Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood-brain barrier.

PURPOSE: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood-brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). METHODS: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. RESULTS: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. CONCLUSIONS: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile.     

Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

Classification tree analysis of second neoplasms in survivors of childhood cancer

Background  

Reports on childhood cancer survivors estimated cumulative probability of developing secondary neoplasms vary from 3,3% to 25% at 25 years from diagnosis, and the risk of developing another cancer to several times greater than in the general population.     

Treatment of the Breast’s Lateral Pole: Adjuvant Maneuver to Pitanguy’s Technique

Surgical procedures for the mammary region currently are assuming an important role in body-contouring surgery. Enhancement of results is a constant challenge to the plastic surgeon. A simple and efficient maneuver for resection of the breast’s lateral pole based on the mammoplasty technique of Professor Ivo Pitanguy is described. This study realized at the Private Clinic Sérgio Carreir?o, Rio de Janeiro, RJ, Brazil.     

Relationship Between Exhaled Carbon Monoxide and Airway Hyperresponsiveness in Asthmatic Patients

The study objectives were to analyze the changes in exhaled carbon monoxide (COex) induced by histamine provocation challenge in asthmatic patients and to evaluate the relationship between COex and airway sensitivity and reactivity. Levels of COex were measured in 105 nonsmoking mildly asthmatic subjects before and after histamine provocation challenge. Dose-response curves were characterized by their sensitivity (PD₂₀) and reactivity. Dose-response slope (DRS), continuous index of responsiveness (CIR), and bronchial reactivity index (BRI) were determined as reactivity indices. Bronchial challenge was positive for 47 subjects and negative for 58. The COex levels rose significantly after bronchial challenge in the positive response group (4.49 ± 0.4 vs. 5.74 ± 0.57 ppm, p = 0.025) and in the negative response group (2.84 ± 0.25 vs 4.00 ± 0.41 ppm, p = 0.000). An inverse relation between basal COex and PD₂₀ was found (r = - 0.318, p = 0.030). In all subjects, a proportional direct relationship between COex and DRS (r = 0.214, p = 0.015), CIR (r = 0.401, p = 0.000), and BRI (r = 0.208, p = 0.012) was observed. On stepwise multiple linear regression analysis, COex only significantly correlated with CIR (multiple r² = 0.174, p = 0.000). In conclusion, exhaled CO determination is a noninvasive inflammatory marker of the respiratory tract, which shows an acceptable association with airway hyperresponsiveness.     

Basal and metoclopramide-stimulated prolactin (PRL) serum levels in users and non-users of a copper intrauterine device (TCu-380 IUD).

The study was undertaken to analyze the basal and metoclopramide-stimulated serum PRL levels in healthy parous women users (group 1, n = 12) and non-users (group 2, n = 12) of a TCu-380 IUD. All women had regular menses and were studied between days 18 to 22 of their cycle; none had lactated nor regularly ingested any type of medication during the last six months. After a 10-12 hour overnight fast, peripheral venous blood samples were obtained through an indwelling catheter at -30, -15 and 0 minutes and at 60, 90 and 120 minutes after oral metoclopramide (10 mg). There were no significant differences in serum PRL between both groups, in basal levels nor throughout the test, whether analyzing the mean values at each sampling time, the sum of PRL levels from 60-120 minutes, or the peak levels. No correlation was observed between PRL levels and any of the clinical or obstetric characteristics of the women in both groups. Serum progesterone was greater than or equal to 4.0 ng/ml in all women. Thus, the use of alpha TCu-380 IUD did not induce any significant changes in basal nor in stimulated serum PRL levels.     

Do cancer patients fully understand clinical trial participation? A pilot study to assess informed consent and patient expectations

Background. Accepted practices of informed consent often result in suboptimal patient understanding of research studies.Methods. This pilot study aimed to assess trial-specific tailored materials, compared to a widely used generic booklet about clinical trials, randomly assigned to 118 candidates for cancer clinical trials. Study outcomes were: satisfaction with decision-making; satisfaction with materials; and subjective understanding of the clinical trial.Results. There were no major differences between groups. Participants rated tailored materials higher as a useful reference.Conclusions. Trial-specific materials hold utility for reference during clinical trials. Studies of informed consent are feasible, although important factors limit research.