Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis.

BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 µM in HVs and between 0.2 and 0.5 µM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 µM and were still above 10 µM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.

Macroprolactinaemia, the major unknown in the differential diagnosis of hyperprolactinaemia.

We report on 10 cases of macroprolactinaemia and discuss recent evidence that many patients with hyperprolactinaemia (8-26%, depending on the population studied) have in fact normal amounts of circulating prolactin but false-high values in commercial assays. This is caused by macromolecular prolactin (also named big-big prolactin or macroprolactin), a complex of prolactin with IgG antibodies leading to apparent hyperprolactinaemia. In spite of the expanding literature on this topic, it remains an underrecognised problem, typically causing unnecessary procedures such as laboratory controls, MRI of the pituitary, treatment with dopamine agonists or even pituitary surgery. Physicians involved with diagnosis and treatment of hyperprolactinaemia (general practitioners, gynaecologists, neurosurgeons, endocrinologists and biochemists) should suspect the presence of apparent hyperprolactinaemia in any patient with a high prolactin value but no related symptoms. Medical laboratories should be aware that their prolactin assay can interfere with macroprolactin and should implement the use of the PEG precipitation test in the work-up of hyperprolactinaemia, a simple and effective means of correctly diagnosing apparent hyperprolactinaemia.