Intravenous administration to rabbits of non-stealth and stealth doxorubicin-loaded solid lipid nanoparticles at increasing concentrations of stealth agent: pharmacokinetics and distribution of doxorubicin in brain and other tissues

The pharmacokinetics and tissue distribution of doxorubicin incorporated in non-stealth solid lipid nanoparticles (SLN) and in stealth solid lipid nanoparticles (SSLN) (three formulations at increasing concentrations of stearic acid-PEG 2000 as stealth agent) after intravenous administration to conscious rabbits have been studied. The control was the commercial doxorubicin solution. The experiments lasted 6 h and blood samples were collected at fixed times after the injections. In all samples, the concentration of doxorubicin and doxorubicinol were determined. Doxorubicin AUC increased as a function of the amount of stealth agent present in the SLN. Doxorubicin was still present in the blood 6 h after the injection of SLN or SSLN, while no doxorubicin was detectable after the i.v. injection of doxorubicin solution. Tissue distribution of doxorubicin was determined 30 min, 2 and 6 h after the administration of the five formulations. Doxorubicin was present in the brain only after the SLN administration. The increase in the stealth agent affected the doxorubicin transported into the brain; 6 h after injection, doxorubicin was detectable in the brain only with the SSLN at the highest amount of stealth agent. In the other rabbit tissues (liver, lungs, spleeen, heart and kidneys) the amount of doxorubicin present was always lower after the injection of any of the four types of SLN than after the commercial solution. In particular, all SLN formulations significantly decreased heart and liver concentrations of doxorubicin.     

Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity

The aim of the present study was to test a possible effect of the monoamine oxidase A (MAOA) and serotonin receptor 2A (5-HT-2A) gene variants on the antidepressant activity of fluvoxamine and paroxetine in a sample of major (n = 248) and bipolar (n = 195) depressives, with or without psychotic features. A total of 443 in-patients were treated with 300 mg fluvoxamine (n = 307) or 20-40 mg paroxetine (n = 136) for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD). Allele variants were determined in each subject using a PCR-based technique. We observed a marginal association between 5-HT-2A variants and antidepressant response while MAOA genotypes were not associated. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, HAMD scores at baseline, pindolol augmentation and SSRIs plasma levels did not significantly influence the observed results. The investigated MAOA and 5-HT-2A gene variants, therefore, do not seem to play a major role in SSRI antidepressant activity.     

Epitope identification and vaccine design for cancer immunotherapy

The development of processes for engineering multi-epitope vaccines based on the identification and selection of epitope packages, along with vaccine design optimization using epitope placements and spacers to optimize processing efficacy, are reviewed. The Epimmune Inc epitope identification process has been applied to numerous cancer types, but also applies to infectious diseases. Epitope-analog efforts in novel vaccine design have also been explored and their uses in prophylactic and therapeutic applications are eagerly anticipated.     

Brain-derived neurotrophic factor regulates expression of vasoactive intestinal polypeptide in retinal amacrine cells

Brain-derived neurotrophic-factor (BDNF) is expressed in the retina and controls the development of subtypes of amacrine cells. In the present study we investigated the effects of BDNF on amacrine cells expressing vasoactive intestinal polypeptide (VIP). Rats received three intraocular injections of BDNF on postnatal days (P) 16, 18, and 20. The animals were sacrificed on P22, P40, P60, P80, and P120, and VIP expression in their retinas was detected by immunohistochemistry (P22, P40) and by radioimmunoassay (RIA; P22, P40, P60, P80, P120) to assess the time course of BDNF effects on VIP. A significant increase in the density of VIP-positive amacrine cells was detected in BDNF-treated retinas, and VIP concentration was up-regulated by 150% both at P22 and at P40 with respect to untreated controls. VIP concentration then slowly declined in the treated retinas over a period of 3 months; however, a statistically significant increase of 50% was still detectable on P120. The impact of endogenous BDNF on the regulation of VIP expression in the retina was analyzed in mice homozygous for a targeted deletion of the BDNF gene locus (bdnf-/-). VIP immunohistochemistry revealed a marked reduction of VIP-positive amacrine cells and of VIP-immunopositive processes in the inner plexiform layer of the BDNF knockout mice. Mice lacking BDNF expressed only 5% of the VIP protein in their retinas compared with the retinas of wild-type mice as measured by RIA. Our data show that BDNF is a major regulator of VIP expression in retinal amacrine cells and exerts long-lasting effects on VIP content.     

Forty-years (1961-2001) of all-cause and coronary heart disease mortality and its determinants: the Corfu cohort from the Seven Countries Study

AIMS: This study examined risk factors in relation to 40-year all-cause and coronary heart disease mortality in the Corfu cohort of the Seven Countries Study. METHODS: The population studied in this analysis consisted of 529 rural middle-aged men enrolled in 1961. Multivariate analysis was performed using the proportional hazards Cox model with all-cause as well as coronary heart disease death as end points and age, blood pressure, serum total cholesterol, smoking, physical activity, body mass index, skinfold thickness, vital capacity and forced expiratory volume as predictors. RESULTS: The 40-year all-cause mortality rate was 87.1% (461 deaths/529 individuals at entry), while the CHD mortality rate was 22.7% (120 deaths/529 individuals at entry). The proportion of CHD deaths varied from 16 to 28.5% of all deaths during the period investigated. Age (hazard ratio (HR)=1.08, P<0.001), smoking (HR=1.40, P<0.01), diastolic blood pressure (HR=1.01, P<0.05), and forced expiratory volume (HR=0.97, P<0.05) were independently associated with 40-year all-cause mortality. Moreover, age (HR=1.093, P<0.001), smoking (HR=1.596, P<0.05), and body mass index (HR=1.05, P<0.05) were independently associated with 40-year CHD mortality. CONCLUSION: Among the investigated cardiovascular risk factors, age, smoking, physical activity, skinfold thickness, diastolic blood pressure, and forced expiratory volume seem to be associated with all-cause mortality, while age, smoking, and body mass index were consistently associated with 40-year CHD mortality.     

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT(3) spinal receptor involvement in acute pain in humans

To investigate a possible antinociceptive role of serotonin receptor subtype 3 (5-HT(3)), we evaluated the effects of a coadministration of ondansetron, a 5-HT(3) selective antagonist, and tramadol, a central analgesic dependent on enhanced serotonergic transmission. Fifty-nine patients undergoing ear, throat, and nose surgery, using tramadol for 24-h postoperative patient-controlled analgesia (bolus = 30 mg; lockout interval = 10 min) were randomly allocated either to a group receiving ondansetron continuous infusion (1 mg. mL(-1). h(-1)) for postoperative nausea and vomiting (Group O) or to a control group receiving saline (Group T). Pain and vomiting scores and tramadol consumption were evaluated at 4, 8, 12, and 24 h. Pain scores were never >4, according to a 0-10 numerical rating scale, in both groups. Group O required significantly larger doses of tramadol at 4 h (213 versus 71 mg, P < 0.001), 8 h (285 versus 128 mg, P < 0.002), and 12 h (406 versus 190 mg, P < 0.002). Vomiting scores were higher in Group O at 4 h (P < 0.05) and 8 h (P = 0.05). We conclude that ondansetron reduced the overall analgesic effect of tramadol, probably blocking spinal 5-HT(3) receptors. IMPLICATIONS: Serotonin is an important neurotransmitter of the descending pathways that down-modulate spinal nociception. In postoperative pain, ondansetron, a selective 5-HT(3) receptor antagonist, increased the analgesic dose of tramadol. We suggest that, when antagonized for antiemetic purpose, 5-HT(3) receptors foster nociception, because of their site-dependent action.     

Severity of coronary artery stenosis at preoperative angiography and midterm mammary graft status

BACKGROUND: The purpose of this study was to evaluate the correlation between the midterm angiographic results of mammary artery grafts and the preoperative stenosis of the target vessel. METHODS: We analyzed preoperative and postoperative angiograms of 93 patients who underwent postoperative midterm (> or = 3 years) angiograms of an internal mammary artery (IMA) to left anterior descending artery graft for clinical or study purposes. Patients were divided into three groups on the basis of the percentage of the coronary artery stenosis at preoperative angiography: < 70%, 70% to 90%, and > 90% stenosis. RESULTS: Preoperative characteristics were similar in the three groups. The overall incidence of IMA occlusion was 19% in the entire population, without significant differences between groups (19% versus 29% versus 14%). The mean mammary artery diameter significantly increased in direct proportion to the severity of the coronary stenosis (2.0 +/- 0.2 mm in the < 70% versus 2.5 +/- 0.3 mm in the 70% to 90% and 2.7 +/- 0.4 mm in the > 90% series; p < 0.05). CONCLUSIONS: Chronic native competitive flow does not significantly affect midterm graft status but does influence mammary graft diameter.