Tolerance effects of non-steroidal anti-inflammatory drugs microinjected into central amygdala,periaqueductal grey,and nucleus raphe Possible cellular mechanism

Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.

Volumetric fluid analysis of fixed monthly anti-VEGF treatment in patients with neovascular age-related macular degeneration

·AIM:To evaluate visual outcomes and changes in fluid after administering monthly anti-vascular endothelial growth factor(VEGF)injections to treat neovascular agerelated macular degeneration(n AMD)with subretinal fluid(SRF)and pigment epithelial detachment(PED).·METHODS:This prospective study included eyes with n AMD previously treated with as-needed anti-VEGF injections.The patients were treated with six monthly intravitreal injections of ranibizumab.Quantitative volumetric segmentation analyses of the SRF and PED were performed.The main outcome measures included best-corrected visual acuity(BCVA),and SRF and PED volumes.·RESULTS:Twenty eyes of 20 patients were included in this study.At the 6-month follow-up,BCVA and PED volume did not change significantly(P=0.110 and 0.999,respectively)but the mean SRF volume decreased from 0.53±0.82 mm3 at baseline to 0.08±0.23 mm3(P=0.002).The absorption rate of the SRF volume was negatively correlated with the duration of previous antiVEGF treatment(P=0.029).Seven of the 20 eyes(35%)showed a fluid-free macula and significant improvement in BCVA(P=0.036)by month 6.·CONCLUSION:Quantifying the SRF can precisely determine the patient’s responsiveness to anti-VEGF treatment of n AMD.

Inhibitory effect of berberine on morphine tolerance and hyperalgesia in mice

OBJECTIVE: To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia. METHODS: Morphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg;30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg;30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphineinduced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency(T0) and post-treatment latency(T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase(NOS) activity and nitric oxide(NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-Daspartate(NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups(5, 10, 20 μmol/L, respectively). Except for the control group, cells were treated with NMDA(HT-22 cells: 20 mmol/L;HEK-293 cells: 50 μmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking. RESULTS: Berberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency(P < 0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE(P < 0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord(P < 0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells(P < 0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA. CONCLUSIONS: Berberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.

Evaluation of Targeted Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma in Tunisia

Introduction: Renal cell carcinoma (RCC) is known to be chemo resistant but with the introduction of targeted therapies;there has been a “revolution” in its treatment strategies. The only targeted therapy available in Tunisia for the treatment of metastatic and/or locally advanced RCC is sunitinib. Objective of the Study: To evaluate therapeutic results and tolerance of sunitinib in metastatic and/or locally advanced RCC. Subjects and Methods: This was a retrospective study covering a period of six years (from January 2008 to January 2014) conducted in 5 medical oncology departments in Tunisia. The population of the study consisted of 29 patients treated with sunitinib for metastatic and/or locally advanced RCC. Results: The mean age of patients was 51 years. Three patients had tumor recurrence and 26 patients had a metastatic RCC. The prognosis was good for 5 patients, intermediate for 19 patients and poor for 5 patients. The median duration of treatment was 5 months. Because of side effects, treatment was discontinued in 12.5% of cases and the dose was reduced in 10.3% of cases. Side effects consisted of asthenia (95.8%), stomatitis (70.8%), anemia (50%), hand-foot syndrome (55.8%) in addition to nausea and vomiting (54.2%). Objective response was observed in 37.5% of patients after 3 months of treatment and in 50% after 6 months. The median progression-free survival was 14 months (95% CI, 7.9 to 20.6). The median overall survival was 22 months (95% CI, 15.6 to 28.7). Conclusion: The prognosis of RCC in Tunisian patients has clearly improved with the introduction of sunitinib, but other therapies with a proven efficacy as a first and second line therapy should be considered.