Biomedical subjects

Ian Doyle

Publications and source records attributed to Ian Doyle.

4 recordsLinked to original sources

PubMed2006

Pneumoproteins as markers of paraquat lung injury: a clinical case.

OBJECTIVE: To describe the changes in lung-specific secretory proteins in biological fluids in a fatal case of paraquat ingestion and to present immunostaining data obtained on postmortem lung tissue specimens. METHODS: A 20-year-old man committed suicide by ingesting 100ml of a 20% paraquat solution. Surfactant associated proteins A (SP-A), B (SP-B) and Clara cell 16kDa protein (CC16) were determined in the serum and on broncho-alveloar lavage performed 18h after admission. Renal failure progressed rapidly and the patient died from refractory hypoxia. Immunostaining studies using antibodies directed against CC16, SP-A and SP-B were performed on postmortem lung tissue specimens. RESULTS: Serum CC16 seemed to increase gradually with the progression of renal impairment. Serum SP-A and SP-B levels increased before any significant changes in pulmonary gas exchanges. The immunostaining study showed that the labeling for SP-A and SP-B was reduced or absent following paraquat toxicity, while Clara cells were relatively preserved. CONCLUSIONS: The elevation of serum CC16 with paraquat toxicity is probably mainly related to a reduced renal clearance. The increase of serum SP-A and SP-B could reflect an increased lung to blood leakage, independently of the alteration of the renal function.

Acute Kidney Injury↗

PubMed2002

A phase I study of the GM-CSF antagonist E21R.

PURPOSE: E21R is a competitive inhibitor of GM-CSF. This is the initial clinical study to investigate the safety, toxicity and pharmacokinetics of escalating doses of E21R. PATIENTS AND METHODS: Cohorts of three patients received doses of 10, 30, 100, 300, 600 and 1000 micro g/kg per day given subcutaneously daily for 10 days. Eligible patients had solid tumours known to express GM-CSF receptors (breast, prostate, colon and lung cancer, and melanoma). No bone marrow involvement or concomitant steroids were permitted. A total of 22 patients received doses ranging from 10 to 1000 micro g/kg per day. There were 18 males and 4 females with a median age of 60 years (range 33 to 81 years). Eight patients had an ECOG performance status of 0, seven a performance status of 1, and seven a performance status of 2. There were ten patients with colon cancer, four with prostate cancer, three with lung cancer, three with melanoma and two with breast cancer. RESULTS: E21R was in general well tolerated and the maximum tolerated dose was not reached. The most severe toxicities were WHO grade 3 injection site erythema in one patient and grade 2 in two patients, grade 2 lethargy in three patients and grade 2 muscle aches and soreness, grade 2 joint pains and grade 2 thirst in one patient each. The primary pharmacokinetic parameters were dose-independent. Dose-dependent transient eosinophilia was noted from day 3. A fall in PSA levels was recorded in two patients with prostate cancer during their initial cycles of E21R, but they subsequently rose again. Serum from patients treated at 600 and 1000 micro g/kg per day antagonized GM-CSF-mediated TF-1 cell proliferation in vitro. CONCLUSION: E21R can be safely given at doses up to 1000 micro g/kg per day.

Adult↗

PubMed2002

Lucinactant (Discovery Laboratories).

Discovery Laboratories Inc (formerly Acute Therapeutics Inc (ATI) is developing lucinactant, originally identified at the Scripps Research Institute and sublicensed from Johnson & Johnson, for the potential treatment of respiratory diseases [174059], [357077], [361765], [422819]. The company anticipated filing an NDA for lucinactant in 2002, and by March 2002, lucinactant was in two pivotal phase III international trials for respiratory distress syndrome (RDS) in premature infants, a phase III trial for meconium aspiration syndrome (MAS) in full-term infants, and a phase II trial for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in adults. The company expected to complete trials by late 2003 [400846], [445166]. In February 2002, lucinactant was awarded Orphan Drug product designation in Europe for the treatment of ALI, which incorporates ARDS [440083]. By April 2001, Orphan Drug status in the US had been granted for lucinactant for MAS [301112], RDS and ARDS [404160]. The FDA also designated the drug a Fast Track product for the treatment of MAS [302120] and ARDS [301562], [302176], [404160].

Journal Article↗

PubMedDate not supplied

Changes in serum pneumoproteins caused by short-term exposures to nitrogen trichloride in indoor chlorinated swimming pools.

Nitrogen trichloride (NCl(3)) is an irritant gas released in the air of indoor pools sanitized with chlorine-based disinfectants. In the present study we investigated the effects of NCl(3) on the pulmonary epithelium of pool attendees by measuring the leakage into serum of three lung-specific proteins (pneumoproteins): the alveolar surfactant-associated proteins A and B (SP-A and SP-B) and the bronchiolar 16 kDa Clara cell protein (CC16). These pneumoproteins were measured in the serum of 29 recreational swimmers (16 children and 13 adults) before and after attending a chlorinated pool with a mean NCl(3) concentration of 490 microg m(-3). Pneumoprotein changes in serum were also studied in 14 trained swimmers performing an intensive 45 min standardized swimming session in a chlorinated pool (mean NCl(3) concentration of 355 microg m(-3)) and for the purposes of comparison in a non-chlorinated pool sanitized by the copper/silver method. Serum CC16 was not increased in recreational swimmers, but in trained swimmers serum levels of this protein peaked immediately after strenuous exercise, both in the copper/silver pool and in the chlorinated pool. This acute increase in airway permeability is probably the consequence of the mechanical stress on the epithelial barrier caused by overinflation and/or hyperventilation during intense exercise. Serum levels of SP-A and SP-B were unaffected by strenuous exercise in the copper/silver pool. The two proteins were, however, significantly increased in a time-dependent manner in recreational and trained swimmers attending the chlorinated pool. The intravascular leakage of SP-A and SP-B was already statistically significant after only 1 h of exposure to pool air without exercising and remained elevated for 12 h after. These changes were not associated with decrements in lung function. The ability of NCl(3) to acutely disrupt the lung epithelium barrier was confirmed in mice using serum CC16 and plasma proteins in bronchoalveolar lavage fluid as permeability markers. The significance of these permeability changes induced by NCl(3) in the deep lung is presently unknown. In view of the increasing and widespread human exposure to this gas not only in indoor pools but also in a variety of other situations, these findings warrant further study.

Adolescent↗