Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors

New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.     

Long-Term Evaluation in Aesthetic Rhinoplasty in an Academic Referral Center

Plastic surgery is based on improving esthetic for the patient. In most services, the surgery outcome is evaluated in a subjective manner.Aimto objectively assess the degree of patient satisfaction one year after rhinoplasty using the Rhinoplasty Outcome Evaluation questionnaire at a referral academic center.Materials and Methods69 patients operated in the otorhinolaryngology service were selected. The patients were operated upon by third year residents during the period from January to December 2007 and answered the questionnaire translated by the authors of this study.Resultswe obtained a mean value of 73.25% of satisfaction for primary rhinoplasty and a mean value of 72.02% of satisfaction for secondary rhinoplasty.Conclusionthe level of satisfaction presented by the patients was considered to be very good.     

Airway management in an infant with congenital centrofacial dysgenesia

The use of a laryngeal mask airway (LMA) on two occasions, ina 53-day-old and 270-day-old male infant with Tessier N.3 andN.4 facial defects, using sedation and topical anaesthesia isdescribed. The LMA was used to manage the airway and facilitateinhalation induction of anaesthesia as the facial deformitieswere thought to be too extensive for the safe use of a facemask.The LMA is an alternative to a facemask and secures the airwayand facilitates the inhalation induction of anaesthesia in paediatricpatients with severe facial deformities. Br J Anaesth 2002; 88: 726–8     

n-Hexane induces Parkinsonism in rodents

A case of human parkinsonism, due ton-hexane exposure, was recently described. On the basis of this observation, we treated mice and rats withn-hexane and its principle toxic metabolite 2,5-hexanedione. The mice underwent a chronic treatment intraperitoneum, the rats were treated stereotaxically into the substantia nigra. At biochemical analysis of the striata, dopamine and homovanillic acid levels were significantly lower compared with control animals; norepinephrine, serotonin, 5-hydroxindolacetic acid levels were unchanged. The rats treated with 2,5-hexanedione showed an apomorphine-induced rotational behavior significantly higher compared to controls. Sincen-hexane and its metabolites are environmental contaminants and by-products of endogenous metabolic pathways, we propose that they may play a role in inducing parkinsonism in humans.     

Effect of inhibition of neuropeptidases on the pain threshold of mice and rats

The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors. The results indicate that both enzymes are relevant to the catabolism of enkephalins in vivo; however, their simultaneous activation requires particular conditions. These conclusions are based on the following observations: (1) Only concomitant intracerebral treatment with both inhibitors led to an increase in the threshold of animal pain, whereas, in the presence of exogenous peptides, the concomitant injection of both inhibitors in mice elicited an analgesic response greater than the sum of the effects of each single inhibitor. (2) This response could be seen only after acute trauma; in fact, when the drugs were injected through a plastic cannula, only enkephalinase A inhibition was effective in increasing analgesia induced by exogenous peptides.     

REGULATION of the CYCLIC GUANOSINE 3''-5'' MONOPHOSPHATE SYSTEM IN HUMAN BRAIN TUMORS

Several reports have suggested that cylcic guanosine 3'-5' monophosphate (cGMP) and cyclic 3'-5' adenosine monophosphate (cAMP) are involved in the regulation of cellular proliferation. Following our previous reports on the cAMP system in human brain tumors, we decided to investigate the cGMP system in the same pathological tissues by studying the activity of guanylate cyclase and cGMP-phosphodiesterase (cGMP-PDE). We found that the activity of both enzymes is lower in neurinomas and glioblastomas than in meningiomas or in normal cerebral cortex. Furthermore, the subcellular distribution of guanylate cyclase in human cerebral cortex differs from that of neurinomas and glioblastomas. On the basis of such observations we have discussed the possibility that the regulatory mechanism of the enzymes related to the cyclic nucleotide metabolism is altered in brain tumors.     

Effect of bestatin and thiorphan on [Met5]enkephalin-Arg6-Phe7-induced analgesia

We investigated the effect of bestatin, a specific inhibitor of aminopeptidase and thiorphan, a specific inhibitor of enkephalinase A, on the analgesic effect induced by the intracerebral injection of heptapeptide [Met5]enkephalin-Arg6-Phe7 (MEAP) in cannulated rats. In contrast with the results obtained when [Met5]enkephalin (ME) was used, bestatin clearly potentiated the analgesic effect of MEAP, but thiorphan was totally ineffective. These observations indicate that the predominant inactivating mechanism for MEAP is the action of an aminopeptidase whereas this enzyme seems to be little involved in the catabolism of ME. The existence of two different catabolic pathways for MEAP and ME suggests that MEAP may act not only as a precursor of ME but also as an independent neuromodulator.