Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476273 (respiratory distress)
 19,632 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A boy, aged 7 months, of consanguineous parents presented with an acute onset of vomiting, fever, nonketotic hypoglycemia and acidosis and died from cardiac arrest after ventricular fibrillation. He had hepatomegaly and echocardiographically a non-obstructive cardiomyopathy. Autopsy was not allowed. After birth the child had suffered from a severe respiratory distress syndrome, transient metabolic acidosis and had a sweaty feet odour. Later on, development was retarded with a severe muscular hypotonia. Post mortem, numerous unusual organic acids were found in high concentrations in urine, e.g. dicarbonic acids, 2-hydroxyisobutyric, isovaleric, 3-hydroxyisovaleric acid, N-acyl glycines, isovalerylglutamic acid and sarcosine. This pattern indicated deficiencies of several acyl-Co A dehydrogenases in the metabolism of leucine, isoleucine, valine, lysine, short-chain fatty acids and sarcosine. This could be confirmed using cultured skin fibroblasts which were shown to degrade the corresponding labeled substrates insufficiently to 14CO2. It is assumed that the functional multiple acyl-Co A dehydrogenation deficiency is caused by a deficiency of a common link in the electron transfer system of these dehydrogenases which is inherited autosomal recessively in this family. Among the 12 patients reported, 7 died within the first 5 days of age.
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PMID:Multiple acyl-Co A dehydrogenation deficiency (MADD) in a boy with nonketotic hypoglycemia, hepatomegaly, muscle hypotonia and cardiomyopathy. Detection of N-isovalerylglutamic acid and its monoamide. 686 97

An idealized model amphipathic alpha-helical decapeptide was synthesized and tested for efficacy as a totally synthetic lung surfactant in simple mixtures with dipalmitoylphosphatidylcholine (DPPC). Quasi-static lung compliance was restored to 92 +/- 3% of the unlavaged value at a pressure of 5 cm H2O in an in vitro lavaged rat lung model. A sustained improvement in gas exchange was also observed when guinea pigs were treated with the synthetic lung surfactant in an in vivo lavaged lung model. DPPC/peptide mixtures rapidly formed low surface tension films in the pulsating bubble surfactometer consistent with a mechanism in which the lipid and peptide mixture spreads rapidly in the lavaged lung to minimize the surface tension at the air/tissue interface. This decapeptide sequence is active in mixtures with DPPC whether the residues are in the all L or all D conformation. However, a peptide with identical sequence, but with alternating D and L amino acid residues, is relatively inactive. Positive charge interactions are not important since a peptide with formylated lysine residues is active. The activity of these decapeptides, with sequences unrelated to any of those in natural lung surfactants, shows that the classic amphipathic alpha-helical hypothesis may be useful in designing peptides that will be effective synthetic lung surfactants in binary mixtures with DPPC. The data demonstrate that a small water-soluble synthetic peptide containing an amphipathic alpha-helical structure combined solely with the major lipid of natural lung surfactant is effective in restoring lung compliance and gas exchange in surfactant-deficient lungs and may be useful in treatment of the respiratory distress syndromes.
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PMID:An amphipathic alpha-helical decapeptide in phosphatidylcholine is an effective synthetic lung surfactant. 843 Sep 72

The present study was undertaken to determine if a synthetic peptide, KLLLLKLLLLKLLLLKLLLLK (KL4), in which K = lysine and L = leucine, in an aqueous dispersion of phospholipids (DPPC and POPG), would expand pulmonary alveoli and improve gas exchange in premature human infants with respiratory distress syndrome (RDS). The KL4 peptide was synthesized to resemble the amino acid pattern of surfactant protein B (SP-B). Forty-seven infants with RDS were treated within 4 h of birth with the KL4-peptide/phospholipid mixture, called KL4-Surfactant. The average arterial-to-alveolar oxygen tension ratios (a/A O2) of 39 patients included in efficacy analyses rose from pretreatment values of 0.14 +/- 0.02 (mean +/- SEM) to 0.40 +/- 0.04 (normal value > or = 0.40) by 12 h of age. Mean airway pressures and oxygenation index values fell concomitantly, and expansion of the lungs was observed on radiographs. The median duration of mechanical ventilation was 5.0 d. Of the 39 included infants, 29 required only a single dose. Radiographic data indicate that those patients requiring a second instillation of KL4-Surfactant but not showing a sustained rise in a/A O2 ratios did, in fact, exhibit expansion of alveoli in the lung. There were no RDS-related deaths; the incidence of complications was no higher than found in other comparable published studies. The data demonstrate that the synthetic peptide, KL4, which mimics the hydrophobic and hydrophilic pattern of SP-B, when formulated in an aqueous dispersion with the phospholipids DPPC and POPG, creates a strong and durable surfactant activity as judged by expansion of pulmonary alveoli and improvement of gas exchange in infants with RDS.
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PMID:The efficacy and safety of KL4-surfactant in preterm infants with respiratory distress syndrome. 854 50

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.
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PMID:Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys. 884 50

Surfactant preparations for the treatment of respiratory distress syndrome (RDS) that contain phospholipids and small amounts of the two hydrophobic proteins, SP-B and SP-C, are presently obtained from animal lungs. Since structural information about SP-B and SP-C is available, it appears possible to design analogues that can replace the native proteins in synthetic surfactants. SP-C contains a single helix, but analogues with the poly-Val sequence of the native molecule do not fold into a native-like alpha-helical conformation. However, replacement of all Val with Leu yields efficient folding into a helical structure and Leu-based SP-C analogues effectively accelerate spreading of surfactant lipids and exhibit some physiological activity in animal models of RDS. The inferior in vivo activity of synthetic surfactants containing SP-C only compared to that of surfactant preparations derived from natural sources may be caused by a lack of covalently linked palmitoyl groups in the analogues and/or absence of SP-B. SP-B is significantly larger than SP-C and has a tertiary fold of several amphipathic helices in a dimeric structure. A single simplified amphipathic helical peptide containing only Leu and Lys does not mimic the surface properties of SP-B in vitro. These circumstances make the design of SP-B analogues from solely structural considerations less likely to be successful than in the case of SP-C.
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PMID:Synthetic surfactant protein analogues. 973 May 86

Natural surfactant preparations containing phospholipids and the hydrophobic surfactant proteins B and C (SP-B and SP-C) are effective in the treatment of respiratory distress syndrome in premature infants. The limited supply, and the risk of infectious agents and immunological reactions have promoted the evaluation of synthetic peptides in surfactant preparations. However, the folding of synthetic SP-C into an alpha-helix is inefficient and alpha-helical SP-C analogues with Val-->Leu substitutions form oligomers. In order to circumvent these problems we have synthesized an SP-C analogue, named SP-C(LKS), which differs from SP-C mainly by the exchange of most of the Val residues in positions 16-28 with Leu residues to promote an alpha-helical conformation, and by the introduction of Lys residues at positions 17, 22 and 27 in order to locate positive charges around the helical circumference and thereby avoid self polymerization. CD spectroscopy showed a spectrum typical for alpha-helical peptides and SDS/PAGE disclosed a single band. The biophysical activity of artificial surfactant preparations containing SP-C(LKS) and phospholipids, with and without native SP-B, was measured using a Wilhelmy balance and a pulsating bubble surfactometer. SP-C(LKS) (3%, w/w) in a mixture of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/phosphatidylglycerol/palmitic acid (68:22:9, by wt.) suspended in 150 mM NaCl, showed rapid spreading at the air-liquid interface and produced a surface tension of <1 mN/m at minimum bubble size (gammamin) and 42 mN/m at maximum bubble size (gammamax) in the pulsating bubble surfactometer. The addition of 2% (w/w) SP-B to the preparation reduced the maximum surface tension to 33-35 mN/m, i.e. both gammamin and gammamax values were similar to those of natural surfactant preparations. Optimal in vitro characteristics were also obtained from a preparation containing SP-C(LKS), SP-B, DPPC and phosphatidylglycerol, i.e. when palmitic acid was omitted from the lipid mixture. SP-B containing surfactant preparations made up in Hepes buffer at pH 6.9, instead of in 150 mM NaCl, had similar biophysical activity provided that palmitic acid was omitted, but decreased activity in the presence of palmitic acid.
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PMID:Biophysical activity of an artificial surfactant containing an analogue of surfactant protein (SP)-C and native SP-B. 1019 Dec 70

Preterm infants with respiratory distress syndrome develop fibrin-rich hyaline membranes within the alveoli and have depressed fibrinolytic activity, which is thought to be due to a relative deficiency of plasminogen. Local fibrin deposition inhibits surfactant function and amplifies inflammation. We hypothesized that plasminogen administration to surfactant-treated preterm lambs would prevent fibrin-rich hyaline membrane formation, resulting in the amelioration of lung pathology and improved lung function. We randomly treated preterm lambs (gestational age 127-129 days) with either 16 mg of lysine-plasminogen (n = 10) or saline (n = 10), and ventilated them for 5 h. There were no significant differences in physiologic measurements of lung function (ventilation efficiency index, oxygenation index, dynamic compliance, quasi-static pressure volume curve), measures of lung injury (alveolar wash protein content and (125)I-albumin recovery) or surfactant pool size. The degree and extent of bronchiolar erosion and hyaline membrane formation were similar in the two groups. Plasminogen administration did not improve lung function or prevent hyaline membrane formation in surfactant-treated lambs.
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PMID:Plasminogen did not affect lung function in surfactant-treated preterm lambs. 1104 71

A disease similar to acute respiratory distress syndrome may occur in neonates after aspiration of meconium. The aim of the study was to compare the inhibitory effects of human meconium on the following surfactant preparations suspended at a concentration of 2.5 mg/mL: Curosurf, Alveofact, Survanta, Exosurf, Pumactant, rabbit natural surfactant from bronchoalveolar lavage, and two synthetic surfactants based on recombinant surfactant protein-C (Venticute) or a leucine/lysine polypeptide. Minimum surface tension, determined with a pulsating bubble surfactometer, was increased >10 mN/m at meconium concentrations >or=0.04 mg/mL for Curosurf, Alveofact, or Survanta, >or=0.32 mg/mL for recombinant surfactant protein-C, >or=1.25 mg/mL for leucine/lysine polypeptide, and >or=20 mg/mL for rabbit natural surfactant. The protein-free synthetic surfactants Exosurf and Pumactant did not reach minimum surface tension <10 mN/m even in the absence of meconium. We conclude that surfactant activity is inhibited by meconium in a dose-dependent manner. Recombinant surfactant protein-C and leucine/lysine polypeptide surfactant were more resistant to inhibition than the modified natural surfactants Curosurf, Alveofact, or Survanta but less resistant than natural lavage surfactant containing surfactant protein-A. We speculate that recombinant hydrophobic surfactant proteins or synthetic analogs of these proteins can be used for the design of new surfactant preparations that are relatively resistant to inactivation and therefore suitable for treatment of acute respiratory distress syndrome.
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PMID:Resistance of different surfactant preparations to inactivation by meconium. 1142 Apr 17

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.
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PMID:Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice. 1577 87

Patent ductus arteriosus is one of the most common congenital abnormalities found in premature infants. Ibuprofen, a nonsteroidal drug that is commonly used as an antipyretic, analgesic and anti-inflammatory agent, is also used to induce closure of symptomatic patent ductus arteriosus in preterm infants. Recently, we gave L-lysine ibuprofen to a preterm infant with respiratory distress to induce closure of a patent ductus arteriosus, and the infant experienced pulmonary hypertension. Only 3 cases of pulmonary hypertension following early administration of an ibuprofen solution buffered with tromethamine have previously been reported. However, this severe side effect has never been observed in multicentre, randomized, double-blind controlled trials, nor in recent reviews or meta-analyses of L-lysine ibuprofen use.
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PMID:Pulmonary hypertension following L-lysine ibuprofen therapy in a preterm infant with patent ductus arteriosus. 1678 60


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