Background and ObjectivesNerve growth factor (NGF) is a neurotrophin with therapeutic possibilities that extend from the nervous system to the eye. We tested the safety, maximal tolerated dose, pharmacokinetics, and antigenicity of a novel human recombinant NGF (rhNGF) eye-drop formulation in a phase I study.MethodsThis prospective, randomized, double-masked, vehicle-controlled trial, sponsored by Dompé SpA (registered as NCT01744704 at ClinicalTrials.gov), enrolled 74 healthy volunteers (24 females, 50 males, age 40.2 ± 11.8 years). Subjects were randomized in three cohorts to receive (1) a single eye-drop containing 0.0175, 0.175, or 0.7 μg rhNGF; (2) a single ascending dose of rhNGF eye drops three times a day for 1 day (total daily dose 2.1, 6.3, or 18.9 μg), or vehicle; or (3) a multiple ascending dose of rhNGF eye drops three times a day for 5 days (total dose 10.5, 31.5, or 94.5 μg), or vehicle. Outcome measures included blood chemistry, urinalyses, vital signs, electrocardiograms (ECGs), serum NGF antibodies, ocular and systemic adverse events (AEs), visual acuity, tear function, intraocular pressure, fundus oculi, and ocular symptoms.ResultsAdministration of rhNGF eye drops did not result in a significant increase of circulating NGF levels and no antidrug antibodies were detected in serum. No serious AEs were recorded, and a few mild, transient ocular AEs related to rhNGF administration were reported only at the highest concentration.ConclusionsrhNGF eye drops were well tolerated, with no detectable clinical evidence of systemic AEs. These results pave the way for the development of clinical trials on rhNGF in ophthalmology.

BackgroundDry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.MethodsForty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.ResultsOf 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.ConclusionsThe data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.Trial registration number NCT02101281.

The nature of histamine receptors in peripheral tissues is still controversial. However, evidence of heterogeneous classes of binding sites for [3H]-mepyramine are reported in the literature. The aim of our study was, therefore, to investigate the nature of this heterogeneity by comparing [3H]-mepyramine binding in a central tissue (cerebellum) and in a peripheral tissue (lung) obtained from guinea pigs and to assess its dependence upon the temperature of incubation. The results revealed that the [3H]-mepyramine interaction in both tissues is temperature-dependent. At 25 degrees C, the interaction between [3H]-mepyramine and the receptors was biphasic in the lung while only a single class of binding site was found in the cerebellum. At 0 degrees C, [3H]-mepyramine interacted with three binding sites in the lung and two in the cerebellum. The behaviour of the reference compounds (clemastine, promethazine and histamine) also supported this temperature-dependence. Moreover, two new compounds (DF 11062 and DF 11113), synthesized in our laboratories and endowed with antihistamine activity, can differentiate between the low affinity site seen at 25 degrees C in the lung and that seen in the cerebellum at 0 degrees C.

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The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.

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