Phentolamine bioequivalence study

OBJECTIVE: To assess the bioequivalence of 2 tablet formulations of phentolamine (Regitine phentolamine 40 mg tablet formulation by Novartis, Brazil, as test formulation, and Vasomax, phentolamine 40 mg tablet formulation by Schering Plough S.A., Brazil, as reference formulation). METHODS: A single 40 mg oral dose of each formulation was administered to 36 male healthy volunteers. The study was conducted after screening, using an open, randomized, 2-period crossover design, a 7-day interval between doses, and wash-out period of at least 4 weeks. Plasma samples for determination of phentolamine were obtained predose and at intervals over 720 min postdose. Plasma concentrations were quantified by reversed-phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM) method. Precision of the method was evaluated using calibration curves and plasma quality control samples. The subjects were monitored throughout the study. Systolic and diastolic blood pressure and pulse rate measurement were taken predose and at intervals up to 720 min. Tolerance of both products was good. No serious adverse reactions were reported. The pharmacokinetic parameters calculated for both compounds included: AUC(0-720 min), AUC(0-infinity), C(max), Ca and k(e). RESULTS: The maximum concentrations reached (C(max)) were compared. Regitine 40 mg formulation C(max) geometric mean ratio was 108.29% (90% CI = 98.58-118.96) of Vasomax 40 mg formulation. The areas under the curve (AUC(0-720 min)) were compared. Regitine 40 formulation (AUC(0-720 min)) geometric mean ratio was 102.33% (90% CI = 97.21-107.72) of Vasomax 40 mg formulation. CONCLUSION: Since the 90% CI for both C(max) and AUC ratio where inside the 80 to 125% interval proposed by the Food and Drug Administration, it is concluded that Regitine 40 mg tablet is bioequivalent to Vasomax for the rate and extent of absorption.     

Measuring risk perception among low-income minority primary care patients

Studying patients' risk perceptions by ascertaining the probabilities of developing a disease is suboptimal, as patients might have difficulty using numerical expressions to depict the probabilities/chances of developing a disease. We surveyed patients at 2 community health centers and assessed risk perception by patients' self-reported chance of developing a disease (expressed in percentages), patients' relative chance of developing a disease compared to others' chance of developing a disease, and patients' ranked chances of developing different diseases. Many patients had difficulties understanding percentages and most patients overestimated their absolute risk. However, most patients indicated that they had a lower chance of developing diseases when compared to others. Patients with known risk factors (smoking) indicated a higher relative risk of developing an associated disease (lung cancer). Patients' ranked chances of developing different diseases were consistent with the actual frequency of developing a disease. Although patients had difficulty expressing risk in percentages, they estimated their risks well through comparisons with others and by ranking of disease frequencies.     

Differential effects of aging on the distribution of calcium-binding proteins in a pretectal nucleus of the chicken brain

The nucleus pretectalis (PT) of birds is an ovoid-shaped visuomotor cell group of the pretectum that receives tectal input and projects back to the optic tectum. We performed immunohistochemical single- and double-labeling to determine the distribution and abundance of neurons containing three calcium-binding proteins, parvalbumin (PV), calretinin (CR), and calbindin (CB), in the PT in chickens at three ages. We found that PV-positive and CR-positive cells co-localize and are largely found in the outer part of PT at all ages. The GluR4 subunit of the AMPA-type glutamate receptor was selectively localized to these neurons. CB-positive neurons, however, were largely absent from the PT in young and adult chickens. The abundance of PV-positive and CR-positive neurons in PT in old birds was indistinguishable from that in the younger birds, but CB-positive perikarya were 10-20-fold more common than in young birds, and were again mainly found in the outer part of PT. The overall abundance of neurons in PT was reduced to about 50% of its former abundance in the old birds, with this loss restricted to the central part of the nucleus. These data indicate that a cell loss process develops in PT as birds age, that parvalbuminergic and calretinergic neurons resist this process, and that this process is associated with increased expression of CB.     

Housemaids and non-fatal occupational injuries

OBJECTIVE: To estimate the annual incidence of non-fatal work injuries according to sociodemographic and occupational variables among housemaids. METHODS: A community-based survey was conducted in a population of 1,650 women aged 10 to 65 years who reported a paid occupation randomly selected in a household sample of the city of Salvador, Brazil. Data was collected through individual questionnaires on living and work conditions and health status. Fisher Exact test was performed for frequency analysis. RESULTS: It was estimated an overall annual incidence of non-fatal work injuries in the study population of 5.0%, which was statistically significant (p<0.05) higher among housemaids (7.3%) than in the group with other occupations (4.5%). Half of the injuries among housemaids were not related with long-term disabilities, and 38.1% women referred not being able to work for two weeks on average after the injury. CONCLUSIONS: Housemaids represent a major contingent of the work force in Brazil and other Latin America countries. The high incidence of non-fatal work injuries in this working group reveals its public health relevance and the need for preventive programs.     

Non-fatal occupational injuries: gender and job contract differences

In Brazil, workers without a formal job contract comprise more than half of the labor force, a contingent formed mainly by women. This study presents estimates of the annual incidence of non-fatal work-related injuries and their distribution by gender and type of job contract in an urban area of Brazil. This was a community-based study with a random cluster area sample of the inhabitants from the city of Salvador, capital of the State of Bahia. The study population included all individuals from 18 to 65 years of age who reported having a paid job (n = 2,947). Data were obtained through individual household interviews. The overall estimated annual incidence rate was 5.80%, with a non-statistically significant difference between men (6.05%) and women (5.53%) or workers with (5.67%) and without (5.92%) a formal job contract. These similarities between work-related accidents across gender and type of job contract highlighted the need for greater attention to this problem among women and informal workers, who are largely ignored in official statistics.     

Extrathoracic obstruction and hypoxemia occurring during exercise in a competitive female cyclist

A 22-year-old competitive female cyclist complained of cough, chest tightness, and wheeze during high-intensity exercise that had previously been diagnosed as exercise-induced bronchospasm (EIB). A loud stridor, a sensation of her "throat closing," and severe dyspnea developed during maximal cycling exercise with concomitant reductions in both inspiratory and expiratory flow rates. A decrease of 25 L/min (26%) in minute ventilation and arterial hypoxemia (PaO(2) decrease, 93 to 76.5 mm Hg) resulted from this obstruction. Spontaneous tidal flow-volume loops (FVLs) during exercise exhibited a sawtooth pattern during inspiration, and substantial drops in flow rates after the stridor developed. However, maximal FVLs were unchanged from baseline following exercise, indicating that the obstruction was not EIB. We suggest that the continuous measurement of spontaneous breath-by-breath tidal FVLs may be a useful diagnostic tool for the identification of exercise-induced extrathoracic obstruction. Additionally, extrathoracic obstruction should be considered as an uncommon but potential cause of inadequate ventilation and arterial hypoxemia during exercise.     

Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: an analysis of 121 patients treated at St Jude Children's Research Hospital.

PURPOSE: The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution. PATIENTS AND METHODS: We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed. RESULTS: At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% +/- 3% and 77% +/- 4%, respectively. In univariate models, positive surgical margins (P =.004), tumor size > or = 5 cm (P <.001), invasivene (P =.002), high grade (P =.028), and intra-abdominal primary tumor site (P =.055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P =.003), intra-abdominal primary tumor site (P =.028), and the omission of radiation therapy (P =.043) predicted local recurrence, whereas tumor size > or = 5 cm (P <.001), invasiveness (P <.001), and high grade (P =.004) predicted distant recurrence. CONCLUSION: In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.     

Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

Purpose

This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.

Methods

Oral irinotecan was administered on days 1–5 and 8–12 with oral gefitinib (fixed dose, 150 mg/m²/day) on days 1–12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5–40 mg/m²/day).

Results

Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1–20), with at least two patients treated on dose levels 2–7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m²) and four (20 mg/m²). One patient experienced grade 3 diarrhea (40 mg/m²). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m²). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses.

Conclusions

The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.