Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration.

Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose-titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one-sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers.

Possible involvement of prolonging spinal µ-opioid receptor desensitization in the development of antihyperalgesic tolerance to µ-opioids under a neuropathic pain-like state.

In the present study, we investigated the possible development of tolerance to the antihyperalgesic effect of µ-opioid receptor (MOR) agonists under a neuropathic pain-like state. Repeated treatment with fentanyl, but not morphine or oxycodone, produced a rapid development of tolerance to its antihyperalgesic effect in mice with sciatic nerve ligation. Like the behavioral study, G-protein activation induced by fentanyl was significantly reduced in membranes obtained from the spinal cord of nerve-ligated mice with in vivo repeated injection of fentanyl. In ß-endorphin-knockout mice with nerve ligation, developed tolerance to the antihyperalgesic effect of fentanyl was abolished, and reduced G-protein activation by fentanyl after nerve ligation with fentanyl was reversed to the normal level. The present findings indicate that released ß-endorphin within the spinal cord may be implicated in the rapid development of tolerance to fentanyl under a neuropathic pain-like state.

GABA(B) receptors do not internalize after baclofen treatment, possibly due to a lack of ß-arrestin association: study with a real-time visualizing assay.

The mechanism of agonist-induced GABA(B) receptor (GABA(B) R) internalization is not well understood. To investigate this process, we focused on the interaction of GABA(B) R with ß-arrestins, which are key proteins in the internalization of most of the G protein-coupled receptors, and the agonist-induced GABA(B) R internalization and the interaction of GABA(B) R with ß-arrestin1 and ß-arrestin2 were investigated in real time using GABA(B) R and ß-arrestins both of which were fluorescent protein-tagged. We then compared these profiles with those of µ-opioid receptors (µOR), well-studied receptors that associate and cointernalize with ß-arrestins. When stimulated by the specific GABA(B) R agonist baclofen, GABA(B) R composed of GABA(B1a) R (GB(1a) R) and fluorescent protein-tagged GABA(B2) R-Venus (GB2 R-V) formed functional GABA(B) R; they elicited G protein-activated inwardly rectifying potassium channels as well as nontagged GABA(B) R. In cells coexpressing GB(1a) R, GB2 R-V, and ß-arrestin1-Cerulean (ßarr1-C) or ß-arrestin2-Cerulean (ßarr2-C), real-time imaging studies showed that baclofen treatment neither internalized GB2 R-V nor mobilized ßarr1-C or ßarr2-C to the cell surface. This happened regardless of the presence of G protein-coupled receptor kinase 4 (GRK4), which forms a complex with GABA(B) R and causes GABA(B) R desensitization. On the other hand, in cells coexpressing µOR-Venus, GRK2, and ßarr1-C or ßarr2-C, the µOR molecule formed µOR/ßarr1 or µOR/ßarr2 complexes on the cell surface, which were then internalized into the cytoplasm in a time-dependent manner. Fluorescence resonance energy transfer assay also indicated scarce association of GB2 R-V and ß-arrestins-C with or without the stimulation of baclofen, while robust association of µOR-V with ß-arrestins-C was detected after µOR activation. These findings suggest that GABA(B) Rs failure to undergo agonist-induced internalization results in part from its failure to interact with ß-arrestins.

S(+)-ketamine suppresses desensitization of γ-aminobutyric acid type B receptor-mediated signaling by inhibition of the interaction of γ-aminobutyric acid type B receptors with G protein-coupled receptor kinase 4 or 5.

BACKGROUND: Intrathecal baclofen therapy is an established treatment for severe spasticity. However, long-term management occasionally results in the development of tolerance. One of the mechanisms of tolerance is desensitization of γ-aminobutyric acid type B receptor (GABABR) because of the complex formation of the GABAB2 subunit (GB2R) and G protein-coupled receptor kinase (GRK) 4 or 5. The current study focused on S(+)-ketamine, which reduces the development of morphine tolerance. This study was designed to investigate whether S(+)-ketamine affects the GABABR desensitization processes by baclofen. METHODS: The G protein-activated inwardly rectifying K channel currents induced by baclofen were recorded using Xenopus oocytes coexpressing G protein-activated inwardly rectifying K channel 1/2, GABAB1a receptor subunit, GB2R, and GRK. Translocation of GRKs 4 and 5 and protein complex formation of GB2R with GRKs were analyzed by confocal microscopy and fluorescence resonance energy transfer analysis in baby hamster kidney cells coexpressing GABAB1a receptor subunit, fluorescent protein-tagged GB2R, and GRKs. The formation of protein complexes of GB2R with GRKs was also determined by coimmunoprecipitation and Western blot analysis. RESULTS: Desensitization of GABABR-mediated signaling was suppressed by S(+)-ketamine in a concentration-dependent manner in the electrophysiologic assay. Confocal microscopy revealed that S(+)-ketamine inhibited translocation of GRKs 4 and 5 to the plasma membranes and protein complex formation of GB2R with the GRKs. Western blot analysis also showed that S(+)-ketamine inhibited the protein complex formation of GB2R with the GRKs. CONCLUSION: S(+)-Ketamine suppressed the desensitization of GABABR-mediated signaling at least in part through inhibition of formation of protein complexes of GB2R with GRK 4 or 5.

Post-transplantation malignancy: a cell autonomous mechanism with implications for therapy.

Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.

Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy.

BACKGROUND: Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine. METHODS: A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum. RESULTS: Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells. CONCLUSIONS: Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Effect of ONO-1101, a novel short-acting ß-blocker on hemodynamic responses to isoflurane inhalation and tracheal intubation.

PURPOSE: We investigated the effect of a new ultrashort-acting ß-blocker, ONO-1101, on hemodynamic responses to isoflurane inhalation and tracheal intubation. METHODS: Fifty-four ASA PS 1 or 2 patients were randomly allocated to receive either ONO-1101, 0.04 mg·kg-1·min-1, or saline prior to tracheal intubation. Anesthesia was induced with thiamylal, 4 mg·kg-1, and vecuronium, 0.15 mg·kg-1. Tracheal intubation was carried out after 3 min controlled mask ventilation with 66% N2O and 3% inspired isoflurane in oxygen. Heart rate and blood pressure were continuously recorded from the start of induction until 5 min after intubation. Plasma concentrations of catecholamines were measured before induction, 3 min after initiating inhalation of isoflurane, and 1 min after tracheal intubation. RESULTS: Significant increases in heart rate occurred in both groups in response to isoflurane inhalation and tracheal intubation, but the magnitude of the increase was significantly less in the ONO-1101 group. Blood pressure increased after tracheal intubation in the saline group but remained unchanged in the ONO-1101 group. Plasma concentrations of norepinephrine increased after induction and intubation in both groups, with no significant difference between the groups. CONCLUSION: ONO-1101 infusion is effective for the attenuation of hemodynamic responses to isoflurane inhalation and tracheal intubation.

[Willingness to implement mental health measures among small-scale enterprise employers in Ohta ward, Tokyo, Japan].

Due to the increase in mental health problems among Japanese workers in recent years, effective approaches to address these problems are of growing concern. Although such an effort is now under way in largescale enterprises (LSEs), small-scale enterprises (SSEs) are lagging behind LSEs for a number of reasons. In the present study, to know the reason, the presidents of 263 SSEs (fewer than 50 employees) in the Ohta ward of Tokyo were surveyed with a self-administered questionnaire from October 1999 to March 2000 (response rate, 51.0%). The main business types were manufacturing (71.2%), transportation & storage (6.1%), and construction (5.3%). The results revealed that employers attribute the mental health problems of employees to "Job content/Aptitude for job (78.6%)", "Communication among employees (71.0%)", "Physical problems/Illness (50.4%)", "Family problems (33.6%)". These results are very similar to those obtained in the same enterprises employees survey in 1996, suggesting that employers perceive the factors responsible for employees' mental health problems with substantial accuracy. Sixty-nine point five percent of the employers answered that they need mental health measures for employees. And 62.7% of employers agreed to take mental health measures in their enterprises. Taken together, it is considered that employers are willing to improve their employees' mental health problems. Nevertheless, 95% of employers are doing nothing to improve the situation. The major reasons cited were 1) Cannot obtain a consultant or counselor (44.8%), 2) Lack of time (43.1%), 3) Manpower shortage (41.4%), 4) Difficulty in ensuring employees' privacy (36.2%), and 5) Lack of financial resources (30.2%). The results of the present study suggest that perception of the mental health problems among employers and employees of SSEs in the Ohta area were close to each other. Effective strategies are needed to improve mental health problems in SSEs.

Pharmacokinetics of oxycodone after intravenous and subcutaneous administration in Japanese patients with cancer pain.

ABSTRACT In Japan, Oxycodone hydrochloride injection formulation has been approved in 2012. However, its pharmacokinetics has been poorly studied. The aim of this study is to evaluate the pharmacokinetics of oxycodone after intravenous and subcutaneous administration of oxycodone hydrochloride injection in Japanese patients with cancer pain. Noncompartmental analysis and population pharmacokinetic analysis were performed. We conducted a multicenter open-label study of oxycodone hydrochloride administered as constant infusion with the dose titrated individually according to the pain intensity in patients with cancer pain. Pharmacokinetic parameters for plasma oxycodone and its metabolites were estimated using pharmacokinetics of oxycodone was evaluated using a total of 344 plasma concentrations obtained from 89 patients. The estimated geometric mean clearance (CL) of oxycodone was 24.3 L per hour after constant intravenous infusion and 29.5 L per hour after constant subcutaneous infusion, respectively. Population pharmacokinetic analysis indicated that body surface area was the influencing factor on CL and there were no pharmacokinetic differences for CL between intravenous and subcutaneous infusion. These results provide important information for the clinical use of oxycodone injection.

Measuring exposed magnetic fields of welders in working time.

The assessment of the occupational electromagnetic field exposure of welders is of great importance, especially in shielded-arc welding, which uses relatively high electric currents of up to several hundred amperes. In the present study, we measured the magnetic field exposure level of welders in the course of working. A 3-axis Hall magnetometer was attached to a subject's wrist in order to place the sensor probe at the closest position to the magnetic source (a cable from the current source). Data was acquired every 5 s from the beginning of the work time. The maximum exposed field was 0.35-3.35 mT (Mean ± SD: 1.55 ± 0.93 mT, N=17) and the average value per day was 0.04-0.12 mT (Mean ± SD: 0.07 ± 0.02 mT, N=17). We also conducted a finite element method-based analysis of human hand tissue for the electromagnetic field dosimetry. In addition, the magnetic field associated with grinders, an air hammer, and a drill using electromagnetic anchorage were measured; however, the magnetic fields were much lower than those generated in the welding process. These results agreed well with the results of the electromagnetic field dosimetry (1.49 mT at the wrist position), and the calculated eddy current (4.28 mA/m(2)) was much lower than the well-known guideline thresholds for electrical nerve or muscular stimulation.

Adhesiolysis and targeted steroid/local anesthetic injection during epiduroscopy alleviates pain and reduces sensory nerve dysfunction in patients with chronic sciatica.

PURPOSE: The aim of this study was to evaluate the effect of adhesiolysis followed by the injection of steroid and local anesthetic during epiduroscopy on sensory nerve function, pain, and functional disability in patients with chronic sciatica. METHODS: Epidural adhesiolysis, using epiduroscopy, followed by the injection of steroid and local anesthetic, was scheduled in 19 patients with chronic sciatica refractory to lumbar epidural block. Sensory nerve function in the legs was tested with a series of 2000-Hz (Abeta-fiber), 250-Hz (Adelta-fiber), and 5-Hz (C-fiber) stimuli, using the current perception threshold (CPT), and CPT values and intensity of pain and Roland Morris Disability Questionnaire (RMDQ) scores were assessed before and 1 and 3 months after the epiduroscopy. RESULTS: At all frequencies, the CPT values in the affected legs of patients before the epiduroscopy were significantly higher than those in the unaffected legs. Epidural adhesiolysis was successfully performed in 16 of the 19 patients. In these patients, the CPT values at 2000 and 250 Hz, and the pain and RMDQ scores 1 and 3 months after the epiduroscopy were significantly lower than those before the epiduroscopy, while the CPT value at 5 Hz did change. CONCLUSION: Epidural adhesiolysis followed by the injection of steroid and local anesthetic during epiduroscopy alleviated pain, and functional disability, and reduced dysfunction of Abeta and Adelta fibers in patients with chronic sciatica.

mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis.

Interactions between mu-opioid receptor (muOR) and cannabinoid CB1 receptor (CB1R) were examined by morphological and electrophysiological methods. In baby hamster kidney (BHK) cells coexpressing muOR fused to the yellow fluorescent protein Venus and CB1R fused to the cyan fluorescent protein Cerulean, both colors were detected on the cell surface; and fluorescence resonance energy transfer (FRET) analysis revealed that muOR and CB1R formed a heterodimer. Coimmunoprecipitation and Western blotting analyses also confirmed the heterodimers of muOR and CB1R. [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAMGO) or CP55,940 elicited K+ currents in Xenopus oocytes expressing muOR or CB1R together with G protein activated-inwardly rectifying K+ channels (GIRKs), respectively. In oocytes coexpressing both receptors, either of which was fused to the chimeric Galpha protein Gqi5 that activates the phospholipase C pathway, both DAMGO and CP55,940 elicited Ca2+-activated Cl(-) currents, indicating that each agonist can induce responses through Gqi5 fused to either its own receptor or the other. Experiments with endogenous Gi/o protein inactivation by pertussis toxin (PTX) supported the functional heterodimerization of muOR/CB1R through PTX-insensitive Gqi5(m) fused to each receptor. Thus, muOR and CB1R form a heterodimer and transmit a signal through a common G protein. Our electrophysiological method could be useful for determination of signals mediated through heterodimerized G protein-coupled receptors.

Desensitization of GABA(B) receptor signaling by formation of protein complexes of GABA(B2) subunit with GRK4 or GRK5.

We investigated the role of G protein coupled-receptor kinases (GRKs) in the desensitization of GABA(B) receptor-mediated signaling using Xenopus oocytes and baby hamster kidney (BHK) cells. Baclofen elicited inward K(+) currents in oocytes coexpressing heterodimeric GABA(B) receptor, GABA(B1a) subunit (GB(1a)R) and GABA(B2) subunit (GB(2)R), together with G protein-activated inwardly rectifying K(+) channels (GIRKs), in a concentration-dependent manner. Repetitive application of baclofen to oocytes coexpressing GABA(B)R and GIRKs did not change peak K(+) currents in the first and second responses, but the latter responses were significantly attenuated by coexpression of either GRK4 or GRK5 with attenuation efficacy of GRK4 > GRK5. Coexpression of other GRKs including GRK2, GRK3, and GRK6 had no effect on GABA(B) receptor-mediated desensitization processes. In BHK cells coexpressing GRK4 fused to Venus (brighter variant of yellow fluorescent protein, GRK4-Venus) with GB(1a)R and GB(2)R, GRK4-Venus was expressed in the cytosol but was translocated to the plasma membranes by GABA(B)R activation. In BHK cells coexpressing GRK4 fused to Cerulean (brighter variant of cyan fluorescent protein, GRK4-Cerulean) with GB(1a)R and GB(2)R-Venus, fluorescence resonance energy transfer (FRET) analysis demonstrated that GRK4-Cerulean formed a protein complex with GB(2)R-Venus. Immunoprecipitation and Western blot analysis confirmed GB(2)R-GRK4 complex formation. GRK5 also formed a complex with GB(2)R on the plasma membranes as determined by FRET and Western blotting but not GRK2, GRK3, and GRK6. Our results indicate that GRK4 and GRK5 desensitize GABA(B) receptor-mediated responses by forming protein complexes with GB(2)R subunit of GABA(B)R at the plasma membranes.