Characterization and multiparameter analysis of visual adverse events in irofulven single-agent phase I and II trials.

PURPOSE: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines. EXPERIMENTAL DESIGN: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis. RESULTS: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses < or =0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of < or =0.50 mg/kg and < or =20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. CONCLUSIONS: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of < or =0.50 mg/kg or < or =20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.     

Evaluation of the nutritional and inflammatory status in cancer patients for the risk assessment of severe haematological toxicity following chemotherapy.

BACKGROUND: The toxicity outcome of cancer patients receiving chemotherapy is difficult to predict. In this study the influence of malnutrition and inflammation on acute haematological toxicity was investigated. PATIENTS AND METHODS: Between January 1999 and January 2000, 48 consecutive cancer patients experienced severe haematological toxicity (SHT), either neutropenic fever or severe thrombocytopenia, following various chemotherapy regimens. Their baseline characteristics were compared with those of 59 control patients. Previous chemotherapy regimens, type of chemotherapy, performance status (PS), calculated creatinine clearance, bilirubin, C-reactive protein (1), alpha-1 acid glycoprotein (2), albumin (3), pre-albumin (4) and the nutritional and inflammatory status (NIS) ratio [NIS = (1 x 2)/(3 x 4)] were studied. Statistical analysis was carried out using either a t-test or a chi-square test. A receiver operating characteristic (ROC) curve determined the cut-off value for NIS. RESULTS: Patients experiencing SHT had a higher PS (P <0.001), inflammatory serum protein levels (P <0.001) and NIS ratio (P <0.0001), but lower haemoglobin (P <0.05) and serum-albumin levels (P <0.0001). Using a cut-off of 0 or 1 for PS and 1 for NIS, sensitivity was 98%, 43% and 89%; specificity was 38%, 90% and 66%, respectively. In 37 patients treated with topotecan as single agent, the determinants for SHT were PS (P <0.0001) and NIS (P <0.0001). CONCLUSIONS: Altered nutritional and inflammatory status correlates with increased risk of severe haematological toxicity following anticancer chemotherapy.     

The need to embrace molecular profiling of tumor cells in prostate and bladder cancer.

PURPOSE: Current treatment strategies for urological cancer are still based on empirical formulae as opposed to treatment tailored for each cancer patient. To individualize treatment, the multiple molecular abnormalities within tumor cell populations needs to be mapped out. The aim of this article is to explain molecular profiling (MP) and its associated techniques so that the process is not purely seen as a research tool but as a future adjunctive measure in patient diagnosis and treatment. EXPERIMENTAL DESIGN: A Medline search of publications relating to MP of prostate and bladder cancer was carried out. A review article was written combining the relevant published literature along with the clinical and scientific experience of both centers. RESULTS: The advent of MP now provides a strategy by which these molecular abnormalities can be assessed. As well as being of diagnostic and prognostic use, these molecular profiles will identify putative molecular abnormalities within tumor cells that may be appropriate for therapeutic modulation. CONCLUSIONS: In prostate and bladder cancer, mapping out the molecular abnormalities could be translated into a valuable tool to help solve difficult issues regarding patient management decisions.     

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.     

Gender inequalities in health among older Brazilian adults.

OBJECTIVE: To investigate gender differences among older Brazilians in their health status and their use of health services. METHODS: Participants were individuals aged 60 years and older included in a national household survey conducted in Brazil in 1998. Data were analyzed by multiple logistic regression, taking into account the design effect due to multistage sampling. RESULTS: There were differences in the health and living conditions of older men and older women that were not explained by age or place of residence. Older women had worse indicators of schooling and personal income but better indicators of housing standards and per capita household income. The older women also reported more chronic diseases, had poorer indicators of independence and physical mobility, sought health services more often, and reported more medical visits in the previous year. Despite their apparent worse health conditions, elderly women in urban areas had lower hospitalization rates in the previous year (odds ratio = 0.89; 95% confidence interval, 0.82-0.96) than did elderly men in urban areas. CONCLUSIONS: Our results indicate that among older Brazilians there are gender inequalities in health that cannot be explained by age and place of residence. The findings raise questions on how health, socioeconomic, and cultural factors influence gender patterns of seeking and using health care in later life in the country. As pressures on health care and health funding increase in Brazil as a result of the aging of the population, there is a need to take a gender perspective into account.     

Combining lung-protective strategies in experimental acute lung injury: The impact of high-frequency partial liquid ventilation.

OBJECTIVE: To evaluate the independent and combined effects of high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV) on gas exchange, pulmonary histopathology, inflammation, and oxidative tissue damage in an animal model of acute lung injury. DESIGN: Prospective, randomized animal study. SETTING: Research laboratory of a health sciences university. SUBJECTS: Fifty New Zealand White rabbits. INTERVENTIONS: Juvenile rabbits injured by lipopolysaccharide infusion and saline lung lavage were assigned to conventional ventilation (CMV), PLV, HFOV, or high-frequency partial liquid ventilation (HF-PLV) with a full or half dose (HF-PLV1/2) of perfluorochemical (PFC). Uninjured ventilated animals served as controls. Arterial blood gases were obtained every 30 mins during the 4-hr study. Histopathologic evaluation was performed using a lung injury scoring system. Oxidative lung injury was assessed by measuring malondialdehyde and 4-hydroxynonenal in lung homogenates. MEASUREMENTS AND MAIN RESULTS: HFOV, PLV, or a combination of both methods (HF-PLV) resulted in significantly improved oxygenation, more favorable lung histopathology, reduced neutrophil infiltration, and attenuated oxidative damage compared with CMV. HF-PLV with a full PFC dose did not provide any additional benefit compared with HFOV alone. HF-PLV1/2 was associated with decreased pulmonary leukostasis compared with HF-PLV. CONCLUSIONS: The combination of HFOV and PLV (HF-PLV) does not provide any additional benefit compared with HFOV or PLV alone in a combined model of lung injury when lung recruitment and volume optimization can be achieved. The use of a lower PFC dose (HF-PLV1/2) is associated with decreased pulmonary leukostasis compared with HF-PLV and deserves further study.     

Pharmacological and structural characterization of a novel phospholipase A2 from Micrurus dumerilii carinicauda venom.

We have isolated a new phospholipase A2 (MiDCA1) from the venom of the coral snake Micrurus dumerilii carinicauda. This toxin, which had a molecular mass of 15,552Da, shared high sequence homology with the PLA2 toxins MICNI A and B from Micrurus nigrocinctus venom (77.7% and 73.1%, respectively). In chick biventer cervicis preparations, MiDCA1 produced concentration- and time-dependent neuromuscular blockade that reached 100% after 120 min (2.4 microM, n = 6); contractures to exogenously applied carbachol (8 microM) and KCl (13 mM) were still seen after complete blockade. In mouse phrenic-nerve diaphragm preparations, MiDCA1 (2.4 microM; n = 6) caused triphasic changes followed by partial neuromuscular blockade. Intracellular recordings of end-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) from mouse diaphragm preparations showed that MiDCA1 increased the quantal content by 386+/-12% after 10 min (n = 14; p<0.05) and caused a triphasic change in the frequency of MEPPs. MiDCA1 also decreased the resting membrane potential, an effect that was prevented by tetrodotoxin and/or low extracellular calcium, but not by d-tubocurarine. The toxin increased the amplitude of mouse sciatic-nerve compound action potentials by 30+/-9% (0.6 microM; p<0.05). Potassium currents elicited in freshly dissociated dorsal root ganglia neurones were blocked by 31+/-1% (n = 4; p<0.05) in the presence of 2.4 microM MiDCA1. These results show that MiDCA1 is a new presynaptic phospholipase A2 that produces neuromuscular blockade in vertebrate nerve-muscle preparations. The triphasic effects seen in mammalian preparations and the facilitatory response were probably caused mainly by the activation of sodium channels, complemented by the blockade of nerve terminal potassium channels. The inability of d-turocurarine to prevent the depolarization by MiDCA1 indicated that cholinergic nicotinic receptors were not involved in this phenomenon.     

Pharmacological evidence for a presynaptic action of venoms from Bothrops insularis (jararaca ilhoa) and Bothrops neuwiedi (jararaca pintada).

Whereas the presynaptic action of Crotalus durissus terrificus venom is well-established, Bothrops venoms have historically been considered to have only postsynaptic and muscular effects. However, some studies have also suggested a presynaptic action for these venoms. In this work, we used chick biventer cervicis preparations to compare the presynaptic actions of two Bothrops venoms (B. insularis and B. neuwiedi) with that of C. d. terrificus venom. At 10 microg/ml, all venoms produced irreversible blockade of the twitch tension responses, with no reduction in acetylcholine (ACh)-induced contractures and only a slight decrease in potassium induced-contractures. The times (in min) required to produce 50% neuromuscular blockade (C. d. terrificus: 16.3+/-0.7, n = 8; B. insularis: 30.0+/-1.9, n = 5; B. neuwiedi: 42.0+/-2.0, n = 8; mean +/- SEM) were significantly different among the venoms (p < 0.01). Lowering the temperature at which the experiments were done (from 37 to 24 degrees C) prevented neuromuscular blockade by the three venoms, indicating that enzyme activity may be involved in this response. At concentrations capable of causing complete neuromuscular blockade, creatine kinase release remained close to levels seen in control preparations incubated with Krebs solution alone (500-1200 IU/l). Commercial crotalic antivenom, but not bothropic antivenom, protected against the neuromuscular blockade caused by B. insularis and B. neuwiedi venoms. These observations indicate that bothropic venoms may contain components which act presynaptically in a manner similar to C. d. terrificus venom, and that at low venom concentrations a direct action on skeletal muscle does not contribute to this presynaptic neurotoxicity.     

Paradoxical brain embolism shadowing massive pulmonary embolism

Patent foramen ovale is frequently observed in the general population. In case of massive pulmonary embolism, the sudden increase in the right heart cavity's pressure may cause a right-to-left shunting across this foramen, which could be associated with conflicting outcomes. Herein, we report a case of reversible cardiac arrest preceded by seizures, and followed by hemodynamic stability without any vasopressor. A brain CT-scan showed a limited ischemic stroke. Initial echocardiographic assessment revealed an acute cor pulmonale and a right-to-left intracardiac shunt across a large patent foramen ovale, suggesting the diagnosis of massive pulmonary embolism that was lately confirmed by a multidetector CT-angiography. Anticoagulation therapy was rapidly complicated by a hemorrhagic transformation of the ischemic stroke leading to a fatal outcome. This case illustrates the double-edged circulatory effect of shunting across a patent foramen ovale in case of massive pulmonary embolism: it may have limited circulatory failure but caused in the meanwhile a fatal paradoxical brain embolism.