Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ-1 subunit.</p> <p>Results</p> <p>Mice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant.</p> <p>Conclusions</p> <p>These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.</p

14-Cmethionine uptake as a potential marker of inflammatory processes after myocardial ischemia and reperfusion

A relationship between L-[methyl-11C]methionine (11C-methionine) uptake and angiogenesis has been suggested in gliomas. However, methionine uptake in myocardial ischemia and reperfusion has received little attention. We investigated the serial changes and mechanisms of 14-Cmethionine uptake in a rat model of myocardial ischemia and reperfusion. Methods: The left coronary artery was occluded for 30 min, followed by reperfusion for 1-28 d. At the time of the study, 14-Cmethionine (0.74 MBq) and 201Tl (14.8 MBq) were injected intravenously at 20 and 10 min before sacrifice, respectively. One minute before sacrifice, the left coronary artery was reoccluded, and 99mTc-hexakis-2-methoxyisobutylisonitrile (150-180 MBq) was injected to verify the area at risk. Histologic sections of the heart were immunohistochemically analyzed using anti-CD68, anti-smooth-muscle a-actin (SMA), and antitroponin I and compared with the autoradiography findings. Results: Both 14Cmethionine (uptake ratio, 0.71 ± 0.13) and 201Tl uptake were reduced in the area at risk at 1 d after reperfusion. However, 3 d after reperfusion, an increased 14-Cmethionine uptake (1.79 ± 0.23) was observed corresponding to the area of still-reduced 201Tl uptake, and the 14-Cmethionine uptake gradually declined until 28 d. The increased 14-Cmethionine uptake area at 3 and 7 d corresponded well to the macrophage infiltrations demonstrated by positive CD68 staining. Anti-SMA staining appeared at 7 d, after which CD68 staining was gradually replaced by the SMA staining, suggesting that methionine uptake in the early phase after ischemia and reperfusion might reflect inflammatory activity. Conclusion: 14-Cmethionine accumulated in the infarcted area, and its uptake corresponded closely to macrophage infiltration at 3-7 d after reperfusion. Methionine imaging may be useful for inflammatory imaging early after myocardial infarction. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc

Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study

AbstractObjectiveDisease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy.Patients and methodsThis was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed.ResultsOverall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax.ConclusionsSuccess rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs