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BackgroundMore potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A).MethodsA group of nine healthy male subjects received intramuscularly 24.5 × 106 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (β2M) and 2′–5′ oligoadenylate synthetase (2′–5′ OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well.ResultsConcerning pharmacokinetics, serum IFNs’ profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and β2M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum β2M peaked around the double from baseline. Serum concentrations of the enzyme 2′–5′ OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild.ConclusionsThe administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies.Trial registrationCuban Public Registry of Clinical Trials RPCEC00000118, May 24, 2011.

Diabetes mellitus remains as a pandemic disease, associated to progressive and irreversible complications including lower extremity ulcerations, derived from a predisposition to ischemia, neuropathy and an intrinsic wound healing failure. The molecular operators supporting wound chronicity remain elusive, but a local deficit of growth factors is invoked as a common cause for proliferative arrest, apoptosis, and cells senescence. The prodegradative environment of these lesions contributes to reduce growth factors availability and receptors' physiology. The introduction of growth factors in the clinical arena was precocious since critical pieces of chronicity pathophysiology had not been identified. The topical administration of these agents failed by the effect of local proteolysis, narrow bioavailability window, inadequate diffusion, and a harsh polymicrobial biofilm. To circumvent these pharmacodynamic limitations, we envisioned an intra-ulcer infiltrative delivery route for epidermal growth factor (EGF), based on the rationale derived from experimental evidences. The clinical development program with this procedure has comprised from a proofof-concept to post-marketing studies in poor-prognosis, ischemic, neuropathic, and neuroischemic wounds, involving more than 300 000 patients along 20 years. Pharmacovigilance studies demonstrated that infiltrated EGF is therapeutically effective and safe to circumvent the limitations of the classic topical administration. This pharmacological intervention has remained as an adjuvant therapy to conventional treatments and wound care protocols. Generation of EGF nanovesicles is envisioned as a promising future direction to trigger the re-epithelialization of stagnant, non-resurfaced diabetic wounds upon topical administration.

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