Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: cannabinoid and non-cannabinoid receptor-mediated mechanisms.

BACKGROUND AND PURPOSE: Tetrazoles were recently developed as inhibitors of the cellular uptake of the endocannabinoid anandamide or of its hydrolysis by fatty acid amide hydrolase (FAAH), but were proposed to act also on non-endocannabinoid-related serine hydrolases. EXPERIMENTAL APPROACH: We tested, in a model of inflammatory pain induced in mice by formalin, five chemically similar inhibitors: (i) OMDM119 and OMDM122, two potent carbamoyl tetrazole FAAH inhibitors with no effect on anandamide uptake; (ii) LY2183240, a carbamoyl tetrazole with activity as both FAAH and uptake inhibitor; (iii) OMDM132, a non-carbamoyl tetrazole with activity only as uptake inhibitor and iv) OMDM133, a non-carbamoyl tetrazole with no activity at either FAAH or uptake. RESULTS: All compounds (2.5-10 mg kg(-1), i.p.) inhibited the second phase of the nocifensive response induced by intraplantar injection of formalin. The effects of OMDM119, OMDM122 and OMDM133 were not antagonized by pretreatment with cannabinoid CB(1) receptor antagonists, such as rimonabant or AM251 (1-3 mg kg(-1), i.p.). The effects of LY2183240 and OMDM132 were fully or partially antagonized by rimonabant, respectively, and the latter compound was also partly antagonized by the CB(2) receptor antagonist, AM630. CONCLUSIONS AND IMPLICATIONS: (i) non-FAAH hydrolases might be entirely responsible for the antinociceptive activity of some, but not all, tetrazole FAAH inhibitors, (ii) the presence of a carbamoylating group is neither necessary nor sufficient for such compounds to act through targets other than FAAH and (iii) inhibition of anandamide uptake is responsible for part of this antinociceptive activity, independently of effects on FAAH.

[Histopathological changes at the surgical site in experimental animals following partial cricoid resection and thyrotracheal anastomosis]. / Cambios histopatológicos en la unión quirúrgica en animales de experimentación sometidos a resección cricoidea parcial y anastomosis tirotraqueal.

OBJECTIVE: To study in an animal model the local healing process after partial cricoid resection with thyrotracheal anastomosis. MATERIAL AND METHODS: Partial cricoid resection with thyrotracheal anastomosis was performed in 17 New Zealand rabbits. Experimental animals were gradually sacrificed and the laryngotracheal complex was removed to proceed to a histopathological study. RESULTS: An acute inflammatory response followed by a chronic inflammatory process was found in the surgical site. Normal tissue architecture was established after an eight week period. Anteroposterior and transverse diameters at all levels of the upper respiratory tract were not significantly altered at any time along the healing process. Experimental animals remained free from symptoms during the follow-up period. CONCLUSIONS: These results support that partial cricoid resection with thyrotracheal anastomosis is a safe procedure for the treatment of severe laryngotracheal stenosis.

Factores pronosticos en el carcinoma de hipofaringe / Prognosis factors in hypopharinx carcinoma

Realizamos un estudio retrospectivo sobre los factores relacionados con el control locorregional, la supervivencia específica y la supervivencia global en los pacientes intervenidos por carcinoma epidermoide de hipofaringe entre los años 1984 y 1998. Tras llevar a cabo el análisis estadístico univariante, la presencia de un estadio ganglionar Ny clínico, la afectación del esófago cervical, la histología ganglionar positiva, la radicalidad de la cirugía sobre el tumor primario y la necesidad de reconstrucciones complejas de la vía digestiva superior se mostraron como factores pronósticos. Después de realizar el análisis multivariante de los datos con significación estadística, sólo la infiltración del esófago cervical y la histología ganglionar positiva permanecieron como factores pronósticos independientes.

Cambios en la via aerea superior inducidos por cirugia ortognatica / Changes in the upper air way induced by orthognatic surgery

Introducción: Las indicaciones tradicionales de la cirugía ortognática son el tratamiento de los desarreglos oclusales no susceptibles de tratamiento exclusivamente ortodóntico, y de las alteraciones de desarrollo del esqueleto facial. Desde hace unos años, la reconstrucción de la vía aérea superior es la nueva indicación surgida para la realización de este tipo de procedimientos. Pacientes y métodos: Realizamos una revisión de 10 pacientes clase II intervenidos de genioplastias y mandibulotomías de avance, por indicaciones estéticas y oclusales. Medimos las dimensiones de los espacios faríngeos superior e inferior en la radiografía lateral de cráneo siguiendo el método de McNamara. Resultados: La media de incremento en el espacio faríngeo superior fue de un 19,1 por ciento. La media de avance en el espacio faríngeo inferior fue de un 41,2 por ciento. Discusión / conclusiones: La cirugía ortognática, gracias a las modificaciones esqueléticas que produce en el maxilar superior y la mandíbula, es un método eficaz para aumentar las dimensiones de la vía aérea superior. Los cambios en el armazón óseo de puntos concretos de esta región tienen repercusiones generalizadas en el espacio aéreo surpraglótico.

[Post-surgical and post-infectious meningoencephalic herniation in the middle ear]. / Hernias meningoencefálicas postquirúrgicas y postinfecciosas en el oído medio.

Meningoencephalic hernia of the middle ear, due to the advent of antibiotics, the surgical microscope, and the new surgical techniques for the treatment of chronic otitis media, is an infrequent pathology in the presents days. The goal of this paper is to present four cases of meningoencephalic hernia of the middle ear, three of then postsurgical and the remaining of inflammatory origin. Diagnosis, treatment and complications are discussed. Meningoencephalic hernia of the middle ear is usually asymptomatic and diagnosis is accidental. Immediate surgical treatment is indicated in order to avoid the potential complications of this disease. Transmastoid approach has been used for three cases and a middle cranial fossa approach was used in the fourth patient.

T3 glottic cancer: oncologic results and prognostic factors.

OBJECTIVES: To analyze oncologic results, prognostic factors, and consideration of transglottic tumors as a separate entity in 73 patients with T3 glottic carcinoma treated by surgery +/- radiation therapy at La Paz University Hospital from 1984 to 1994. METHODS: Sixty-four patients underwent a total laryngectomy; neck dissection was performed in 50 patients; 29 patients received postoperative radiotherapy. RESULTS: The 5-year overall survival, cause-specific survival, and relapse-free survival rates were 58.1%, 66.8%, and 63.7%. Univariate analysis revealed prognostic significance for age, dyspnea, initial tracheostomy, and pathologic lymph node status. No difference was found when comparing survival and relapse rates between transglottic and glottic tumors. CONCLUSION: Surgery provides acceptable rates of cancer control and survival for patients with T3 glottic carcinoma. Older patients, patients with positive neck nodes, and those presenting with dyspnea have worse prognosis. The term transglottic is merely descriptive and has little impact on prognosis.

Synthesis and activity on human neutrophil functions of fMLF-OMe analogs containing alkyl spacers at the central position.

We report here the synthesis and activity of new analogs of the N-formyl and N-tert-butyloxycarbonyl (Boc) derivatives of the tripeptide Met-Leu-Phe-OMe containing an achiral omega-amino acid residue replacing the hydrophobic central leucine. The tripeptides HCO-Met-NH-(CH2)n-CO-Phe-OMe and Boc-Met-NH-(CH2)n-CO-Phe-OMe (n = 3-5) containing the central homomorphic residue of 5-aminopentanoic acid (delta-aminovaleric acid; delta-Ava; n = 4) and the two non-homomorphic residues of 4-aminobutanoic acid (gamma-aminobutyric acid; gamma-Abu; n = 3) and 6-aminohexanoic acid (epsilon-aminocaproic acid; epsilon-Aca; n = 5) have been examined. The activity as agonists and antagonists in chemotaxis, lysozyme release, and superoxide anion production of the new analogs has been determined. The N-Boc derivatives 2a and 2b, incorporating the gamma-Abu and the delta-Ava residues, show good and selective antagonist activity on superoxide anion production.

A concise synthesis of photoactivatable 4-aroyl-L-phenylalanines.

An efficient preparation of the title compounds from 4-iodo-L-phenylalanines using a carbonylative Stille cross-coupling reaction as the key-step is described.

Peptides containing the sulfonamide junction. 2. Structure and conformation of Z-Tau-Pro-D-Phe-NHiPr.

The taurine (Tau) containing N-protected pseudotripeptide isopropylamide Z-Tau-Pro-D-Phe-NHiPr (1) has been specifically designed and synthesized as suitable model to test the ability of the sulfonamido group to participate as H-bond acceptor to a type II beta-turn and to get information on the preferred rotameric conformation around the S-N bond and the hybridization state of the nitrogen atom. The present structural investigation reveals that, although the sulfonamide junction is invariably folded in a gauche mode, the beta-turn structure, stabilized by the 4 --> 1 hydrogen bond, is not found in the crystal and the sulfonamido oxygen atoms are not involved in any intra- or intermolecular hydrogen-bond interaction. More than one conformer populates the CDCl(3) solution with only a minor contribution by the expected beta-turn. The Pro nitrogen is significantly pyramidalized and the nitrogen lone pair points in opposite direction to that of the Pro C(alpha)H bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z-Tau-Pro-Phe-NHiPr.

4-Amino-1,2-dithiolane-4-carboxylic acid (Adt) as cysteine conformationally restricted analogue. Synthetic protocol for Adt containing peptides.

An efficient and versatile protocol to incorporate the achiral and C(alpha,alpha)-tetrasubstituted 4-amino-1,2-dithiolane-4-carboxylic acid Adt (1) residue into peptides is described. The 2,2-bis[(benzylthio)methyl]glycine N-carboxy anhydride (5) was found to be the key reactive intermediate from which both Boc-Adt-OMe (8) and the glutathione analogue H-Glu(-Adt-Gly-OH)-OH (12) can be obtained.

Resultados de la cirugía del hiperparatiroidismo primario / Outcomes of primary hiperparathyroidism surgery

Objetivos: Estudiar las características clínicas de los pacientes intervenidos por hiperparatiroidismo primario, la curación a largo plazo, tanto bioquímica como sintomática, así como la mejoría subjetiva en la calidad de vida. Métodos: Desde enero de 1992 a diciembre de 1996, 69 pacientes fueron operados por hiperparatiroidismo primario en el Servicio de O.R.L. del Hospital Universitario La Paz; 52 de ellos (76 por ciento) fueron citados en nuestra consulta para ser sometidos a una exploración O.R.L. rellenar un cuestionario y serles realizado un estudio completo del metabolismo fosfocálcico. Resultados: Un 14,7 por ciento de nuestros pacientes se encontraba asintomático en el momento del diagnóstico de su hiperparatiroidismo primario; 48 de los 52 pacientes (92,3 por ciento) normalizaron su metabolismo fosfocálcico tras recibir tratamiento quirúrgico. La mejoría sintomática, excepto para la litiasis renal de repetición, no alcanzó nivel de significación estadística. Un 67,4 por ciento de las personas operadas refirió mejoría en su calidad de vida. Conclusiones: La paratiroidectomía es una intervención efectiva y satisfactoria para el tratamiento del hiperparatiroidismo primario

Combined hormonal therapy with high-dose diethylstilbestrol diphosphate (DES-DP) intravenous infusion plus vindesine (VND) for the treatment of advanced prostatic carcinoma: a controlled study.

Fifty-one patients with stage D prostate cancer, who had failed primary hormone treatment, were treated with diethylstilbestrol diphosphate (DES-DP) 1.5 g 24 hr intravenous infusion from day 1 to day 7 (group A). In group B, patients were treated with DES-DP as in A, plus vindesine (VND) 3 mg/m2 intravenously on days 8, 15, and 22. Cycles were repeated every 28 days for six consecutive cycles. All 51 patients were evaluable for response, toxicity, time to progression, and survival. Pretreatment clinical and laboratory characteristics were comparable. The National Prostatic Cancer Project Criteria were used for evaluation. A minimum of two cycles were required for evaluation of response. No complete response was seen. In group A, 9 "partial response" and 7 "no change" (80%), and in group B, 11 "partial response" and 12 "no change" (74%) were registered. Median survival time was 40 weeks. Toxicity ranged from mild to moderate. DES-DP + VND seemed to improve duration of objective response compared to DES-DP alone, but the difference was not significant.

[Radiotherapy of inoperable, loco-regional epidermoid carcinoma of the lung. 5-year experience]. / Radioterapia del carcinoma epidermoidale del polmone inoperabile in fase loco-regionale. Esperienza di cinque anni.

Results of chest radiotherapy on 48 patients with inoperable squamous-cell carcinoma are reported; 25 patients had continuous treatment whereas the remaining 23 patients had split-course. Objective remission was obtained in 71% of the cases; mean survival was 11.7 months for the whole series, and 14 months for responders. An advantage in objective remission rate for patients having a dose of 60 Gy or more was found. Split-course resulted in similar survival and objective remission rate but was less toxic than continuous treatment. In 43% of cases the disease progressed only loco-regionally. Radiotherapy was interrupted because of toxicity in 23% of cases and there was only a case of life-threatening toxicity.

[Palliative radiotherapy of bone metastases. Comparison between 2 fractionations]. / Radioterapia palliativa delle metastasi ossee. Confronto tra due frazionamenti.

One hundred and twenty two symptomatic osseous metastases in 74 patients were treated with palliative irradiation, using two dose/time treatment plans. Pain relief was obtained in 92% of valuable cases (complete response in 68% and improvement in 24%). The complete responses were obtained in 4 weeks in 64% of responsive patients. The median duration of response was 166 days. In advanced cancer patients the short course radiotherapy achieved the same quality and duration of pain relief as conventional treatment.

[Intestinal bacterial flora in normal adults]. / Flora batterica intestinale in adulti normali.

In this preliminary study we have examined 12 healthy men aged between 20-60 years, by three specimens each. All the isolated could be assigned to genera by biochemical tests and gas-liquid chromatography. The results showed a 10(8)/g concentration of aerobe bacteria in faeces and a 10(10)/g concentration of anaerobe non sporing bacteria. The results of the count of Clostridia showed a variability among the examined individuals. The predominant groups of aerobes in the faeces were found to be E. coli and S. faecalis spp. and the predominant group of non sporing anaerobes were Bacteroides and Bificobacteria. These results were similar to the data obtained from foreign AA., showing the predominance of anaerobes in the faeces and particularly of Bacteroides.

[Methods for collection, transport and culture media]. / Modalità di prelievo, di trasporto e terreni di coltura.

A crucial factor affecting the ultimate success of anaerobic cultures is a proper specimen collection, with care to avoid inclusion of normal flora often present on human mucosa. In general, material for anaerobic cultures is best obtained using a needle and syringe, from which the air must be expelled. Then the specimens should be placed immediately into an anaerobic transport broth and then in suitable culture pre-reduced media.

[Technics for isolation, incubation and preliminary identification tests]. / Tecniche d'isolamento, d'incubazione e test preliminari d'identificazione.

In this report the AA. emphasize the fact that anaerobes are mostly isolated from mixed cultures in which several bacteria are present. Therefore they suggest to grow all the bacteria under the best conditions and consequently to select the anaerobes from the aerobes. Furthermore they describe the selecting techniques used at Istituto Superiore di Sanità and Clinica Medica III, to attain this aim and enumerate the best methods used for anaerobic incubation.

[A definitive identification method: gas-liquid chromatography]. / Metodi di identificazione definitiva: cromatografia gas-liquido.

The definitive identification of many anaerobes requires the use of gas-liquid chromatography to detect alcohol and volatile acids end-products of their metabolism. In this study we have used the gas-liquid chromatography for the identification of 360 non sporing anaerobes isolated from faeces of healthy individuals. These analyses were performed on a Variant-Aerograph mod. 2700 gas chromatography fitted with a column without phosphoric acid. The results showed a good percentage of typing (83%).