[Thymectomy in myasthenia gravis]. / Timectomía en la miastenia gravis.

OBJECTIVE: To analyze outcome after thymectomy in patients with myasthenia gravis (MG). MATERIAL AND METHODS: Thirty-five patients with MG underwent surgery in our service between June 1987 and June 1998. Ten had associated thymomas. Preoperative Osserman classification showed 2 at level I, 20 at level IIA, 11 at level IIB and 2 at level III. Extended thymectomy through a medial sternotomy was performed in all. RESULTS: Postoperative complications developed in three patients (1 medullary aplasia, 1 postoperative reintubation, 1 myasthenic crisis). Mean follow-up was 89 months, with 22.8% achieving complete remission and 97.1% reporting improvements. The results were similar in the 10 patients with thymomas (20% full remission and 90% showing improvement). By DeFilippi classification, 22.8% were in class 1, 22.8% in class 2, 51.4% in class 3 and 2.8% in class 4. By Osserman classification, 9 were in the same category before and after surgery, 12 had improved one level, 10 had improved 2 levels, 3 had improved 3 levels and 1 patient had improved 4 levels. CONCLUSION: Thymectomy is an appropriate therapeutic procedure in the multidisciplinary treatment of patients with MG and it is the approach of choice for patients with associated thymomas. The intra- and post-operative complication rate is low and the rate of clinical improvement is high.

Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).

2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories and is currently scheduled to enter clinical trials in 2001. The mechanism or mechanisms of action of XK469 remain to be elaborated. Accordingly, an effort was initiated to establish a pharmacophore hypothesis to delineate the requirements of the active site, via a comprehensive program of synthesis of analogues of XK469 and evaluation of the effects of structural modification(s) on solid tumor activity. The strategy formulated chose to dissect the two-dimensional parent structure into three regions-I, ring A of quinoxaline; II, the hydroquinone connector linkage; and III, the lactic acid moiety-to determine the resultant in vitro and in vivo effects of chemical alterations in each region. Neither the A-ring unsubstituted nor the B-ring 3-chloro-regioisomer of XK469 showed antitumor activity. The modulating antitumor effect(s) of substituents of differing electronegativities, located at the several sites comprising the A-ring of region I, were next ascertained. Thus, a halogen substituent, located at the 7-position of a 2-(4-[(2-quinoxalinyl)oxy]phenoxy)propionic acid, generated the most highly and broadly active antitumor agents. A methyl, methoxy, or an azido substituent at this site generated a much less active structure, whereas 5-, 6-, 8-chloro-, 6-, 7-nitro, and 7-amino derivatives all proved to be essentially inactive. When the connector linkage (region II) of 1 was changed from that of a hydroquinone to either a resorcinol or a catechol derivative, all antitumor activity was lost. Of the carboxylic acid derivatives of XK469 (region III), i.e., CONH2, CONHCH3, CON(CH3)2, CONHOH, CONHNH2, CN, or CN4H (tetrazole), only the monomethyl- and N,N-dimethylamides proved to be active.

Induction of the estrogen specific mitogenic response of MCF-7 cells by selected analogues of estradiol-17 beta: a 3D QSAR study.

Analogues of estradiol-17 beta (E2) have been evaluated for estrogen receptor (ER) binding affinity and mitogenic potential in the human breast cancer cell line MCF-7. These 42 compounds represent subtle modifications of the natural estrogen structure through the placement of hydroxyl, amino, nitro, or iodo groups around the ring system in addition to, or as replacement of, the 3- and 17 beta-hydroxyls of E2. The mitogenic activity of the analogues was found to be related to ER binding only to a limited extent. In order to elucidate structural features that are uniquely responsible for receptor binding affinity or mitogen potential of estrogens, the three-dimensional quantitative structure-activity (QSAR) method Comparative Molecular Field Analysis (CoMFA) was employed. Separate CoMFA models for receptor binding and cell growth stimulation were optimized through the use of various alignment rules and region step size. Whereas the CoMFA contour plots did outline the shared structural requirements for the two measured biological properties, specific topological features in this set of estrogens were delineated that distinguish mitogenic potential from ER binding ability. In particular, steric interference zones which affected growth extend in a band from above the A-ring to position 4 and below, whereas the ER binding steric interference zones are limited to isolated polyhedra in the 1, 2 and 4 positions and the alpha face of the B-ring. In addition, electronegative features located around the A-, B-, or C-rings contribute to receptor affinity. However, growth is dependent only on electronegative and electropositive properties near the 3-position. In a final QSAR model for the mitogenic response, the value of ER binding was included along with structural features as a descriptor in CoMFA. The resulting 3D-QSAR has the most predictive potential of the models in this study and can be considered a prototype model for the general evaluation of a steroidal estrogen's growth stimulating ability in MCF-7 cells. For example, the location of D-ring contours illustrate the model's preference for 17 beta-hydroxy steroids over the less mitogenic 17 alpha- and 16 alpha-hydroxy compounds. In addition, the enhanced mitogenic effect of steric bulk in the 11 alpha-position is also evident. The QSAR studies in this report illustrate the fact that while ER binding may be a required factor of the estrogen dependent growth response in MCF-7 cells, particular structural characteristics, in addition to those responsible for tight receptor binding, must be present to induce an optimal mitogenic response. Therefore, this report demonstrates that the CoMFA QSAR method can be utilized to characterize structural features of test compounds that account for different types of estrogenic responses.

[Short and long term follow-up of spontaneous pneumothorax treated using video-thoracoscopy]. / Seguimiento a corto y largo plazo del neumotórax espontáneo tratado por videotoracoscopia.

The outcome of video-assisted thoracoscopic treatment of spontaneous pneumothorax was analyzed. Eighty-three procedures were performed in 79 patients (58 men, 21 women: mean age 28.3 years, range 16 to 76 years). The reasons for intervention were recurring pneumothorax in 53 patients, contralateral pneumothorax in 10 (one of whom was treated on both sides), bilateral involvement in 3, and persistent air leakage in 13. Seven patients (8.4%) also required open thoracotomy. In 72 (88%) of the remaining 76 procedures, only video thoracoscopy was used. Three patients (3.6%) underwent video-assisted thoracotomy. Mean postoperative hospital stay was 5.1 days (2 to 24 days). No related deaths occurred but surgical complications were reported for 3 (3.9%). Significant postoperative complications developed in 9 cases (11.8%). One patient with prolonged air leakage underwent a second procedure, video-assisted thoracotomy, 12 days after the first intervention. Seventy-one of the 72 patients received follow-up examinations, with a mean follow-up period of 28.1 months (range 54 days to 54 months). Three recurrences (3.9%) were recorded but there were no cases of chronic pain requiring analgesia. We conclude that video thoracoscopy is an effective approach, with the advantage of being minimally invasive. We therefore believe it should be the procedure of choice, once improved morbidity and recurrence rates are observed, as these factors are influenced by the learning curve.

[Severe hypoglycemia secondary to a fibrous pleural tumor]. / Hipoglucemias severas secundarias a tumor fibroso pleural.

A case with recurrent hypoglycemias following a thoracic tumor is presented. Neurologic symptoms due to hypoglycemia were dominant. Subcutaneous somatostatin was administrated preoperatively and hypoglycemia was controlled following tumor resection. Histology analysis shows a localized fibrous pleural tumor. Origin has been widely questioned but now it is accepted to be mesenchymal and not mesothelial. Lung disease owing to chronic compression of the tumor made necessary a lobectomy. Postoperative atelectasis required reoperation and a pneumonectomy was performed. To date insulin-like factors secreted by the tumor are supposed to be responsible for hypoglycemics discharges.

Crystal structure, receptor binding, and gene regulation of 2- and 4-nitroestradiols.

Crystal structures of 2-nitroestradiol and 4-nitroestradiol showed two different molecular conformations for each compound. The crystal structure of 4-nitroestradiol, as well as that of 4-nitroestrone-3-methyl ether, displayed a nitro group in which the oxygens were perpendicular to the aromatic ring and were this nonconjugating. On the other hand, the nitro-oxygens in 2-nitroestradiol were periplanar, with the aromatic ring permitting conjugating. This latter structure bound to estrogen receptor with 1/1000th the affinity of estradiol and was inefficient in gene stimulation. 4-Nitroestradiol possessed a relative binding affinity 40-fold greater than that of the 2-nitro derivative and actively induced responsive genes at a concentration of 10(-8) M. Whereas binding affinity can be explained primarily by polar groups and skeletal structure, gene induction may be linked to electronic induction in ring A that causes a requisite electronegative isopotential around the molecule. This electronegative characteristic also produces conformational changes in the alicyclic backbone of the estrogen, specially ring B, which could interfere with the molecular fit of the nitroestradiols with estrogen receptor.

Caparratriene, an active sesquiterpene hydrocarbon from Ocotea caparrapi.

Caparratriene (1), a new sesquiterpene hydrocarbon with significant growth inhibitory activity (IC50 = 3.0 +/- 0.5 x 10(-6) M) against CEM leukemia cells, was isolated from the oil of Ocotea caparrapi (Nates) Dugand. The structure of 1, determined by spectroscopic techniques, corresponded to (E,E)-3,7,11-trimethyl-2,4,10-dodecatriene (C15H26).

Identification and antitumor activity of a reduction product in the murine metabolism of pyrazoloacridine (NSC-366140).

PURPOSE: Pyrazoloacridine (PZA) is a newly developed anticancer agent currently undergoing clinical trials. Its mode of action has not been elucidated but the presence in its chemical structure of a 5-nitro functional group and its activity against oxygen-deficient cancerous cells argue in favor of enzymatic nitro reduction as a possible pathway for its antitumor activity. In order to assess the involvement of the nitro functionality in PZA activity, as well as to determine other metabolic products, a pharmacological and chemical study of PZA was designed. METHODS: Urine and stool samples were collected from mice before and after treatment with PZA. Samples were fractionated using chromatographic methods and then evaluated using mass spectrometry (MS). One of the characterized metabolites was synthesized and tested in vitro and in vivo for anticancer activity. RESULTS: One major fraction from mouse stool was initially characterized by MS as the 5-aminopyrazoloacridine (5-APZ). This compound was chemically synthesized by catalytic hydrogenation of PZA was stabilized as the hydrochloride salt. 5-APZ was marginally cytotoxic in vitro and was inactive in vivo against a tumor cured by PZA (Panc 03). CONCLUSIONS: Bioreduction of the nitro group to an amine compound from PZA represents a pathway in the metabolic sequence of PZA. The inactivity of the chemically generated amine product does not provide conclusive evidence that this pathway is not involved in the cytotoxicity of PZA because other intermediates in the nitro reduction pathway may have a role in the activity of PZA. In particular, the hydroxylamine derivative of PZA could give answers to the involvement of this pathway in PZA cytotoxicity.

Skeletal conformations and receptor binding of some 9,11-modified estradiols.

The effect of the modification of the 9-11 positions on the skeletal conformation of estradiol (E2) has been analyzed by X-ray crystallography and MM2 molecular mechanics. The 11 beta-hydroxyl and 11-keto analogs of E2 maintained ring conformations which were similar to the natural hormone (E2). Introduction of a double bond at position 9-11 induced a flattening of the entire steroid molecule. An 11 alpha-hydroxyl group brought about significant changes in the alicyclic rings of E2. 9 beta-Estradiol and 11-keto-9 beta-estradiol formed ring conformations which were significantly bent from E2 (below the plane of the A-ring). Examination of the affinity of these C-ring analogs of E2 for the human estrogen receptor has shown extreme variations. A hydroxyl group placed either alpha or beta at the 11-position yielded ligands with vastly different and reduced affinities for the receptor. The low affinity of 11 alpha-hydroxyestradiol (1/300th of E2) may be due to the drastic structural change induced in the alicyclic portion of the molecule, as well as, to the steric or electrostatic effects of the alpha-hydroxyl group upon the receptor protein. An 11 beta-hydroxyl group diminished the receptor binding to 1/60th that of E2 without alicyclic ring distortions, whereas a 9-11 unsaturation reduced the binding to 1/5th although this steroid displayed a flattening of rings B, C, and D. The 11-keto function, which had little effect on the conformation of the estrogen nucleus, reduced the affinity of this ligand to 1/1000th that of E2. The negative bend at the C-ring of 11-keto-9 beta-estradiol and 9 beta-estradiol prevented these ligands from binding receptor. Some of the observed receptor interactions were related to structural alterations in the estrogen ring system induced by modifications on the 9-11 region.

Binding, X-ray and NMR studies of the three A-ring isomers of natural estradiol.

The effect of the position of the phenolic hydroxyl on the conformations of the three A-ring isomers of estradiol, namely, estra-1,3,5(10)-trien-1,17 beta-diol (10), estra-1,3,5(10)-trien-2,17 beta-diol (3), and estra-1,3,5(10)-trien-4,17 beta-diol (6), has been analyzed by X-ray crystallography. The results of these analyses were correlated with the absorptions of the angular methyl groups in the [1H]NMR spectra of these isomers and natural estradiol (E2). It was observed that the changes in chemical shift of protons at C18 corresponded to skeletal modifications in the steroid structure which changed the anisotropic effect of the hydroxyl group at C17. Examination of the affinity of these A-ring isomers of E2 for the estrogen receptor has shown the 2-hydroxylated isomer 3 to retain 1/5th the affinity of E2 for its binding protein. The 1- and 4-hydroxylated derivatives (10 and 6, respectively) bound to a much lesser extent. The receptor affinities of these estrogen analogues may be related to the angle between the 18-methyl and the 17 beta-hydroxyl groups (or the dihedral angle between the planar A-ring and the angular C18 methyl) as well as the position of the A-ring hydroxyl group.

Synthesis and in vitro evaluation of some modified 4-thiopyrimidine nucleosides for prevention or reversal of AIDS-associated neurological disorders.

Oxygen-sulfur exchange at the C-4 carbonyl of several modified pyrimidine nucleosides, including 3'-azido-3'-deoxythymidine (AZT), is described in an effort to enhance the lipophilicity and, thereby, the delivery to the central nervous system of the sulfur analogues without compromising the anti-HIV activities of the parental structures. Preparation of 3'-azido-3'-deoxy-4-thiothymidine (3) proceeded from 4-thiothymidine (1) and utilized the same methodology developed for the initial synthesis of AZT. Thiation of 2',3'-didehydro-3'-deoxythymidine (4a) and 2',3'-didehydro-2',3'-dideoxyuridine (4c) was carried out with Lawesson's reagent on the corresponding 5'-O-benzoate esters, 4b and 4d, to give 5a and 5c, respectively. The latter, on alkaline hydrolysis, gave 2',3'-didehydro-3'-deoxy-4-thiothymidine (5b) and 2',3'-didehydro-2',3'-dideoxyuridine (5d), respectively. The same series of reactions were applied to the 5'-O-benzoate esters of 2',3'-dideoxyuridine (6a) and 3'-deoxythymidine (6b) to give 2',3'-dideoxy-4-thiouridine (7d) and 3'-deoxy-4-thiothymidine (7b), respectively. Characterization of the saturated and unsaturated thionucleosides included mass spectrometric studies. Under electron impact conditions, the thiated analogues gave more intense parent ions than the corresponding oxygen precursors. The lipophilicity of thymidine and the 3'-deoxythymidine derivatives are enhanced significantly, as indicated, by increases in corresponding P values (1-octanol-0.1 M sodium phosphate) upon replacement of the 4-carbonyl oxygens by sulfur. Compounds 5b, 5d, 7b, and 7d were evaluated for their effects on HIV-induced cytopathogenicity of MT-2 and CEM cells. Only 5b and 7b were moderately active in protecting both cell lines against the cytolytic effect of HIV. The inhibitory effects of analogues 5b, 5d, 7b, and 7d on thymidine phosphorylation by rabbit thymus thymidine kinase were evaluated. Only 3 showed moderate affinity (Ki = 54 microM) for the enzyme. The generally weak anti-HIV activities of the remaining thio analogues are consistent with correspondingly low susceptibilities to thymidine kinase phosphorylation as estimated from the respective Ki values of the synthetic nucleosides. However, the phosphorylation of the 5'-monophosphate derivatives to their respective 5'-triphosphates must also be considered in connection with the weak in vitro anti-HIV effects of these thiated compounds.

Comparación de dos instrumentos en la evaluación del nivel socio-económico en los pacientes del centro de pediatria Albina Patiño / Comparison of two methods of evalutation by the socio-economic status at the pediatric Hospital Albina Patiño

Tradicionalmente, el C.P.A.P. estratifica a sus pacientes de acuerdo a su nivel socio-económico, para lo cual utiliza una ficha social que otorga un nivel en forma subjetiva, puesto que no considera un puntaje ni una escala por cada variable utilizada. Con el fin de detectar los errores cometidos en esta escala, se realiza un estudio comparativo utilizando un instrumento probado como es la escala de Graffar (modificado). Se estudiaron 194 pacientes seleccionados aleatoriamente a los cuales se aplican ambos instrumentos, en distintos ambientes y por distintas personas. Los resultados muestran una diferencia significativa (p<0.05) en los niveles encontrados con ambos sistemas.