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Biomedical subjects

D Arndt

Publications and source records attributed to D Arndt.

At least 19 recordsLinked to original sources
PubMed2004

Chromosomal aberrations in uranium and coal miners.

PURPOSE: To compare chromosomal aberrations in peripheral lymphocytes of Wismut uranium miners (WUM) and Ruhr coal miners (RCM). MATERIALS AND METHODS: Peripheral lymphocytes from 66 WUM and 29 RCM were cultured and analysed for structural chromosomal aberrations in Giemsa-stained M1 metaphases. Cytogenetic data from 23 male white-collar workers from public services were used as a historical control group. RESULTS: The frequencies of chromosomal aberrations and sister chromatid exchanges in WUM and RCM were quite similar. Compared with public services workers, WUM and RCM had significantly higher frequencies of chromosomal aberrations. CONCLUSIONS: Chromosomal aberrations in WUM are not induced by radioactive particles inhaled during underground mining but as in RCM rather result from factors such as age, lifestyle, illnesses, medications and diagnostic irradiations.

Adult↗
PubMed2001

The composition-dependent presence of free (micellar) alkylphospholipid in liposomal formulations of octadecyl-1,1-dimethyl-piperidino-4-yl-phosphate affects its cytotoxic activity in vitro.

This study was performed to investigate the effect of cholesterol content, surface charge and sterical stabilization on the physico-chemical properties of liposomes prepared from the cancerostatic alkylphospholipid, octadecyl-1,1-dimethyl-piperidino-4-yl-phosphate (D21266), and their relationship to in vitro cytotoxicity. Stable incorporation of OPP into liposomes was found to be highly dependent on the cholesterol content. 31P-NMR spectroscopy as well as analysis of the lipid composition of OPP-containing liposome formulations revealed an increase in the amount of non-liposome-associated, micellar OPP as the cholesterol content decreased. The fraction of non-liposome-associated OPP constituted about 10% of total OPP when cholesterol was present in equimolar amounts (45.5/45.5 mol %) and increased to approximately 30% at a twofold excess of OPP over cholesterol (58.8/29.4 mol %). In monolayer incorporation studies it was shown that the existence of an increasing micellar pool of lipids leads to increased lipid transfer into the target monolayer. Liposome formulations containing more OPP than cholesterol were also found to display greater cytotoxicity. However, all liposome formulations were less cytotxic than pure (micellar) OPP. Cytotoxicity was not affected by the incorporation of N-methoxy-polyethyleneglycol2000-phosphoethanolamine, a lipid that is known to reduce liposome uptake into phagocytic cells. The results demonstrate that the increase in cell toxicity correlates with the increase in non-liposome-associated, micellar OPP, which can readily exchange into cellular membranes.

Breast Neoplasms↗
PubMed2001

[Minilaparoscopy below the left costal border with radially expanding STEP-Trocar-System in patients with previous pelvic surgery--results of a pilot study].

As a part of a prospective study of 20 patients with previous pelvic surgery, the efficacy of using a 2/3 mm dilatable STEP device (InnerDyne, Inc., Sunnyvale, USA) for the first insertion in the area below the left costal border was tested, using 2 or 3.3 mm minilaparoscopes (Storz). Despite the high incidence of periumbilical omental and bowel adhesions (55%), no complications were observed in any of the 20 patients with previous pelvic surgery. Herewith could be confirmed that the use of a minilaparoscope in the area below the left costal border represents in high risk patients a safe and minimally invasive method for preventing or reducing the number of trocar-related injuries during first trocar insertion. In combination with the use of 2/3 mm disposable STEP-trocars if clinically required an atraumatic dilation and safe insertion of reusable 5 mm, 10 mm or 12 mm trocars is enabled.

Adult↗
PubMed2001

Prediction of metabolic activity from genotype: the gene-dose effect of N-acetyltransferase.

Metabolic activity of the polymorphic N-acetyltransferase (NAT2) is determined by the mutation pattern of the NAT2 gene. This results in interindividual differences in the metabolic capacity (the phenotype), with continuous distribution of the activities rather than qualitative distinction between rapid and slow acetylators. To determine whether the phenotype might be predicted solely from the mutation pattern of NAT2, quantitative relationships were calculated between mutation patterns of the NAT2 gene and the phenotype of NAT2 assessed either in vitro or in vivo. Healthy volunteers were examined for the velocity at which they metabolized sulfamethazine, and human liver cytosols were measured for NAT2 enzymatic activity, obtaining in vivo and in vitro metabolic phenotype, respectively. Typing of the NAT2 gene was performed by polymerase chain reaction, restriction fragment length analysis, or allele-specific polymerase chain reaction. Multiple linear regression analysis provided quantitative relationships between allelic pattern and the NAT2 activities measured in vivo and in vitro. Estimates showed the influence of particular allelic configurations on enzyme activity in vitro and the extent of acetylation of the probe drug in vivo, resulting in a strict gene-dose effect. Comparison of in vitro results with in vivo phenotyping figures showed a high degree of correspondence, indicating that the one is the reflection of the other.

Adult↗
PubMed2001

Cancerostatic octadecylpiperidinoylphosphate liposomes: effect of composition on uptake by and toxicity to J774 mouse macrophage cells and MT1 breast cancer cells in vitro.

Liposomes prepared from the cancerostatic octadecyl-(N,N-dimethylpiperidino-4-yl)-phosphate (OPP) were investigated in order to characterize the influence of composition on cytotoxicity and to minimize side effects on the immune system. Differently composed liposomes with respect to charge, cholesterol content and steric stabilization were used. Fluorescence measurements and the MTT assay were applied to investigate the effect of uptake and cytotoxicity, respectively, on J774 mouse macrophages and MT1 human breast cancer cells in vitro. Because of their endocytotic capability, uptake was generally higher for macrophages compared with tumour cells. OPP liposomes, which are negatively charged, cholesterol-poor and sterically stabilized, showed the lowest total and internal uptake by both cell lines. On the other hand, these liposomes were also the most cytotoxic ones for both cell lines investigated, with an inhibitory concentration of between 50 and 80 microM. Cytotoxicity does not correlate with cellular uptake and is most likely caused by other mechanisms. The results demonstrate that cancerostatic liposomes have composition-dependent toxic effects on macrophages which have to be seriously considered. For therapeutic experiments in vivo liposomes should be negatively charged and sterically stabilized and composed of OPP and cholesterol in a molar ratio of approximately 1.

Animals↗
PubMed1999

Pharmacokinetics of sterically stabilized hexadecylphosphocholine liposomes versus conventional liposomes and free hexadecylphosphocholine in tumor-free and human breast carcinoma bearing mice.

The pharmacokinetics of free and different liposomal formulations of hexadecylphosphocholine (HPC) was investigated in tumor-bearing (human mammary tumor MaTu) and tumor-free mice after intravenous and intraperitoneal administration. The levels of HPC were evaluated at different times in serum, normal tissues, and tumor. The purpose was to test the hypothesis that the enhanced therapeutic efficacy of sterically stabilized HPC liposomes in comparison to conventional vesicles and free HPC is due to its pharmacokinetics. Conventional non-compartmental pharmacokinetic analysis and an elaborate three- and four-compartmental model were used for explaining the experimental data. The serum levels of HPC obtained with sterically stabilized liposomes were only consistently higher in comparison to conventional vesicles and free HPC in the first 4 h. In the xenografted MaTu carcinoma, the differences of the HPC content between the different groups are unexpectedly low and do not reflect the high therapeutic activity [5] of sterically stabilized HPC liposomes. Detailed analysis shows that the liposomally encapsulated drug displays a modified pharmacokinetic behavior, which may also involve lymphatic absorption of the liposomal drug.

Animals↗
PubMed1998

Physical properties and pharmacological activity in vitro and in vivo of optimised liposomes prepared from a new cancerostatic alkylphospholipid.

Liposomes from octadecyl-(1,1-dimethyl-4-piperidino-4-yl)-phosphate (OPP), a new alkylphospholipid derivative with an improved cancerostatic activity, were prepared for the first time and the activity in vitro and in vivo was characterised. The formation of liposomes (MLV, SUV and LUVET) differing in cholesterol content, charge, and sterical stabilisation is possible without serious problems, despite the lysolipid-like structure of the OPP. Liposomes with a low amount of cholesterol and with PEG2000DSPE-coating were the most stable OPP liposomes, both in buffer and in serum. The cytotoxicity of micellar or liposomal OPP against breast cancer cell lines in vitro was in the range of 20-60 microM. The cytotoxicity of the liposomal formulation was inversely related to the content of cholesterol, whereas the sterical stabilisation and/or the incorporation of a positive charge had only a very moderate modulating effect on the inhibition of cell proliferation. The strongest antitumour effect on the xenotransplanted breast cancer MT-3 in vivo was obtained with sterically stabilised OPP liposomes with low CH content. The beneficial therapeutic effect of these liposomes was accompanied by better tolerance and a significant inhibition of haemolysis compared to micellar OPP.

Animals↗
PubMed1997

Antineoplastic activity of sterically stabilized alkylphosphocholine liposomes in human breast carcinomas.

New sterically stabilized liposomes derived from the antitumor agent hexadecylphosphocholine with reduced uptake by the mononuclear phagocyte system and improved antitumor activities were developed and tested. The bilayer of such sterically stabilized liposomes consists of hexadecylphosphocholine, cholesterol and polyethylene glycol-linked phosphoethanolamine. The measurement of carbon clearance in mice shows that these stabilized liposomes, in contrast to conventional alkylphosphocholine liposomes, are not largely engulfed by the mononuclear phagocyte system. Their therapeutic activity on experimental human breast carcinomas MaTu. MT-1 and MT-3 was tested in nude mice. Especially in the MaTu models the sterically stabilized hexadecylphosphocholine liposomes resulted in significantly reduced tumor growth in comparison to conventional hexadecylphosphocholine liposomes or free hexadecylphosphocholine. The enhanced therapeutic efficacy of sterically stabilized hexadecylphosphocholine liposomes is probably related to the extended circulation time of the formulation and its accumulation in tumors.

Animals↗
PubMed1996

Effect of sterical stabilization on macrophage uptake in vitro and on thickness of the fixed aqueous layer of liposomes made from alkylphosphocholines.

A serious problem using liposomes for therapeutic purposes is the fast removal from blood circulation by components of the reticuloendothelial system (RES) most likely after opsonization of the vesicles. This study was performed to quantify the reduction in macrophage uptake in vitro of sterically stabilized liposomes (PEG-liposomes) prepared from hexadecylphosphocholine, cholesterol and poly(ethylene glycol2000) distearoylphosphoethanolamine (PEG2000DSPE) for the first time. The uptake was determined using HPC-liposomes of different defined size (125, 250 and 1000 nm) without and with sterical stabilization by incorporating 5 mol% of PEG2000DSPE. HPTS was used as fluorescence marker allowing the discrimination between general uptake and the part of liposomes internalized into the low pH-compartment (Daleke, L.D., Hong, K. and Papahadjopoulos. D. (1990) Biochim. Biophys. Acta 1024, 352-366). Liposomal uptake by J774 mouse macrophage-like cells was time-dependent. Both the uptake and internalization were clearly reduced for PEG-liposomes compared to plain liposomes. Sterical stabilization reduced the general uptake of liposomes in vitro by more than 50% and the internalization by about 50-60%. PEG-liposomes additionally showed a delay in internalization into the macrophages during the first 6 h. Size of used liposomes had only a minor influence on liposomal uptake but highest concentration of lipid was found for large multilammelar vesicles (MLV). The fixed aqueous layer thickness (FALT) was determined by zeta potential measurements of plain and sterically stabilised HPC-liposomes (100 nm) in solutions of different ion concentrations. The calculation of the thickness was based on the linear correlation between ln zeta (zeta-potential) and kappa (Debye Hückel-Parameter). FALT was calculated and found to be for plain HPC-liposomes 0.83 +/- 0.17 nm and for PEG-HPC-liposomes 3.57 +/- 0.17 nm. Exchange of the HPC by an alkylphospholipid with different head group has no or only minor effect (PEG-OPP-liposomes 3.44 +/- 0.31 nm). Thus the reduced uptake of HPC-LUVET correlates with an increased thickness of the fixed aqueous layer around these liposomes and could support the hypothesis that the thickness is an important property responsible for preventing opsonization and resulting finally in a reduced macrophage uptake.

Animals↗
PubMed1996

Preparation and properties of sterically stabilized hexadecylphosphocholine (miltefosine)-liposomes and influence of this modification on macrophage activation.

The aim of the study was to investigate for the first time the preparation, physical properties and macrophage activating effect of sterically stabilized liposomes made from hexadecylphosphocholine (HPC, Miltefosine) using different poly(ethylene glycol) lipids for coating. We could demonstrate that it is possible to prepare different liposomal vesicle types (MLV, SUV and LUVET) without any problem and with a high stability in buffer (release of hydrophilic marker was < 5% after half a year) and in plasma (t1/2 up to several days). The preparation method, including size of polycarbon membrane filter used for the preparation of LUVETs had the main influence on vesicle size and size distribution. The addition of a charged lipid like DCP and different amounts of PEG-lipid up to 10% had no effect on size and stability of PEG-LUVETs. A comparison of activating potency of PEG-HPC-vesicles with commonly used HPC-liposomes was performed with mouse peritoneal macrophages. HPC-liposomes induced a clear release of NO and TNF from mouse peritoneal macrophages especially in a synergistical action with LPS. On the contrary the effect of PEG-liposomes was similar to control cells after a combined activation in vivo/in vitro. The reduced interaction of these liposomes with the MPS was also demonstrated by an unchanged carbon ink uptake after treatment of mice (i.p.) with liposomes prepared with and without PEG-lipid. PEG-HPC-liposomes combine the advantages of HPC, liposomes and PEG-coating, resulting in a promising preparation for treatment of mammary cancers.

Animals↗
PubMed1995

Influence of hexadecylphosphocholine on the release of tumor necrosis factor and nitroxide from peritoneal macrophages in vitro.

Hexadecylphosphocholine (HPC) has been investigated intensively for its cancerostatic properties. One explanation for the mechanism of action of HPC assumes that it plays a role in stimulation of the immune system. In particular, its potency to activate macrophages has already been recognised for different lyso- and ether lipids. Important steps in the cascade for developing cytotoxic effects of macrophages on tumor cells are the release of nitric oxide radicals (NO) and/or tumor necrosis factor (TNF). The aim of our study was to examine the role of HPC as primer and/or trigger for macrophage activation to cytotoxicity. In our experiments we used HPC in free (micellar) or liposomal form in different primer/trigger combinations with lipopolysaccharide (LPS). A weak change in morphology was revealed by electron microscopy, if macrophages were harvested from mice previously treated with HPC or HPC multilamellar vesicles. This observation was quantified by the measurement of NO, TNF and cytotoxic activity of the peritoneal macrophages. A specific release of NO was induced by the combination of in vivo treatment with liposomal HPC and subsequent stimulation by LPS in vitro. This process started only after 12 h of in vitro incubation of macrophages with the endotoxin. The release of TNF was dependent of the primer/trigger combination used. A moderate priming effect was obtained with HPC in liposomal form independently of the trigger. On the other hand, liposomes as priming agents were found to induce a dramatic increase in TNF release after in vitro coculture with the trigger LPS. The high release of NO and TNF is accompanied by only a weak increase in tumor cytostasis. The best results were once more found with macrophages primed with liposomal HPC and then triggered with LPS.

Animals↗
PubMed1995

Alkylphosphocholine-induced production of nitric oxide and tumor necrosis factor alpha by U 937 cells.

The human histiocytic cell line U 937, which expresses a number of monocyte markers and properties, was investigated with regard to its ability to be activated for NO and tumor necrosis factor (TNF) release after treatment with alkylphosphocholines (APC) and APC liposomes. Using APC multilamellar vesicles (MLV) a clear dose-dependent increase of NO production could be demonstrated for U 937 cells, whereas the corresponding soluble substances had no effect. The time course of NO release was characterised by a peak between 2 h and 12 h and a strong decrease after 24 h. LPS caused no NO release nor the production of TNF in U 937 cells. The simultaneous incubation of the cells with lipopolysaccharide and APC or APC-MLV, led to a strong increase in TNF production. Closer investigation of the time sequence of this synergistic effect demonstrated that cells, that had first been treated with hexadecylphosphocholine (HPC)-MLV and 4 h later with lipopolysaccharide secreted significantly more TNF into the supernatants than in the experiment where both substances were added simultaneously. From these results it was concluded that APC-MLV are possibly able to act as a primer in the process of lipopolysaccharide mediated TNF induction. Furthermore, a positive influence of phorbol 12-myristate 13-acetate (PMA) on the ability of U 937 cells to produce TNF following a treatment with HPC or HPC-MLV could be observed. PMA-pretreated cells were shown to release much more TNF compared to control cells, which led to the supposition that the immunomodifying activity of APC becomes effective only in more highly differentiated cell types.

Cell Line↗
PubMed1994

Antineoplastic activity of alkylphosphocholines (APC) in human breast carcinomas in vivo and in vitro; use of liposomes.

This study examines the in vitro and in vivo activity of alkylphosphocholines (APC) in experimental human breast carcinomas. Three analogs, hexadecylphosphocholine (HPC), octadecylphosphocholine (OPC) and eicosanylphosphocholine (EPC) were investigated. Three hormone receptor negative cell lines were sensitive to all three APCs in vitro whereas the receptor positive MCF-7 line was more resistant. Sensitivity was seen in 4/6 hormone receptor negative tumors in vivo, with HPC being the most active analog. There were no antitumor effects in the four receptor positive models. The reasons for these differences in response between hormone receptor negative and -positive lines are not yet understood and require further study. Gastrointestinal toxicity and hemolysis, the major side effects of the APCs, were reduced by the use of liposomal preparations.

Administration, Oral↗
PubMed1994

Phospholipid analogues: side chain- and polar head group-dependent effects on phosphatidylcholine biosynthesis.

In recent studies we showed that the phospholipid analogue hexadecylphosphocholine inhibits phosphatidylcholine biosynthesis by affecting the translocation of the rate-limiting enzyme of phosphatidylcholine biosynthesis, CTP:phosphocholine cytidylyltransferase (EC 2.7.7.15), to membranes, where it is active (Geilen et al. 1992. J. Biol. Chem. 267: 6719-6724). The present study was performed to investigate the structure-dependency of this effect. It is shown that the inhibitory properties of phospholipid analogues are dependent on their alkyl side chain length (dodecylphosphocholine < tetradecylphosphocholine < hexadecylphosphocholine < heptadecylphosphocholine < octadecylphosphocholine > eicosadecylphosphocholine). Furthermore, it is demonstrated that this inhibition of phosphatidylcholine biosynthesis by phospholipid analogues is also dependent on the polar head group (hexadecylphosphocholine >> hexadecylphosphoethanolamine = hexadecylphosphoserine). These effects result from an inhibition of the CTP:phosphocholine cytidylyltransferase and are not due to an inhibition of choline uptake or differences in the cellular uptake of the phospholipid analogues investigated.

Animals↗
PubMed1994

Radioiodine therapy during an unknown remained pregnancy and radiation exposure of the fetus. A case report.

PURPOSE: A papillary thyroid cancer staged as p T2N3M0 was treated in a 28-year-old woman by surgery, percutaneous radiation and radioiodine therapy (10 single applications ranging from 3300 to 3840 MBq with an average radioactivity of 3350 MBq). In the course of radioiodine therapy an attended gynaecologist found the woman pregnant in the 24th week of gravidity. Because the pregnancy remained unknown until this time radioiodine was administered during the 2nd and the 22nd week of pregnancy, each time 3700 MBq. Because of the risk of malformations this pregnancy was interrupted after consultation and taking the recommendations of the so-called Danish rule as a basis for the decision. METHODS: Ovarian and fetal doses as well as the fetal thyroid exposure has been estimated as exactly as possible using data at hand. The fetus was studied with regard to possible consequences of radiation exposure by pathologico-anatomical, cytogenetic and radiobiological methods. RESULTS: The accumulated ovarian doses resulting from the radioiodine administrations before pregnancy was estimated to 2200 mGy, the fetal doses resulting from the two administrations during pregnancy to 250 mGy in each case, and the fetal thyroid dose to between 90 Gy and 900 Gy for the 2nd therapy during pregnancy. In the fetus the most important changes were found within the thyroid gland (atrophy, sclerosis, subcapsular interstitial fibrosis, necrobiosis of follicular epithelial cells). On the other hand, analysing the karyotype using dermal fibroblastic cell cultures, no radiation induced chromosomal aberrations were seen. CONCLUSION: Despite of all precautionary measures it seems to be conceivable that in extremely rare cases--in our 35-year experience with more than 20,000 radioiodine therapies only the present case--an early pregnancy may remain undetected. The results of these studies give useful information on effects to be expected as a result of radioiodine application during certain periods of pregnancy. They may help to extend the radiobiological knowledge with regard to the fetal period.

Abortion, Therapeutic↗