Distribution and metabolism of hexadecylphosphocholine in mice

Breiser, A.; Kim, D. J.; Fleer, E. A. M.; Damenz, W.; drube, A.; Berger, M.; Nagel, G. A.; Eibl, Hansjörg; Unger, Clemens

doi:10.1007/bf02535556

Cited by 72 publications

(43 citation statements)

References 7 publications

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“…al., 1978;Hoffman et al, 1986;Breiser et al, 1987). At the present time, we believe the most parsimonious hypothesis to be that ATLs are more potent than natural lipids because of their greater metabolic stability.…”

Section: Discussionmentioning

confidence: 75%

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Lohmeyer

Workman²

1995

Br J Cancer

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Summary A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (±)-2-{Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2-yl]methoxylphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 jiM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 M) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 jIM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids.

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Section: Discussionmentioning

confidence: 75%

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Lohmeyer

Workman²

1995

Br J Cancer

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“…In previous studies, we demonstrated that alkylphosphocholines can be applied orally without overt side effects (5,13). After a daily oral application of the alkylphosphocholine He-PC (10 mg/kg) to rats, a steady-state level of about 100 ,uM was obtained in serum (30) (7).…”

Section: Resultsmentioning

confidence: 95%

“…The remarkable activity of He-PC in the spleens and bone marrow of mice might be explained, at least in part, by a favorable distribution of the compound in the reticuloendothelial system (5,18). Specifically, destruction of intracellular amastigotes in the reticuloendothelial system is achieved by activated macrophages; and different cytokines, such as gamma interferon, interleukin-4, or tumor necrosis factor alpha, contribute to the induction of antileishmanial macrophage activation (12,27).…”

Section: Resultsmentioning

confidence: 99%

Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice

Kuhlencord

Maniera

Eibl

et al. 1992

Antimicrob Agents Chemother

175

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Hexadecylphosphocholine (He-PC), a novel phospholipid derivative, was tested against Leishmania donovani and Leishmania infantum, the causative agents of visceral leishmaniasis. In vitro, promastigotes were highly susceptible to He-PC; the 50% inhibitory concentrations were between 0.89 and 2.25 micrograms/ml for the different leishmanial strains. In vivo, a marked antileishmanial activity in infected BALB/c mice could be demonstrated after oral administration of He-PC. Whereas parasite suppression and killing in the liver were comparable after 5 days of treatment with He-PC (10 or 20 mg/kg of body weight per day administered orally) and sodium stibogluconate (120 mg of pentavalent antimonal agent per kg/day administered subcutaneously), a superior reduction in the parasite load in the spleen and bone marrow was observed after oral treatment with He-PC. After a 4-week treatment period, parasite suppression in the spleen was better than that observed with standard sodium stibogluconate therapy by a factor of more than 600.

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“…A partir de doses de 30 mg/Kg duas vezes por dia, concentrações de 155 -189 nmol/g de tecido são alcançados (DORLO et al, 2008). A miltefosina é eliminada lentamente, com uma meia-vida de 96 horas (BRESISER et al, 1987). Este fármaco é indicado principamente para o tratamento de leishmaniose visceral em dose de 50 ou 100 mg/Kg em pacientes com menos ou mais de 25 kg respectivamente.…”

Section: Miltefosinaunclassified

Nanoencapsulação do fármaco miltefosina em micelas poliméricas de poli(óxido de etileno)-poli(óxido de propileno)

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Distribution and metabolism of hexadecylphosphocholine in mice

Cited by 72 publications

References 7 publications

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids

Hexadecylphosphocholine: oral treatment of visceral leishmaniasis in mice

Nanoencapsulação do fármaco miltefosina em micelas poliméricas de poli(óxido de etileno)-poli(óxido de propileno)

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