Renal and gastric lesions after phenylbutazone and indomethacin in the rat

Arnold, L.; Collins, Catherine; Starmer, G. A.

doi:10.3109/00313027409077340

Cited by 46 publications

(11 citation statements)

References 21 publications

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“…The acidic drugs, on the other hand, accumulate in the glandular mucosa of the stomach and the kidney cortex. Correspondingly, these drugs cause ulcer formation (Rainsford, 1975), electrolyte and water retention, or even acute pathological changes in the kidney (Morales & Steyn, 1971;Arnold, Collins & Starmer, 1974 Figure 2. Lighter regions correspond to intense areas of radioactivity.…”

Section: Discussionmentioning

confidence: 99%

Biodistribution of mild analgesics.

Brune¹,

Rainsford²,

Schweitzer³

1980

Brit J Clinical Pharma

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1 Macro‐autoradiographic methods were used to assess the biodistribution of [3H]‐, or [14C]‐acidic (aspirin, indomethacin, phenylbutazone) and non‐acidic (antipyrine, aminopyrine, paracetamol) mild analgesics in rats with carrageenan‐induced inflammation. 2 At anti‐inflammatory doses all the acidic drugs (and/or their metabolites) were found to reach high concentrations in the stomach wall, liver, blood and bone marrow, kidney cortex and the inflamed tissue, that is, the tissues in which these drugs exert their therapeutic or side‐ effects. 3 In contrast, at analgesic doses, the non‐acidic mild analgesics (and/or their metabolites) are equally distributed throughout the body with the exception of the gastro‐intestinal lumen and the liver. This distribution pattern correlates well with the lack of acute side‐effects and anti‐inflammatory action of these drugs at therapeutic doses.

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Section: Discussionmentioning

confidence: 99%

Biodistribution of mild analgesics.

Brune¹,

Rainsford²,

Schweitzer³

1980

Brit J Clinical Pharma

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“…Equivalent nephrotoxic signs were observed with DP-155 at a dose 5 times higher, indicating 5-fold better renal safety. The tubular damage expressed by increased NAG to creatinine ratio is most likely due to ischemia and this may indicate reduction in renal blood flow (Arnold et al, 1974). Renal safety was further studied by a more specific model.…”

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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“…High concentrations in these compartments could then cause impaired cellular function giving rise to, e.g., reduced pain perception in inflamed tissue and also to cell damage as found in the mucosa of the stomach and tubulus epithelia in the kidney [17].…”

Section: The Pharmacokinetic Conceptmentioning

confidence: 99%

“…All these drugs cause alterations in stomach and kidney which, depending on the dose given, range from irritation and functional impariment [12] to vast necrosis of cellular components in these organs [17]. It has been argued that both effects might be due to inhibition of PG-synthesis in these organs because PG's appear to be physiological inhibitors o f secretion of hydrochloric acid in the stomach [18] and might also regulate electrolyte elimination and regional blood flow in the kidney [19].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: Evidence for the importance of pharmacokinetics

Brune¹,

Gräf²,

Glatt³

1976

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A variety of acidic and non-acidic compounds are potent inhibitors of prostaglandin (PG) synthesis in vitro. However, only a few, namely the acidic nonsteroid anti-inflammatory drugs (NSAID) are useful anti-inflammatory analgesics in the clinic. Since inhibition of PG-synthesis is believed to be the main target of NSAID in inflammation this superiority of acidic compounds remains unexplained. We have considered that one explanation could be that only acidic NSAID appear in high concentrations in inflamed tissue to inhibit PG-synthesis sufficiently. To test this hypothesis the following experiments were carried out: (A) PG-synthesis and its inhibition by acidic and non-acidic NSAID was measured in vivo at the site of inflammation. It was found that in therapeutic doses only acidic NSAID were capable to reduce PG-synthesis significantly. (B) Measurement of drug concentration in inflamed tissue showed that only acidic NSAID were found in significantly higher concentrations in inflamed than in control tissue. From these observations it is concluded that a specific pharmacokinetic behaviour of acidic NSAID leading to high concentrations in inflamed tissue is a decisive aspect of their anti-inflammatory action.

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Renal and gastric lesions after phenylbutazone and indomethacin in the rat

Cited by 46 publications

References 21 publications

Biodistribution of mild analgesics.

Biodistribution of mild analgesics.

Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: Evidence for the importance of pharmacokinetics

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