Dose response and toxicity of doxorubicin microspheres in a rat tumor model.

The therapeutic response and toxic effects of chemotherapy using several doses of doxorubicin in conventional solution form or bound to an ion-exchange resin were compared in a rat tumor model, to assess the relationship of drug dose to therapeutic efficacy and associated toxicity. Single bolus injections of 3.0, 4.5, 6.0, 7.5 and 9.0 mg/kg were administered via the abdominal aorta to rats bearing hindlimb tumors. Tumor size was measured serially and the growth rates of treated groups were compared with a control growth curve. In addition, the effect of empty microspheres on tumor growth rate was assessed. The levels of circulating white blood cells were measured and compared to control levels to provide an indication of the severity of bone marrow toxicity experienced by each form of treatment. Finally, any difference in the distribution of doxorubicin to tumor, hindlimb and cardiac tissue following administration of doxorubicin as free drug or on microspheres was ascertained. Empty ion-exchange resin exerted a small although significant detrimental effect on tumor growth which may be explained by the embolization of microspheres in the precapillary blood vessels of the tumor resulting in a transient delay in tumor growth rate. The lowest dose of doxorubicin produced a significantly better therapeutic response when administered in the free drug form, but higher doses elicited an equivalent delay in tumor growth for both drug microsphere and free drug groups in a dose-dependent manner, with the maximum anti-tumor response occurring at the highest dose. Treatment with free doxorubicin at high doses resulted in significant reductions of circulating white blood cells suggesting the occurrence of bone marrow toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ictal chronology and interictal spikes predict perfusion patterns in temporal lobe epilepsy: a multivariate study.

Typical (TPP) and atypical (APP) perfusion patterns (PP) may be seen in ictal SPECT of patients with temporal lobe epilepsy (TLE). APP may pose problem in the lateralization of the epileptogenic zone (EZ). We aimed to investigate predictive variables for the occurrence of TPP and APP. Fifty-one TLE patients were submitted to successful anterior-mesial temporal lobectomy. Univariate (UVA) and multivariate (MVA) analysis were performed upon clinical data, distribution of interictal spikes, and ictal chronology of seizures. From MVA, a final predictive model (FPM) was determined to better predict TPP and APP. Forty patients showed TPP (78.5%) and 11 patients APP (21.5%). Accuracy of ictal SPECT was higher in the unilateral (UIS) than in the bilateral (BIS) interictal spikes group (P = 0.05). FPM showed that patients exhibiting BIS, with shorter proportion of the electrographic seizure occurring after completion of tracer injection, and longer clinical than EEG seizure duration had more APP (P = 0.003). Generalized tonic-clonic seizures did not result in more APP. We concluded that analysis of ictal SPECT in TLE requires the knowledge of TPP and APP, the distribution of interictal spikes on temporal lobes and the ictal chronology of seizures. BIS showed that beyond a more complex epileptogenicity and seizure propagation, they may also lead to APP.     

The supraoptic nucleus in hypothyroid and undernourished rats: an experimental morphometric study

The supraoptic nuclei of both male and female 30-day-old rats rendered hypothyroid by daily subcutaneous injection of propylthiouracil were studied and the results were compared with age- and sex-matched rats fed ad libitum (control rats) and with undernourished rats. Morphometric methods were used to evaluate the volume of the supraoptic nucleus and the areal and numerical densities of its neurons. These parameters allowed us to estimate the total number of neurons of this nucleus. In addition, the mean cross-sectioned area and mean nuclear diameter of the same neurons were also evaluated. The volume of the supraoptic nucleus was reduced both in hypothyroid and undernourished animals when compared with normal controls. The areal and numerical densities of neurons from the former groups were increased and the volume density of the neuropil was reduced. As a consequence, the total number of neurons was found to be identical in all groups studied. Furthermore, the mean nuclear diameters and cross-sectioned areas of the supraoptic neurons were similar in all groups. The volumetric differences and the increased packing found were always more marked for hypothyroid than for undernourished rats. Differences were not detected between male and female groups. The present results support the view that the increased cell packing in hypothyroid animals depends upon a reduction in the neuropil of the nucleus, as has been described under similar conditions in other central nervous system areas displaying identical patterns of neurogenesis. In addition, it was found that the effects of undernourishment cannot be discriminated from those dependent on neonatal hypothyroidism.     

Treatment and prognostic factors in patients with hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma is a leading cause of death from cancer worldwide. Survival of patients depends on tumor extension and liver function, but yet there is no consensual prognostic model. AIMS: To evaluate the influence on survival of pretreatment parameters (clinico-laboratorial, liver function, tumor extension, Okuda and Cancer of the Liver Italian program (CLIP) staging) and treatment modalities. METHODS: We retrospectively analyzed 207 patients, diagnosed between 1993 and 2003. The initial treatment was: surgery--six patients; radiofrequency ablation--21; percutaneous ethanol injection--29; transarterial chemoembolization--49; tamoxifen--49; supportive care alone--53. Factors determining survival were assessed by Kaplan-Meier method and Cox regression models. RESULTS: Median survival was 24 months. In univariate analysis, Child-Pugh classification and Model for end-stage liver disease (MELD) score, portal vein thrombosis (PVT), tumor size, number of lesions, Okuda and CLIP scores were all associated with prognosis (P < 0.001). Alpha-fetoprotein levels were not predictive of survival. Independent predictors of survival were ascites, bilirubin, PVT and therapeutic modalities (P < 0.001). In early stage hepatocellular carcinoma (HCC), survival was similar for both percutaneous ablation modalities, either radiofrequency or ethanol injection (P = NS). In advanced HCC, survival was better in patients receiving tamoxifen than supportive care alone (P < 0.001). CONCLUSION: This study reinforces the importance of baseline liver function (Child-Pugh classification and MELD score) in the survival of patients with HCC, although staging systems allowed the stratification of patients in different prognostic groups. Ascites, bilirubin and PVT were independent pretreatment predictors of survival. All treatments influenced the patient's outcome, whether in early or advanced stages.     

Insulin resistance is associated with circulating fibrinogen levels in nondiabetic patients receiving peritoneal dialysis.

BACKGROUND: Insulin resistance (IR) and inflammation are associated with increased risk of cardiovascular disease in the general population. Continuous glucose absorption in peritoneal dialysis (PD) may induce hyperglycemia and hyperinsulinemia. METHODS: We evaluated IR in nondiabetic patients receiving PD, and analyzed the association between IR and systemic inflammation biomarkers by performing a cross-sectional study on ambulatory dialysis. A total of 25 nondiabetic patients receiving PD and 25 healthy individuals, matched for gender, age, and body mass index (BMI), were included. The PD group was composed of 11 men and 14 women, with a mean age of 47 +/- 14 years and mean BMI of 25.5 +/- 4.7 kg/m(2). The control group was composed of 10 men and 15 women, with a mean age of 45 +/- 12 years and BMI of 24.0 +/- 2.8 kg/m(2). RESULTS: IR was evaluated by the homeostasis model assessment method (HOMA-IR). Inflammation was assessed through high-sensitivity C-reactive protein (CRP) and fibrinogen. Body composition and truncal fat were evaluated by dual energy x-ray absorptiometry. HOMA-IR was significantly higher (P < .0001) in subjects receiving PD (4.9, range: 2.3-9.3 mmol/L x muU/mL) compared with healthy subjects (1.2, range: 0.4-4.8 mmol/L x muU/mL). As expected, compared with controls, patients receiving PD had significantly higher levels of insulin (26.5 +/- 7.5 muU/mL vs 6.3 +/- 3.4 muU/mL; P < .0001), CRP (6.3, range: 0.3-61.1 mg/L vs 2.4, range: 0.6-5.9 mg/L; P = .001), and fibrinogen (379 +/- 101 mg/dL vs 268 +/- 66 mg/dL; P < .0001). However, there were no significant differences in body and truncal fat mass between the groups. A significant correlation between HOMA-IR and fibrinogen (Rho = 0.48; P = .01) was observed. However, no correlation was found between HOMA-IR and CRP. Also, no significant correlations were found between HOMA-IR and body fat mass (Rho = 0.11), and between HOMA-IR and truncal fat mass (Rho = 0.19). CONCLUSIONS: Patients receiving PD demonstrate a state of IR that is associated with high circulating levels of fibrinogen. This suggests that hyperfibrinogenemia may be involved in the pathogenesis of IR in this setting.     

Prediction of the Deposition of Dry Powder Aerosols

The trajectory, mass fluxes, and deposition of aerosolized particles in a complex tubular system have been predicted. A procedure based on Lagrangian stochastic modeling is proposed to enable the anticipation of such phenomena, taking advantage of experimental results to characterize the air flow. The predictions have been obtained for pharmaceutical aerosols delivered by dry powder inhalers. A critical assessment of the dispersion model has been carried out using data available in the literature. The procedure assumes a low volume fraction of particles in the simulation of turbulent dispersion, but deposition is physically based on the interaction between the particles and both solid and liquid surfaces. The results were confirmed by experimental tests of powder deposition, run according to the European Pharmacopoeia. A parametric study was also carried out with the aim of providing a more complete evaluation of the model’s performance. The comparison between predictions and experimental results has shown that the model properly describes the deposition of aerosolized particles.     

Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers.

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.