Heat-Treated Fungizone Retains Amphotericin B Antifungal Activity Without Renal Toxicity in Rats Infected with Aspergillus Fumigatus

PURPOSE: The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B (AmpB) following administration of Fungizone (FZ) and a heat-treated form of FZ (HFZ) to rats infected with Aspergillus fumigatus. METHODS: Infected rats were administered FZ and HFZ at a dosing regimen of 1 mg/kg i.v. once daily for 4 consecutive days. Following administration the number of colony forming units (CFUs) of Aspergillus fumigatus in different organs and serum creatinine concentrations were determined. RESULTS: FZ and HFZ had similar overall effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to controls. Except for the serum creatinine concentrations reported in the nontreated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine. CONCLUSIONS: Taken together, these findings suggest that HFZ at 1 mg/kg once daily x 4 days appears to be as effective as FZ as an antifungal agent without renal toxicity.     

An assessment of DDT and other chlorinated compounds and the reproductive success of American robins (Turdus migratonrius) breeding in fruit orchards

Although DDT was banned in the 1970s, American robins (Turdus migratorius) breeding in fruit orchards of the Okanagan Valley, British Columbia, continue to be contaminated with DDT and its metabolites. The objectives of our study were (1) to assess organochlorine (OC) contamination in robins breeding in Okanagan orchards (1993–1995, 1997–1998) and (2) to determine if exposure affected reproductive success when compared to robins from non-orchard habitat (lower mainland, British Columbia). Robins in orchards had total DDT egg residues of 48.64 mg/kg (geometric mean; n=92) while those in non-orchard habitat had 1.10 mg/kg (geometric mean; n=26), wet weight. The probability of nest survival during the incubation period was 96.7% (confidence interval: 95.7–97.5%; n=165) in orchard habitat and 96.7% (confidence interval: 94.6–98.1%; n=28) in non-orchard habitat. During the nestling period the probability of nest survival was 98.2% (confidence interval: 97.2–98.9%; n=123) in orchard habitat and 96.2% (confidence interval: 92.8–98.0%; n=34) in non-orchard habitat. Clutch (p<0.0001) and brood size (p=0.0133) were larger in orchards (n=150 and n=93, respectively) compared to non-orchard nests (n=42 and n=23, respectively) with no difference in fledge rate. DDE (r ²=0.11, p=0.0030, n=68) and dieldrin (r ²=0.29, p<0.0001, n=68) were negatively correlated with fledge rate in robin eggs collected from orchard habitat, however, low r ² values signify minimal biological significance. Although American robins nesting in Okanagan orchards are exposed to high OC levels, reproductive success does not appear to be negatively impacted.     

Thin section dual-phase multidetector-row computed tomography detection of peritoneal metastases in gynecologic cancers

PURPOSE: To determine the sensitivity, specificity, and accuracy of multidetector-row computed tomography (CT) using thin sections and multiplanar reconstruction for the detection of peritoneal implants in patients with ovarian cancer. METHOD: Seventeen thin section dual-phase multidetector-row CT scans were performed on 17 women with potential peritoneal metastases from ovarian cancer, which scans were then followed by surgery. Axial and multiplanar images from the CT scans were reviewed by 2 observers, and the results were compared with the operative and clinical notes. RESULTS: Peritoneal metastases were detected by both readers in all 7 patients presenting with ovarian cancer and disease at laparotomy. Metastases were detected in 5/6 patients with recurrent tumor by observer 1 and in 4/6 patients by observer 2. Sensitivity, specificity, and accuracy for detecting peritoneal metastases at individual sites in the abdomen and pelvis were improved when both axial and multiplanar images were reviewed. Sensitivities were highest for the paracolic gutters and infracolic omentum (>70%). Approximately 50% of liver and diaphragmatic lesions were detected. Specificities approached 100% for all sites and accuracies were >80% for most sites of disease. CONCLUSION: The sensitivity, specificity, and accuracy of CT for peritoneal metastases in patients is high using thin slices and axial and multiplanar review of the data.     

Cyclosporine Binds to the Neutral Lipid and Potentially Other Binding Sites of Lipid Transfer Protein I

Purpose. The objective of this study was to determine if cyclosporine (CSA) binds directly to the neutral lipid-binding site of lipid transfer protein I (LTP I). Methods. This was accomplished by determining LTP I concentrations and cholesteryl esters (CE) and CSA radioactivity of eluted fast protein liquid chromatography (FPLC) fractions following an injection of different treatment groups (i.e., LTP I alone, ³H-CE liposomes alone, ³H-CSA liposomes alone, ³H-CE liposomes + LTP I, and ³H-CSA liposomes + LTP I) onto an FPLC column. Our hypothesis is that CSA will bind to the neutral lipid-binding site of LTP I because of its high solubility/interaction with cholesterol and triglycerides. Results. Coincubation of LTP I with ³H-CE liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and the appearance of a broad LTP I peak at fractions 30-34 compared to control. Coincubation of LTP I with ³H-CSA liposomes resulted in a significant decrease in the LTP I peak reported at fraction 10 and fraction 30 compared to control. In addition, 30% of the original radioactivity associated with ³H-CSA liposomes was found coeluted with the unbound LTP I peak at fraction 10. Taken together, these findings suggest that CSA does bind to the neutral lipid-binding site of LTP I but may also bind to other regions along the LTP I molecule. Conclusions. We have determined that LTP I mediated transfer of CSA between lipoproteins may be a result of the direct binding of CSA to LTP I at both its neutral binding site and potentially other binding sites along the molecule. These findings provide further evidence that the distribution/redistribution of drugs among plasma lipoproteins facilitated by LTP I may serve as a possible mechanism for determining the ultimate fate of drug compounds     

Femoral nailing with transverse locking screws through the femoral neck

We treated 55 patients with subtrochanteric or comminuted femoral fractures with a transverse locking femoral nail (Alta, Howmedica). This nail was positioned more cephalad than usual so that at least one fixation screw was located in the femoral neck or head. Forty-seven fractures (20 subtrochanteric and 27 diaphyseal) were available for follow-up averaging 12 months (3-35). The time to radiographic healing averaged 7 months (3-21). There was one delayed union, one non-union, two superficial infections, one broken proximal screw, one compartment syndrome of the thigh, and one peroneal nerve palsy. There were no femoral neck fractures, avascular changes of the femoral head, or gluteal irritation at the most recent follow up. The described technique appears safe and effective, is technically easy, and avoids intra-articular screws.     

Heat-induced superaggregation of amphotericin B modifies its interaction with serum proteins and lipoproteins and stimulation of TNF-alpha

The purpose of the present study was to examine the influence of heat-induced superaggregation of Amphotericin B (AmB) in the Fungizone (FZ) formulation on its interaction with human serum components and relate this to reduced toxicity. Whole serum distribution studies showed that a significantly lower percentage of AmB from HFZ was recovered in the high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride-rich lipoprotein (TRL) fractions and a greater percentage recovered in the lipoprotein-deficient plasma (LPDP), though the majority of both preparations were recovered in LPDP. Circular dichroism (CD) and difference absorption spectroscopy were used to determine the stability of FZ and heat-treated FZ (HFZ) in the presence of HDL, LDL, serum, and albumin. The CD studies indicate that the "core" aggregate of HFZ is more stable in the presence of HDL and LDL, whereas the FZ is less stable and more dynamic with the core aggregate dissociating to a greater extent in the presence of either purified lipoprotein. Absorption studies with whole serum and purified albumin suggest that FZ aggregates are far less stable in the presence of albumin than HFZ and that interaction with serum albumin is a dominant feature for both drug preparations. HFZ also has a different effect on the cytokine response in vitro. Studies using THP-1 human monocytes show that HFZ provokes a smaller release of tumor necrosis factor (TNF)-alpha than FZ. This cytokine may be associated with the unpleasant side effects of AmB. These findings suggest that heat-induced superaggregation of AmB alters its interaction with HDL, LDL, serum proteins, and monocytes, and these findings may be important in explaining the reduced toxicity of the superaggregated form of AmB.