Biomedical subjects

D Arndt

Publications and source records attributed to D Arndt.

78 records · Page 5Linked to original sources

PubMedDate not supplied

Antineoplastic activity and toxicity of some alkylating cytostatics (cyclophosphamide, CCNU, cytostasan) encapsulated in liposomes in different murine tumour models.

The encapsulation of Cyclophosphamide in MLV (PC:CH 1:1) revealed a total loss of antineoplastic activity in the P 388 tumour model compared to an equal dose of the free drug, though a moderate toxicity, registered as decrease of leukocyte and platelet counts, was still present. CCNU in liposomes of different size and composition showed in lower doses a diminished therapeutic effectiveness in the P388 or L 1210 leukaemia and the B 16 melanoma, while in higher doses toxic deaths occurring with the free drug could be prevented totally by using liposomes. Liposomal encapsulation also influenced body weight change and leukocyte counts, causing them to be less drastically reduced than with use of the free drug. The entrapment of Cytostasan, an N-lost derivative, had the same effect on the increase of lifespan of tumour-bearing animals (mammary carcinoma 1142 A) as equal doses of the free drug and caused only a slight improvement of toxicity. In general, liposomal encapsulation of alkylating cytostatics seems advantageous only for certain lipophilic drugs.

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PubMedDate not supplied

Preparation, characterization, therapeutic efficacy and toxicity of liposomes, containing the antitumour drug cis-dichlorodiamineplatinum(II).

Cis-dichlorodiamineplatinum(II) (cis-DDP) was encapsulated in reverse phase evaporation vesicles (REV, 0.6 mg cis-DDP/ml lipid solution) and multilayered liposomes (MLV, 0.3 mg cis-DDP/ml lipid solution) with different cholesterol content. The identity of cis-DDP in free and encapsulated form was checked by various techniques. Particle size, homogeneity of liposomes and distribution of cis-DDP in REVs were shown by electron microscopy. The examination of entrapped cis-DDP in REVs relating to buffer and serum stability, in vitro and in vivo antitumour activity and nephrotoxicity proved that all points are strongly influenced by the cholesterol (CH) content. Enclosed cis-DDP in phosphatidyl (PC)-REV has the same, and in PC: CH-REV, a lower effect in vitro and in vivo compared to treatment with the free drug. Irrespective of the application of tumour cells and substance (i.v., i.p.) in optimal therapeutic doses, an equal increase in life-span (ILS) was registered with the free drug and with PC-cis-DDP-REV, while cis-DDP in PC: CH-REV had a significantly reduced effectiveness. Liposomal encapsulation of cis-DDP also influenced body weight change and leucocyte counts. The blood urea nitrogen (BUN) level, as an indicator of renal toxicity, was only moderately increased after very high doses of cis-DDP (24 mg/kg) in PC: CH-REV.

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PubMedDate not supplied

The preparation and characterization of lipid vesicles containing esters of sucrose and fatty acids.

Encapsulation and electron microscopy studies have shown that aqueous dispersions of several nonionic emulsifiers with sucrosepalmitatestearate (SPS) structure and cholesterol (Chol) result in synthetic lipid vesicles. This was demonstrated for the commercial emulsifier sucrosepalmitatestearate for the first time. Such vesicles were able to entrap aqueous solutes, for instance the fluorescence marker carboxyfluorescein (CF) for a period of more than 10 weeks with latencies of about 90 per cent. Though SPS/Chol-vesicles tended to flocculate--especially in concentrated solutions--the efflux of entrapped solutes after storage was lower in these vesicles compared with liposomes consisting of natural egg phosphatidylcholine (EPC) and cholesterol.

Carboxylic Acids↗

PubMedDate not supplied

In vivo distribution and antitumour activity of liposomal 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine.

3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (FUdR-dipalmitate), a lipophilic prodrug of 5-fluoro-2'-deoxyuridine (FUdR), was incorporated in different types of liposomes. The in vivo distribution and intrahepatic deacylation of liposomal FUdR-dipalmitate was found to be strongly dependent on liposome composition and on drug to lipid ratio. The use of fluid-type liposomes (egg PC/PS/CHOL) rendered FUdR-dipalmitate more susceptible to enzymatic breakdown than solid-type liposomes (DSPC/DPPG/CHOL). A decrease of the retention of the drug in the body was also obtained when FUdR-dipalmitate was incorporated in solid-type liposomes with high drug to lipid ratio (1:10) than with low ratio (1:50). In spite of these substantial differences in the rates at which FUdR was liberated from liposomes with different fluidity, size, or drug to lipid ratio, only minor differences in therapeutic effect were observed in a number of murine tumour models (P388 leukaemia, Lewis Lung carcinoma, B16 melanoma and a C26 adenocarcinoma liver metastasis model). The lipophilic prodrug of FUdR exhibited antitumour activity at 100-600 times lower doses than the free drug. However, at these therapeutic doses FUdR-dipalmitate was also far more toxic. This prohibited the use of higher doses to increase antitumour activity.

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PubMedDate not supplied

Measurement of carbon clearance in mice as toxicity parameter for liposomal preparations.

The measurement of carbon clearance in female BDF1 mice was used for the characterization of affinity of empty multilamellar (MLV) or small unilamellar vesicles (SUV) made from HEPC:CH:DCP 1:1:0,25 to the reticuloendothelial system (RES). Five mice each were treated i.v. with the corresponding liposomes or physiologic saline. At different times after treatment india ink was administered i.v. and its elimination over 15 minutes was determined by measuring the extinction in blood at 650 nm. MLV had a significant influence on the phagocytic function of RES, leading to a three-fold prolongation of elimination half time after 8h. At 48 hours the normal function of RES was restored. This effect was already seen with a dose of 0.05 ml MLV/mouse corresponding to 1.06 mg lipid. On the contrary, SUV caused no change of carbon clearance up to a dose of 0.8 ml/mouse. From these results we conclude that liposomes, especially MLV, can lead to a measurable but reversible impairment of RES function, while SUV are better suited for a by-pass of this tissue and a probable reaching of other targets, as, for example tumors.

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PubMedDate not supplied

Cytotoxic effects of alkylphosphocholines or alkylphosphocholine-liposomes and macrophages on tumor cells.

The influence of the alkylphosphocholines (APC) on macrophage activation to tumor cytotoxicity was investigated in vitro with both mouse peritoneal and rat liver macrophages. For this purpose the compounds were used either in micellar or in liposomal form. The cytotoxic effect of micellar or liposomal APC was increased with prolongation of the aliphatic chain and was reduced for the liposomal form. Peritoneal macrophages incubated with APC-liposomes gave a comparable cytotoxic effect on MethA cells to that of the free, highly toxic APC alone. These liposomes can activate rat liver macrophages (Kupffer cells) in vitro to a moderate tumor cytotoxicity on C26 colon carcinoma cells, while the micellar APC were toxic to macrophages. A significant release of NO-radicals from peritoneal macrophages was obtained with Liposomes but not with micellar lipid. The release of tumor necrosis factor (TNF) was stimulated by incubation with micellar or liposomal HPC. Whereas the micellar HPC was comparable to lipopolysaccharide (LPS) in TNF release stimulation, the HPC-liposomes caused a much higher release.

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