Pharmacokinetics, tissue distribution, and excretion of sitafloxacin, a new fluoroquinolone antibiotic, in rats, dogs, and monkeys

The pharmacokinetics, tissue distribution and excretion of sitafloxacin (CAS 127254-12-0, DU-6859a) were investigated in rats, dogs, and monkeys following single intravenous or single oral administration of 14C-labelled sitafloxacin at a dose of 4.69 mg/kg. Following single administration of the oral dose, serum concentrations of radioactivity peaked at 0.5 h in rats, 2.3 h in dogs, and 2.5 h in monkeys. The apparent absorption ratios of 14C-sitafloxacin based on the AUC0-infinity were 31%, 51%, and 93% in rats, dogs, and monkeys, respectively. In rats, the drug-related radioactivity had been distributed to most organs and tissues 30 min after oral dosing, and had been essentially eliminated after 24 h. The highest levels of radioactivity were observed in the kidneys and liver, whereas the concentrations in the cerebrum and spinal cord were much lower than the serum value. The urinary recoveries of radioactivity after intravenous dosing were 45.5 % in rats, 32.3 % in dogs, and 77.8 % in monkeys. In bile duct-cannulated rats, 57.8 % of the orally administered radioactivity was excreted in the bile within 48 h, and at least 45 % of the sitafloxacin-related material secreted in the bile was re-absorbed from the gastrointestinal tract. These results indicate that sitafloxacin is rapidly absorbed and widely distributed into various tissues. Sitafloxacin-related material is eliminated primarily through both renal and biliary excretion in rats, and possibly in dogs, whereas renal excretion is the major route of elimination in monkeys.     

Serotonin modifies corticotropin-releasing factor-induced behaviors of chicks

Glucagon-like peptide-1 (GLP-1) decreased corticotropin-releasing factor (CRF)-induced behaviors in neonatal chicks, and serotonin is one of the possible mechanisms through which GLP-1 affects CRF-induced behaviors. The present experiments were conducted to confirm the effect of serotonin on CRF-induced behaviors. In Experiment 1, chicks were intracerebroventricularly injected with either saline, 0.1 microg of CRF, 5.0 microg of serotonin, or 0.1 microg of CRF plus 5.0 microg of serotonin. Injection of CRF caused excitation as evidenced by increased spontaneous activities and distress vocalizations (DVs) compared to the control group. The effect of CRF was attenuated by serotonin since chicks became quiet after given CRF with serotonin. Sleep-like behaviors were observed in the serotonin group. The number of defecations was increased by CRF and decreased by serotonin. Both CRF and serotonin increased plasma corticosterone, and the effect was synergistic. Serotonin dose-dependently decreased locomotor activities of chicks after central administration of 0.1 microg of CRF, 0.1 microg of CRF plus 2.5, 5.0, or 10.0 microg of serotonin in Experiment 2. CRF-induced DVs were modified by serotonin. Instead of DVs, tender and low-pitched vocalizations were observed in chicks treated with CRF plus serotonin, the voice frequencies of which were less than 10 kHz. In conclusion, serotonin attenuated the CRF-induced behaviors while stimulating corticosterone release. These results indicate that the role of serotonin is dependent on the behaviors being measured.     

Serotonergic modulation of psychological stress-induced alteration in synaptic plasticity in the rat hippocampal CA1 field

In order to elucidate possible involvement of the serotonergic neuronal system in the stress-induced alteration in synaptic plasticity, the effects of contextual fear conditioning (CFC) on long-term potentiation (LTP) in the hippocampal CA1 field were examined in 5-HT-depleted rats by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 200 microg/rat, i.c.v.). LTP induction was suppressed by footshock (FS) stimulation in 5-HT-lesioned rats and vehicle-treated controls. When rats were exposed to CFC, which was received 24 h after FS stimulation, LTP was also blocked in both-treated groups. CFC-induced impairment of LTP, however, significantly attenuated in 5-HT-lesioned rats when compared with that in controls. Fear-related freezing behavior after FS stimulation occurred similarly in both treated groups, whereas the behavior observed during exposure to CFC significantly reduced in 5-HT-lesioned rats. These results suggest that the serotonergic mechanism is involved in the psychological stress-induced alteration in synaptic plasticity, which appears to be associated with fear-related behavior.     

Gamma-linolenic acid prevents conjugated linoleic acid-induced fatty liver in mice

OBJECTIVE: The present study was done to clarify the mechanism by which conjugated linoleic acid (CLA) induces fatty liver in mice and to attenuate this symptom by adding other dietary fatty acids. METHODS: Mice were given CLA short (12 h) or long (4 wk) term or given CLA with linoleic acid (LA) or gamma-linolenic acid (GLA) in the long term (4 wk). Total lipids, triacylglycerol, and prostaglandin E(2) (PGE(2)) levels in the liver were determined. RESULTS: A single administration of CLA significantly increased PGE(2) levels in the liver 12 h after administration. However, long-term administration of CLA significantly decreased the liver PGE(2) level and induced fatty liver. GLA increased PGE(2) levels, and coadministration with GLA, but not with LA, prevented the CLA-induced fatty liver. CONCLUSIONS: These data suggest that CLA initially stimulates PGE(2) production followed by depletion of PGE(2) sources in the liver. The fatty liver associated with PGE(2) reduction by CLA ingestion can be attenuated by GLA in mice.     

Final height and pubertal growth in Japanese patients with congenital hypothyroidism detected by neonatal screening

Aim: To investigate the final adult heights and pubertal growth patterns in Japanese patients with congenital hypothyroidism (CH) detected by neonatal screening. Methods: A retrospective chart review was conducted of female patients >15 y of age (n = 18) and male patients >18 y of age (n = 9), who were detected by neonatal screening and kept on continuous thyroid hormone replacement therapy. Final height standard deviation scores (FHSDS) and target height standard deviation scores (THSDS) were determined. Parameters characterizing the pubertal growth process (such as age at onset of pubertal growth spurt and age at peak pubertal growth) were obtained from each patient's growth rate chart. Menarchial age was determined in each female patient by reviewing the medical record. The impact on FHSDS of the etiology of CH, the severity of CH, the time of initiation of therapy and the adequacy of treatment during the first year of life was assessed. Results: All patients had received initial thyroid hormone treatment no later than 50 d of age, and had reached their final height. The mean FHSDS for female and male patients were +0.17 ± 0.99 and -0.03 ± 0.99, respectively. The mean FHSDS-THSDS for female and male patients was +0.09 ± 0.77 and -0.19 ± 0.53, respectively. No difference was seen in pubertal growth parameters for either gender compared with that of the reference population, except for a greater peak height velocity and pubertal height gain in male patients. The mean menarchial age was identical to that of the reference population. No significant relationship was found between the FHSDS and any of the factors investigated.

Conclusion: The adult height of patients with CH detected by neonatal screening was equivalent to that of the reference population and their target height. As long as early intervention and satisfactory management are ensured, severe CH does not appear to reduce final adult height.     

VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation

We investigated the expression of two candidate transducers of noxious stimuli in peripheral tissues, the vanilloid receptor subtype 1 (VR1) and the P2X(3), a subunit of the ionotropic P2X receptor for ATP, in spared L4 DRG neurons following L5 spinal nerve ligation, a neuropathic pain model. VR1 mRNA expression increased in the small- and medium-sized DRG neurons from the first to 28th day after injury, and this up-regulation corresponded well with the development and maintenance of thermal hyperalgesia of the hind paw. The increase in VR1-immunoreactive (ir) neurons was confirmed at the third day after surgery. In contrast, there was no change in expression of P2X(3) mRNA over 4 weeks after ligation, or in the percentage of P2X(3)-ir neurons observed 3 days after surgery. Our data suggests that increased VR1 in the spared L4 DRG may contribute to the exaggerated heat response observed in this neuropathic pain model. Taken together with the previous reports that P2X(3) expression increases in the spared DRG neurons in other neuropathic pain models, there appears to be differences in the phenotypic changes and pathomechanisms of the various neuropathic pain models.