The effects of intrathecal tramadol on spinal somatosensory-evoked potentials and motor-evoked responses in rats

Tramadol has been proven to exert a local anesthetic-type effect on peripheral nerves in both clinical and laboratory studies. In this study, we evaluated the effects of tramadol on sensory and motor neural conduction when administered intrathecally in the rat. Tramadol (0, 1, or 2 mg) was administered through an intrathecal catheter. Spinal somatosensory-evoked potentials (SSEPs) were recorded at the thoracolumbar junction after stimulation of the sciatic nerve. An evoked compound muscle action potential (CMAP) was recorded in the intrinsic muscles of the foot in response to electric stimulation of the lower thoracic (T1213) interspinous space. Both SSEP and CMAP were obtained before drug application as the pretreatment baseline and at 5, 15, and 30 min after treatment, and at 30- or 60-min intervals thereafter for another 4.5 h. SSEP was averaged from 20 responses, whereas CMAP was obtained from a single stimulation. Reproducible SSEPs and CMAP were consistently recorded in all rats. Intrathecal tramadol dose-dependently reduced the amplitude and delayed the latency in both SSEPs and CMAP. Generally, the suppressive effects occurred immediately after injection and recovered over 2 h. Combined administration with 20 micro g of intrathecal naloxone did not attenuate the inhibition of spinal SSEPs. We conclude that intrathecal tramadol causes a dose-related suppressive effect on both sensory and motor neural conduction in the spinal cord. IMPLICATIONS: Spinal somatosensory-evoked potentials and evoked compound muscle action potential were used to evaluate the effects of intrathecal tramadol on sensory and motor neural conduction. Intrathecal tramadol dose-dependently reduced the amplitude and delayed the latency of both spinal somatosensory-evoked potentials and compound muscle action potential. These results indicate that tramadol exerts a dose-related central neural blockade.     

Detection of recurrent nasopharyngeal carcinomas after radiotherapy with technetium-99m tetrofosmin single photon emission computed tomography in patients with indeterminate magnetic resonance imaging findings

The aim of this study is to evaluate the effectiveness of technetium-99m tetrofosmin (Tc-99m TF) single photon emission computed tomography (SPECT) of head and neck for detecting suspected recurrence of nasopharyngeal carcinomas (NPCs) when magnetic resonance imaging (MRI) findings are indeterminate. MRI was performed 4 months after radiotherapy and 26 NPC patients with indeterminate MRI findings were included. MRI, Tc-99m TF SPECT, and biopsy were performed within 1 week. The final results were based on histopathologic findings and clinical follow-up for at least 6 months. For detecting recurrent NPC in indeterminate MRI findings, the sensitivity, specificity, and accuracy of Tc-99m TF SPECT were 92.3%, 100.0%, and 96.2%, respectively. Based on this result, we can suggest Tc-99m TF SPECT is effective to detect recurrent NPC when MRI findings are indeterminate. However, further studies including a larger NPC patient population are warranted to determine the exact role and clinical usefulness of Tc-99m TF SPECT to differentiate benign lesions and recurrent NPC when MRI findings are indeterminate.     

Locally administered nerve growth factor suppresses ginsenoside Rb1-enhanced peripheral nerve regeneration

A high-dose of nerve growth factor (NGF) mixed with ginsenoside Rb1 (GRb1) was encapsulated by collagen and placed in silicone rubber chambers, which were used to repair dissected Sprague-Dawley rat sciatic nerves with 15 mm gaps. Six weeks after surgery, no axons or Schwann cells were seen in these chambers. By comparison, nerves treated with collagen-GRb1 alone had regenerated axons and Schwann cells in their endoneurial areas. We suggest that excessive NGF may not promote but, rather, suppress developing nerves.     

c-Abl stabilizes p73 by a phosphorylation-augmented interaction

The proapoptotic function of c-Abl is in part mediated by its functional interaction with p73, a p53 homologue. Although it has been shown that c-Abl-mediated p73 activation in response to genotoxic stress is associated with an increase of p73 protein levels, the underlying mechanism remains unclear. We show here that c-Abl increases the cellular p73 abundance through a mode of posttranslational regulation. Analogous to its functional activation of p73, the kinase activity is essential for c-Abl to up-regulate p73 protein levels. Analysis of phosphorylation-resistant mutants of p73 reveals that the effect of c-Abl is mediated by its direct phosphorylation on the p73 protein. Consequence to the phosphorylation is a marked increase of the association between c-Abl and p73 via the binding of tyrosine-phosphorylated p73 to the c-Abl Src homology 2 (SH2) domain. Of functional importance of this phosphorylation-induced interaction in p73 stabilization is the demonstration that expression of a c-Abl SH2 domain peptide, which impedes phosphorylation-dependent association, results in an almost complete abrogation of c-Abl-dependent p73 accumulation. Importantly, expression of the c-Abl SH2 domain peptide also leads to an efficient inhibition of cisplatin-induced accumulation of endogenous p73, highlighting the biological significance. In keeping with its retained phosphorylation sites, the NH(2)-terminal truncated (Delta N) isoforms of p73, which are antiapoptotic, are also phosphorylated and stabilized by c-Abl, suggesting a possibility that c-Abl contributes to either pro- or antiapoptotic process depending on the expression profile of p73 isoforms.     

Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth

Black cohosh is an increasingly popular alternative to estrogen replacement therapy for the relief of menopausal symptoms, primarily hot flushes. However, an important consideration for long-term therapy is potential toxicity and carcinogenicity. Therefore, we undertook a study to assess the estrogenic activity of black cohosh to examine its safety for those with, or at high risk of developing, breast cancer. Several assays were utilized as listed: RNAse protection assays, which ascertain the regulation of the expression of E2-responsive genes; estrogen-responsive-element (ERE)-luciferase, which determines modulation of the ER function by transactivation of the ERE; the Ishikawa cell system, which has an E2-regulated endogenous alkaline phosphatase; and colony formation of ER-expressing breast cancer cells, which indicates possible progression of early stage breast cancer into a more aggressive state. Black cohosh extracts did not demonstrate estrogenic activity in any of these assay systems. This is an encouraging step in the assessment of the safety of black cohosh for treatment of menopausal hot flushes.     

Emergence of ceftriaxone-resistant Salmonella isolates and rapid spread of plasmid-encoded CMY-2-like cephalosporinase,Taiwan

Of 384 Salmonella isolates collected from 1997 to 2000 in a university hospital in Taiwan, six ceftriaxone-resistant isolates of Salmonella enterica serovar Typhimurium were found in two patients in 2000. The resistance determinants were on conjugative plasmids that encoded a CMY-2-like cephalosporinase. During the study period, the proportion of CMY-2-like enzyme producers among Escherichia coli increased rapidly from 0.2% in early 1999 to >4.0% in late 2000. Klebsiella pneumoniae isolates producing a CMY-2-like beta-lactamase did not emerge until 2000. The presence of bla(CMY)-containing plasmids with an identical restriction pattern from Salmonella, E. coli, and K. pneumoniae isolates was found, which suggests interspecies spread and horizontal transfer of the resistance determinant. Various nosocomial and community-acquired infections were associated with the CMY-2-like enzyme producers. Our study suggests that the spread of plasmid-mediated CMY-2-like beta-lactamases is an emerging threat to hospitalized patients and the public in Taiwan.     

The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production

Reactive oxygen species produced by neutrophils contribute to the pathogenesis of focal cerebral ischemia/reperfusion injury and signal the inflammatory response. We have previously shown that honokiol, an active principle extracted from Magnolia officinalis, has a protective effect against focal cerebral ischemia/reperfusion injury in rats that paralleled a reduction in reactive oxygen species production by neutrophils. To elucidate the underlying mechanism(s) of the antioxidative effect of honokiol, peripheral neutrophils isolated from rats were activated with phorbol-12-myristate-13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) in the presence or absence of honokiol. In this study, we found that honokiol inhibited PMA- or fMLP-induced reactive oxygen species production by neutrophils by three distinct mechanisms: (1) honokiol diminished the activity of assembled-NADPH oxidase, a major reactive oxygen species producing enzyme in neutrophils by 40% without interfering with its protein kinase C (PKC)-dependent assembly; (2) two other important enzymes for reactive oxygen species generation in neutrophils, i.e., myeloperoxidase and cyclooxygenase, were also inhibited by honokiol by 20% and 70%, respectively; and (3) honokiol enhanced glutathione (GSH) peroxidase activity by 30%, an enzyme that triggers the metabolism of hydrogen peroxide (H2O2). These data suggested that honokiol, acting as a potent reactive oxygen species inhibitor/scavenger, could achieve its focal cerebral ischemia/reperfusion injury protective effect by modulating enzyme systems related to reactive oxygen species production or metabolism, including NADPH oxidase, myeloperoxidase, cyclooxygenase, and GSH peroxidase in neutrophils.     

A cytotoxic butenolide,two new dolabellane diterpenoids,a chroman and a benzoquinol derivative formosan Casearia membranacea

Investigation of a cytotoxic chloroform-soluble fraction of the stem of Casearia membranacea (Flacourtiaceae) led to the isolation of five new compounds, including one butenolide, casealactone (1), one chroman, caseamemin (2), two dolabellane diterpenoids, casearimene A (3) and casearimene B (4), one benzoquinol ether, casearinone (5), together with fifteen known compounds, including two amides, N- trans-feruloyltyramine (6) and N- cis-feruloyltyramine (7), six steroids, beta-sitosterol (8), stigmast-5-ene-3beta,7alpha-diol (9), stigmast-5-ene-3beta,7beta-diol (10), stigmastane-3beta,5alpha,6beta-triol (11), beta-sitostenone (12), beta-sitosterol 3- O-beta-glucoside (13), two triterpenoids, squalene (14) and friedelin (15), one lignan, (+/-)-syringaresinol (16), two benzenoids, syringaldehyde (17) and vanillic acid (18), one ester, methyl hexadecanoate (19), and anthraquinone (20), respectively. Among these isolates, 1 showed cytotoxicity against P-388 and HT-29 cancer cell lines in vitro, and 6 and 7 showed cytotoxicity against the P-388 cancer cell line. The structures of these compounds were determined by means of spectroscopic techniques, and the structure of 3 was confirmed by X-ray crystallographic analysis.     

Preparation and evaluation of sustained release microspheres of potassium chloride prepared with ethylcellulose

The water-insoluble polymer ethylcellulose is used as a retardant to prepare the sustained release of potassium chloride microspheres by drying in a liquid process. The effect of sustained release of potassium from ethylcellulose microspheres was evaluated by the in vitro dissolution test, and was compared to a commercial product (Slow-K). The results showed that ethylcellulose microspheres loaded with potassium chloride could be easily prepared and satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-93 and 36%, respectively. However, the potassium/ethylcellulose 2/2 (30-45 mesh) microspheres showed the similar sustained release effect of commercial product.     

Noninvasive Characterization of Regional Variation in Drug Transport into Human Stratum Corneum in Vivo

Purpose. To investigate the mechanisms underlying the regional variations in drug transport into human stratum corneum (SC) of two model compounds of different lipophilicity and molecular size, 4-cyanophenol (CP) and cimetidine (CM), in vivo by non-invasive, quantitative attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Methods. Saturated solutions of CP and CM were applied to the skin surface of eleven Chinese men, at five anatomical sites, including forearm, back, thigh, leg, and abdomen, for 10-15 min and 3-5 h, respectively. After the skin surface was cleansed of remaining chemicals, the SC was tape-stripped sequentially up to 20 times, and the drug concentration profiles in the tape-stripped SC were determined using ATR-FTIR spectroscopy. Thickness of the SC was estimated simultaneously using two-point measurements of transepidermal water loss before and after completion of tape stripping. Estimation of partition, diffusion, and permeability coefficients was achieved by analysis of the data using the unsteady-state diffusion equation. Results. The rank orders of regional variation in partition and diffusion coefficients of CP and CM were different. The rank order of regional variation in permeability coefficients was similar for both drugs and decreased in the order of back > forearm > thigh > leg abdomen, but the variation was more prominent for CM. Conclusions. Regional variation in SC transport of CP was mainly influenced by its intrinsic diffusivity across the SC, whereas variation in transport of CM could be attributed to both thermodynamic and kinetic differences among different anatomical skin sites.