The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit.

BACKGROUND: High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation. RESULTS: New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups. CONCLUSIONS: Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.

Surfactant blocks lipopolysaccharide signaling by inhibiting both NFκB and PARP activation in experimental ARDS.

Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome and is responsible for the expression of the inducible isoform of nitric oxide synthase (iNOS). Because cells are exposed to low pH within the microenvironment of inflammatory lesions, the potential role of low environmental pH on iNOS expression was investigated. Low environmental pH-induced iNOS gene transcription involved the activation of nuclear factor-κB (NF-κB) transcription factor and IκB kinases. Here, we find that exposure of cells to low environmental pH increased both nitrite accumulation and activation of NF-κB-signaling pathway by Western blot and immunohistochemistry. In addition, treatment with surfactant prevents NF-κB translocation to the nucleus by preventing phosphorylation of IκBα, and its subsequent degradation by IKKα, and canceling low pH-induced nitrite accumulation. Surfactant also inhibited the LPS-induced PARP activation. Therefore, surfactant may regulate lung homeostasis by neutralizing acidic microenvironment in inflammatory lesions that leads to the upregulation of iNOS activity through the activation of NF-κB pathway and by PARP activation.

The potential of liposomes as dental drug delivery systems.

The potential of liposomes as a drug delivery system for use in the oral cavity has been investigated. Specifically targeting for the teeth, the in vitro adsorption of charged liposomal formulations to hydroxyapatite (HA), a common model substance for the dental enamel, has been conducted. The experiments were performed in human parotid saliva to simulate oral-like conditions. It was observed, however, that precipitation occurred in tubes containing DPPC/DPTAP or DPPC/DPPG-liposomes in parotid saliva with no HA present, indicating that constituents of parotid saliva reacted with the liposomes. The aggregation reactions of liposome-parotid saliva mixtures were examined by turbidimetry and by atomic force microscopy. Negatively charged DPPC/DPPS and DPPC/PI-liposomes were additionally included in these experiments. The initial turbidity of positive DPPC/DPTAP-liposomes in parotid saliva was very high, but decreased markedly after 30 min. AFM images showed large aggregates of micelle-like globules known to be present in saliva. The turbidity of the various negatively charged liposome and parotid saliva mixtures stayed relatively constant throughout the measuring time; however, their initial turbidities were different; mixtures with DPPC/DPPG-liposomes were the most turbid and DPPC/DPPA-liposomes the least. Pyrophosphate (PP) was added to the various liposome-parotid saliva mixtures to examine the effect of Ca(2+) on the interactions. The effect of PP treatment of the negatively charged liposome-parotid saliva mixtures was most pronounced with DPPC/DPPG-liposome mixtures where it caused a sudden drop in turbidity. For positive DPPC/DPTAP liposome and parotid saliva mixtures, the effect of PP was minimal. These experiments showed that saliva constituents may interact with liposomes. An appropriate liposomal drug delivery system intended for use in the oral cavity seems to be dependent on the liposomal formulation. Based on the present results, negatively charged DPPC/DPPA-liposomes seem to be most suitable for use in the oral cavity as they were found to be the least reactive with the components of parotid saliva.

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

BACKGROUND: Respiratory 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. OBJECTIVES: To 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 STRATEGY: Standard 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 CRITERIA: Randomized 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 ANALYSIS: Primary 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 RESULTS: Two 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' CONCLUSIONS: In 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.

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

BACKGROUND: Respiratory 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. OBJECTIVES: To 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 STRATEGY: Standard 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 CRITERIA: Randomized 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 ANALYSIS: Primary 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 RESULTS: Two 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' CONCLUSIONS: In 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. Further well designed studies of adequate size and power will be needed to confirm and refine these findings.

Exogenous surfactant therapy for ARDS.

Regardless of the cause, a common pathophysiological feature of patients with acute respiratory distress syndrome is a dysfunction of the endogenous surfactant system. Although exogenous surfactant therapy has proven to be an effective treatment for neonatal respiratory distress syndrome, no similar current effective therapy exists for patients with acute respiratory distress syndrome. This is mainly due to the complexity of the lung injury that is involved with this disorder. Results from clinical trials, to date, have failed to show an improvement in patient survival after administration of exogenous surfactant; however, ongoing and future research efforts suggest that this therapy may eventually be feasible.

A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants.

BACKGROUND AND OBJECTIVE: Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved through the addition of peptides, such as sinapultide, that mimic the action of human surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non-protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived surfactant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syndrome (RDS) and RDS-related death. METHODS: We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of < or =32 weeks gestational age, to receive colfosceril palmitate (n = 509), lucinactant (n = 527), or beractant (n = 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dysplasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Primary outcomes, air leaks, and causes of death were assigned by an independent, masked, adjudication committee with prespecified definitions. The study was monitored by an independent data safety monitoring board. RESULTS: Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52-0.89). There was no significant difference in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25-0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18-0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less common with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56-0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45-1.00). CONCLUSIONS: Lucinactant is a more effective surfactant preparation than colfosceril palmitate for the prevention of RDS. In addition, lucinactant reduces the incidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS.

Lucinactant: in neonatal respiratory distress syndrome.

Lucinactant, formerly known as KL(4) surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, which is designed to mimic the actions of human surfactant protein B. It has been developed for use in the prevention or treatment of respiratory distress syndrome (RDS), a common problem in premature infants, which results from a deficiency or degradation of pulmonary surfactant. Lucinactant is administered intratracheally soon after birth as a replacement surfactant. In the pivotal randomized, double-blind, prophylaxis trial in premature infants, the incidence of RDS at 24 hours after birth was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate, a synthetic non-protein-containing surfactant. RDS-related mortality at 14 days was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate or beractant, a bovine-derived surfactant. In another randomized, double-blind, prophylaxis trial in premature infants, the rate of survival without bronchopulmonary dysplasia at 28 days of age in lucinactant recipients was not inferior to that in recipients of poractant alfa, a porcine-derived surfactant. Lucinactant was generally well tolerated. Adverse events were transient and related to the administration procedure. There were no differences in the incidences of complications of prematurity between lucinactant and the other surfactants.

Kinetics of surfactant in respiratory diseases of the newborn infant.

Deficiency or dysfunction of pulmonary surfactant plays a critical role in the pathogenesis of respiratory diseases in the newborn. We describe the studies made by applying two recently developed methods to measure surfactant kinetics. The first allows the measurement of endogenous surfactant phosphatidylcholine (PC) synthesis and kinetics by a constant intravenous infusion of glucose or fatty acids labeled with stable isotope 13C. The second method consists of endotracheal administration of a tracer dose of 13C-labeled dipalmitoyl-phosphatidylcholine (DPPC) to measure disaturated-phosphatidylcholine (DSPC) half-life and apparent pool size. We present the results of surfactant kinetics in some of the respiratory diseases of the newborn infant.

Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma.

Allergen-induced inhibition of pulmonary surfactant in asthma may promote airway oedema and consequently potentiate the severity of the asthmatic response. A randomised, single-blind, cross-over study of an inhaled synthetic phospholipid dry-powder surfactant (Pumactant) was conducted in atopic, asthmatic subjects with previously documented early and late asthmatic responses (EAR and LAR) to an inhaled allergen. This was conducted to evaluate the role of exogenous surfactant administration on EAR and LAR. A total of seven subjects had complete evaluable data and received the full dose of Pumactant. Asthmatic subjects inhaled two separate doses of 400 mg Pumactant prior to an allergen exposure. The first dose was administered 8 h in advance and the second dose 30 min in advance. The dosage occurred through a purpose-built administration device. This was followed by a standard bronchial-provocation test, and forced expiratory volume in one second (FEV1) was measured at regular intervals over a 10-h period. Pumactant was well tolerated and, surprisingly, abolished the EAR but not the LAR in all seven subjects. The mean area under the curve between 0-2 h (EAR) following bronchial provocation test was 0.08 for the Pumactant treatment group (PT) and 13.29 for the no treatment (NT) group. The maximum drop in FEV1 for EAR was 4.19% and 23.98% in the PT and the NT group, respectively. The demonstration of inhibition of the early asthmatic response by exogenous surfactant, provides the first evidence that pulmonary surfactant dysfunction may also contribute to the very early asthmatic response to allergen. Exogenous surfactant administration could serve as a useful adjunct in controlling the early allergen-induced symptoms in patients with allergic asthma.

Experiencia en 100 prematuros con enfermedad de membrana hialina tratados con surfactante sintético / Preterm newborns with hyaline membrane disease treated with synthetic surfactant. a 100 cases experience

Introducción. El objetivo de este estudio fue describir y analizar los resultados obtenidos en 100 prematuros con enfermedad de membrana hialina tratados con ventilación mecánica intermitente (VMI) y surfactante sintético.Material y métodos. En un período de 3 años, se estudiaron 100 prematuros menores de 37 semanas de edad gestacional, mayores de 500 g con enfermedad de membrana hialina que requirieron VMI y a los cuales se les administró surfactante sintético en la modalidad de rescate, siguiendo un protocolo establecido y con un máximo de 3 dosis. Se evaluaron a las 6 y 24 horas: presión media de la vía aérea (MAP), gradiente alvéolo-arterial de oxígeno (DA-aO2) e índice de oxigenación (IO2), además de registrar sus principales complicaciones.Resultados. La mayor parte de los prematuros fueron de sexo masculino, con peso promedio de 1 609 g (ñ764) y 86 por ciento con peso adecuado para edad gestacional y con una media de 31.1 (ñ 3.7) semanas. Presentaron asfixia perinatal 80 por ciento de los prematuros, la mayoría fueron obtenidos por cesárea, requiriendo intubación endotraqueal y VMI desde el nacimiento. Del grupo de 100 prematuros 33 por ciento recibió una dosis de surfactante, 29 por ciento 2 dosis y 38 por ciento 3 dosis, mostrando los 3 grupos mejoría en MAP, DA-aO2 e IO2, posterior a las 6 horas y siendo más evidente a las 24 horas de su administración. La persistencia de conducto arterioso y la sepsis resultaron las complicaciones predominantes. El promedio en días en VMI y los de estancia hospitalaria fueron de 13 (ñ 14) y de 42 (ñ 25) respectivamente. La mortalidad global fue de 20 por ciento y la mortalidad para los menores de 1 000 g fue de 48 por ciento. Conclusiones. Con la aplicación del surfactante sintético se encontró mejoría importante de casi todos los parámetros respiratorios estudiados. El surfactante sintético es en la actualidad un arma terapéutica útil en el recién nacido con enfermedad de membrana hialina y en VMI.

Effects of inhaled nitric oxide and surfactant treatment on lung function and pulmonary hemodynamics in bronchoalveolar-lavage-induced respiratory failure.

Our aim was to study whether inhaled nitric oxide (iNO) moderates respiratory failure induced by bronchoalveolar lavage (BAL) without severe pulmonary hypertension. The following successive treatments, interrupted by 20-30-min rest periods, were given to piglets: iNO (20 ppm for 20 min), exogenous surfactant, iNO, Nomega-nitro-L-arginine methyl ester (L-NAME), and iNO. The controls inhaled NO first after L-NAME. Lung mechanics and hemodynamics were measured serially. The pulmonary to systemic arterial pressure ratio decreased during iNO and tended to increase after its discontinuation. In contrast, the iNO-induced decreases in severity of respiratory failure were not reversible during the rest periods. In a second experiment, iNO/placebo and surfactant containing (3)H-labeled dipalmitoyl phosphatidylcholine were given to rabbits. The surfactant aggregates and the surface activity from postmortem BAL, and extravascular lung water, were studied. Inhaled NO improved the surface activity and increased the large surfactant aggregates. There was no detectable decrease in extravascular lung water. The results suggest that a low dose of iNO has a beneficial effect on the gas exchange that is in part unrelated to its effect on the pulmonary vasculature.

Modified natural and synthetically reconstituted surfactant therapies for acute lung injury caused by endotoxin in rats.

BACKGROUND: Impairment of surfactant is involved in development of acute respiratory distress syndrome. To develop artificial surfactant substitute for clinical use, we prepared synthetically reconstituted surfactant (SRS) by adding porcine surfactant-associated protein B and C (SP-B and SP-C) to synthetic phospholipids, and compared its effect with that of modified natural surfactant (MNS) in rats with acute lung injury caused by endotoxin. METHODS: Escherichia coli endotoxin (71+18 mg x kg(-1), mean+/-SD) was injected into the tracheas of 27 anesthetized and mechanically ventilated rats (FI(O2) of 1.0). When the PaO2 had decreased to below 26.7 kPa, the rats were randomly assigned to three groups. The MNS and SRS groups (n=9, each) were given 100 mg x kg(-1) of MNS and SRS through the airway, respectively. The control group (n=9) was given air in the same volume. RESULTS: The PaO2 of the control group remained below 13.3 kPa until the end of the experiment (6 h after the assignment). The PaO2 of the MNS group increased to 45.3+/-9.5 kPa and that of the SRS group to 45.5+/-3.7 kPa 0.5 h after the assignment (P<0.05 vs. control group). The PaO2 of both groups remained above 40 kPa throughout the experiment. CONCLUSION: In this acute lung injury model, the effects of replacement therapy with surfactant consisting of synthetic phospholipids, SP-B and SP-C, were the same as those observed with MNS. These results warrant development of surfactant substitutes based on natural SP-B and SP-C, and synthetic phospholipids.

Abnormal surfactant metabolism and function in preterm ventilated baboons.

We evaluated surfactant metabolism and function and the effects of antenatal glucocorticoids in very preterm baboons. Pregnant baboons were randomized to receive saline (controls) or 6 mg betamethasone (beta) 48 and 24 h before delivery at 125 +/- 2 d gestation (term is 184 d). The newborn baboons were treated with [14C]dipalmitoylphosphatidylcholine-labeled surfactant and ventilated for 6 d. Lung function for six control and six betamethasone-treated animals was similar. Recoveries of 14C-saturated phosphatidylcholine (Sat PC) were similar: 4.8% (control) and 3.6% (beta) in alveolar wash and 15.4% (control) and 17.7% (beta) in total lungs. Alveolar and total lung pool sizes of Sat PC were about 23 and 190 micromol/kg, respectively. The preterm baboons secreted 8.7% (control) and 6.5% (beta) of de novo synthesized Sat PC labeled with 3H-palmitate from Day 5 to Day 6. These preterm baboons had high estimated Sat PC synthetic and net tissue accumulation rates but low secretion of Sat PC. The large aggregate surfactant fractions from the preterm baboons had high minimal surface tensions and were less effective when used to treat surfactant-deficient preterm rabbits than surfactant from newborn or adult baboons. Ventilation of the preterm baboon was associated with surfactant functional and metabolic abnormalities that were not altered by antenatal glucocorticoids.

The lubricating ability of biomembrane models with dipalmitoyl phosphatidylcholine and gamma-globulin.

Two kinds of friction tests were conducted to investigate the lubricating effect of the injection of amphiphilies on the osteoarthritic joint. The effects of the addition of L alpha-dipalmitoyl phosphatidyl-choline (L alpha-DPPC) riposomes and gamma-globulin in a saline solution of sodium hyaluronate (HA) were evaluated through pendulum friction tests. The frictional characteristics of pig shoulder joints were confirmed to depend on the viscosity of the lubricants only in the physiologically low load condition and in the condition immediately after loading. Detergent (polyoxyethylene p-t-octylphenyl ether) was successfully used to remove adsorbed films from the articular surfaces. The friction coefficient of natural synovial joints was significantly increased in a mode of mixed lubrication with the HA solution of 0.2 g/dl by the treatment of the surface with the detergent. The addition of L alpha-DPPC riposomes or gamma-globulin significantly improved the boundary lubricating ability of the articular surfaces treated with the detergent, depending on the quantity of those additives. It appears that the L alpha-DPPC riposomes and gamma-globulin can form protective films on the articular surfaces like a biomembrane. Moreover, the reciprocating frictional behaviour in sliding pairs of pig articular cartilages and glass plates was studied in order to elucidate the tribological role of those constituents in the boundary lubricating film on the articular surface. Pig synovial fluid and water solutions of HA were used as lubricants. The synovial fluid had superior lubricating ability compared to the HA solution of equivalent viscosity under a physiologically high load condition. This fact seems to be responsible for the boundary lubricating ability of constituents other than hyaluronic acid. Langmuir-Blodgett (LB) films of L alpha-DPPC on the glass plate were kept at a low and stable friction coefficient, depending on the number of film layers. In conditions of mixed films with L alpha-DPPC and gamma-globulin, the frictional behaviour was improved by increasing the quantity of gamma-globulin. A model is proposed in which the effective adsorbed films are composed of proteins, phospholipids and other conjugated constituents on the articular surfaces to be accurate in describing the boundary lubricating mechanism. The mechanism is controlled by hydrophobic groups in those amphiphilies.

Artificial reconstituted pulmonary surfactant in prevention and treatment of respiratory distress syndrome in neonates.

AIM: To test an artificial reconstituted pulmonary surfactant (APS) for prevention and treatment of respiratory distress syndrome (RDS). METHODS: A membrane-formed method combined with supersonic dispersing was used to prepare APS. A pulsating bubble surface tension measurement was established to compare surface properties of APS with natural pulmonary surfactant (NPS). A preliminary clinical trial was made for prevention and treatment of RDS. RESULTS: The APS reduced surface tension from 44.0 mN/m to < 1.0 mN/m in vitro. The changes of APS lipid contents were < 5% of labeled content at 37 degrees C. Clinical trial showed that the APS prevented RDS in 20/20 and cured RDS in 2/2 premature neonates. CONCLUSION: The APS had good surface properties similar to NPS.

Exogenous surfactant use in neonates.

OBJECTIVE: To review exogenous surfactant use in the treatment of respiratory distress syndrome (RDS) in premature neonates. DATA SOURCES: A MEDLINE search and extensive review of journals was conducted to identify the information for this review from 1983 to 1995 using the following key words: prematurity, surfactant, clinical trials, beractant, Survanta, colfosceril, Exosurf, and neonatal respiratory distress syndrome. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Emphasis was placed on controlled studies involving beractant and colfosceril palmitate. DATA SYNTHESIS: Results of published clinical trials using beractant or colfosceril palmitate in premature infants at risk for RDS have shown improvement in the need for supplemental oxygen and ventilatory support over the course of RDS and a reduction in pneumothorax. However, there was little impact on the incidence of intraventricular hemorrhage. Clinical trials studying the treatment of established RDS have also shown similar improvements. In a comparison of prophylactic versus late treatment, no distinct advantage of preventive treatment was found, except among infants less than 26-28 weeks gestation. Single versus multiple-dose studies have shown no specific advantage of more than two doses of colfosceril palmitate. A comparison trial of beractant and colfosceril palmitate has shown no difference in outcome. Long-term follow-up studies have been encouraging among infants being treated with exogenous surfactant. CONCLUSIONS: The use of beractant and colfosceril palmitate in premature infants has clearly decreased morbidity and mortality associated with RDS. Only one trial has compared the efficacy of beractant with that of colfosceril in the treatment of RDS. There does not appear to be a distinct advantage of one product over another. Early treatment of infants at highest risk for RDS, those less than 26-28 weeks gestation, seems to be beneficial over waiting for RDS to progress in severity. Further research needs to be performed to determine the optimal dosing and timing of these agents, as well as comparative trials studying efficacy. Criteria for use of these products need to be further defined to decrease the incidence of unnecessary treatment.

Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys.

Studies were conducted to assess the efficacy and safety of a synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome (RDS) in preterm (approximately 80% of normal gestation) infant rhesus monkeys. Surfactant was prepared consisting of the phospholipids dipalmitoylphosphatidyl choline and palmitoyl-oleoyl phosphatidyl glycerol and a synthetic peptide modeled after surfactant protein B (SP-B), "KL4-Surfactant" contained a peptide having the sequence KLLLLKLLLLKLLLLKLLLLK, where "K" is lysine and "L" is leucine. The peptide was selected because it mimics the repeating stretches of hydrophobic residues with intermittent basic hydrophilic residues seen in SP-B. KL4-Surfactant was shown to have biophysical activity assessed as the ability to lower surface tension at an air-liquid interface in a pulsating bubble surfactometer. Thirty premature rhesus monkeys were treated shortly after birth with one dose of KL4-Surfactant. The arterial to alveolar oxygen partial pressure ratio (a/A) was found to rise from a pretreatment level of 0.11 +/- 0.01 (mean +/- SEM), indicative of severe RDS, to 0.40 +/- 0.02 at 12-13 h post-treatment. The improvement in oxygenation persisted throughout the study period, with a mean a/A at 22-23 h of 0.45 +/- 0.07. Chest radiographs and gross and microscopic examination of the lungs all confirmed the reversal of the atelectasis seen before treatment. Animals treated with a dose of 200 mg/kg showed a faster, more consistent, and greater response than did a group treated with an average dose of 127 mg/kg. There was no evidence of toxicity after treatment with the higher dose as demonstrated by physiologic, hematologic, biochemical, and pathologic data. The importance of the peptide in the synthetic surfactant was apparent from the results obtained with a control group of nine premature monkeys treated with a non-peptide-containing surfactant; the a/A of this group was 0.15 +/- 0.03 at nine hours of age as compared with a value of 0.38 +/- 0.02 for 30 comparable animals receiving KL4-Surfactant.