Safety of Purified Poloxamer 188 in Sickle Cell Disease: Phase I Study of a Non‐ionic Surfactant in the Management of Acute Chest Syndrome

Ballas, Samir K.; Files, Beatrice; Luchtman‐Jones, Lori; Benjamin, Lennette J.; Swerdlow, Paul; Hilliard, Lee; Coates, Thomas D.; Abboud, Miguel R.; Wojtowicz‐Praga, Slawomir; Grindel, J M

doi:10.1081/hem-120035919

Cited by 51 publications

(40 citation statements)

References 28 publications

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“…Intravenous administration of P188 in dogs caused a transient increase in pulmonary resistance and no long-lasting effect on pulmonary mechanics and diffusing capacity for carbon monoxide (44). P188 infusion reduced the duration of acute chest syndrome and vasoocclusive crisis in patients with sickle cell disease (45,46). It improved microvascular blood flow by reducing blood viscosity and adhesive frictional forces and was found to reverse diminished venular diameter and red cell velocity in these patients (47).…”

Section: Discussionmentioning

confidence: 99%

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Plataki¹,

Lee²,

Rasmussen³

et al. 2011

A25. Translating Acute Respiratory Distress Syndrome and Ventilator Induced Lung Injury: Mechanisms to Outcomes

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Rationale: Wounded alveolus resident cells are identified in human and experimental acute respiratory distress syndrome models. Poloxamer 188 (P188) is an amphiphilic macromolecule shown to have plasma membrane-sealing properties in various cell types. Objectives: To investigate whether P188 (1) protects alveolus resident cells from necrosis and (2) is associated with reduced ventilatorinduced lung injury in live rats, isolated perfused rat lungs, and scratch and stretch-wounded alveolar epithelial cells. Methods: Seventy-four live rats and 18 isolated perfused rat lungs were ventilated with injurious or protective strategies while infused with P188 or control solution. Alveolar epithelial cell monolayers were subjected to scratch or stretch wounding in the presence or absence of P188. Measurements and Main Results: P188 was associated with fewer mortally wounded alveolar cells in live rats and isolated perfused lungs. In vitro, P188 reduced the number of injured and necrotic cells, suggesting that P188 promotes cell repair and renders plasma membranes more resilient to deforming stress. The enhanced cell survival was accompanied by improvement in conventional measures of lung injury (peak airway pressure, wet-to-dry weight ratio) only in the ex vivo-perfused lung preparation and not in the live animal model. Conclusions: P188 facilitates plasma membrane repair in alveolus resident cells, but has no salutary effects on lung mechanics or vascular barrier properties in live animals. This discordance may have pathophysiological significance for the interdependence of different injury mechanisms and therapeutic implications regarding the benefits of prolonging the life of stress-activated cells.

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Section: Discussionmentioning

confidence: 99%

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Plataki¹,

Lee²,

Rasmussen³

et al. 2011

A25. Translating Acute Respiratory Distress Syndrome and Ventilator Induced Lung Injury: Mechanisms to Outcomes

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“…The diagnosis of ACS was confirmed according to established criteria as described previously (23). Serum samples were collected from 41 of 43 patients who were enrolled in the study.…”

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confidence: 99%

Secretory Phospholipase A₂Levels in Patients with Sickle Cell Disease and Acute Chest Syndrome

et al. 2006

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In a multicenter study (eight centers), we determined secretory phospholipase A(2) (sPLA(2)) levels in patients with sickle cell disease and acute chest syndrome (ACS). The diagnosis of ACS was made according to established criteria. The sPLA2 levels were determined in blood samples collected at baseline (time of diagnosis) and serially thereafter up to day 22-35 follow-up visits. Thirty-four of 43 (80%) patients with ACS had enzyme levels > or =1.00 AU at baseline. The enzyme levels decreased significantly on Days 2 through Days 25-35 after baseline. Nine of 43 (20%) patients had baseline sPLA2 values of <1.00 AU with six of them never exceeding 1.00 AU at any point in time during follow-up. The data indicate that the reliability of sPLA(2( for predicting the development of ACS is not perfect (100%) as was previously reported but occurs in about 80% of the patients.

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“…It seems likely that the membrane-sealing cytoprotective effect contributes to reducing inflammation. In addition, P188 has been reported to inhibit phospholipase A 2 (PLA2) in vitro and in vivo (33,34). Because PLA2 is emerging as a key mediator of I/R injury, inhibition of PLA2 probably contributes to protective effects of P188 in these studies (35).…”

Section: Discussionmentioning

confidence: 98%

Poloxamer 188 Prolongs Survival of Hypotensive Resuscitation and Decreases Vital Tissue Injury After Full Resuscitation

Zhang¹,

Hunter²,

Gonzalez³

et al. 2009

Shock

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Hypotensive resuscitation prolongs survival of patients with severe bleeding until they can undergo hemorrhage control. However, its value is limited by continuing ischemic injury. Purified poloxamer 188 (P188), a copolymer with rheological and cytoprotective activities, was known to reduce mortality of hemorrhagic shock when used as an adjunct to full resuscitation with fresh whole blood and crystalloid. Studies were undertaken to determine if it could prolong survival and reduce reperfusion injury during prolonged hypotensive resuscitation when added to the best regimen currently available. Unanesthetized rats were bled to a MAP of 30 mmHg for 30 min under computer control. They then received hypotensive resuscitation with Hextend or Hextend + P188 to maintain a MAP of 60 mmHg until death. Poloxamer 188 improved autoresuscitation, reduced fluid requirements, and increased the survivable duration of hypotensive resuscitation by more than 3 h (P < 0.01). Additional studies assessed tissue damage after shock and hypotensive resuscitation with Hextend followed by full resuscitation with crystalloid. In these studies, P188 blunted the no-reflow phenomenon and largely prevented myocardial injury, pulmonary inflammation, small bowel damage, renal tubular necrosis, hepatic central lobular necrosis, and apoptosis of splenic germinal centers that occurred during full resuscitation. Additional studies demonstrated that P188 increased survival from 0% to 75% in 50% volume-controlled hemorrhage (P < 0.001). Finally, P188 did not increase bleeding in uncontrolled hemorrhage produced by 75% tail amputation. Because P188 prolongs survival, decreases fluid requirements, and reduces tissue damage, it deserves further consideration as an adjunct to hypotensive resuscitation.

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Safety of Purified Poloxamer 188 in Sickle Cell Disease: Phase I Study of a Non‐ionic Surfactant in the Management of Acute Chest Syndrome

Cited by 51 publications

References 28 publications

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Secretory Phospholipase A₂Levels in Patients with Sickle Cell Disease and Acute Chest Syndrome

Poloxamer 188 Prolongs Survival of Hypotensive Resuscitation and Decreases Vital Tissue Injury After Full Resuscitation

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Safety of Purified Poloxamer 188 in Sickle Cell Disease: Phase I Study of a Non‐ionic Surfactant in the Management of Acute Chest Syndrome

Cited by 51 publications

References 28 publications

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Poloxamer 188 Facilitates The Repair Of Alveolus Resident Cells In Ventilator Injured Lungs

Secretory Phospholipase A2Levels in Patients with Sickle Cell Disease and Acute Chest Syndrome

Poloxamer 188 Prolongs Survival of Hypotensive Resuscitation and Decreases Vital Tissue Injury After Full Resuscitation

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Product

Resources

About

Secretory Phospholipase A₂Levels in Patients with Sickle Cell Disease and Acute Chest Syndrome