Improvement of the gastric tolerance of non-steroidal anti-inflammatory drugs by polyene phosphatidylcholine (Phospholipon® 100)

Leyck, S.; Dereu, N.; Etschenberg, E.; Ghyczy, Miklós; Graf, Erich Otto; Winkelmann, Johannes; Parnham, Michael J.

doi:10.1016/0014-2999(85)90469-8

Cited by 33 publications

(23 citation statements)

References 9 publications

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“…The protective effect of phosphatidylcholine against gastric ulcers caused by NSAIDs given a simultaneous administration of phosphatidylcholine (Phospholipon PHOSPHOLIPON® 100 (Lipoid GmbH) (pure phosphatidyl-choline)) and NSAIDs was also described in various other publications (29,49,72). Here, the reduction in ulcer formation depended on the type of NSAID used.…”

Section: Reduction Of Side Effectsmentioning

confidence: 68%

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Kromp²,

et al. 2010

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Phospholipids become increasingly important as formulation excipients and as active ingredients per se. The present article summarizes particular features of commonly used phospholipids and their application spectrum within oral drug formulation and elucidates current strategies to improve bioavailability and disposition of orally administered drugs. Advantages of phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low membrane penetration potential, but also improvement or alteration of uptake and release of drugs, protection of sensitive active agents from degradation in the gastrointestinal tract, reduction of gastrointestinal side effects of non-steroidal anti-inflammatory drugs and even masking of bitter taste of orally applied drugs. Technological strategies to achieve these effects are highly diverse and offer various possibilities of liquid, semi-liquid and solid lipid-based formulations for drug delivery optimization.

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Section: Reduction Of Side Effectsmentioning

confidence: 68%

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Kromp²,

et al. 2010

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“…Regulation (e.g., reduction) of gastric epithelial permeability in response to acid exposure is an important local protection mechanism, mediated by PGE 2 , which is inhibited by COX-1 inhibitors, including indomethacin, but not COX-2 inhibitors (Takezono et al, 2004). It is also known that unsaturated phospholipids reduced gastrotoxicity (Leyck et al, 1985), and the DP-155 structure is ideal in this respect. Indomethacin is also known for inducing a high prevalence of lesions in the small and large bowels (Whittle, 1998;Rainsford et al, 2003), including ulceration and inflammation that can cause hypoproteinemia, anemia, and perforation of the gut (Bjarnason et al, 1987;Hawkey, 1998).…”

Section: Dp-155 Safer Indomethacin Reducing A␤ 1-42 1253mentioning

confidence: 99%

A Novel Phospholipid Derivative of Indomethacin, DP-155 [Mixture of 1-Steroyl and 1-Palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl Choline], Shows Superior Safety and Similar Efficacy in Reducing Brain Amyloid β in an Alzheimer's Disease Model

Dvir¹,

Friedman²,

Lee³

et al. 2006

J Pharmacol Exp Ther

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Indomethacin has been suggested for the treatment of Alzheimer's disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-sn-glycero-3-phosophatidyl choline), a lecithin derivative of indomethacin. Safety was tested by daily oral administration of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely reduced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicycloprostaglandin E 2 . An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of A␤42 in the brains of Tg2576 mice. Indomethacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin's half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing A␤42 brain levels, despite the low systemic blood concentrations of indomethacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering A␤42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155's potential as an improved indomethacin-based therapy for AD.Indomethacin belongs to the nonsteroidal anti-inflammatory drug (NSAID) family. The use of NSAIDs was found to have an inverse correlation with the prevalence and severity of Alzheimer's disease (AD) in epidemiological and clinical studies (in t' Veld et al., 2001). Alzheimer's disease is characterized by three pathological hallmarks: extracellular amyloid ␤ (A␤) plaques, intracellular neurofibrillary tangles (composed of hyperphosphorylated Tau protein), and neuronal and synaptic loss. The pathology development is accompanied by marked inflammatory processes (microglial and astrocytic reaction) (McGeer and McGeer, 1999). Indomethacin inhibits A␤ plaque formation via ␥-secretase inhibition, which is a cyclooxygenase (COX)-independent process (Weggen et al., 2001). In addition, NSAIDs have COX-dependent anti-inflammatory and neuroprotective effects (Halliday et al., 2000;Weggen et al., 2001 ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; AD, Alzheimer's disease; A␤, amyloid ␤; COX, cyclooxygenase; GI, gastrointestinal; PGE, prostaglandin E; GFR, glomerular filtration rate; DP-155, mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl...

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“…For the first time, Bechara et al described lipoma histological changes after treatment with a commercial mixture; in particular they reported: between 4 and 48 h a lobular neutrophilic infiltrate, at day lOan infiltration of T lymphocytes, and after 60 days, macrophage infiltrate (6). PC, the predominant phospholipid of cell membranes and of the circulating blood lipoproteins, is a bile component that facilitates fat emulsification, absorption, transport and is reused via the enterohepatic circulation (7).…”

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confidence: 99%

Effects of Phosphatidylcholine and Sodium Deoxycholate on Human Primary Adipocytes and Fresh Human Adipose Tissue

Palumbo

Melchiorre

et al. 2010

Int J Immunopathol Pharmacol

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Recent studies introduced the novel concept of chemical lipolysis where phosphatidylcholine (PC), an active component of commercial preparations, plays a pivotal role. Other studies suggested that sodium deoxycholate (DOC), an excipient contained in medical preparations, could be the real active component performing an adipocytolytic action. We investigated the effects of PC and DOC on human primary adipocyte cultures and on human fresh adipose tissue. Human adipocytes isolated by Rodbell's method, were cultured onto type I collagen-coated glass coverslips, placed into 24-well tissue culture plates. Cells were incubated with or without DOC (5–7–9%), PC (5%) or DOC/PC mixture and observed under phase contrast microscope. After incubation, cells were stained with Oil Red-O and with acridine orange/ethidium bromide to observe necrotic cells with phase contrast microscope and fluorescent microscope, respectively. Histological specimens from adipose tissue biopsies were observed with phase contrast microscopy and with scanning electron microscopy. To investigate the lipid pattern variability in the different experimental conditions, culture medium obtained from the different treatments was subjected to lipid extraction and subsequently to thin layer chromatography (TLC). Microscopic observation of adipocytes showed that DOC treatment led to a detrimental morphological effect in a dose-dependent manner. PC treatment did not significantly affect adipocyte viability. On the contrary, results from experiments aimed to analyze the effects of PC/DOC combined treatment suggested a PC protective role against the DOC harmful effects on adipocytes. Results indicated that clinical effects, observed in local treatment with pharmaceutical preparation, could be due only to DOC, a detergent inducing nonspecific lysis of cell membranes following adipocyte necrosis. On the other hand, PC could likely be incorporated in the lipid bilayer, thus strongly reducing the disruptive DOC effects.

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Improvement of the gastric tolerance of non-steroidal anti-inflammatory drugs by polyene phosphatidylcholine (Phospholipon® 100)

Cited by 33 publications

References 9 publications

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Phospholipids and Lipid-Based Formulations in Oral Drug Delivery

Effects of Phosphatidylcholine and Sodium Deoxycholate on Human Primary Adipocytes and Fresh Human Adipose Tissue

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