Aerosol, chemical and physical properties of dry powder synthetic lung surfactant for noninvasive treatment of neonatal respiratory distress syndrome.

Inhalation of dry powder synthetic lung surfactant may assist spontaneous breathing by providing noninvasive surfactant therapy for premature infants supported with nasal continuous positive airway pressure. Surfactant was formulated using spray-drying with different phospholipid compositions (70 or 80 total weight% and 7:3 or 4:1 DPPC:POPG ratios), a surfactant protein B peptide analog (KL4, Super Mini-B, or B-YL), and Lactose or Trehalose as excipient. KL4 surfactant underperformed on initial adsorption and surface activity at captive bubble surfactometry. Spray-drying had no effect on the chemical composition of Super Mini-B and B-YL peptides and surfactant with these peptides had excellent surface activity with particle sizes and fine particle fractions that were well within the margins for respiratory particles and similar solid-state properties. Prolonged exposure of the dry powder surfactants with lactose as excipient to 40 °C and 75% humidity negatively affected hysteresis during dynamic cycling in the captive bubble surfactometer. Dry powder synthetic lung surfactants with 70% phospholipids (DPPC and POPG at a 7:3 ratio), 25% trehalose and 3% of SMB or B-YL showed excellent surface activity and good short-term stability, thereby qualifying them for potential clinical use in premature infants.

Aerosol delivery of dry powder synthetic lung surfactant to surfactant-deficient rabbits and preterm lambs on non-invasive respiratory support.

Background: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. Methods: A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, in vitro surface activity with captive bubble surfactometry, and in vivo activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. Results: FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated in vitro surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Conclusions: Aerosol delivery of DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.

Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant.

STUDY OBJECTIVE: To determine an appropriate empiric oral sirolimus dose adjustment when given concurrently with posaconazole oral suspension in patients who undergo hematopoietic stem cell transplant (HSCT). DESIGN: Retrospective cohort study. SETTING: Comprehensive cancer center in the United States. SUBJECTS: Seventy five allogeneic HSCT patients who received posaconazole oral suspension and oral sirolimus concurrently between 2009 and 2011. MEASUREMENTS AND MAIN RESULTS: Sirolimus concentrations were recorded at baseline and for up to 28 days after posaconazole initiation. The sirolimus concentration/dose (C/D) ratio was determined for each sirolimus concentration obtained. Following analysis of patient data and based on the initial empiric sirolimus dose reduction, patients were stratified into two groups: ≥50% sirolimus dose reduction (Group 1) and <50% sirolimus dose reduction (Group 2). The mean sirolimus C/D ratio was 2.29 ng/mL/mg prior to posaconzole initiation. Coadministration of posaconazole and sirolimus resulted in an increase in the steady state sirolimus C/D ratio to 6.24 ng/mL/mg, which occurred approximately 17-20 days after initiation of posaconazole. The mean maximum sirolimus concentration was significantly higher in Group 2 compared to Group 1 (12.64 ng/mL vs. 9.24 ng/mL, p=0.001). Significantly more patients in Group 2 than Group 1 experienced at least one sirolimus concentration >15 ng/mL (27% vs. 2.6%, p=0.003). CONCLUSION: Coadministration of posaconazole oral suspension with oral sirolimus increases the sirolimus C/D ratio by approximately 2.7-fold in HSCT patients. An initial empiric oral sirolimus dose reduction between 50% and 65% may be recommended for most clinically stable patients with close sirolimus concentration monitoring for at least 3 weeks following posaconazole initiation.

Effects of a formulary change from granulocyte colony-stimulating factor to granulocyte-macrophage colony-stimulating factor on outcomes in patients treated with myelosuppressive chemotherapy.

STUDY OBJECTIVE: To evaluate the effects on efficacy and safety of a formulary change from granulocyte colony-stimulating factor (G-CSF) to granulocyte-macrophage CSF (GM-CSF). DESIGN: Retrospective chart review. SETTING: Single-center academic institution. PATIENTS: Fifty-six patients aged 18 years or older with breast cancer, lung cancer, melanoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma who developed neutropenia within 4 weeks after treatment with myelosuppressive chemotherapy and who had been given five or more doses of CSF as primary or secondary prophylaxis from January 1995-March 2002. Twenty-nine patients treated before January 2000 were given G-CSF; after the formulary change in January 2000, 27 patients were primarily given GM-CSF. MEASUREMENTS AND MAIN RESULTS: The primary efficacy end point was time to an absolute neutrophil count of 1.5x10(3)/mm3 or greater after treatment with CSF. Second and third efficacy end points, respectively, were frequency of febrile neutropenia and effect of CSF treatment on schedule and dose intensity of subsequent chemotherapy cycles. Primary and secondary safety end points, respectively, were frequency of adverse events and use of resources used to manage these events. The time to neutrophil recovery was similar with G-CSF and GM-CSF. Febrile neutropenia was more common in the patients given GM-CSF. Chemotherapy dose delays also were more common in patients treated with GM-CSF, as was the frequency of fever. Use of resources (platelet and red blood cell transfusions, intravenous antibiotics, and hospitalizations) was greater in the patients treated with GM-CSF. CONCLUSION: The formulary change to GM-CSF was associated with a higher frequency of febrile neutropenia, resultant chemotherapy dose delays, more adverse events, and greater use of resources to manage the adverse events. These results suggest that G-CSF and GM-CSF are not therapeutically equivalent, with G-CSF having a superior safety and efficacy profile for the prevention of chemotherapy-induced neutropenic events.