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This article analyzes the main coordination needs linked to the diagnosis and treatment of oncological diseases, presenting the various integration tools that our healthcare organization adopted to guarantee continuity of care at the IRCCS IFO (Istituto di Ricovero e Cura a Carattere Scientifico Istituti Fisioterapici Ospitalieri) in Rome. The object of investigation is the disease management team (DMT) organization for the diagnosis and treatment of people suffering from oncological disease and the consequences in terms of improving their management.

To evaluate the effectiveness of videothoracoscopic surgery in the treatment of complicated parapneumonic pleural effusion and to determine whether there is a difference in the videothoracoscopic surgery outcome before or after the chest tube drainage.

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Delirium and transient neurologic dysfunctions (TND) often complicate the postoperative course after surgery for acute type-A aortic dissection (AAD). We evaluated the role of clonidine on neurological outcome and respiratory function in 30 consecutive patients undergoing surgery for AAD. Patients were prospectively randomized to receive either clonidine (0.5 microg/kg bolus, followed by continuous infusion at 1-2 microg/kg/h) or placebo (NaCl 0.9%) in on starting and throughout the weaning period from the mechanical ventilation. Incidence of delirium and TND, Delirium Detection Score (DDS), weaning parameters [respiratory rate to tidal volume ratio - f/VT; pressure-frequency product (PFP); partial pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/FiO(2)); partial pressure of carbon dioxide (PaCO(2))], weaning duration and intensive care unit (ICU) length of stay were recorded. The two groups were similar for preoperative and operative variables and also for the incidence of postoperative complications. DDS was lower in the clonidine group (P<0.001). Patients weaned with clonidine showed lower f/VT and PFP, higher PaO(2)/FiO(2) and PaCO(2), lower DDS, weaning period and the related ICU length of stay (P<0.001). This was further confirmed in patients developing delirium/TND. Intravenous clonidine after surgery for AAD reduces the severity of delirium, improves the respiratory function, shortens the weaning duration and the ICU length of stay.

ABSTRACTBAL19403 is a macrolide antibiotic from a novel structural class with potent activity against propionibacteria in vitro. The antibacterial spectrum of BAL19403 covers clinical isolates with mutations in the 2057 to 2059 region of 23S rRNA that confer resistance to erythromycin and clindamycin. The basis of this improved activity was investigated by ribosome binding assays and by a coupled transcription and translation assay. The latter was specifically developed for the use of ribosomes from Propionibacterium acnes. BAL19403 inhibited protein expression by ribosomes from erythromycin-sensitive and erythromycin-resistant P. acneswith similar potencies if the resistance was due to G2057A or A2058G mutations. BAL19403 showed a >10-fold higher activity than erythromycin against ribosomes from a strain with the erm(X) gene. Erm(X) confers high levels of macrolide and lincosamide resistance by dimethylation of A2058. Assays with such ribosomes showed that BAL19403 was potent enough to inhibit half of the total activity with a 50% inhibitory concentration very close to the value measured with erythromycin-sensitive ribosomes. We concluded from our data that the P. acnesstrain with the erm(X) gene had a mixed population of ribosomes, with macrolide-sensitive and macrolide-resistant species.

ABSTRACTAmphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.

The pharmacokinetics and pharmacodynamics of oral and IV omeprazole after a single dose were studied in 9 patients with the Zollinger-Ellison syndrome to determine whether the increased dose required to control gastric acid hypersecretion could be explained on the basis of altered pharmacokinetics. Each patient was studied both after receiving a single IV bolus of omeprazole (40 mg) and after receiving a single oral dose of omeprazole (80 mg). Intravenous and oral omeprazole doses were administered 1 week apart. Gastric acid secretion and plasma concentrations of omeprazole after drug administration were determined in each patient. The area under the plasma concentration curve, clearance, and volume of distribution after IV omeprazole administration and the area under the plasma concentration curve, peak plasma concentration, and time required to reach the peak after oral omeprazole administration were not different from those reported previously for normal subjects and patients with peptic ulcer disease. Mean (±SEM) bioavailability of oral omeprazole for all patients was 68% ± 16%, which was similar to the bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability (20% ± 8%) than the others, and their basal acid outputs were significantly higher than those of the other 7 patients. For all patients there was an inverse correlation between bioavailability and basal acid output (r= 0.76; P< 0.02). The mean (±SEM) elimination half-lives of IV and oral omeprazole were not different (2.3 ± 0.4 vs. 2.4 ± 0.5 hours) but were significantly longer than those reported previously for normal subjects (P< 0.02). The duration of action correlated with the elimination half-life of the drug (r= 0.87; P< 0.003) and area under the plasma concentration curve (r= 0.72; P< 0.03). The mean durations of action of IV and oral omeprazole were not significantly different (34 ± 7.2 vs. 35 ± 6.2 hours). It was concluded that altered pharmacokinetics do not account for the increased drug requirement of omeprazole in patients with the Zollinger-Ellison syndrome. In contrast to a previous study, the oral and IV omeprazole had the same duration of action, suggesting that intermittent bolus administration of parenteral omeprazole will obviate the need for continuous infusion of histamine H2-receptor antagonists in patients requiring parenteral antisecretory drugs. Furthermore, an IV dose every 12 hours controlled acid secretion in all patients, suggesting this as the recommended dose interval in patients requiring parenteral drug therapy.

Extracellular and intracellular aminopeptidases were produced from Lactobacillus caseissp. caseigrown in skim milk whey permeate, but those grown in MRS medium produced intracellular enzyme only. Extracellular enzyme was produced by intact cells rather than by cell lysis. The enzyme was highly unstable during storage at −20°C or −80°C or upon cell breakage. Aminopeptidase production from cells, regardless of their growth medium, was predominantly associated with growth. Cells released aminopeptidase on extraction with Triton X-100, phosphate buffer, or lysozyme in decreasing order of activity.

An improved bioassay for fluconazole was developed. This assay is sensitive in the clinically relevant range (2 to 40 micrograms/ml) and analyzes plasma, serum, and cerebrospinal fluid specimens; bioassay results correlate with results obtained by high-pressure liquid chromatography (HPLC). Bioassay and HPLC analyses of spiked plasma, serum, and cerebrospinal fluid samples (run as unknowns) gave good agreement with expected values. Analysis of specimens from patients gave equivalent results by both HPLC and bioassay. HPLC had a lower within-run coefficient of variation (less than 2.5% for HPLC versus less than 11% for bioassay) and a lower between-run coefficient of variation (less than 5% versus less than 12% for bioassay) and was more sensitive (lower limit of detection, 0.1 micrograms/ml [versus 2 micrograms/ml for bioassay]). The bioassay is, however, sufficiently accurate and sensitive for clinical specimens, and its relative simplicity, low sample volume requirement, and low equipment cost should make it the technique of choice for analysis of routine clinical specimens.

The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventy-five patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had > 30% increases in creatinine clearance, whereas 13 had > 30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.

The safety and pharmacokinetics of weekly dapsone and weekly dapsone plus pyrimethamine were examined in adult patients with human immunodeficiency virus infection who were at risk for pneumocystis pneumonia because of a prior episode or a CD4+ T-cell count less than 250 cells per mm3. Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found to be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg plus pyrimethamine at 25 mg once weekly. Twenty-six patients each were followed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity. Five patients receiving dapsone developed documented pneumocystis pneumonia, while four and two patients receiving dapsone plus pyrimethamine developed documented and presumptive pneumocystis pneumonia, respectively. To evaluate the tolerability of a higher dose of pyrimethamine, 11 patients had their regimen changed to dapsone at 200 mg plus pyrimethamine at 75 mg, which was well tolerated by 10 of the patients for a median period of 11 weeks. The pharmacokinetics of dapsone and pyrimethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were observed when multiple-dose regimens of dapsone were compared with single-dose dapsone and when multiple-dose regimens of dapsone with pyrimethamine were compared with multiple-dose dapsone alone. When administered weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study suggests that the efficacy of these regimens in preventing pneumocystis pneumonia, however, may be less than that of trimethoprim-sulfamethoxazole.

A unilamellar liposomal formulation of amphotericin B (LAmB) known as AmBisome was safely administered intravenously to 20 rabbits at 0.5, 1.0, 2.5, 5, or 10 mg/kg of body weight, whereas of 12 rabbits given desoxycholate amphotericin B (DAmB) intravenously at 0.5, 1.0, or 1.5 mg/kg, 2 died of acute cardiac toxicity when DAmB was administered at the highest dose. Single-dose LAmB (1 mg/kg) achieved a maximum concentration in serum (Cmax) of 26 +/- 2.4 micrograms/ml and an area under the curve to infinity (AUC0-infinity) of 60 +/- 16 micrograms.h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower Cmax (4.7 +/- 0.2 micrograms/ml; P = 0.001) and a lower AUC0-infinity (30.6 +/- 2.2 micrograms.h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher Cmax (287 +/- 14 micrograms/ml) and AUC0-infinity (2,223 +/- 246 micrograms.h/ml) occurred, indicating saturable elimination. After chronic dosing (n = 4) with LAmB at 5.0 mg/kg/day for 28 days or DAmB at 1.0 mg/kg/day for 28 days, LAmB achieved daily peak levels of 122.8 +/- 5.8 micrograms/ml and trough levels of 34.9 +/- 1.8 micrograms/ml, while DAmB reached a peak of only 1.76 +/- 0.11 microgram/ml and a trough of 0.46 +/- 0.04 microgram/ml (P < or = 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 +/- 39 micrograms/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 +/- 6 micrograms/g after DAmB dosing (1 mg/kg/day) (P = 0.002). Accumulation in kidneys, however, remained 14-fold lower (P =0.04) following LAmB dosing (0.87 +/- 0.61 microgram/g) than after DAmB dosing (12.7 +/- 4.6 microgram/g). Nephrotoxicity occurred in only one of four LAmB treated animals, while it occurred in all four chronically DAmB-treated animals: mild hepatozicity with transaminase elevations was seen in one LAmB-treated rabbit. We conclude that LAmB safely achieved higher Cmax(s) and AUC0-infinity(s) and demonstrated saturable, nonlinear elimination from plasma via reticuloendothelial organ uptake. Take reduced nephrotoxicity of LAmB correlated with diminished levels of amphotericin B in the kidneys.

An effort was made to fabricate and characterize monolithic, coherent two-dimensional arrays of grating surface emitting (GSE) lasers emitting in the 0.9-1.1- mu m wavelength region using strained InGaAs/AlGaAs quantum-well lasers. The two-dimensional arrays of GSE distributed Bragg reflector (DBR) lasers were grown on both GaAs and AlGaAs substrates by atmospheric pressure organometallic vapor-phase epitaxy, using a graded-index separate-confinement-heterostructure (GRINSCH) geometry with a single InGaAs strained quantum well. The emitting aperture of these arrays was 0.04 mm by 5.0 mm when a 10*10 section of the wafer was probe tested at 12 A. Typically, the full width half-power of the single-lobed longitudinal far field was about 0.02 degrees . The tested lasing wavelengths of the 10*10 arrays from different wafers ranged from 0.95 and 1.03 mu m. The device is a monolithic, coherent array and performs comparably to previously reported devices based on AlGaAs/GaAs.

The article offers the author's account and sentiments about the special reservations given to people with disabilities, as one who also have special needs. He believes that the condition of people with disabilities gives them certain freedoms and entitlements, which he suspects underlies much of their antisocial behavior. An account from the author of his experience from showing his antisocial behavior in a parking reserve is noted.

Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. In clinical studies bosutinib has demonstrated efficacy and an acceptable safety profile in patients with Philadelphia chromosome–positive chronic myelogenous leukemia (CML). The current analysis estimated the association of bosutinib pharmacokinetic (PK) exposure at steady-state with safety and efficacy.Oral bosutinib 500 mg/day was administered to patients with chronic phase (CP), accelerated phase, and blast phase CML who were resistant/intolerant to prior TKI therapy in a phase 2 trial, and to patients with newly diagnosed CP CML in a phase 3 trial. Patients with paired PK and pharmacodynamic data were included in the analysis. Bosutinib exposure metrics (area under the curve [AUC], maximal plasma concentration [Cmax], and minimum plasma concentration [Cmin]) were derived from a previously developed 2-compartment PK model with first-order absorption and an absorption lag. Evaluated safety metrics (ordinal metrics) included gastrointestinal events (diarrhea, nausea, vomiting), rash, aminotransferase elevations, and hematologic events (thrombocytopenia, neutropenia); safety data were pooled from both studies, and the maximum toxicity for each patient was assigned to a 5-point scale (0–4) based on severity (no event to grade 4 event, respectively). Response rates based on an intent-to-treat analysis were evaluated separately for each study and coded as binary variables, where 0 indicated no response and 1 indicated response.A total of 749 patients were included in the pooled safety analysis: mean age was 50.2 years (range, 18–91 years); 54% were male. An exposure-response relationship (Emax model) was identified for the incidence of diarrhea (but not severity), with a predicted probability of diarrhea incidence ranging from 0.575 to 0.797 for the lowest and highest bosutinib AUC bins, respectively. There was also a weak exposure-response relationship (log-linear model) for the incidence (but not severity) of rash, with a predicted probability of rash incidence ranging from 0.216 to 0.419. However, there was no evidence to support an exposure-response relationship for the incidence or severity of nausea, vomiting, neutropenia, thrombocytopenia, or elevation of alanine and aspartate aminotransferases. In 266 patients with resistance/intolerance to prior TKI therapy, no exposure-response relationship for major cytogenetic response (MCyR) at 24 weeks was found. Although an exposure-response relationship (linear or log-linear model) was observed for cumulative complete hematologic response (CHR) in patients with prior TKI exposure, the relationship was paradoxical, with higher bosutinib exposure associated with a lower probability of cumulative CHR; the predicted probability of cumulative CHR ranged from 0.926 to 0.743 for the lowest and highest AUC bins, respectively. In 245 newly diagnosed patients with CP CML, exposure-response relationships were observed for complete cytogenetic response (CCyR), major molecular response (MMR), and CHR at 1 year. CCyR at 1 year could be related to AUC and Cmin, but not Cmax, using a sigmoid Emax model, with a predicted probability of CCyR ranging from 0.476 to 0.650. The exposure-response relationship for MMR at 1 year could be described using an Emax model for AUC and Cmax or a log-linear model for Cmin, with a predicted probability of MMR ranging from 0.238 to 0.497. The relationship of CHR at 1 year with AUC and Cmin, but not Cmax, could be described using an Emax model, with a predicted probability of CHR ranging from 0.605 to 0.763.An exposure-response relationship was identified for incidence of diarrhea and rash, but not for the incidence or severity of other investigated toxicities commonly observed with bosutinib treatment. Additionally, an exposure-response relationship was found for CCyR, MMR, and CHR at 1 year in newly diagnosed patients with CP CML, but the relationship between bosutinib exposure and efficacy was less clear in the pretreated population. The absence of exposure-response relationships for some safety and efficacy metrics may reflect bosutinib concentrations that exceeded the half-maximal inhibitory concentration (IC50) for these metrics and reached a plateau effect.Amantea: Pfizer Inc: Employment, Equity Ownership. Mould:Projections Research Inc: Employment; Pfizer Inc: Consultancy. Upton:Pfizer Inc: Consultancy. Pearce:Pfizer Inc: Employment. Hsyu:Pfizer Inc: Employment, Equity Ownership.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipients had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill; three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiograms, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimated volume of distribution and estimated clearance, ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.