Importância do metabolismo no planejamento de fármacos

It is widely recognized that pharmacokinetic optimization needs to be addressed early in drug discovery to reduce the high failure rate in bringing drugs to market. Poor absorption, too short duration of action due to high elimination rate, or the presence of active metabolites are examples of properties that can potentially lead to unsuccessful clinical programmes. Here I describe a brief overview of advantages and molecular strategies for improving metabolic and pharmacokinetic properties applied to the discovery of fluconazol, beta-blockers, ritonavir and ezetimibe and to the development of the prodrugs enalapril and bambuterol.

Simple method for mass production of polypyrrole/carbon nanotubes hybrid artificial muscle

Large scale preparation of hybrid electrical actuators represents an important step for the production of low cost devices. Interfacial polymerization of polypyrrole in the presence of multi-walled carbon nanotubes represents a simple technique in which strong interaction between components is established, providing composite materials with potential applications as actuators due to the synergistic interaction between the individual components, i.e., fast response of carbon nanotubes, high strain of polypyrrole, and diversity in the available geometry of resulting samples.

Rheological behavior of Chlorella sp. e Scenedesmus sp. cultures in different biomass concentrations

Studies involving the use of microalgae are increasingly intensifying for the potential they present to produce biofuels, because they are a renewable energy source that does not compete directly with food production, and because they enable the obtaining of a fuel with less environmental impact when compared to fossil fuel. In this context, the use of microalgae is directly associated to its capacity to be produced on a large scale and to be extracted from the culture medium. Rheological studies are important for obtaining the information needed in the elaboration of projects and equipment that will be used in various operations existing in systems of production and extraction of algal biomass. In the evaluation of different levels of dry biomass concentration, studies have been conducted of the rheological behavior of cultures of Chlorella sp. BR001 and Scenedesmus sp. BR003. The Power Law model adjusted well to the data of shear stress as a function of strain rate. In all concentrations the cultures showed non-Newtonian behavior. It was observed to Scenedesmus sp. BR003 little effect of biomass concentration on the apparent viscosity and shear stress.

Mechanical properties of castor beans subject to different drying temperatures aiming to disrupt the bean coat

In castor oil extraction process, the bean coat is abrasive to the equipment and releases substances that modify the oil color, reducing its quality. A potential solution would be to run the extraction by compressing only the endosperm. Due to lack of information, the objective of this study was to evaluate the influence of forced air drying at 40, 60, 80 and 100 ºC and farmyard drying, in the mechanical properties of the beans, aiming to break the bean coat. Castor beans were subjected to compression tests, in two perpendicular directions, at a strain rate of 0.6 mm.s-1. Average values of force, deformation energy, strain, all at rupture, and stiffness were used to evaluate the effects of dehydration. It was observed that the heat treatments did not alter the mechanical properties of castor beans, the strain and stiffness values discriminate the differences between the directions and had the lowest coefficients of variation. It was concluded that forced air drying, more costly than farmyard drying, does not bring benefits to the decortication. However, regardless the heat treatment used, the mechanical stress lengthwise is the most suitable to promote decortication.

Nova técnica de alimentação enteral em fístulas esôfago-jejunais

BACKGROUND: A new procedure for the treatment of esophageal fistula, mainly associated to the ebb esophagojejunal in patients submitted to the total gastrectomy and reconstruction with loop jejunal Rouxen-Y anastomosis is present. METHODS: The method is based in the use of "probe standard enteral prolongated with drain to laminate adapted in extremity", which results in advanced positioning inside the jejunum, making the administration of enteral nutrition possible and impeding ebb esophagojejunal. RESULTS: The authors discuss the theoretical advantages of the procedure and they suggest that the treatment of esofagic fistula with probe prolonged enteral would be suitable in the treatment of the fistula esophagojejunal by preventing the ebb esophagojejunal, which would result in smaller period of duration of the fistula esophagojejunal and it would prevent the high mortality rate. CONCLUSIONS: Preliminary studies demonstrated that this is a technically easy, low cost procedure through the endoscopic use. A prospective evaluation for morbility and mortality related to the method is needed.

Exclusão vascular do fígado em lesões venosas hepáticas complexas

Injuries to the main hepatic veins carry a very high mortality rate, regardless of the technique used for repair. Isolated reports of survivors have, for the most part, been managed by hepatic vascular exclusion (EVE) techniques, usually with an atriocaval shunt. Herein we report a case of a severe intrahepatic major hepatic vein injury successfully managed with EVE.

Uso de balão intra-hepático para controle temporário da hemorragia em lesão da veia cava retro-hepática

Juxtahepatic veins, retrohepatic vena cava or major hepatic veins injuries carry a very high mortality rate regardless the technique used for its repair. Isolated survivor reports have for the most part been managed by vascular isolation techniques, usually with atriocaval shunt. We report one case with a unique management technique in a patient who sustained gunshot wound to the retrohepatic vena cava. Hemorrhage control had been obtained by intrahepatic balloon tamponade after others maneuvers have failed. The balloon was left in situ for two days as damaged control laparotomy principles and planned reoperation has been chosen.

Pectus excavatum: abordagem terapêutica

The pectus excavatum treatment has two different approaches: non-surgical techniques (modified dynamic thoracic compressor, exercises and the vacuum bell) or surgical techniques (silastic or solid silicone implant, open surgical repair like sternochondroplasty and minimally invasive repair). The introduction of Nuss procedure improved the pectus excavatum treatment, but its low acceptance was due to the high complication rate (e.g. cardiac perfuration). The thoracoscopy use for bar mediastinal passage reduced the complication rate. In comparison with sternochondroplasty, the Nuss procedure has smaller incision, less blood loss and less operative time. However, it has more reoperations, complications, longer hospital stay and more readmission rates, more time of thoracic epidural catheter for postoperative analgesia and more need for analgesic after being discharged. Although Nuss procedure has been used in children, patients under ten years must be only observed. The Nuss procedure is applicable to moderate or light symmetrical pectus excavatum, without costal protrusion, in young and adolescents patients. Furthermore, the sternochondroplasty is applicable to severe or asymmetric pectus excavatum, with or without inferior costal protrusion. Therefore, Nuss procedure and sternocondroplasty are not antagonistic procedures, and they must be used in accordance with a treatment organogram and the technique choice must be by functional and aesthetic outcome.

Growth and leaf demography of two Cecropia species

Allometry, growth and leaf demography of two Cecropia species, one with ant mutualist (C. glazioui) and another without it (C. hololeuca), were studied in an Atlantic Rain Forest area in the State of Rio de Janeiro, SE Brazil. Stem diameter was allometrically related to height in both species. Cecropia glazioui showed higher annual growth rates and longer internodes than C. hololeuca. Leaf phenology showed a seasonal pattern in both species, but the number of leaves on each plant was more variable along the year in C. hololeuca than in C. glazioui. Survivorship curves for leaves were intermediate between Deevey's Type I and Type II curves, with young leaves of C. glazioui showing a greater survival rate and life expectancy than those of C. hololeuca. Low variability in leaf production throughout the year and high survival rate for young leaves of C. glazioui may be characteristics related to its association with ants.

Acute leukemias in Piauí: comparison with features observed in other regions of Brazil

Differences in age and sex distribution as well as FAB (French-American-British classification) types have been reported for acute leukemias in several countries. We studied the demographics and response to treatment of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) between 1989 and 2000 in Teresina, Piauí, and compared these results with reports from Brazil and other countries. Complete data concerning 345 patients (230 ALL, 115 AML) were reviewed. AML occurred predominantly in adults (77%), with a median age of 34 years, similar to that found in the southeast of Brazil but lower than the median age in the United States and Europe (52 years). FAB distribution was similar in children and adults and FAB-M2 was the most common type, as also found in Japan. The high frequency of FAB-M3 described in most Brazilian studies and for Hispanics in the United States was not observed. Overall survival for adults was 40%, similar to other studies in Brazil. A high mortality rate was observed during induction. No clinical or hematological parameter influenced survival in the Cox model. ALL presented the characteristic peak of incidence between 2-8 years. Most of the cases were CD10+ pre-B ALL. In 25%, abnormal expression of myeloid antigens was observed. Only 10% of the patients were older than 30 years. Overall survival was better for children. Age and leukocyte count were independent prognostic factors. These data demonstrate that, although there are regional peculiarities, the application of standardized treatments and good supportive care make it possible to achieve results observed in other countries for the same chemotherapy protocols.

Vertical growth phase and positive sentinel node in thin melanoma

Sentinel node (SN) status is the most important prognostic factor for localized melanoma. Usually, patients with Breslow thickness of less than 1.0 mm are not included in SN protocols. However, the literature presents a rate ranging from 3 to 7% of nodal recurrence in thin melanoma. Ulceration, regression and high mitotic rate have been considered to be indications for an SN biopsy. The metastatic potential of the vertical growth phase is uncertain. To correlate pathological features in thin melanoma with SN metastasis, we reviewed 358 patients submitted to SN biopsy. Seventy-seven patients with lesions of 1 mm or smaller were included in the study group. Histological evaluation of the primary tumor included thickness, Clark level, mitotic rate, ulceration, regression, and growth phase. Lymphoscintigraphy was performed on all patients. Lymphatic mapping and gamma probe detection were both used for SN biopsy. Histological examination of SN consisted of hematoxylin-eosin and immunohistochemical staining. Median follow-up was 37 months. Six patients had micrometastases. Statistical analysis by the Fisher test showed that ulceration (P = 0.019), high mitotic rate (P = 0.008) and vertical growth phase (P = 0.002) were positively correlated with micrometastases. If other studies confirm these results, more melanoma patients must be submitted to SN biopsy.

Immune factors and immunoregulation in tuberculosis

Pathogens causing tuberculosis and other chronic infectious diseases of major public health importance commonly have complex mechanisms involved in their persistence in the host despite specific and sometimes strong immune responses. These diseases are also associated with the lack of efficient vaccines, difficult therapeutics and a high mortality rate among susceptible individuals. Here, we will review features of the host immune response that contribute to the occurrence of disease. In addition, we propose that the immune responses observed in tuberculosis cannot be interpreted solely on the basis of a Th1-Th2 counter-regulatory paradigm since there is growing evidence that natural regulatory T cells may play an important role in the regulation of host immune responses against Mycobacterium tuberculosis. Thus, the development of more effective vaccines against this bacterial disease should take into account the role of natural regulatory T cells in the progression to severe disease and persistence of infection. Finally, new treatments based on manipulation of regulatory T cells should be investigated.

Cryptic mosaicism involving a second chromosome X in patients with Turner syndrome

The high abortion rate of 45,X embryos indicates that patients with Turner syndrome and 45,X karyotype could be mosaics, in at least one phase of embryo development or cellular lineage, due to the need for the other sex chromosome presence for conceptus to be compatible with life. In cases of structural chromosomal aberrations or hidden mosaicism, conventional cytogenetic techniques can be ineffective and molecular investigation is indicated. Two hundred and fifty patients with Turner syndrome stigmata were studied and 36 who had female genitalia and had been cytogenetically diagnosed as having "pure" 45,X karyotype were selected after 100 metaphases were analyzed in order to exclude mosaicism and the presence of genomic Y-specific sequences (SRY, TSPY, and DAZ) was excluded by PCR. Genomic DNA was extracted from peripheral blood and screened by the human androgen receptor (HUMARA) assay. The HUMARA gene has a polymorphic CAG repeat and, in the presence of a second chromosome with a different HUMARA allele, a second band will be amplified by PCR. Additionally, the CAG repeats contain two methylation-sensitive HpaII enzyme restriction sites, which can be used to verify skewed inactivation. Twenty-five percent (9/36) of the cases showed a cryptic mosaicism involving a second X and approximately 14% (5/36), or 55% (5/9) of the patients with cryptic mosaicism, also presented skewed inactivation. The laboratory identification of the second X chromosome and its inactivation pattern are important for the clinical management (hormone replacement therapy, and inclusion in an oocyte donation program) and prognostic counseling of patients with Turner syndrome.

Overexpression of kermit/dGIPC is associated with lethality in Drosophila melanogaster

Insertional mutagenesis is an important tool for functional genomics in Drosophila melanogaster. The insertion site in the KG00562 mutant fly line has been mapped to the CG8709 (herein named DmLpin) locus and to the 3’ of kermit (also called dGIPC). This mutant line presents a high lethality rate resulting from a gain of function. To obtain some insight into the biological role of the mutated locus, we have characterized the mutation and its relation to the high mortality of the KG00562 fly line. In this mutant, we did not detect one of the DmLpin transcripts, namely DmLpinK, but we did detect an unusual 2.3-kb mRNA (LpinK-w). Further investigation revealed that the LpinK-w transcript results from an aberrant splicing between the untranslated first exon of DmLpinK and the mini-white marker gene. Lack of DmLpinK or LpinK-w expression does not contribute to lethality, since heterozygous KG00562/Def7860 animals presented lethality rates comparable to those of the wild type. In contrast, the overexpression of kermit was associated with lethality of the KG00562 fly line. Significantly higher levels of kermit were detected in the Malpighian tubules of KG00562/+ flies that presented higher lethality rates than wild-type or KG00562/Def7860 animals, in which the lethality was rescued. In agreement with a recently reported study, our data support the hypothesis that misexpression of kermit/dGIPC could interfere with Drosophila development, with further investigations being needed in this direction.

Evaluation of 99mTc-HYNIC-βAla-Bombesin(7-14) as an agent for pancreas tumor detection in mice

Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using99mTc-HYNIC-βAla-Bombesin(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that99mTc-HYNIC-βAla-Bombesin(7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that99mTc-HYNIC-βAla-Bombesin(7-14)may be useful for the detection of pancreatic adenocarcinoma.