qualities. Some techniques applied in the field are introduced to date and a review of some of the current applications for this type of technology. Section 2 describes laser-induced periodic surface structures (LIPSSs), which are induced in low- and high-fluence regime. Section 3 describes the influences of laser-induced structures for the fabrication of fiber-optic sensors, with experimental techniques and results in our research group. These sections explore ultrashort laser pulses applications, roughly going from lower to higher energy (power, intensity) ones

Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics.

ABSTRACT A distributed model has been used to clarify the mechanism of the restricted and differential distribution of the quinolone antibiotics in the rat central nervous system (CNS). The symmetrical permeability clearances across the blood-brain barrier (BBB), PS BBB , and across the blood-cerebrospinal fluid barrier (BCSFB), PS CSF , and the active efflux clearances across the BBB, PS BBB,eff , were obtained from a nonlinear least squares regression analysis combined with the fast inverse Laplace transforming program for in vivo data. The values of PS BBB,eff were 10-to 260-fold greater than those of PS BBB , providing kinetic evidence to support the hypothesis that a significant efflux transport across the BBB is responsible for the limited distribution of quinolones in brain tissue. Moreover, by simulation studies, we could demonstrate the concentration profiles in the brain as a function of the distance from the ependymal surface. However, active efflux transport across the BCSFB has been suggested to have only a slight effect on the apparent elimination from the cerebrospinal fluid. Comparing the apparent brain tissue-to-unbound serum concentration ratio at steady state, it has been suggested that the net flux across the BBB, i.e., the ratio of PS BBB to the sum of PS BBB and PS BBB,eff , is a determinant for the differential distribution of these quinolones in brain tissue. Such a putative active efflux transport system would play a significant role in decreasing the brain interstitial fluid concentration of quinolones. The side effect of quinolone antimicrobial agents (quinolones) on the CNS such as confusion, hallucinations, anxiety, agitation, depression and convulsive seizures is one of the most serious problems associated with their use as chemotherapeutic agents The present study investigated the process governing the restricted distribution of quinolones in the CNS based on the distributed model. In this study, we determined the initia

Absorption, Metabolism, and Excretion of [ 14 C]Imidafenacin, a New Compound for Treatment of Overactive Bladder, After Oral Administration to Healthy Male Subjects

ABSTRACT: The absorption, metabolism, and excretion of imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide], a new antimuscarinic drug developed for treatment of overactive bladder, were assessed in six healthy male subjects after a single oral administration of 0.25 mg of [ 14 C]imidafenacin (approximately 46 Ci). The highest radioactivity in the plasma was observed at 1.5 h after administration. The apparent terminal elimination half-life of the total radioactivity was 72 h. Approximately 65.6 and 29.4% of the administered radioactivity were recovered in the urine and feces, respectively, within 192 h after administration. The metabolite profiling by high-performance liquid chromatography-radiodetector and liquid chromatography/tandem mass spectrometry demonstrated that the main component of radioactivity was unchanged imidafenacin in the 2-h plasma. The N-glucuronide conjugate (M-9) was found as the major metabolite and the oxidized form of the 2-methylimidazole moiety (M-2) and the ringcleavage form (M-4) were detected as the minor metabolites in the 2-h plasma, but M-4 was found to be the main component in the 12-h plasma. Unchanged imidafenacin, M-9, M-2, and other oxidized metabolites were excreted in the urine, but the unchanged imidafenacin and M-9 were not found in the feces. Two unique metabolites were found in the urine and feces, which were identified as the interchangeable cis-and trans-isomers of 4,5-dihydrodiol forms of the 2-methylimidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) after oral administration, circulates in human plasma as the unchanged form, its glucuronide, and other metabolites, and is then excreted in urine and feces as the oxidized metabolites of 2-methylimidazole moiety. Imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide] In the pharmacokinetic assays in the preclinical toxicology studies, imidafenacin was absorbed rapidly with absolute bioavailability of 5.6% in rats and 36.1% in dogs after oral administration (Masuda et al., unpublished observations). Orally administered [ 14 C]imidafenacin was excreted as many metabolites in the feces, and the total recovery in the urine and feces were more than 95% of the administered dose in rats and dogs (Sato et al., unpublished observations). In phase I clinical trials, the plasma concentration and urinary excretion of imidafenacin increased dose dependently in the range from 0.025 to 0.5 mg of single oral dose, and the apparent elimination half-life ranged from 2.6 to 3.0 h Article, publication date, and citation information can be found a

Noninvasive assessment of the cardiac baroreflex Response to downward tilting and comparison with the phenylephrine method

AbstractOBJECTIVESWe studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV).BACKGROUNDThe method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting.METHODSSixteen healthy male volunteers were studied (mean age ± SD 27.5 ± 4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70° upright tilting, the table was returned to supine position at a speed of 3.2°/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 μg/kg). Heart rate variability under resting conditions also was analyzed.RESULTSIn all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS).CONCLUSIONSWe conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method

Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy

An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM

Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against drug-induced lung injury/fibrosis in an animal model

<p>Abstract</p> <p>Background</p> <p>To determine whether oral administration of geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP) 70, protects against drug-induced lung injury/fibrosis <it>in vivo</it>.</p> <p>Methods</p> <p>We used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry.</p> <p>Results</p> <p>We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the <it>de novo </it>induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice.</p> <p>Conclusion</p> <p>GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.</p