Animal-derived Surfactant Preparations Research Articles

Synthetic surfactant with a combined SP-B and SP-C analogue is efficient in rabbit models of adult and neonatal respiratory distress syndrome

Respiratory distress syndrome (RDS) in premature infants is caused by insufficient amounts of endogenous lung surfactant and is efficiently treated with replacement therapy using animal-derived surfactant preparations. On the other hand, adult/acute RDS (ARDS) occurs secondary to for example, sepsis, aspiration of gastric contents, and multitrauma and is caused by alveolar endothelial damage, leakage of plasma components into the airspaces and inhibition of surfactant activity. Instillation of surfactant preparations in ARDS has so far resulted in very limited treatment effects, partly due to inactivation of the delivered surfactants in the airspace. Here, we develop a combined surfactant protein B (SP-B) and SP-C peptide analogue (Combo) that can be efficiently expressed and purified from Escherichia coli without any solubility or purification tag. NMR spectroscopy shows that Combo peptide forms α-helices both in organic solvents and in lipid micelles, which coincide with the helical regions described for the isolated SP-B and SP-C parts. Artificial Combo surfactant composed of synthetic dipalmitoylphosphatidylcholine:palmitoyloleoylphosphatidylglycerol, 1:1, mixed with 3 weights % relative to total phospholipids of Combo peptide efficiently improves tidal volumes and lung gas volumes at end-expiration in a premature rabbit fetus model of RDS. Combo surfactant also improves oxygenation and respiratory parameters and lowers cytokine release in an acid instillation-induced ARDS adult rabbit model. Combo surfactant is markedly more resistant to inhibition by albumin and fibrinogen than a natural-derived surfactant in clinical use for the treatment of RDS. These features of Combo surfactant make it attractive for the development of novel therapies against human ARDS.

Surfactant replacement therapy: from biological basis to current clinical practice.

This review summarizes the current knowledge on the physiological action of endogenous and exogenous pulmonary surfactant, the role of different types of animal-derived and synthetic surfactants for RDS therapy, different modes of administration, potential risks and strategies of ventilation, and highlights the most promising aims for future development. Scientists have clarified the physicochemical properties and functions of the different components of surfactant, and part of this successful research is derived from the characterization of genetic diseases affecting surfactant composition or function. Knowledge from functional tests of surfactant action, its immunochemistry, kinetics and homeostasis are important also for improving therapy with animal-derived surfactant preparations and for the development of modified surfactants. In the past decade newly designed artificial surfactants and additives have gained much attention and have proven different advantages, but their particular role still has to be defined. For clinical practice, alternative administration techniques as well as postsurfactant ventilation modes, taking into account alterations in lung mechanics after surfactant placement, may be important in optimizing the potential of this most important drug in neonatology.

Efficient delipidation of a recombinant lung surfactant lipopeptide analogue by liquid-gel chromatography.

Pulmonary surfactant preparations extracted from natural sources have been used to treat millions of newborn babies with respiratory distress syndrome (RDS) and can possibly also be used to treat other lung diseases. Due to costly production and limited supply of animal-derived surfactants, synthetic alternatives are attractive. The water insolubility and aggregation-prone nature of the proteins present in animal-derived surfactant preparations have complicated development of artificial surfactant. A non-aggregating analog of lung surfactant protein C, SP-C33Leu is used in synthetic surfactant and we recently described an efficient method to produce rSP-C33Leu in bacteria. Here rSP-C33Leu obtained by salt precipitation of bacterial extracts was purified by two-step liquid gel chromatography and analyzed using mass spectrometry and RP-HPLC, showing that it is void of modifications and adducts. Premature New Zealand White rabbit fetuses instilled with 200mg/kg of 2% of rSP-C33Leu in phospholipids and ventilated with a positive end expiratory pressure showed increased tidal volumes and lung gas volumes compared to animals treated with phospholipids only. This shows that rSP-C33Leu can be purified from bacterial lipids and that rSP-C33Leu surfactant is active against experimental RDS.

Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome.

A wide variety of surfactant preparations have been developed and tested including synthetic surfactants and surfactants derived from animal sources. Although clinical trials have demonstrated that both synthetic surfactant and animal derived surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of animal derived surfactant products, perhaps due to the protein content of animal derived surfactant. To compare the effect of animal derived surfactant to protein free synthetic surfactant preparations in preterm infants at risk for or having respiratory distress syndrome (RDS). Searches were updated of the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014), PubMed, CINAHL and EMBASE (1975 through November 2014). All languages were included. Randomized controlled trials comparing administration of protein free synthetic surfactants to administration of animal derived surfactant extracts in preterm infants at risk for or having respiratory distress syndrome were considered for this review. Data collection and analysis were conducted according to the standards of the Cochrane Neonatal Review Group. Fifteen trials met the inclusion criteria. The meta-analysis showed that the use of animal derived surfactant rather than protein free synthetic surfactant resulted in a significant reduction in the risk of pneumothorax [typical relative risk (RR) 0.65, 95% CI 0.55 to 0.77; typical risk difference (RD) -0.04, 95% CI -0.06 to -0.02; number needed to treat to benefit (NNTB) 25; 11 studies, 5356 infants] and a marginal reduction in the risk of mortality (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD -0.02, 95% CI -0.04 to -0.00; NNTB 50; 13 studies, 5413 infants).Animal derived surfactant was associated with an increase in the risk of necrotizing enterocolitis [typical RR 1.38, 95% CI 1.08 to 1.76; typical RD 0.02, 95% CI 0.01 to 0.04; number needed to treat to harm (NNTH) 50; 8 studies, 3462 infants] and a marginal increase in the risk of any intraventricular hemorrhage (typical RR 1.07, 95% CI 0.99 to 1.15; typical RD 0.02, 95% CI 0.00 to 0.05; 10 studies, 5045 infants) but no increase in Grade 3 to 4 intraventricular hemorrhage (typical RR 1.08, 95% CI 0.91 to 1.27; typical RD 0.01, 95% CI -0.01 to 0.03; 9 studies, 4241 infants).The meta-analyses supported a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of animal derived surfactant preparations (typical RR 0.95, 95% CI 0.91 to 1.00; typical RD -0.03, 95% CI -0.06 to 0.00; 6 studies, 3811 infants). No other relevant differences in outcomes were noted. Both animal derived surfactant extracts and protein free synthetic surfactant extracts are effective in the treatment and prevention of respiratory distress syndrome. Comparative trials demonstrate greater early improvement in the requirement for ventilator support, fewer pneumothoraces, and fewer deaths associated with animal derived surfactant extract treatment. Animal derived surfactant may be associated with an increase in necrotizing enterocolitis and intraventricular hemorrhage, though the more serious hemorrhages (Grade 3 and 4) are not increased. Despite these concerns, animal derived surfactant extracts would seem to be the more desirable choice when compared to currently available protein free synthetic surfactants.

Synthetic surfactant: primary data

Treatment of premature newborn rabbits with synthetic surfactants containing both an SP-B and an SP-C analogue in a simple phospholipid mixture has similar tidal volumes as those treated with animal-derived surfactant preparations and will also to some extent prevent the alveoli to collapse at end expiration, even if no positive end-expiratory pressure is applied. The stabilising effect seems to depend on the structure of the peptides as well as the phospholipid composition. Thus, optimal synthetic surfactants containing two peptides combined with a complex phospholipid composition seem to be ideal to replace natural surfactants within a near future.

Is there a Difference in Surfactant Treatment of Respiratory Distress Syndrome in Premature Neonates? A Review

Exogenous surfactant treatment of premature infants with Respiratory Distress Syndrome (RDS) has been the standard of care for more than two decades. There are now many studies comparing various surfactant preparations. Data are clear that the synthetic surfactants without surfactant proteins are inferior to animal derived surfactant preparations. In the United States, commercially available surfactants are beractant, calfactant, poractant alfa, and lucinactant. Relative efficacy of the various available animal derived surfactants in the United States appear to favor poractant alfa, the surfactant preparation with the highest concentrations of phospholipids and high concentration of surfactant proteins, allowing a higher initial dose of phospholipids in preterm infants less than 32 weeks. A new synthetic surfactant with a surfactant protein analog, lucinactant, has been recently been approved for use in the United States. Synthetic surfactants hold the possibility of surfactant treatments without potential animal-born infectious agents or animal proteins that could induce an immune response in fragile premature infants with multiple medical problems. New surfactant administration strategies are described, complimenting new respiratory support strategies, designed to minimize invasive mechanical ventilation and decrease the frequency of chronic lung disease. Minimally invasive surfactant administration strategies are being developed to accommodate these new respiratory support strategies. The goal of this manuscript is to review the available surfactant preparations and their administration strategies.

A Pharmacoeconomic Analysis of In-Hospital Costs Resulting from Reintubation in Preterm Infants Treated with Lucinactant, Beractant, or Poractant Alfa

Reintubation and subsequent mechanical ventilation (MV) in preterm infants after surfactant replacement therapy are associated with excess morbidity and mortality and likely increase in-hospital costs. Specific surfactant therapy selection for prevention of respiratory distress syndrome (RDS) in preterm infants receiving conventional MV may impact not only clinical outcomes but also pharmacoeconomic outcomes. We conducted a pharmacoeconomic analysis of the impact of surfactant selection and reintubation and subsequent MV of preterm infants on health care resource utilization. Rates of reintubation and duration of MV after reintubation were determined from 1546 preterm infants enrolled in two surfactant trials comparing lucinactant to beractant and poractant alfa. Hospital costs were obtained from a 2010 US database from 1564 preterm infants with RDS, with a direct cost of $2637 per day for MV in the neonatal intensive care unit. Cost of reintubation by study and treatment was estimated as the incidence of reintubation multiplied by days on MV therapy after reintubation multiplied by cost per day for direct MV costs, standardized per 100 surfactant-treated infants. There were no differences between studies or treatment groups in the overall extubation rate. Average MV duration following reintubation was similar between groups in both trials; however, reintubation rates were significantly lower (p<0 05) for infants treated with lucinactant than for those receiving beractant or poractant alfa. The observed differences in reintubation rates resulted in a projected cost saving of $160,013 to $252,203 per 100 infants treated with lucinactant versus animal-derived surfactants. In this analysis, higher reintubation rates following successful extubation in preterm infants receiving animal-derived surfactant preparations significantly increased estimated in-hospital costs, primarily due to excess costs associated with MV. This analysis suggests that surfactant selection may have a significant pharmacoeconomic impact on cost of patient care. Additional cost assessment of potential reduction in reintubation-associated morbidity is warranted.

Response to Cummings

We would like to thank Dr Cummings for giving us the opportunity to explain our study results. Results from nine randomized, controlled, trials (RCTs),1, 2, 3, 4, 5, 6, 7, 8, 9 including the one that has been just published (e-pub ahead of print) by Dizdar et al.9 and meta-analyses10, 11, 12 comparing animal-derived surfactants, namely, poractant alfa (PA), beractant (BE), bovactant (BO) and/or calfactant (CA), have consistently shown faster weaning of oxygen and mean airway pressure, less need for redosing, fewer days on oxygen and mechanical ventilation, shorter length of stay (LOS) as well as survival advantage in babies treated with PA. These advantages with PA over BE, CA or BO are likely related to major biological and/or biochemical differences between these animal-derived surfactant preparations. PA contains the highest amount of phospholipids when compared with BE or CA. Higher amount of phospholipids has been shown to downregulate oxidative functions in monocytes and confer better anti-inflammatory properties.13 In addition, bacterial growth in different surfactant preparations is influenced by microbial species and the composition and dose of the surfactant. PA was bactericidal in a dose-dependent fashion and differed from BE and BO, a surfactant preparation similar to CA.14 PA contains the highest amount of plasmalogens (PL) when compared with BE.15 BO contains the lowest amount of PL.15 PL are anti-oxidant phospholipids and presence of higher amounts of PL in the tracheal aspirates from pre-term infants has been shown to be associated with a lower risk for bronchopulmonary dysplasia (BPD).16 Also, the amount of surfactant-associated protein B (SP-B) is highest in PA when compared with BE or CA. SP-B is the most important SP in helping the phospholipids to rapidly adsorb at the air–liquid interphase and in decreasing surface tension. Furthermore, the phospholipid molecular species of PA is much closer to that of human surfactant.17, 18

Poractant alfa and beractant treatment of very premature infants with respiratory distress syndrome

Comparison of the differences between availability of animal-derived surfactant preparations used to treat premature infants is incomplete. The objective of this study was to assess the short-term treatment efficacy of the two most commonly used surfactant preparations in the United States, beractant (100 mg kg(-1) initial and subsequent doses) and poractant alfa (200 mg kg(-1) initial and 100 mg kg(-1) subsequent doses), in very premature, mechanically ventilated infants <30 weeks gestation with respiratory distress syndrome (RDS). Inborn infants at two institutions, open label, 1:1, randomized controlled trial. Level of respiratory support for first 72 h of life. Morbidities of prematurity observed during the neonatal intensive care unit hospitalization. We studied 52 infants 24 0/7 to 29 6/7 weeks gestation; 25 received poractant alfa (27.1±1.6 weeks, birth weight of 930±231 g) and 27 received beractant (26.7±1.7 weeks, P=0.343 and birth weight 900±271 g, P=0.668). Respiratory support for the first 72 h of life was lower in the poractant alfa than beractant group for mean airway pressure (MAP, P=0.003) and respiratory index (MAP × FiO(2), P=0.032). Infants in the poractant alfa group had a greater number of infants extubated at 48 (13/25 vs 6/27, P=0.027) and 72 h (15/25 vs 8/27, P=0.029) than the beractant group. Although the study was not powered to detect morbidities of prematurity, the prevalence of PDA and air leaks was less in the infants treated with poractant alfa than in those treated with beractant. Rates of bronchopulmonary dysplasia (8/23 vs 11/22, P=0.303) or death (2/25 [corrected] vs 5/27, P=0.272) were similar in the infants treated with poractant alfa and beractant, respectively. This study suggests significant short-term benefits to the use of the larger initial dose of poractant alfa than beractant in very premature infants with RDS. Further studies involving a larger number of preterm infants are needed to assess long-term effects.

PICO Summary: Do protein containing synthetic surfactant preparations improve pulmonary outcomes more than animal derived surfactant preparations in preterm infants with the need for mechanical ventilation for RDS?

PICO Summary: Do protein containing synthetic surfactant preparations improve pulmonary outcomes more than animal derived surfactant preparations in preterm infants with the need for mechanical ventilation for RDS?

Cochrane review: Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome

AbstractBackgroundRespiratory distress syndrome (RDS) is a significant cause of morbidity and mortality in preterm infants. RDS is caused by a deficiency, dysfunction, or inactivation of pulmonary surfactant. Numerous surfactants of either animal extract or synthetic design have been shown to improve outcomes. New surfactant preparations that include peptides or whole proteins that mimic endogenous surfactant protein have recently been developed and tested.ObjectivesTo assess the effect of administration of synthetic surfactant containing surfactant protein mimics compared to animal derived surfactant extract on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS.Search strategyStandard search methods of the Cochrane Neonatal Review Group were used. The search included MEDLINE (1966 ‐ May 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) in all languages. In addition, published abstracts of the Society of Pediatric Research were searched electronically. For abstract books that did not include key words, the search was limited to the relevant sections on pulmonary and neonatology. The bibliography cited in each publication was obtained and searched in order to identify additional relevant articles.Selection criteriaRandomized and quasi‐randomized controlled clinical trials were considered for this review. Studies that enrolled preterm infants or low birth weight infants at risk for or having RDS who were treated with either a synthetic surfactant containing surfactant protein mimics or an animal‐derived surfactant preparation were included for this review. Studies that either attempted to treat or prevent respiratory distress syndrome were included.Data collection and analysisPrimary outcome measures, including mortality, chronic lung disease and multiple secondary outcome measures were abstracted by the reviewers. Statistical analysis was performed using Review Manager software. Categorical data was analyzed using relative risk, risk difference, and number needed to treat. 95% confidence intervals reported. A fixed effects model was used for the meta‐analysis. Heterogeneity was assessed using the I‐squared statistic.Main resultsTwo studies were identified that compared protein containing synthetic surfactants to animal derived surfactant preparations. In a meta‐analysis of these two studies, infants who received protein containing synthetic surfactant compared to animal derived surfactant extract did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks [typical RR 0.81 (95% CI 0.64, 1.03)], chronic lung disease at 36 weeks [typical RR 0.99 (95% CI 0.84, 1.18)], or the combined outcome of mortality or chronic lung disease at 36 weeks [typical RR 0.96 (95% CI 0.82, 1.12)]. There were also no differences in any of the secondary outcomes regarding complications of prematurity between the two surfactant groups with the exception of necrotizing enterocolitis. A decrease in the risk of necrotizing enterocolitis was noted in infants who received protein containing synthetic surfactants compared to animal derived surfactant extract [typical RR 0.60 (95% CI 0.42, 0.86)]. However, this was a secondary outcome in both of the primary studies and there was moderate heterogeneity between the studies.Authors' conclusionsIn two trials of protein containing synthetic surfactants compared to animal derived surfactant extract, no statistically different clinical differences in death and chronic lung disease were noted. In general, clinical outcomes between the two groups were similar. Further well designed studies of adequate size and power will help confirm and refine these findings.Plain Language SummaryProtein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndromeRespiratory distress syndrome (RDS) is a significant cause of illness in preterm infants. Respiratory distress syndrome is caused by a deficiency or a dysfunction of the chemicals that line the lung, called pulmonary surfactant. Numerous preparations that contain surfactants of either animal origin or synthetic design have been developed and tested to treat or prevent respiratory distress syndrome. In general, these surfactant preparations have decreased lung rupture (pneumothorax), decreased the risk of dying, and increased the number of survivors without lung damage. From previous research, the surfactants that are obtained from animals seem to have a better effect than the synthetic surfactants. This might be due to the surfactant proteins contained in animal surfactant that are absent in the previously available synthetic surfactants.Recently developed synthetic surfactant preparations include whole surfactant proteins or parts of the proteins (called peptides) that act like surfactant protein. These preparations have been recently tested in comparison to the animal derived surfactant preparations.Two recent trials of protein containing synthetic surfactant compared to animal derived surfactant preparations have demonstrated a trend towards decreasing death and decreasing rates of bowel disease (necrotizing enterocolitis), while other clinical outcomes were similar. Further studies will help refine recommendations concerning use of protein containing synthetic surfactants.

Do beractant dosing intervals make a difference?

Introduction: Surfactant dosing in extremely premature infants is not based on rigorous human pharmacokinetic data. Beractant (Survanta ) is an animal-derived surfactant. The manufacturer's package insert suggests a dosing interval of sooner than 6 after a preceding dose. Other animal-derived surfactant preparations are commonly dosed at 12 hour intervals. We evaluated Survanta use following a change in the re-treatment dosing interval from no less than 6 (Q6 h) to no less than 12 hours (Q12 h) in June 2007. Method: We used a retrospective comparison of two cohorts, Q6 h and Q12 h, born at <31 weeks' gestation or with birth weights < 1100 grams treated with Survanta for respiratory distress syndrome (RDS). Infants could receive up to 4 doses, if clinically indicated. Results: Infants in the Q12 group (n = 77) and the Q6 group (n = 140) had similar birth weight (mean ± SD; 1079 ± 351 vs. 1117 ± 326 g, p = 0.44), birth in a tertiary center (inborn) (84% vs. 84%, p = 1.0), prenatal treatment with steroids (88% vs 81%, p = 0.17), Cesarean section delivery (78% vs. 73%, p = 0.51), and singleton birth (64% vs. 62%, p = 0.93). However, infants in the Q12 group had a slightly lower gestational age (mean ± SD; 27 ± 2v s 28± 2 wk, p = 0.014) and had a higher proportion of male infants (62% vs 48%, p = 0.047.The Q12 group also had a higher but not statistically significant proportion of white infants (82% vs. 69%, p = 0.053) than the Q6 group. Infants in the Q12 group received fewer surfactant doses per patient (mean ± SD; 1.91 ± 0.54 vs. 2.11 ± 0.63, p = 0.018) and less frequently received more than two doses of surfactant (8% vs. 21%, p = 0.012) compared to the Q6 group. The Q12 and the Q6 groups had similar rates of chronic lung disease (CLD) (23% vs. 18%, p = 0.25), death (18% vs. 14%, p = 0.44), duration of mechanical ventilation (mean±SD; 21 ± 21 vs. 18 ± 25 days, p = 0.477), and total hospital length of stay (mean ± SD; 58 ± 39 vs. 59 ± 33 days, p = 0.94). Conclusions: Administering Survanta to premature infants at 12 hour intervals was associated with using less surfactant to treat RDS compared to dosing at 6 hour intervals and similar measured respiratory parameters, including duration of hospitalization and mechanical ventilation and rates of death and CLD. We speculate that using a longer Survanta dosing interval would also result in significant cost savings.

Animal-derived surfactant treatment of respiratory distress syndrome in premature neonates: a review.

Exogenous surfactant treatment of premature infants with respiratory distress syndrome (RDS) has been the standard of care for the past two decades. There are many studies comparing various surfactant preparations. Data are clear that the synthetic surfactants without surfactant proteins are inferior to animal-derived surfactant preparations. Less compelling are the data regarding the relative efficacy of the various animal-derived surfactants available, but a pattern has evolved favoring surfactant preparations with higher concentrations of phospholipids and surfactant proteins. A higher initial dose of phospholipids may also be important, especially for preterm infants less than 32 weeks of gestation. Development has begun of new synthetic surfactants with surfactant protein analogs or recombinant surfactant proteins, which are not yet available in the United States. Synthetic surfactants hold the possibility of surfactant treatments without potential animal-born infectious agents or animal proteins that could induce an immune response in fragile premature infants with multiple medical problems. The goal of this review is to assess the comparison of available animal-derived surfactants and what is known of their comparison. with the newer synthetic surfactants. In addition, the possible direct and indirect effects of surfactant administration on regional blood flow are discussed, with their potential relationship to the volume of surfactant administered.

Animal-derived surfactants for the treatment and prevention of neonatal respiratory distress syndrome: summary of clinical trials

Available literature suggests that the advantage of animal-derived surfactants over first-generation synthetic agents derives from the presence of surface-active proteins and their phospholipid content. Here we summarize the results of clinical trials comparing animal-derived surfactant preparations with other animal-derived surfactants and with both first-and second-generation synthetic surfactants. Published clinical trials of comparisons of animal-derived surfactants were summarized and compared. Comparisons emphasized differences in (1) key surfactant components attributed with efficacy and (2) differences in published outcomes. For the most important outcomes, mortality and chronic lung disease, currently available natural surfactants are essentially similar in efficacy. When examining secondary outcomes (pneumothorax, ventilator weaning, and need for supplemental oxygen), it appears that both calfactant and poractant have an advantage over beractant. The weight of the evidence, especially for study design and secondary outcomes, favors the use of calfactant. However, the superiority of poractant over beractant, when the higher initial dose of poractant is used, strengthens the case for use of poractant as well. Clinical trials suggest that the higher surfactant protein-B content in calfactant, and perhaps the higher phospholipid content in poractant (at higher initial dose), are the factors that most likely confer the observed advantage over other surfactant preparations.

Inflammatory cytokine mRNA in monocytes is modified by a recombinant (SP-C)-based surfactant and porcine surfactant

Respiratory distress syndrome (RDS) is mainly caused by a deficiency of surfactant in structurally immature lungs. Therapy for RDS consists of mechanical ventilation and administration of exogenous surfactant. Animal-derived surfactant preparations that are used to treat newborn infants show inhibition of proinflammatory cytokines. There are no data available concerning the effects of the new generation of surfactants. In the present study, the effects of an animal-derived surfactant (Curosurf) and a synthetic surfactant (Venticute) on lipopolysaccharide (LPS)-induced inflammation were tested in human monocyte THP-1 cells. The effects were measured as changes in messenger RNA (mRNA) expression of the chemokine interleukin-8 (IL-8), proinflammatory TNF-alpha and the anti-inflammatory IL-10 cytokine. Both surfactant preparations inhibited the LPS-induced increase in TNF-alpha expression. A comparison of both preparations revealed a similar effect on IL-10 expression. However, IL-10 expression was higher after incubation with Venticute. Curosurf increased IL-8 expression at higher concentrations, but Venticute had no effect. The anti-inflammatory effect of an animal-derived surfactant and a new-generation synthetic surfactant preparation may influence postnatal pulmonary inflammation.

Biomimicry of Surfactant Protein C

Since the widespread use of exogenous lung surfactant to treat neonatal respiratory distress syndrome, premature infant survival and respiratory morbidity have dramatically improved. Despite the effectiveness of the animal-derived surfactant preparations, there still remain some concerns and difficulties associated with their use. This has prompted investigation into the creation of synthetic surfactant preparations. However, to date, no clinically used synthetic formulation is as effective as the natural material. This is largely because the previous synthetic formulations lacked analogues of the hydrophobic proteins of the lung surfactant system, SP-B and SP-C, which are critical functional constituents. As a result, recent investigation has turned toward the development of a new generation of synthetic, biomimetic surfactants that contain synthetic phospholipids along with a mimic of the hydrophobic protein portion of lung surfactant. In this Account, we detail our efforts in creating accurate mimics of SP-C for use in a synthetic surfactant replacement therapy. Despite SP-C's seemingly simple structure, the predominantly helical protein is extraordinarily challenging to work with given its extreme hydrophobicity and structural instability, which greatly complicates the creation of an effective SP-C analogue. Drawing inspiration from Nature, two promising biomimetic approaches have led to the creation of rationally designed biopolymers that recapitulate many of SP-C's molecular features. The first approach utilizes detailed SP-C structure-activity relationships and amino acid folding propensities to create a peptide-based analogue, SP-C33. In SP-C33, the problematic and metastable polyvaline helix is replaced with a structurally stable polyleucine helix and includes a well-placed positive charge to prevent aggregation. SP-C33 is structurally stable and eliminates the association propensity of the native protein. The second approach follows the same design considerations but makes use of a non-natural, poly-N-substituted glycine or "peptoid" scaffold to circumvent the difficulties associated with SP-C. By incorporating unique biomimetic side chains in a non-natural backbone, the peptoid mimic captures both SP-C's hydrophobic patterning and its helical secondary structure. Despite the differences in structure, both SP-C33 and the SP-C peptoid mimic capture many requisite features of SP-C. In a surfactant environment, these analogues also replicate many of the key surface activities necessary for a functional biomimetic surfactant therapy while overcoming the difficulties associated with the natural protein. With improved stability, greater production potential, and elimination of possible pathogenic contamination, these biomimetic surfactant formulations offer not only the potential to improve the treatment of respiratory distress syndrome but also the opportunity to treat other respiratory-related disorders.

Review: Surfactant respiratory therapy using Surfaxin/sinapultide

Respiratory distress syndrome (RDS) is a leading cause of mortality and morbidity in preterm infants. Surfactant replacement therapy has been widely used to prevent and treat RDS in these newborns and has now become a standard of care. First-generation synthetic surfactants such as Exosurf did not contain any surfactant protein. This disadvantage was overcome with animal-derived surfactant preparations which contain specific proteins but has the limitation of being derived from animal sources. This has led to development of newer synthetic surfactants such as lucinactant (Surfaxin, Discovery Laboratories, Philadelphia) which contains the protein B mimic synthetic peptide, sinapultide. Recent phase 3 clinical trials with Surfaxin show promising results with similar efficacy as animal derived surfactants and yet avoiding the disadvantage associated with animal products. The purpose of this paper is to summarise results of recent clinical trials of Surfaxin use in newborns with RDS.

Une nouvelle génération de surfactants de synthèse

There are numerous pulmonary conditions in which qualitative or quantitative anomalies of the surfactant system have been demonstrated. In premature newborns with immature lungs, a functional deficit in surfactant is the main physiopathologic mechanism of the neonatal respiratory distress syndrome (RDS). Since the landmark pilot study of Fujiwara, published more than 20 years ago, the efficacy of exogenous surfactant for the treatment of neonatal RDS has been established by numerous controlled studies and meta-analyses. Enlightened by a growing insight into both the structure and function of the different surfactant components, a new generation of synthetic surfactants has been developed. Various complementary approaches have confirmed the fundamental role of the two hydrophobic proteins, SP-B and SP-C, in the surfactant system, thus opening the way to the design of analogues, either by chemical synthesis or expression in a prokaryotic system. An example of these peptide-containing synthetic surfactant preparations, lucinactant (Surfaxin), has been recently tested in comparison to a synthetic surfactant that does not contain protein as well as to animal derived surfactant preparations. Major clinical outcomes between lucinactant and animal-derived surfactant preparations were fund similar in two randomized controlled trials, opening the way to a new generation of synthetic surfactants in the near future.

Overview of Surfactant Replacement Trials

Clinical trials have evaluated the overall efficacy of surfactant therapy, as well as the relative efficacy of different surfactant preparations, the optimal timing of administration and the optimal dosage. Surfactant therapy leads to significant clinical improvement in infants at risk for, or having, respiratory distress syndrome (RDS). Clinical trials that compared the effects of synthetic or animal-derived surfactant preparations to placebo or no therapy demonstrate that surfactant therapy lead to rapid improvement in oxygenation, decreased ventilator support, decreased risk of pneumothorax, and mortality. Earlier treatment, prophylactic treatment of infants at high risk of developing RDS, and selective re-treatment leads to improved clinical outcome as well. Currently available animal-derived surfactants are superior to non-protein-containing synthetic surfactants. Ongoing evaluation will determine if important differences in animal-derived products are noted. Future trials will evaluate third-generation surfactant products and further refine what constitutes optimal use of surfactant.