Amelioration of experimental acute pancreatitis with a potent platelet-activating factor antagonist

Formela, Laura; Wood, Landon; Whittaker, Mark; An, Ke

doi:10.1002/bjs.1800811224

Cited by 75 publications

(25 citation statements)

References 20 publications

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“…Table 2 lists measures that have been beneficial when instituted once acute pancreatitis is under way and shows that the common denominator is the control of mast cell pathology [9, 28, 29, 57, 71, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98]. Since impedance to exocytosis in the acinar cell is the detonating event and this is best explained by oxidant-induced interruption to the flow of methyl groups [1], it is logical to regard the resumption of that flow as the reason why re-feeding with methionine [73]or treatment with an analogue of ascorbate [74]– which facilitates the recycling of methyl groups from homocysteine via the folate-vitamin B 12 shuttle – ameliorate in the choline-deficient ethionine-supplemented (CDE) dietary model of severe disease.…”

Section: Formulating a Treatment Strategymentioning

confidence: 99%

Towards a Novel Treatment Strategy for Acute Pancreatitis

Braganza¹

2001

Digestion

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In part 1 it was argued that a ‘free radical-mast cell’ template for the aetiogenesis of acute pancreatitis accommodates the evidence, whereas the prevailing ‘trypsin-cytokine’ template does not. In this sequel I examine the ramifications of the new philosophy in relation to speedier diagnosis, prognostic aids and, above all, a programme of active treatment which – once validated in experimental studies – could be implemented by the first medical respondent.

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Section: Formulating a Treatment Strategymentioning

confidence: 99%

Towards a Novel Treatment Strategy for Acute Pancreatitis

Braganza¹

2001

Digestion

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“…Treatment of experimental acute pancreatitis with various PAF antagonists has shown a reduction in local and systemic inflammatory changes (68)(69)(70). The only PAF antagonist that has been studied in humans is lexipafant, a molecule that specifically binds to the PAF receptor and which is more potent than other PAF antagonists (71).…”

Section: Platelet Activating Factor (Paf) Antagonistsmentioning

confidence: 99%

Update on the Management of Acute Severe Pancreatitis

Ponette¹,

Wilmer²

2001

Acta Clinica Belgica

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Acute severe pancreatitis is an agressive disease with a mortality rate of up to 30 percent. In recent years therapy has shifted away from early surgery to intensive medical care.This article focuses on several issues of the management of acute severe pancreatitis emphasising evidence from recent clinical trials and recommendations from recent consensus conferences.Since a correct assessment of the severity of the disease is mandatory as early as possible in the treatment, several multiple scoring factor systems and individual risk factors are explained. The indications and the optimal timing of ERCP are discussed. Prophylactic administration of antibiotics, intravenously or by means of a selective digestive decontamination scheme, seems to be beneficial in decreasing morbidity but not mortality. Adequate nutritional support, preferably achieved by enteral feeding, is an important component in the supportive therapy. Protease inhibitors and anti-secretory drugs have not proven to be of benefit in improving outcome. Immunomodulating substances like platelet activating antagonists are promising but further studies are necessary to confirm the results of the early studies. Finally, indications for surgery are discussed.

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“…Progression of the disease and the involvement of PAF have been studied in detail in rat and rabbit models where acute pancreatitis has been induced experimentally using either caerulein administration [24, 30, 62, 65, 66], infusion of bile salts [61, 67, 68], injection of lipopolysaccharides [64], or microvascular ischaemia [69]. These studies have revealed that PAF significantly potentiates pancreatic tissue damage.…”

Section: Mode Of Action Of Paf In Acute Pancreatitismentioning

confidence: 99%

“…Treatment of experimental acute pancreatitis with various PAF antagonists has consistently shown significant local and systemic effects to reduce inflammatory changes (table 2) [24, 25, 30, 62, 66, 67, 69, 79, 80]. In most studies, PAF antagonist administration before or at the time of induction of pancreatitis reduces pancreatic inflammation and oedema, and leads to lower serum levels of pancreatic enzymes.…”

Section: Paf Antagonistsmentioning

confidence: 99%

“…In most studies, PAF antagonist administration before or at the time of induction of pancreatitis reduces pancreatic inflammation and oedema, and leads to lower serum levels of pancreatic enzymes. One report of administration after induction of pancreatitis by microvascular ischaemia showed a reduction in local damage [69]. Systemic effects, particularly the pulmonary changes of oedema and inflammatory infiltration can be reduced by PAF antagonists given at, or after, induction of the pancreatitis [81, 82](table 2).…”

Section: Paf Antagonistsmentioning

confidence: 99%

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Platelet-Activating Factor and Platelet-Activating Factor Antagonists in Acute Pancreatitis

Johnson

1999

Dig Surg

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Introduction: Acute pancreatitis causes platelet-activating factor (PAF) to be released which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF has also been implicated as a key mediator in the progression of severe acute pancreatitis, which can lead to complications and unacceptably high mortality rates. Mode of Action of PAF in Acute Pancreatitis: Synthesis of PAF is sensitive to biologically active mediators seen in many inflammatory processes. PAF significantly potentiates pancreatic tissue damage; it causes serum amylase and lipase levels to rise significantly, causes scattered haemorrhages and may serve as a primary mediator of inflammation. PAF Antagonists: Several classes of compounds show significant PAF antagonisms, and all have shown significant local and systemic effects to reduce inflammatory changes. Only lexipafant, however, has been studied in human acute pancreatitis. Lexipafant specifically binds to the PAF receptor and is more potent than other PAF antagonists. In clinical trials lexipafant reduces organ failure and suppresses some aspects of the inflammatory response. Conclusion: Our understanding of the pathology of systemic complications, and of a central role of PAF in mediating an inappropriate inflammatory response has improved in recent years. Confirmation of clinical findings with lexipafant will indicate an effective new therapy for the treatment of severe acute pancreatitis.

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Amelioration of experimental acute pancreatitis with a potent platelet-activating factor antagonist

Cited by 75 publications

References 20 publications

Towards a Novel Treatment Strategy for Acute Pancreatitis

Towards a Novel Treatment Strategy for Acute Pancreatitis

Update on the Management of Acute Severe Pancreatitis

Platelet-Activating Factor and Platelet-Activating Factor Antagonists in Acute Pancreatitis

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