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101.
BACKGROUND: Although the core feature of dementia is progressive cognitive disruption, non-cognitive behavioural problems are expressed in most patients with dementia during the course of their illness. While psychotropic drugs are frequently used to control behavioural symptoms, comorbidities, which are very common in the geriatric population, could often limit their use. Gabapentin may be a potential treatment in such situations. METHODS: In this open, baseline comparison study 20 patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities (paralytic ileus, open-angle glaucoma, ischaemic cardiopathy, hepatic failure or severe prostatic hyperplasia) received gabapentin for 15 months. Patients were allowed to continue any previous therapy for concurrent diseases. However, concomitant antipsychotic or benzodiazepine intake was not permitted. RESULTS: Gabapentin appeared to be efficacious and well tolerated in this patient population, and did not appear to interact with other drugs. General benefit is reflected by a reduction of caregiver stress. No patients withdrew before the end of the study and no serious adverse events were reported. CONCLUSION: The results of this study in patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities indicate that gabapentin provides significant and sustained efficacy in terms of behaviour, with associated reductions in caregiver burden. The results of an ongoing larger, randomised, double-blind study of gabapentin are keenly awaited and may help to provide a safer and more efficacious treatment option for this group of patients. 相似文献
102.
Iron-induced oxidant stress in alcoholic liver fibrogenesis. 总被引:2,自引:0,他引:2
Antonello Pietrangelo 《Alcohol》2003,30(2):121-129
Iron is an essential micronutrient. However, because human beings have no means to control iron excretion, excess iron, regardless of the route of entry, accumulates in parenchymal organs and threatens cell viability. Indeed, when iron-buffering capability is overwhelmed, oxidative stress-induced cell damage and fibrogenesis may arise, mainly in the liver, the main storage site for iron in the body. Results of recent studies have clearly shown that these pathologic events are induced by iron-generated reactive oxygen species and lipid peroxidation by-products. Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix components in the liver, is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidant stress is involved in this process (1) as the primary cause of parenchymal cell necrosis or (2) as activator of cells that are effectors [e.g., hepatic stellate cells, (myo)fibroblasts] or key mediators (e.g., Kupffer cells) of hepatic fibrogenesis (or through both mechanisms). Beyond their effect as direct cytotoxic agents, iron and free radicals may trigger increased synthesis of collagen in myofibroblast-like cells as well as activate granulocytes and Kupffer cells, resulting in an increased formation of cytokines and eicosanoids and further reactive oxygen species. This may constitute a cascade of amplifying loops, which perpetuate the fibrogenic process. The fibrogenic potential of iron is even more dramatic when iron acts in concert with other hepatotoxins such as alcohol. In this instance, even if tissue iron levels are only slightly elevated, the toxic effect of alcohol or its metabolites may be amplified and propagated with rapid acceleration of the liver disease. At the molecular level, the presence of catalytically active "free iron" may (1) contribute directly to the hepatotoxicity of alcohol or (2) enhance the generation of cytokine and fibrogenic mediators from resident Kupffer cells (or be involved in both ways). A challenge for future research is to develop therapeutic tools able to block "redox-active" free iron in the cell. 相似文献
103.
104.
Nonlethal conditioning for the induction of allogeneic chimerism and tolerance to islet allografts 总被引:6,自引:0,他引:6
BACKGROUND: We reported that tolerance to skin grafts can be achieved by chimerism induction by way of nonlethal conditioning. In the present study, we evaluated the outcome of islet allografts implanted either simultaneously or after donor bone marrow cell (BMC) infusion when nonlethal conditioning was used. METHODS AND RESULTS: B10 (H-2b) mice were conditioned with antilymphocyte serum (ALS), 100 cGy total body irradiation (TBI), and given 30 x 10(6) allogeneic (B10.BR, H-2k) BMC on day 0. On day 2, cyclophosphamide was given intraperitoneally (IP), followed by a second BMC infusion on day 3. After chimeras were typed for allogeneic BMC engraftment on day 28, animals were rendered diabetic chemically and transplanted under the kidney capsule with islet allografts genetically matched or disparate to the BM. Donor-specific islet grafts were accepted (median survival time [MST] > 180 days, n=6), whereas all major histocompatibility complex (MHC)-disparate third-party BALB/c (H-2d) islet grafts were rejected (MST=13.8 days, n=4). When B10.BR BMC and islets were given simultaneously, graft acceptance (MST >140 days, n=4) was observed. Surprisingly, when MHC-disparate third-party islets (BALB/c) were given together with B10.BR BMC, long-term survival was also observed (MST >100 days, n=3). These findings suggested that conditioning alone at the time of islet implant might induce long-term engraftment without further treatment. However, only chimeric animals accepted a second-set donor-specific graft, whereas all other groups rejected it. CONCLUSION: Our data indicates that stable allogeneic chimerism and islet indefinite survival can be achieved by the use of a nonmyeloablative protocol. The results of the conditioning-only experiments are consistent with the possibility of graft accommodation. 相似文献
105.
Bolognesi ML Cavalli A Andrisano V Bartolini M Banzi R Antonello A Rosini M Melchiorre C 《Il Farmaco; edizione pratica》2003,58(9):917-928
Ambenonium (1), an old AChE inhibitor, is endowed with an outstanding affinity and a peculiar mechanism of action that, taken together, make it a very promising pharmacological tool for the treatment of Alzheimer's disease (AD). Unfortunately, the bisquaternary structure of 1 prevents its passage through the blood brain barrier. In a search of centrally active ambenonium derivatives, we planned to synthesize tertiary amines of 1, such as 2 and 3. In addition, to add new insights into the binding mechanism of the inhibitor, we designed constrained analogues of ambenonium by incorporating the diamine functions into cyclic moieties (4-12). The biological evaluation of the new compounds has been assessed in vitro against human AChE and BChE. All tertiary amine derivatives resulted more than 1000-fold less potent than 1 and, unlike prototype, did not show any selectivity between the two enzymes. This result, because of recent findings concerning the role of BChE in AD, makes our compounds, endowed with a well-balanced profile of AChE/BChE inhibition, valuable candidates for further development. To better clarify the interactions that account for the high affinity of 1, docking simulations and molecular dynamics studies on the AChE-1 complex were also carried out. 相似文献
106.
Macchia M Antonello M Bertini S Di Bussolo V Fogli S Giovannetti E Minutolo F Rapposelli S Danesi R 《Il Farmaco; edizione pratica》2003,58(1):85-89
Conformationally restrained analogues of ceramide containing thiouracil or uracil moieties in their polar head, substituted with an ethyl group in their 6-positions, proved to inhibit cell proliferation and induce apoptosis. A series of new thiouracil and uracil analogues of ceramide possessing several 6-alkyl- or 6-arylalkyl-substituents, were synthesized and tested as inhibitors of cell proliferation. The lipophilic substituents introduced in the 6-position were pure alkyls (n-propyl, n-butyl, i-butyl, neo-pentyl), or aryl-alkyls (2-phenylethyl). Although a significant antiproliferative activity was maintained in most compounds synthesized, none of them showed any improvement with respect to their 6-ethyl-substituted counterparts. 相似文献
107.
Mai A Massa S Pezzi R Rotili D Loidl P Brosch G 《Journal of medicinal chemistry》2003,46(23):4826-4829
Chemical manipulations performed on aroyl pyrrolyl hydroxyamides, a new class of HDAC inhibitors previously reported by us, led to (aryloxopropenyl)pyrrolyl hydroxyamides 3a-g. Such compounds, showing better inhibitory activity against maize HD1-A than HD1-B (two homologues of mammalian class IIa and I HDACs, respectively), are the first class of IIa-selective inhibitors (fold selectivity: 7-78). They could be useful as tools for probing the biology of these enzymes and eventually as new anticancer agents with low toxicity. 相似文献
108.
Danesi R de Braud F Fogli S de Pas TM Di Paolo A Curigliano G Del Tacca M 《Pharmacological reviews》2003,55(1):57-103
In mammalian cells, the process of malignant transformation is characterized by the loss or down-regulation of tumor-suppressor genes and/or the mutation or overexpression of proto-oncogenes, whose products promote dysregulated proliferation of cells and extend their life span. Deregulation in intracellular transduction pathways generates mitogenic signals that promote abnormal cell growth and the acquisition of an undifferentiated phenotype. Genetic abnormalities in cancer have been widely studied to identify those factors predictive of tumor progression, survival, and response to chemotherapeutic agents. Pharmacogenetics has been founded as a science to examine the genetic basis of interindividual variation in drug metabolism, drug targets, and transporters, which result in differences in the efficacy and safety of many therapeutic agents. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. However, these studies have yielded contradictory results because of the small number of molecular determinants of drug response examined, and in several cases this approach was revealed to be reductionistic. This limitation is now being overcome by the use of novel techniques, i.e., high-density DNA and protein arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics represents the natural evolution of pharmacogenetics since it addresses, on a genome-wide basis, the effect of the sum of genetic variants on drug responses of individuals. Development of pharmacogenomics as a new field has accelerated the progress in drug discovery by the identification of novel therapeutic targets by expression profiling at the genomic or proteomic levels. In addition to this, pharmacogenetics and pharmacogenomics provide an important opportunity to select patients who may benefit from the administration of specific agents that best match the genetic profile of the disease, thus allowing maximum activity. 相似文献
109.
110.
Different antiseptic formulations have shown limitations when applied to disinfecting intact skin, notably short-term tolerability and/or efficacy. The purpose of this study was optimizing a new antiseptic formulation specifically targeted at intact skin disinfection and evaluating its in vitro microbicidal activity and in vivo efficacy. METHODS: The biocidal properties of the antiseptic solution containing 0.5% chloramine-T diluted in 50% isopropyl alcohol (Cloral; Eurospital SpA Trieste, Italy) were measured in vitro versus gram-positive-, gram-negative-, and acid-alcohol-resistant germs and fungi with standard suspension tests in the presence of fetal bovine serum. Virus-inhibiting activity was evaluated in vitro against human cytomegalovirus, herpes simplex virus, poliovirus, hepatitis B virus, and hepatitis C virus. Tests used different methods for the different biologic and in vitro replication capacity of these human viruses. Lastly, Cloral tolerability and skin colonization retardation efficacy after disinfection were studied in vivo. RESULTS: The antiseptic under review showed fast and sustained antimicrobial activity. The efficacy of Cloral against clinically important bacterial and viral pathogens and fungi was highlighted under the experimental conditions described in this article. Finally, microbial regrowth lag and no side effects were documented in vivo after disinfection of 11 volunteers. CONCLUSIONS: A stable chloramine-T solution in isopropyl alcohol may be suggested for intact skin antisepsis. 相似文献