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N L McIntosh

Publications and source records attributed to N L McIntosh.

6 recordsLinked to original sources
PubMed2000

Role of drug release and liposome-mediated drug delivery in governing the therapeutic activity of liposomal mitoxantrone used to treat human A431 and LS180 solid tumors.

A previous study suggested that drug release is the dominating factor controlling biological activity of liposomal mitoxantrone in tissues where the rate of liposome accumulation is rapid. The studies described here attempted to address the question: under conditions where the rate of liposome accumulation is slow, does drug release or liposome-mediated drug delivery become the dominant factor controlling therapeutic activity? Liposomal mitoxantrone formulations exhibiting different drug-release characteristics were injected i.v. in mice bearing human carcinoma xenografts: A431 human squamous cell carcinoma and LS180 human colon cell carcinoma in SCID/RAG 2 mice. When lipid and drug levels were measured in established (>100-mg) tumors, accumulation was more rapid in the LS180 tumors (C(max) 4 h) than in the A431 tumors (C(max) 48 h). Mean area under the curve values for mitoxantrone measured over a 96-h time course in A431 tumors were 505, 304, and 93 microg. g(-1). h(-1) for 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Chol), 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol, and free mitoxantrone, respectively. When a similar analysis was completed in LS180 tumors, the area under the curve values were 999, 749, and 251 microg. g(-1). h(-1) for DSPC/Chol, DMPC/Chol, and free mitoxantrone, respectively. Although drug delivery was less after administration of the DMPC/Chol liposomal mitoxantrone compared with the DSPC/Chol formulation, LS180 solid-tumor growth curves showed the treatment with the DMPC/Chol formulation produced greater delays in tumor growth compared with animals treated with the DSPC/Chol formulation. These data emphasize the importance of designing liposomal formulations that release drug after localization within a region of tumor growth.

Animals↗
PubMed2000

Kupffer cells do not play a role in governing the efficacy of liposomal mitoxantrone used to treat a tumor model designed to assess drug delivery to liver.

A tumor model designed to assess liposome-mediated drug delivery to liver has been used in an attempt to better understand the mechanism of activity of liposomal mitoxantrone, a liposomal anticancer drug formulation that appears to be uniquely effective in treating this tumor model. Reductions in liposomal mitoxantrone accumulation in the liver were achieved either by use of poly(ethylene)glycol (PEG)-modified lipids or by methods designed to deplete liver phagocytes, a method referred to as hepatic mononuclear phagocytic system (MPS) blockade. A 2-fold reduction in mitoxantrone delivery to the liver was obtained using a mitoxantrone formulation with PEG-modified lipids, and a 3-fold reduction was obtained when liposomal mitoxantrone was given to animals pretreated to induce hepatic MPS blockade. Results demonstrate that the liposomal mitoxantrone formulation prepared with PEG-modified lipids was significantly less active than the formulations that did not contain PEG lipids, with median survival times of 17 days and 100% 60-day survival, respectively. In contrast, hepatic MPS blockade had no effect on the therapeutic activity of 1,2-dimyristoyl phosphatidylcholine/cholesterol (DMPC/Chol) mitoxantrone (100% 60-day survival). These data suggest that the hepatic MPS does not play a role in mediating the therapeutic activity of DMPC/Chol mitoxantrone in the treatment of liver localized disease. Results with formulations prepared with a PEG-stabilized surface, however, suggest that nonspecific methods to decrease liposome cell interactions inhibit the therapeutic activity of DMPC/Chol mitoxantrone.

Animals↗
PubMedDate not supplied

Comparison of total nutrient admixture stability using two intravenous fat emulsions, Soyacal and Intralipid 20%.

The safe clinical use and physical stability of a total nutrient admixture (TNA) system containing a soybean oil emulsion (Intralipid) has been reported. A study was conducted to compare the physical stability of four admixtures which were divided into two groups based upon the ratios (1:1:1 and 2:1:1) of amino acids (8.5%), dextrose (70%), and fat emulsion (20%). The fat component in each group contained either a new soy bean fat emulsion, Soyacal, or Intralipid. The quantities of all electrolytes, trace elements and vitamin additives were the same. All solutions were stored at 4 degrees C for 28 days and then held at ambient temperature for 5 days for a total 33-day study period. Each admixture was serially analyzed on days 0, 1, 2, 3, 5, 7, 14, 21, 28, 29, 30, 31, 32, and 33. Examination of gross visual appearance and determinations of pH were performed. Osmolality was measured by means of freezing point depression (Advanced Digimatic Osmometer, Advanced Instruments, Inc., Needham Heights, MA). A Brookhaven particle analyzer was used to measure lipid particle size and particle size distribution. Electron and light microscopy were used to verify maximum particle size and distribution on days 0, 7, 14, 21, 28, and 29. The type of lipid emulsion used did not affect the pH or osmolality of the admixtures. Admixtures prepared with the 2:1:1 ratio had slightly higher pH (0.07) and lower osmolality (350 mOsm/kg). The range of mean diameters for the admixtures prepared with Soyacal and Intralipid were 0.283 to 0.310 micron and 0.314 to 0.351 micron, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMedDate not supplied

Effect of amino acid solutions on total nutrient admixture stability.

The stability of total nutrient admixture (TNA) systems containing a soybean oil emulsion (Soyacal) has been reported with only one amino acid (AA) solution. This study was conducted to compare the physical stability of 10 TNA systems varied only by the AA solution used. All systems contained electrolytes, vitamins, trace elements, and heparin. The volume ratios of AA, dextrose 70% and lipid emulsion 20% were 1:1:1. Solutions were stored at 4 degrees C for 14 days and then held at ambient temperature for an additional 4 days. Each TNA was serially analyzed on days 0, 1, 3, 5, 7, 14, 15, 16, 17, and 18 for gross visual appearance, pH, osmolality, mean particle diameter, and particle size distribution. The AA solutions evaluated include: Travasol 8.5% and 10%; Aminosyn 8.5% and 10%, Aminosyn RF 5.2%; FreAmine III 8.5% and 10%; FreAmine HBC 6.9%; HepatAmine 8.0%; and NephrAmine 5.4%. The pH values of the Aminosyn solutions were lower than those of other products; however, the pH values of all TNA systems were greater than 5.7, which supported particle stability. The osmolality was not affected by the AA solutions. Based upon particle size distribution, 95% of all particles were less than 0.608 micron in diameter, with means ranging from 0.286 micron to 0.309 micron. The largest particle observed by light microscopy was 6.9 micron. These data indicate that TNA systems prepared with the 10 AA solutions and Soyacal 20% are physically stable.

Amino Acids↗
PubMedDate not supplied

Evidence for macrophage involvement in the enhancement of tumor growth delay with X-ray/Fluosol-DAR/O2 combination therapy.

The perfluorochemical emulsion, Fluosol-DAR, in combination with breathing a 95% oxygen atmosphere, has been shown to enhance the response of several solid tumors to radiation treatment. In this study, the number of macrophages present in two murine tumors was assessed in the absence of Fluosol-DA treatment and at various times post-Fluosol-DA treatment using a rosetting assay. The number of macrophages in the Lewis lung carcinoma and the FSaII fibrosarcoma, after an initial decrease, increased nearly 2-fold (at 14 days) after a single Fluosol-DA injection. Tumor response was assessed by tumor growth delay and excisional tumor cell survival assays in two tumor systems. Greater dose modifying effects were consistently observed when tumors remained in situ. Some animals were treated with carrageenan, a macrophage poison, prior to implantation of Lewis lung tumor. Animals treated with carrageenan, Fluosol-DA and carbogen prior to and during X-ray treatment exhibited a dose modifying factor (DMF) of 1.74 +/- 0.08. Animals treated similarly but without carrageenan pretreatment demonstrated a DMF of 2.61 +/- 0.22. Fluosol-DA administered 24 hours prior to carbogen breathing and X-rays resulted in a greater tumor growth delay than when the perflorochemical was injected immediately prior to radiation/carbogen treatment. The relatively nonimmunogenic FSaII tumor/C3H/Sed host system gave similar results but instead of dose modification, parallel displacements in the dose response curves were seen. Again, Fluosol-DA administrated 24 hours prior to radiation was more effective in sensitizing the tumor than immediate administration. These results suggest that Fluosol-DA in addition to functioning as an oxygen-carrier produces a nonspecific activation of the immune system.

Animals↗