Compositions and methods for administering PPARγ agonists, surfactant peptides and phospholipids
The present disclosure provides compositions and therapies that can address both the symptoms and disorders associated with insufficient surfactant production and hyperoxia. In one embodiment, the composition can be formulated for aerosol delivery during ventilation therapy. The composition can comprise one or more of the following: a PPAR gamma agonist, a surfactant peptide, and one or more phospholipids. The compositions are formulated to provide the complementary benefits of reducing the likelihood of developing or the severity of RDS in infants, as well as protecting and promoting lung maturation in a hyperoxic environment.
1. A method of preventing or treating surfactant deficiency or dysfunction in a patient in need thereof, comprising aerosol administration of composition comprising:
a PPAR (peroxisome proliferator-activated receptor) gamma agonist;
one or more surfactant peptides; and
one or more phospholipids,
wherein the patient is an infant wherein at least one of the one or more surfactant peptides comprises:
(i) a first fragment comprising the amino acid sequence of XWLXRALIKRIQAZI (SEQ ID NO: 1) or a first amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1 and
(ii) a second fragment comprising the amino acid sequence of RZLPQLVXRLVLRXS (SEQ ID NO: 2) or a second amino acid sequence having at least 90% sequence identity to SEQ ID NO: 2,
wherein (a) X is any amino acid but at least one amino acid at the X positions is tyrosine, and (b) Z is any amino acid but not methionine.
2. The method of claim 1 , wherein the surfactant deficiency or dysfunction comprises a respiratory distress syndrome in an infant or a respiratory distress syndrome secondary to surfactant deficiency or lung immaturity in a premature or near-term infant.
3. The method of claim 1 , wherein the PPAR gamma agonist is a thiozolidinedione (TZD).
4. The method of claim 3 , wherein the TZD is selected from the group consisting of: a rosiglitazone, a troglitazone, a farglitazar, a phenylacetic acid, a GW590735, a GW677954, a GW1929, an S2648, an Avandia, an Avandamet, a ciglitazone, a pioglitazone, an adaglitazone, a 15 deoxy prostaglandin J2, a 15-deoxy-delta12,14 PGJ2, GW-9662, a MCC-555, a LG100754, an nTZDpa, and a Telmisartan.
5. The method of claim 4 , wherein the TZD is a pioglitazone.
6. The method of claim 1 , wherein the PPAR gamma agonist is an endogenous natural compound with PPAR gamma activity or a metabolite thereof.
7. The method of claim 1 , wherein the surfactant peptide further comprises an insertion sequence at the N-terminal end of the first fragment.
8. The method of claim 1 , wherein none amino acid at the X positions of the surfactant peptide is cysteine.
9. The method of claim 1 , wherein the one or more phospholipid is selected from the group consisting of dipalmitoylphosphatidylcholine (DPPC), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylglycerol (PG), palmitoyloleoylphosphatidylglycerol (POPG), cholesterol (Chol), 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoylsn-glycero phosphocholine (POPS), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), DEPN-8, PG-1 and combinations thereof.
10. The method of claim 9 , wherein the one or more phospholipid comprises DPPC, POPC, and POPG.
11. The method of claim 10 , wherein the DPPC, POPC, and POPG are at ratio of about (4-6):(2-4):(1-3).