Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.     

Corticospinal excitability in patients with secondary dystonia due to focal lesions of the basal ganglia and thalamus

ObjectiveTo investigate the possible correlations between clinico-radiological features and pathophysiological mechanisms in patients with dystonia secondary to focal brain lesions.MethodsSingle and paired-pulse transcranial magnetic stimulation was used to assess corticospinal excitability in 10 patients (4 females; mean age 61) and a group of normal controls. Active threshold, latency and amplitude of motor evoked potentials (MEPs), silent period (SP) duration and short-interval intracortical inhibition (SICI) were evaluated.ResultsPatients with lesions involving the putamen and caudate presented with dystonic postures at rest. TMS assessment in these subjects showed increased MEP amplitude on the affected side and a bilateral decrease of SP duration and SICI. When the lesion spared the putamen and caudate, mainly involving the thalamus, the clinical picture was dominated by slow repetitive involuntary movements and tremor. In the affected side of these subjects the MEP amplitude was reduced and the MEP threshold was increased.ConclusionsWhen putamen and caudate were lesioned, the patients presented with dystonic postures at rest; furthermore the patients showed changes of corticospinal excitability in comparison to both healthy subjects and other dystonic patients.SignificanceThere are correlations between type of dystonia, site of the lesion and neurophysiological findings.     

Sudden hearing loss in a patient hepatitis C virus (HCV) positive on therapy with alpha-interferon: a possible autoimmune-microvascular pathogenesis

Alpha interferon (alpha-IFN) is used for the treatment of various systemic disorders. Side-effects of alpha-IFN therapy can involve numerous organ systems, but sudden hearing loss has only once been recorded. We report a case of sudden hearing loss occurring in a patient with chronic hepatitis C treated with alpha-IFN and recovered five days after the discontinuation of this agent. This is the first record of anti-endothelial cell antibodies detection in a patient with sudden hearing loss. The finding of anti-endothelial cell antibodies suggests an association between sudden hearing loss and microvascular damage during interferon therapy.     

Imidazo[2,1-b]thiazole system: a scaffold endowing dihydropyridines with selective cardiodepressant activity

The synthesis, characterization, and functional in vitro assays in cardiac tissues and smooth muscle (vascular and nonvascular) of a number of 4-imidazo[2,1- b]thiazole-1,4-dihydropyridines are reported. The binding properties for the novel compounds have been investigated and the interaction with the binding site common to other aryl-dihydropyridines has been demonstrated. Interestingly, the novel 4-aryl-dihydropyridines are L-type calcium channel blockers with a peculiar pharmacological behavior. Indeed, the imidazo[2,1- b]thiazole system is found to confer to the dihydropyridine scaffold an inotropic and/or chronotropic cardiovascular activity with a high selectivity toward the nonvascular tissue. Finally, molecular modeling studies were undertaken for the most representative compounds with the aim of describing the binding properties of the new ligands at molecular level and to rationalize the found structure-activity relationship data. Due to the observed pharmacological behavior of our compounds, they might be promising agents for the treatment of specific cardiovascular pathologies such as cardiac hypertrophy and ischemia.     

自体骨髓干细胞移植治疗心力衰竭的研究进展

细胞移植已为病损心脏细胞重建及衰竭心脏功能恢复提供了一种全新的治疗方法。骨髓干细胞具有自我更新、定向分化成为包括心肌细胞等多种组织细胞的潜能,其增殖分化能力能持续终生,已成为细胞移植治疗心力衰竭的主要细胞源。本文就自体骨髓干细胞治疗心力衰竭可行性、与其他移植细胞相比较的优势、临床应用现状及目前问题与展望作一综述。