NOVEL ANTITUMOR AGENTS STRUCTURALLY RELATED TO AMINOBISPHOSPHONATES AND STILBENES

Cancer is one of the principal causes of death in the world and its therapy research leads a strong, but nowadays without great results, interest by scientific community. The treatment given for cancer is highly variable and dependent on a number of factors including the type, location and amount of disease and the health status of the patient (surgery, radiation, chemotherapy, hormonal treatment, antibodies, immunotherapy) but the discover of compounds able to kill selectively the affected cells is the main goal for medicinal chemists. With the aim to decrease their toxicity often the different types of treatment are used in combination, either simultaneously or sequentially. In this thesis, the design, synthesis and biological evaluation of two different kinds of anticancer compounds are described. The synthesis of novel aminobisphosphonates compounds leads to the development of new molecules which induce the immune system, enhancing its antitumor effect. This project is involved in immunotherapy field, a promising and no toxic anticancer therapy approach. Moreover, the synthesis of new natural stilbenes related compounds, involved in the cytotoxic chemotherapy field, lead us to develop a set of high activity molecules, which are promising for further pre-clinical and clinical studies

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology

The processing of actions and-action words in Amyotrophic Lateral Sclerosis patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with prime conse- quences on the motor function and concomitant cognitive changes, most frequently in the domain of executive functions. Moreover, poorer performance with action-verbs versus object-nouns has been reported in ALS patients, raising the hypothesis that the motor dysfunction deteriorates the semantic representation of actions. Using action-verbs and manipulable-object nouns sharing semantic relationship with the same motor represen- tations, the verb-noun difference was assessed in a group of 21 ALS-patients with severely impaired motor behavior, and compared with a normal sample's performance. ALS-group performed better on nouns than verbs, both in production (action and object naming) and comprehension (word-picture matching). This observation implies that the interpretation of the verb-noun difference in ALS cannot be accounted by the relatedness of verbs to motor representations, but has to consider the role of other semantic and/or morpho- phonological dimensions that distinctively define the two grammatical classes. More- over, this difference in the ALS-group was not greater than the noun-verb difference in the normal sample. The mental representation of actions also involves an executive-control component to organize, in logical/temporal order, the individual motor events (or sub- goals) that form a purposeful action. We assessed this ability with action sequencing tasks, requiring participants to re-construct a purposeful action from the scrambled pre- sentation of its constitutive motor events, shown in the form of photographs or short sentences. In those tasks, ALS-group's performance was significantly poorer than controls'. Thus, the executive dysfunction manifested in the sequencing deficit ebut not the selec- tive verb deficite appears as a consistent feature of the cognitive profile associated with LS. We suggest that ALS can offer a valuable model to study the relationship between (frontal) motor centers and the executive-control machinery housed in the frontal brain, and the implications of executive dysfunctions in tasks such as action processing

Diagnostic criteria for small fibre neuropathy in clinical practice and research

The diagnostic criteria for small fibre neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources, and the design of clinical trials. To address these issues, we performed a reappraisal study of 150 patients with sensory neuropathy and a prospective and follow-up validation study of 352 new subjects with suspected sensory neuropathy. Small fibre neuropathy diagnostic criteria were based on deep clinical phenotyping, quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD). Small fibre neuropathy was ruled out in 5 of 150 patients (3.3%) of the reappraisal study. Small fibre neuropathy was diagnosed at baseline of the validation study in 149 of 352 patients (42.4%) based on the combination between two clinical signs and abnormal QST and IENFD (69.1%), abnormal QST alone (5.4%), or abnormal IENFD alone (20.1%). Eight patients (5.4%) had abnormal QST and IENFD but no clinical signs. Further, 38 patients complained of sensory symptoms but showed no clinical signs. Of those, 34 (89.4%) had normal QST and IENFD, 4 (10.5%) had abnormal QST and normal IENFD, and none had abnormal IENFD alone. At 18-month follow-up, 19 of them (56%) reported the complete recovery of symptoms and showed normal clinical, QST and IENFD findings. None of those with one single abnormal test (QST or IENFD) developed clinical signs or showed abnormal findings on the other test. Conversely, all eight patients with abnormal QST and IENFD at baseline developed clinical signs at follow-up. The combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of small fibre neuropathy than the combination of abnormal QST and IENFD findings in the absence of clinical signs. Sensory symptoms alone should not be considered a reliable screening feature. Our findings demonstrate that the combined clinical, functional and structural approach to the diagnosis of small fibre neuropathy is reliable and relevant both for clinical practice and clinical trial design

Food knowledge depends upon the integrity of both sensory and functional properties: a VBM, TBSS and DTI tractography study

Food constitutes a fuel of life for human beings. It is therefore of chief importance that their recognition system readily identifies the most relevant properties of food by drawing on semantic memory. One of the most relevant properties to be considered is the level of processing impressed by humans on food. We hypothesized that recognition of raw food capitalizes on sensory properties and that of transformed food on functional properties, consistently with the hypothesis of a sensory-functional organization of semantic knowledge. To test this hypothesis, patients with Alzheimer's disease, frontotemporal dementia, primary progressive aphasia, and healthy controls performed lexical-semantic tasks with food (raw and transformed) and non-food (living and nonliving) stimuli. Correlations between task performance and local grey matter concentration (VBM) and white matter fractional anisotropy (TBSS) led to two main findings. First, recognition of raw food and living things implicated occipital cortices, typically involved in processing sensory information and, second, recognition of processed food and nonliving things implicated the middle temporal gyrus and surrounding white matter tracts, regions that have been associated with functional properties. In conclusion, the present study confirms and extends the hypothesis of a sensory and a functional organization of semantic knowledge

efficacy of botulinum toxin type a treatment of functional impairment of degenerative hip joint preliminary results

Objective: the aim of this study was to investigate the effect of botulinum toxin type a injection into the adductor muscles in reducing pain and improving joint mobility and quality of life in patients affected by hip osteoarthritis. Methods: a total of 39 outpatients, mean age 68 years (age range 41–82 years), were evaluated using the harris hip Score to test hip function, a visual analogue scale to measure pain intensity and the Short Form 36 (SF-36) questionnaire to assess patient well-being and quality of life at baseline, 2, 4 and 12 weeks after treatment with botulinum toxin type a. a total of 400 u of botulinum toxin type a (Dysport) was injected into the adductor longus muscle and the adductor magnus muscle. Results: The Harris Hip Score increased significantly after 2, 4 and 12 weeks (df 3, χ 2 = 45.1; p < 0.0001). A significant decrease in pain intensity was detected at all the follow-up visits, after 2, 4 and 12 weeks (df 3; χ 2 = 27.8; p < 0.001). the SF-36 score was significantly higher 4 and 12 weeks after treatment. At each evaluation visit a significant correlation was detected between decreased pain and improved hip mobility. Conclusion: Botulinum toxin type a induced a reduction in pain, indicating that this might be an innovative, less invasive treatment in patients affected by severe hip osteoarthritis, with remarkable effects on the clinical management of this disease

Patient-Reported Side Effects of Intradetrusor Botulinum Toxin Type A for Idiopathic Overactive Bladder Syndrome

Objective: The aim of the study was a prospective assessment of patient-reported side effects in an open-label study after intradetrusor botulinum toxin injections for idiopathic overactive bladder (OAB). Patients and Methods: Botulinum toxin A injection was performed in 56 patients with idiopathic OAB. Patients were followed up for 6 months concerning side effects and patients' satisfaction. Results: Different types of side effects were assessed such as dry mouth (19.6%), arm weakness (8.9%), eyelid weakness (8.9%), leg weakness (7.1%), torso weakness (5.4%), impaired vision (5.4%) and dysphagia (5.4%). In all cases, symptoms were mild and transient. Urological complications such as gross hematuria (17.9%), acute urinary retention (8.9%) and acute urinary tract infection (7.1%) were noticed. In all cases, acute urinary retention was transient and treated with temporary intermittent self-catheterization. There was no statistically significant correlation between dosage and observed side effects. Patients' satisfaction rate was high (71.4%). Conclusion: Intradetrusor injection of botulinum toxin was associated with a high rate of neurourological side effects. In general, side effects were transient, mild and did not require special treatment. Copyright (C) 2010 S. Karger AG, Base

Progressive multifocal leukoencephalopathy in a patient with Good's syndrome

Good's syndrome (GS) is an immunodeficiency characterised by thymoma, hypogammaglobulinemia and impaired T-cell function. The clinical symptoms are recurrent or chronic infections from common or opportunistic pathogens and diarrhoea. Encephalitis is rare, mostly associated to cytomegalovirus. We present a 65-year-old woman who developed blindness, motor deficits and cognitive changes over a 4-month period. MRI of the brain showed symmetric subcortical white matter changes in the occipital lobes, first thought to correspond to posterior reversible encephalopathy syndrome. A thymoma was found and operated. The patient had no B cells, low immunoglobulins and an inverted CD4/CD8 ratio. GS was diagnosed. In the cerbrospinal fluid >1  million JC virus copies/mL were found and a repeat MRI now showed a picture compatible with progressive multifocal leucoencephalopathy (PML). Her disease had a fatal outcome. The present case is the second reported association between GS and PML