Epidural and Intrathecal n-Butyl-p-Aminobenzoate Solution in the Rat: Comparison with Bupivacaine

Background: Epidural administration of an aqueous suspension of n-butyl-p-aminobenzoate (BAB) to humans results in long-lasting sensory blockade without motor block. The dose-response of BAB administered epidurally and intrathecally as a solution was studied in rats to define the local anesthetic properties in an established animal model.

Methods: The time course of changes in tail withdrawal latency and motor function were determined in rats after epidural or intrathecal administration of solutions of BAB or bupivacaine. The dose-response relation was determined and median effective dose values were calculated.

Results: After epidural and intrathecal administration of BAB solutions, the onset and duration of the antinociceptive action were comparable to bupivacaine. Median effective dose values for tail-withdrawal latency of 6 s or more were significantly greater for BAB. After both routes of administration, BAB clearly affected motor function.     

Vocalization Responses After Spinal Administration of Bicuculline or Strychnine in Rats

Objective. Spinal administration of compounds decreasing inhibition of spinal nociceptive pathways, such as antagonists of GABA or glycine receptors, leads to vocalization. This can be quantified semiautomatically and could be used as a research model. Materials and Methods. Vocalization after intrathecal administration of bicuculline and strychnine was measured in Sprague-Dawley rats. Results. Both bicuculline and strychnine produced short, dose-related vocalization responses that were not significantly different between models of peripheral inflammation and neuropathic pain and normal controls, except for reduced strychnine-induced vocalization during inflammation. The strychnine-induced vocalization responses were also reduced in freely moving rats and increased by light tactile stimulation. Conclusions. Bicuculline-induced vocalization seems to be related to facilitation of nociceptive transmission, and could have limited use as a model of nociception at the spinal level. However, peripheral inflammation or neuropathic pain did not affect it. Strychnine-induced vocalization responses seem to be related to non-noxious somatosensory input.     

Pharmacological validation of ritanserin and risperidone in the drug discrimination test procedure in the rat

The results presented here indicate that 0.16 mg/kg LSD, 2.50 mg/kg 8-OHDPAT, 1.25 mg/kg d-amphetamine, 10.00 mg/kg cocaine, 40.00 mg/kg chlordiazepoxide, 2.50 mg/kg xylazine, and 0.04 mg/kg fentanyl can be used as discriminative stimuli in a two-lever drug discrimination test procedure in the rat. The central 5-HT₂ antagonist ritanserin and the 5-HT₂ and catecholamine (CA)-antagonist risperidone were tested for stimulus generalization with, and possible antagonism of, the discriminative stimulus properties of the various training drugs. With both drugs at all doses tested, no stimulus generalization was observed with any of the training drugs. Ritanserin completely blocked the discriminative stimulus properties of LSD at 40.00 mg/kg but was, at doses up to 40.00 mg/kg, unable to block the discriminative stimulus properties of any of the other training drugs. Risperidone completely antagonized the stimulus properties of LSD and d-amphetamine, partially blocked cocaine, and possessed minor effects on 8-OHDPAT and fentanyl. Whereas ritanserin was almost without any effects or response rate, risperidone mostly reduced response rate at doses starting between 0.16 and 0.63 mg/kg. However, the complete antagonism of the LSD and d-amphetamine was observed without effects on response rate. Globally, these results confirm ritanserin to be a selective 5-HT₂ antagonist without any effects on conditioned behaviour. Risperidone was found to be a potent 5-HT₂ and DA antagonist, affecting conditioned behaviour by interfering with response rate and with the response-reinforcement contingency.     

Reduction of Abeta levels in the Sprague Dawley rat after oral administration of the functional gamma-secretase inhibitor, DAPT: a novel non-transgenic model for Abeta production inhibitors

Considerable effort has been made to develop drugs that delay or prevent neurodegeneration. These include inhibitors of Abeta-generating proteases for the treatment of Alzheimer's disease. Testing the amyloid hypothesis in vivo requires molecules that are capable of entering the CNS and that produce a substantial reduction in brain Abeta levels. Plaque-developing APP transgenic mice are currently widely used as an in vivo model of choice as these animals produce readily measurable amounts of human Abeta. They are very useful in the testing of a variety of amyloid-lowering approaches but their use for compound screening is often limited by their cost. Transgenic animals also require extensive, time-consuming breeding programs and can show high inter-animal differences in the expression level of the transgene. Hence, we considered it important to develop and characterize a new and simple non-transgenic animal model for testing Abeta modulation. For this purpose, Wild-type adult Sprague Dawley rats were treated with DAPT, a functional gamma-secretase inhibitor, and the Abeta40 and Abeta42 levels in brain-tissue and body fluids were assessed. We showed that DAPT, given orally, significantly lowered Abeta40 and Abeta42 peptide levels in brain extract, CSF, and the plasma dose- and time-dependently. We can conclude that our data establish the usefulness of the wild-type rat model for testing small-molecule inhibitors of Abeta production.     

Effects of adrenaline, an alpha 2-adrenoceptor agonist, the volume of injection, and the global pain state of the animal on the activity of epidural sufentanil

A study was made of the effects of different volumes of injection product, adrenaline, the alpha 2-adrenoceptor-agonist medetomidine and Mycobacterium butyricum on epidural sufentanil in the rat. Increasing the volume of epidural sufentanil, and similarly decreasing the concentration of the injection product, resulted in a potentiation of the analgesic properties of epidural sufentanil without affecting the effects of the drug on the pinna and cornea reflexes and on muscle tonus. An analogue effect was observed if rats were tested for epidural analgesia during a chronic pain phase after inoculation with Mycobacterium butyricum. Adding adrenaline to epidural sufentanil also resulted in an increased analgesia but there was also a minor potentiation of all other behavioural parameters measured. The alpha 2-adrenoceptor-agonist medetomidine, clearly potentiated all behavioural effects induced by epidural sufentanil. As a consequence, there was no gain in specificity for epidural analgesia. Medetomidine, however, clearly reversed the normally observed skeletal muscle rigidity into a muscle hypotonia. Globally, these results thus indicate that manipulations of the volume of injection, the additional treatment with other drugs and the pain state of the animal can alter the activity of epidural sufentanil. Therefore, it might be concluded that the differences in the duration of analgesia observed with epidural sufentanil between human and animal studies can be partially explained in terms of differences between the experimental conditions.     

The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16-1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26-2.02) and in studies using PCR (HR 1.40; 95% CI 1.18-1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86-1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.     

Examining the Needs of Bereaved Parents in the Pediatric Intensive Care Unit: A Qualitative Study

The pediatric intensive care unit (PICU) is a high-tech setting aimed at restoring health to critically ill children. When childhood death occurs in the PICU, it constitutes a special context for parent bereavement. The purpose of this interdisciplinary qualitative research was to gain a deeper understanding of parents' needs around the time of their child's death in the PICU. Through interviews and focus groups with bereaved parents and hospital chaplains, categories of parents' needs emerged. Deeper understanding of parents' needs will allow health professionals to better support parents during bereavement as well as to provide more customized care.