Trabectedin is a feasible treatment for soft tissue sarcoma patients regardless of patient age: a retrospective pooled analysis of five phase II trials.

BACKGROUND: This retrospective pooled analysis assessed the effect of age on the efficacy and safety of trabectedin in young and elderly patients with recurrent advanced soft tissue sarcoma (STS). METHODS: Data from 350 adults with STS treated in five phase II trials with trabectedin were divided in the younger (<60 years; n=267) and the older cohort (≥60 years; n=83). RESULTS: The response rate did not differ with age (younger: 10.1% vs elderly 9.6%). No significant differences were found in median progression-free survival (PFS) in younger (2.5 months) and older (3.7 months) cohort with a comparable PFS rates at 3 (45.1% vs 55.1%) and 6 months (29.5% vs 36.4%). Similar median overall survival was observed in both cohorts (13.0 vs 14.0 months). Reversible neutropenia and aspartate aminotransferase/alanine aminotransferase elevation were the most common abnormalities. A higher incidence of grade 3/4 neutropenia (43.6% vs 60.2%) and fatigue (6.3% vs 14.4%) was observed in older patients. In 24 patients aged ≥70 years, no significant differences in efficacy or safety outcomes were found. CONCLUSION: This analysis demonstrated that trabectedin is a feasible treatment in young and elderly patients with STS, with meaningful clinical benefits and an acceptable safety profile, essential in palliative treatment of elderly patients.

[Glutamate-related excitotoxicity neuroprotection with memantine, an uncompetitive antagonist of NMDA-glutamate receptor, in Alzheimer's disease and vascular dementia]. / Neuroproteccion con memantina (antagonista no competitivo del receptor NMDA-glutamato) frente a la excitotoxicidad asociada al glutamato en la enfermedad de Alzheimer y en la demencia vascular.

AIM: To review the therapeutic efficacy of memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-glutamate receptor. DEVELOPMENT: Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia with ageing worldwide. The main AD symptoms are a gradual loss of cognitive function and a functional impairment. Glutamatergic excitatory neurotransmission, an important process in learning and memory, is severely disrupted in AD, probably due to the oxidative stress associated with the beta-amyloid peptide (1-42) increase. The glutamate-related excitotoxicity, mainly mediated by NMDA subtype of the glutamate receptors, is a common clue of pathogenesis for neurodegenerative disorders. CONCLUSIONS: Memantine, a moderate-affinity, voltage-dependent, uncompetitive antagonist of NMDA receptor, shows neuroprotective effects in patients with moderate-to-severe AD. Memantine is a drug with neuroprotective and cognition-enhanced properties, which can be combined with other treatments for AD. Thus, memantine does not stop or reverse AD, but its moderating effect in protecting the brain from the toxic levels of calcium, allows normal signaling among brain neurons. The efficacy and safety profile of memantine have been reported in several clinical trials for treatment of AD and vascular dementia.

Lack of effect of nitric oxide on KCl, acetylcholine and substance P induced contractions in ileal longitudinal muscle of the rat.

The aim of this study was to determine whether an excess of nitric oxide (NO) (mimicked by addition of NO donors) might produce by itself changes in the contractile responses to acetylcholine (ACh), substance P (SP) and KCl in the longitudinal muscle of the rat ileum. We also studied the calcium handling properties of this tissue in presence of NO donors. The NO donors assayed sodium nitroprusside (SNP) and 3-morpholinosydnonimine hydrochloride (SIN-1), induced different responses. SNP caused an immediate contraction followed by a sustained relaxation, whereas SIN-1 induced an immediate relaxation followed by a contraction. Even after prolonged incubations (up to 90 min), the NO donors SNP and SIN-1 were unable to modify the ACh- and SP-concentration-response curves, as well as the response to 30 mM KCl. The nifedipine-resistant component of the ACh-induced contraction was not modified in presence of SNP. Cyclopiazonic acid (CPA) induced a contraction that was not modified when the tissue was pre-incubated with SNP. Nifedipine caused a sharp relaxation when added during the CPA-induced contraction and, when added previously, it reduced the CPA-induced contractile response. It is concluded that NO excess is not, by itself, responsible for the altered responses to KCl. ACh and SP. The contractility changes observed in the longitudinal muscle of the rat ileum during inflammation could rather be related to the presence of other inflammatory mediators.

Actions of NO donors and endogenous nitrergic transmitter on the longitudinal muscle of rat ileum in vitro: mechanisms involved.

The aim of this work has been to characterize and to compare the responses of the rat ileal longitudinal muscle to the nitric oxide (NO) donors, sodium nitroprusside (SNP) and morpholinosydnonimine hydrochloride (SIN-1). SNP (10(-5)-10(-3) M) caused a contraction followed by a relaxation, both components being concentration-dependent. In contrast, SIN-1 (10(-5)-10(-4) M) caused a relaxation followed by a contraction. Neither the neural blocker tetrodotoxin (TTX) nor atropine were able to change the response to SNP, whereas nifedipine abolished its contractile component. In contrast, TTX and nifedipine diminished both the relaxation and the contraction in response to SIN-1, whereas atropine decreased only the contractile component. The specific guanylate cyclase inhibitor oxadiazolo-quinoxalin-1-one (ODQ) decreased the relaxation induced by SNP but did not modify that caused by SIN-1. The K+ channel blockers charybdotoxin, apamin and tetraethylamonium were unable to modify the response to SNP. In contrast, both TEA and apamin significantly decreased the relaxation induced by SIN- 1. The relaxation resulting from electrical field stimulation (EFS) of enteric nerves in non-adrenergic non-cholinergic conditions is mainly but not exclusively nitrergic, as incubation with the NO synthase inhibitor L-NNA markedly decreases such relaxation. EFS-induced relaxation is also sensitive to ODQ. We conclude that SNP acts mainly on smooth muscle cells activating L-type Ca2+ channels, which result in contraction, and activates the soluble guanylate cyclase, which results in relaxation. In contrast SIN-1 has mixed--neuronal and muscular--effects, the contraction being caused both by acetylcholine release from neurons and by direct activation of L-type Ca2+ channels on smooth muscle cells. SIN-1-induced relaxation is cGMP-independent and it is likely to occur as a consequence of both, neuronal release of inhibitory transmitter(s) and by activation of apamin sensitive K+ channels. The effect of the nitrergic transmitter released from enteric nerves is different from those caused by SIN-1 but shows similarities with those caused by SNP.