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1.
Pediatrics ; 151(6)2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37232099

RESUMO

Childhood interstitial lung disease (chILD) is a collective term for a group of rare lung disorders of heterogeneous origin. Surfactant dysfunction disorders are a cause of chILD with onset during the neonatal period and infancy. Clinical signs of tachypnea and hypoxemia are nonspecific and usually caused by common conditions like lower respiratory tract infections. We report on a full-term male newborn who was readmitted to the hospital at 7 days of age with marked tachypnea and poor feeding during the respiratory syncytial virus season. After exclusion of infection and other, more common congenital disorders, chILD was diagnosed using chest computed tomography and genetic analysis. A likely pathogenic heterozygous variant of SFTPC (c.163C>T, L55F) was detected by whole exome sequencing. The patient received supplemental oxygen and noninvasive respiratory support and was treated with intravenous methylprednisolone pulses and hydroxychloroquine. Despite the treatment, his respiratory situation deteriorated continuously, leading to several hospitalizations and continuous escalation of noninvasive ventilatory support. At 6 months of age, the patient was listed for lung transplant and transplanted successfully aged 7 months.


Assuntos
Doenças Pulmonares Intersticiais , Proteína C , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/terapia , Mutação , Proteína C/genética , Proteína C/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Tensoativos , Taquipneia
2.
J Pediatr ; 225: 90-96.e1, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32553868

RESUMO

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.


Assuntos
Produtos Biológicos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Fosfatidilcolinas/uso terapêutico , Fosfolipídeos/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Biomarcadores/metabolismo , Displasia Broncopulmonar/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Oxigênio/uso terapêutico , Resultado do Tratamento
3.
Neonatology ; 115(2): 134-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30453306

RESUMO

BACKGROUND: Limited supply and complicated manufacturing procedure of animal-derived surfactants make the development of synthetic surfactants warranted. The synthesis of surfactant protein (SP)-B and SP-C is complicated and several analogues have been developed. Mini-BLeu is an analogue that corresponds to the first and last helix of SP-B joined by a loop and linked by 2 disulphide bridges. SP-C33Leu is an SP-C analogue that can be cost-efficiently produced, but no such analogue has yet been described for SP-B. OBJECTIVE: To design short SP-B analogues which lack disulphide bridges, are easy to produce and are efficacious in a preterm rabbit fetus model of neonatal RDS. METHODS: Synthetic surfactants were prepared by adding 2 or 8% (w/w) of synthetic variants of Mini-B27, similar to Mini-BLeu but with a short loop, or different peptides covering helix 1 of SP-B to 2% (w/w) of SP-C33Leu in 80 mg/mL of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/egg yolk phosphatidylcholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, 50: 40: 10 (by weight). Premature newborn rabbit fetuses were treated with 200 mg/kg of the surfactant preparations and ventilated with defined pressures for 30 min without positive end-expiratory pressure. Tidal volumes were registered during the experiments and lung gas volumes were measured at the end of the ventilation period. RESULTS: Synthetic surfactant containing the Mini-B27 analogue with 2 disulphides gives similar lung gas volumes as treatment with an animal-derived surfactant preparation, but all other SP-B analogues gave lower lung gas volumes. All synthetic surfactants studied gave no significant differences in compliances except the surfactant containing the Mini-B27 analogue without cysteines that performed somewhat better at 30 min. CONCLUSION: The helix-loop-helix SP-B analogues tested in this study require the presence of 2 disulphide bridges for optimal activity in a rabbit RDS model.


Assuntos
Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Humanos , Recém-Nascido , Peptídeos/química , Peptídeos/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/química , Proteína C Associada a Surfactante Pulmonar/química , Surfactantes Pulmonares/química , Coelhos , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Volume de Ventilação Pulmonar/efeitos dos fármacos
4.
Pediatr Pulmonol ; 52(7): 929-938, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28221717

RESUMO

BACKGROUND: Though natural surfactants (SF) are clinically superior to protein-free synthetic preparations, CHF-5633, a synthetic SF containing SP-B and SP-C analog peptides is a potential alternative to natural SF for treating neonatal respiratory distress syndrome (RDS). Nevertheless, information is lacking regarding the safety of this new treatment for the neonatal brain. We sought to compare the cerebral and pulmonary effects of this new synthetic surfactant (CHF5633) with those of natural porcine surfactant (Cursosurf) in premature lambs with RDS. METHODS: Twenty-one preterm lambs were randomly assigned to receive CHF5633, Curosurf, or no treatment (control). Pulmonary (gas exchange, lung mechanics) and cerebral (carotid artery blood flow, cerebral oxygen metabolism) effects were measured every 30 min for 6 h. Pulmonary and cerebral histological analysis were also performed. RESULTS: After delivery, lambs developed severe RDS (FIO2 :1, pH < 7.15, PaCO2 > 70 mmHg, PaO2 < 40 mmHg, Cdyn < 0.1 mL/cmH2 O/kg). By 30 min after treatment, animals in both SF-treated groups had consistently better gas exchange and lung mechanics than controls. After CHF5633 administration, PaCO2 , carotid artery blood flow, and cerebral oxygen delivery tended to slowly decrease compared to other groups. By 2 h, SF-treated groups had similar values of all parameters studied, these remaining steady for the rest of the experiment. Lambs administered CHF5633 obtained better lung and brain injury scores than controls. CONCLUSION: Intratracheal administration of a bolus of CHF5633 improves pulmonary status in preterm lambs with severe RDS, obtaining better lung and brain injury scores than controls and favorable cerebral hemodynamics, comparable to those with gold standard Curosurf treatment.


Assuntos
Encéfalo/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Fosfatidilcolinas/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Animais , Animais Recém-Nascidos , Produtos Biológicos/uso terapêutico , Gasometria , Encéfalo/patologia , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Hemodinâmica , Pulmão/patologia , Pulmão/fisiologia , Masculino , Fosfolipídeos/uso terapêutico , Troca Gasosa Pulmonar/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Ovinos , Suínos
5.
Pediatr Res ; 81(2): 369-375, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27973472

RESUMO

BACKGROUND: CHF5633 is a new generation synthetic surfactant containing both SP-B and SP-C analogues developed for the treatment of respiratory distress syndrome. Here, the optimal dose and its performance in comparison to the animal-derived surfactant poractant alfa were investigated. METHODS: In vitro surfactant activity was determined by means of the Wilhelmy balance and the capillary surfactometer. The dose-finding study was performed in preterm rabbits with severe surfactant deficiency. CHF5633 doses ranging from 50 to 300 mg/kg were used. Untreated animals and animals treated with 200 mg/kg of poractant alfa were included for comparison. RESULTS: In vitro, minimum surface tension (γmin) was decreased from values above 70 to 0 mN/m by both surfactants, and they formed rapidly a film at the air-liquid interface. In vivo studies showed a clear dose-dependent improvement of lung function for CHF5633. The pulmonary effect of CHF5633 200 mg/kg dose was comparable to the pulmonary response elicited by 200 mg/kg of poractant alfa in preterm rabbits. CONCLUSION: CHF5633 is as efficient as poractant alfa in our in vitro and in vivo settings. A clear dose-dependent improvement of lung function could be observed for CHF5633, with the dose of 200 mg/kg being the most efficient one.


Assuntos
Produtos Biológicos/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Fosfatidilcolinas/uso terapêutico , Fosfolipídeos/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Tensoativos/uso terapêutico , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Recém-Nascido Prematuro , Pulmão/efeitos dos fármacos , Gravidez , Prenhez , Proteína B Associada a Surfactante Pulmonar/sangue , Proteína C Associada a Surfactante Pulmonar/sangue , Surfactantes Pulmonares/uso terapêutico , Coelhos , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Tensão Superficial , Suínos
6.
Biochemistry ; 52(43): 7523-31, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24099305

RESUMO

Amyloid diseases are defined by tissue deposition of insoluble, fibrillar ß-sheet polymers of specific proteins, but it appears that toxic oligomeric species rather than the fibrils are the main cause of tissue degeneration. Many proteins can form amyloid-like fibrils in vitro, but only ~30 proteins have been found to cause mammalian amyloid disease, suggesting that physiological mechanisms that protect against amyloid formation exist. The transmembrane region of lung surfactant protein C precursor (proSP-C) forms amyloid-like fibrils in vitro, and SP-C amyloid has been found in lung tissue from patients with interstitial lung disease (ILD). ProSP-C contains a BRICHOS domain, in which many ILD-associated mutations are localized, and the BRICHOS domain can prevent SP-C from forming amyloid-like fibrils. Recent data suggest that recombinant BRICHOS domains from proSP-C and Bri2 (associated with familial dementia and amyloid formation) interact with peptides with a strong propensity to form ß-sheet structures, including amyloid ß-peptide associated with Alzheimer's disease. Such interactions efficiently delay formation of fibrils and oligomers. The BRICHOS domain is defined at the sequence level and is found in ~10 distantly related proprotein families. These have widely different or unknown functions, but several of the proteins are associated with human disease. Structural modeling of various BRICHOS domains, based on the X-ray structure of the proSP-C BRICHOS domain, identifies a conserved region that is structurally complementary to the ß-sheet- and/or amyloid-prone regions in the BRICHOS domain-containing proproteins. These observations make the BRICHOS domain the first example of a chaperone-like domain with specificity for ß-prone regions.


Assuntos
Amiloide/química , Glicoproteínas de Membrana/química , Modelos Moleculares , Fragmentos de Peptídeos/química , Proteína C Associada a Surfactante Pulmonar/química , Proteínas Adaptadoras de Transdução de Sinal , Amiloide/efeitos dos fármacos , Amiloide/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/metabolismo , Animais , Sequência Conservada , Demência/tratamento farmacológico , Demência/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/uso terapêutico , Nootrópicos/química , Nootrópicos/metabolismo , Nootrópicos/uso terapêutico , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Domínios e Motivos de Interação entre Proteínas , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Proteína C Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/metabolismo , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Homologia de Sequência de Aminoácidos
7.
PLoS One ; 7(7): e39392, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22808033

RESUMO

Although superiority of synthetic surfactant over animal-driven surfactant has been known, there is no synthetic surfactant commercially available at present. Many trials have been made to develop synthetic surfactant comparable in function to animal-driven surfactant. The efficacy of treatment with a new synthetic surfactant (CHF5633) containing dipalmitoylphosphatidylcholine, phosphatidylglycerol, SP-B analog, and SP-C analog was evaluated using immature newborn lamb model and compared with animal lung tissue-based surfactant Survanta. Lambs were treated with a clinical dose of 200 mg/kg CHF5633, 100 mg/kg Survanta, or air after 15 min initial ventilation. All the lambs treated with air died of respiratory distress within 90 min of age. During a 5 h study period, Pco(2) was maintained at 55 mmHg with 24 cmH(2)O peak inspiratory pressure for both groups. The preterm newborn lamb lung functions were dramatically improved by CHF5633 treatment. Slight, but significant superiority of CHF5633 over Survanta was demonstrated in tidal volume at 20 min and dynamic lung compliance at 20 and 300 min. The ultrastructure of CHF5633 was large with uniquely aggregated lipid particles. Increased uptake of CHF5633 by alveolar monocytes for catabolism was demonstrated by microphotograph, which might be associated with the higher treatment dose of CHF5633. The higher catabolism of CHF5633 was also suggested by the similar amount of surfactant lipid in bronchoalveolar lavage fluid (BALF) between CHF5633 and Survanta groups, despite the 2-fold higher treatment dose of CHF5633. Under the present ventilation protocol, lung inflammation was minimal for both groups, evaluated by inflammatory cell numbers in BALF and expression of IL-1ß, IL-6, IL-8, and TNFα mRNA in the lung tissue. In conclusion, the new synthetic surfactant CHF5633 was effective in treating extremely immature newborn lambs with surfactant deficiency during the 5 h study period.


Assuntos
Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/uso terapêutico , Fosfatidilcolinas/síntese química , Fosfatidilcolinas/uso terapêutico , Nascimento Prematuro/tratamento farmacológico , Proteína B Associada a Surfactante Pulmonar/síntese química , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/síntese química , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/síntese química , Surfactantes Pulmonares/uso terapêutico , 1,2-Dipalmitoilfosfatidilcolina/química , Animais , Animais Recém-Nascidos , Líquido da Lavagem Broncoalveolar/química , Citocinas/biossíntese , Citocinas/imunologia , Esquema de Medicação , Humanos , Recém-Nascido , Pulmão/imunologia , Complacência Pulmonar/efeitos dos fármacos , Fosfatidilgliceróis/química , Nascimento Prematuro/imunologia , Proteolipídeos/química , Respiração Artificial , Carneiro Doméstico , Volume de Ventilação Pulmonar/efeitos dos fármacos
8.
Am J Respir Crit Care Med ; 183(8): 1055-61, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21148720

RESUMO

RATIONALE: Patients with acute lung injury have impaired function of the lung surfactant system. Prior clinical trials have shown that treatment with exogenous recombinant surfactant protein C (rSP-C)-based surfactant results in improvement in blood oxygenation and have suggested that treatment of patients with severe direct lung injury may decrease mortality. OBJECTIVES: Determine the clinical benefit of administering an rSP-C-based synthetic surfactant to patients with severe direct lung injury due to pneumonia or aspiration. METHODS: A prospective randomized blinded study was performed at 161 centers in 22 countries. Patients were randomly allocated to receive usual care plus up to eight doses of rSP-C surfactant administered over 96 hours (n = 419) or only usual care (n = 424). MEASUREMENTS AND MAIN RESULTS: Mortality to 28 days after treatment, the requirement for mechanical ventilation, and the number of nonpulmonary organ failure-free days were not different between study groups. In contrast to prior studies, there was no improvement in oxygenation in patients receiving surfactant compared with the usual care group. Investigation of the possible reasons underlying the lack of efficacy suggested a partial inactivation of rSP-C surfactant caused by a step of the resuspension process that was introduced with this study. CONCLUSIONS: In this study, rSP-C-based surfactant was of no clinical benefit to patients with severe direct lung injury. The unexpected lack of improvement in oxygenation, coupled with the results of in vitro tests, suggest that the administered suspension may have had insufficient surface activity to achieve clinical benefit.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Lesão Pulmonar Aguda/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Troca Gasosa Pulmonar/efeitos dos fármacos , Proteína C Associada a Surfactante Pulmonar/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Respiração Artificial , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Crit Care Med ; 38(7): 1584-91, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20400897

RESUMO

OBJECTIVE: Inhalative application of substantial amounts of pulmonary surfactant to the acutely inflamed lung represents a desirable therapeutic approach but was impossible under clinical conditions because of the technical limitations of currently available devices. We developed a new dry powder aerosolizer for administration of a recombinant surfactant protein-C-based surfactant, determined aerosol characteristics, and evaluated its use in animal models of acute lung injury. DESIGN: Laboratory experiment. SETTING: University laboratory. SUBJECTS: Rabbits and mice. INTERVENTIONS: The efficacy of an aerosol application of recombinant surfactant protein-C surfactant was assessed in three animal models of acute lung injury: in rabbits with acute lung injury caused by repetitive lavage with prolonged and injurious ventilation; in rabbits at day 4 after inhalative application of bleomycin; and in bleomycin-challenged, spontaneously breathing mice. MEASUREMENTS AND MAIN RESULTS: Analysis of aerosolizer characteristics revealed favorable properties making inhalative surfactant treatment in acute lung injury/acute respiratory distress syndrome possible. The generated aerosol had a mass median aerodynamic diameter of 1.6 microm, with 85% of all particles being smaller than 5 microm. The average mass of surfactant being aerosolized was approximately 800 mg/min, thus allowing delivery of large amounts of surfactant. Biochemical and biophysical surfactant properties remained unaltered after aerosolization. In both rabbit models aerosolization of approximately 500 mg recombinant surfactant protein-C surfactant resulted in a far-reaching restoration of gas exchange and compliance, with Pao2/Fio2 values approaching control values. In bleomycin-challenged, spontaneously breathing mice, surfactant aerosolization resulted in a restoration of compliance. CONCLUSIONS: The described dry powder aerosolizer may be applicable to surfactant therapy of acute lung injury/acute respiratory distress syndrome. This conclusion is based on four main factors. High doses comparable to those used for intratracheal instillation in humans can be generated within a relatively short time period, the device can be connected to the inspiratory limb of the ventilator circuit, the aerosolized surfactant material is biophysically fully active, and therapeutic efficacy was proven in three different animal models of acute lung injury/acute respiratory distress syndrome.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Lesão Pulmonar Aguda/fisiopatologia , Administração por Inalação , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pós , Proteína C Associada a Surfactante Pulmonar/administração & dosagem , Proteína C Associada a Surfactante Pulmonar/química , Coelhos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Especificidade da Espécie
11.
Neonatology ; 98(1): 91-9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20110733

RESUMO

BACKGROUND: Respiratory distress syndrome (RDS) is currently treated with surfactant preparations obtained from natural sources and attempts to develop equally active synthetic surfactants have been unsuccessful. One difference in composition is that naturally derived surfactants contain the two hydrophobic proteins SP-B and SP-C while synthetic preparations contain analogues of either SP-B or SP-C. It was recently shown that both SP-B and SP-C (or SP-C33, an SP-C analogue) are necessary to establish alveolar stability at end-expiration in a rabbit RDS model, as reflected by high lung gas volumes without application of positive end-expiratory pressure. OBJECTIVES: To study the efficacy of fully synthetic surfactants containing analogues of both SP-B and SP-C compared to surfactants with only one protein analogue. METHODS: Premature newborn rabbits, treated with synthetic surfactants, were ventilated for 30 min without positive end-expiratory pressure. Tidal volumes as well as lung gas volumes at end-expiration were determined. RESULTS: Treatment with 2% Mini-B (a short-cut version of SP-B) and 2% SP-C33, or its C-terminally truncated form SP-C30, in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, 68:31 (w/w) resulted in median lung gas volumes of 8-9 ml/kg body weight, while animals treated with 2% Mini-B surfactant or 2% SP-C33/SP-C30 surfactant had lung gas volumes of 3-4 ml/kg, and those treated with Curosurf, a porcine surfactant, 15-17 ml/kg. In contrast, mixing SP-C33 with peptides with different distributions of positively charged and hydrophobic residues did not improve lung gas volumes. CONCLUSIONS: The data indicate that synthetic surfactants containing analogues of both SP-B and SP-C might be superior to single-peptide surfactants in the treatment of RDS.


Assuntos
Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Tensoativos/uso terapêutico , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Peptídeos/química , Peptídeos/uso terapêutico , Nascimento Prematuro , Proteína B Associada a Surfactante Pulmonar/química , Proteína C Associada a Surfactante Pulmonar/química , Coelhos , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Tensoativos/química , Volume de Ventilação Pulmonar/efeitos dos fármacos
12.
Arzneimittelforschung ; 56(1): 25-32, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16478002

RESUMO

UNLABELLED: Surfactant therapy does not lead to a uniform, optimal and sustained effect on gas exchange in neonatal respiratory distress syndrome (RDS) and acute respiratory distress syndrome (ARDS). The aim of the present study therefore was to compare the effects of a lipid-enriched and protein-modified natural surfactant preparations with a licensed, clinically used bovine surfactant preparation - SF-Ril (Alveofact). METHODS: SF-Ril was enriched with phosphatidylglycerol, sphingomyeline, phosphatidylethanolamine plasmalogen, phosphatidylethanolamine. Furthermore, SF-Ril was modified with increased surfactant protein B (SP-B)/surfactant protein C (SP-C) content and finally a mercaptoethanol (ME) treated preparation for breaking the sulfhydril bondage of SP-B/SP-C by chemical reduction in methylene chloride using ME was developed. Finally ME was removed by vacuum extraction. These modified surfactants were tested at a dosage of 100 mg/ kg each in a model of respiratory failure induced by lung lavage in male adult rats and compared with SF-Ril at an identical dosage. Mechanical ventilation was standardised with fraction of inspiratory oxygen (FiO2) 1.0 and time-cycled pressure limited ventilation 16/0.8 cmH2O before and 26/6 cmH2O (peak inspiratory pressure/positive endexpiratory pressure) after lung lavage (target arterial oxygen pressure [pa02] < 100 mmHg), respiratory rate 36/min, inspiration/expiration time ratio 1:2. RESULTS: During the observation period of 120 min, the sphingomyeline substituted and protein-modified (ME reduced) surfactant preparations exerted improved and sustained oxygenation compared with SF-Ril. Similar effects were observed for tidal volumes. All other preparations were equal or inferior to SF-Ril in our model. CONCLUSION: For the development of surfactant preparations less prone for inactivation the above mentioned data may provide useful information, provided they can be confirmed in further investigations employing other alternative models.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Proteínas/metabolismo , Surfactantes Pulmonares/farmacologia , Surfactantes Pulmonares/uso terapêutico , Animais , Animais Recém-Nascidos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Dióxido de Carbono/sangue , Bovinos , Química Farmacêutica , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Oxigênio/sangue , Proteína B Associada a Surfactante Pulmonar/química , Proteína B Associada a Surfactante Pulmonar/farmacologia , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/química , Proteína C Associada a Surfactante Pulmonar/farmacologia , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/química , Respiração Artificial , Irrigação Terapêutica , Volume de Ventilação Pulmonar
13.
Expert Opin Investig Drugs ; 15(1): 47-58, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16370933

RESUMO

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.


Assuntos
Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , 1,2-Dipalmitoilfosfatidilcolina/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , 1,2-Dipalmitoilfosfatidilcolina/uso terapêutico , Produtos Biológicos/administração & dosagem , Produtos Biológicos/uso terapêutico , Vias de Administração de Medicamentos , Esquema de Medicação , Humanos , Proteína C Associada a Surfactante Pulmonar/administração & dosagem , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Síndrome do Desconforto Respiratório/mortalidade , Taxa de Sobrevida
14.
Crit Care Med ; 33(7): 1549-56, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16003061

RESUMO

BACKGROUND: Patients who survive acute respiratory distress syndrome (ARDS) often report decreased general health-related quality of life (HRQOL) following hospital discharge. The extent to which this impairment is due to pulmonary or nonpulmonary causes is unclear. We describe the pattern of recovery of patients surviving ARDS to illuminate any relationships between lung spirometry values, pulmonary symptoms, and overall HRQOL. METHODS: Seventy-three survivors of ARDS were enrolled in a 12-month follow-up study as part of a phase III randomized, multicenter trial. Patients were contacted at 3, 6, and 12 months after enrollment to complete generic and disease-specific HRQOL questionnaires and have lung spirometry tests performed. RESULTS: For all domains of the Medical Outcomes Study Short Form-36 (SF-36) and the St. George's Respiratory Questionnaire (SGRQ) at all time intervals, survivors of ARDS had significantly lower scores than age- and sex-matched population values. Over the 12-month follow-up period, we observed significant improvements to the overall Physical Component Score, but the Mental Component Score of the SF-36 and the SGRQ scores were not statistically different. Physical performance measures suggested that by 12 months, 57% had not returned to "normal activity." At 12 months, lung spirometry tests demonstrated mild abnormalities that were stable over time (64% and 49% had <80% predicted forced expiratory volume in 1 sec [Fev1] and forced vital capacity [Fvc], respectively). At 12 months, the forced expiratory volume in 1 sec correlated strongly with the physical function domain of the SF-36 (correlation coefficient = 0.601; p < .01) and moderately with all domains of the SGRQ (correlation coefficient = -0.36, -50; p < .01 in all cases). In addition, there were several strong to moderate correlations between the various domains of the SF-36 and SGRQ. CONCLUSIONS: Survivors of ARDS have considerable respiratory symptoms and reduced HRQOL that is still prevalent at 12 mos following onset of injury. There are significant correlations between lung spirometry, pulmonary symptoms, and overall HRQOL, thus suggesting the acute lung injury/ARDS is causally contributing to the observed long-term outcome.


Assuntos
Qualidade de Vida , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Indicadores Básicos de Saúde , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Testes de Função Respiratória , Sobreviventes
15.
Biol Neonate ; 87(4): 338-44, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15985757

RESUMO

Surfactant preparations have been proven to improve clinical outcome of infants at risk for or having respiratory distress syndrome (RDS). In clinical trials, ani mal-derived surfactant preparations reduce the risk of pneumothorax and mortality when compared to non-protein-containing synthetic surfactant preparations. In part, this is thought to be due to the presence of surfactant proteins in animal-derived surfactant preparations. Four native surfactant proteins have been identified. The hydrophobic surfactant proteins B (SP-B) and C (SP-C) are tightly bound to phospholipids. These proteins have important roles in maintaining the surface tension-lowering properties of pulmonary surfactant. Surfactant protein A (SP-A) and D (SP-D) are extremely hydrophilic and are not retained in the preparation of any commercial animal-derived surfactant products. These proteins are thought to have a role in recycling surfactant and improving host defense. There is concern that animal-derived products may have some batch-to-batch variation regarding the levels of native pulmonary surfactant proteins. In addition, there is concern regarding the hypothetical risk of transmission of viral or unconventional infectious agents from an animal source. New surfactant preparations, composed of synthetic phospholipids and essential hydrophobic surfactant protein analogs, have been developed. These surfactant protein analogs have been produced by peptide synthesis and recombinant technology to provide a new class of synthetic surfactants that may be a suitable alternative to animal-derived surfactants. Preliminary clinical studies have shown that treatment with these novel surfactant preparations can ameliorate RDS and improve clinical outcome. Clinicians will need to further understand any differences in clinical effects between available products.


Assuntos
Proteína A Associada a Surfactante Pulmonar/análogos & derivados , Proteína B Associada a Surfactante Pulmonar/análogos & derivados , Proteína C Associada a Surfactante Pulmonar/análogos & derivados , Proteína D Associada a Surfactante Pulmonar/análogos & derivados , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Proteína A Associada a Surfactante Pulmonar/uso terapêutico , Proteína B Associada a Surfactante Pulmonar/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Proteína D Associada a Surfactante Pulmonar/uso terapêutico
18.
N Engl J Med ; 351(9): 884-92, 2004 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-15329426

RESUMO

BACKGROUND: Preclinical studies suggest that exogenous surfactant may be of value in the treatment of the acute respiratory distress syndrome (ARDS), and two phase 2 clinical trials have shown a trend toward benefit. We conducted two phase 3 studies of a protein-containing surfactant in adults with ARDS. METHODS: In two multicenter, randomized, double-blind trials involving 448 patients with ARDS from various causes, we compared standard therapy alone with standard therapy plus up to four intratracheal doses of a recombinant surfactant protein C-based surfactant given within a period of 24 hours. RESULTS: The overall survival rate was 66 percent 28 days after treatment, and the median number of ventilator-free days was 0 (68 percent range, 0 to 26); there was no significant difference between the groups in terms of mortality or the need for mechanical ventilation. Patients receiving surfactant had a significantly greater improvement in blood oxygenation during the initial 24 hours of treatment than patients receiving standard therapy, according to both univariate and multivariate analyses. CONCLUSIONS: The use of exogenous surfactant in a heterogeneous population of patients with ARDS did not improve survival. Patients who received surfactant had a greater improvement in gas exchange during the 24-hour treatment period than patients who received standard therapy alone, suggesting the potential benefit of a longer treatment course.


Assuntos
Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , APACHE , Análise de Variância , Causalidade , Método Duplo-Cego , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteína C Associada a Surfactante Pulmonar/efeitos adversos , Surfactantes Pulmonares/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/terapia , Taxa de Sobrevida , Falha de Tratamento
19.
Curr Opin Crit Care ; 10(1): 18-22, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15166845

RESUMO

PURPOSE OF REVIEW: Currently, three phase III surfactant replacement trials for acute lung injury (ALI)/acute respiratory distress syndromes (ARDS) patients are underway. Although the efficacy of surfactant replacement therapy will first have to be proved in these phase III trials, recent reports indicate some enticing possibilities for the future of surfactant therapy. RECENT FINDINGS: Patients requiring mechanical ventilation show alterations in their endogenous surfactant composition. Depending on the type of lung injury or the elapsed time, modifications to surfactant preparations could enhance the efficacy of these preparations. Surfactants that closely resemble natural surfactant, especially those containing surfactant proteins (SP-B/C) and nonphospholipids (cholesterol), are able to restore normal surfactant physiology. Furthermore, lipids that are able to withstand degradation by lipases could further enhance surfactant therapy. SUMMARY: If surfactant therapy fulfills the promises expected from the ongoing phase III trials, future surfactant preparations may even enhance therapy efficacy and restore the altered endogenous surfactant pool as soon as possible.


Assuntos
Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Animais , Produtos Biológicos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Humanos , Lipídeos/uso terapêutico , Fosfolipídeos/uso terapêutico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Proteínas Associadas a Surfactantes Pulmonares/fisiologia , Surfactantes Pulmonares/administração & dosagem , Síndrome do Desconforto Respiratório/fisiopatologia
20.
Anesth Analg ; 98(5): 1273-9, table of contents, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15105199

RESUMO

UNLABELLED: Our aim in the current study was to determine whether recombinant surfactant protein-C (rSP-C) surfactant improves acute lung injury (ALI) induced by intratracheal acidified milk products. Twenty-eight rabbits were randomly divided into four groups. ALI was induced with intratracheal acidified infant formula (0.8 mL/kg, pH 1.8) in 3 groups. The control group received intratracheal acidified saline. Therapy groups received 1 of 2 doses of intratracheal rSP-C surfactant (0.5 or 2 SP-C mg/kg) 30 min after the acidified infant formula. The lungs were ventilated with 100% oxygen for 4 h after induction of ALI. Acidified infant formula dramatically reduced oxygenation and lung compliance, and increased resistance. Both doses of rSP-C improved the variables [mean PaO(2) (mm Hg) and compliance (mL/cm H(2)O) at 4 h: 61 and 0.4 for infant formula, 162 and 1.0 for small-dose rSP-C, and 152 and 1.2 for large-dose rSP-C, respectively; P < 0.05]. Pulmonary leukosequestration and edema, and severe morphological changes were attenuated by rSP-C treatment (ALI score: 14, 7, 7 in infant formula, small-dose rSP-C, and large-dose rSP-C; P < 0.05). The efficacy was similar for the two doses of rSP-C. These findings suggest that intratracheal administration of rSP-C ameliorates ALI induced by aspiration of acidified milk products. IMPLICATIONS: Small or large doses of recombinant surfactant protein-C surfactant given 30 min after intratracheal acidified infant formula attenuated physiological, biochemical, and morphological lung damage.


Assuntos
Lesão Pulmonar , Pneumonia Aspirativa/tratamento farmacológico , Proteína C Associada a Surfactante Pulmonar/uso terapêutico , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Gasometria , Líquido da Lavagem Broncoalveolar/citologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Alimentos Infantis , Intubação Intratraqueal , Contagem de Leucócitos , Medições Luminescentes , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Consumo de Oxigênio/efeitos dos fármacos , Contagem de Plaquetas , Pneumonia Aspirativa/patologia , Pneumonia Aspirativa/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Proteína C Associada a Surfactante Pulmonar/administração & dosagem , Coelhos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologia
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