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1.
ACS Chem Neurosci ; 9(7): 1735-1742, 2018 07 18.
Article in English | MEDLINE | ID: mdl-29648788

ABSTRACT

Opioid peptides are key regulators in cellular and intercellular physiological responses, and could be therapeutically useful for modulating several pathological conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochemical (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr1-ψ[( Z)CF═CH]-Gly2 peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degradation, and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compound into a stable and centrally distributed in vivo probe. In contrast, the Tyr1-ψ[CF3CH2-NH]-Gly2 peptidomimetic decreased stability by accelerating proteolysis at the Gly3-Phe4 position.


Subject(s)
Enkephalin, Leucine/pharmacokinetics , Peptidomimetics/chemistry , Peptidomimetics/pharmacokinetics , Animals , Biological Transport , Brain/drug effects , Brain/metabolism , Drug Stability , Enkephalin, Leucine/chemistry , Enkephalin, Leucine/metabolism , Female , Humans , Mice, Inbred BALB C , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Peptidomimetics/metabolism , Rats, Sprague-Dawley , Solubility
2.
Am J Hematol ; 89(4): 363-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24273151

ABSTRACT

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.


Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Iron Chelating Agents/therapeutic use , Pyridones/therapeutic use , Salvage Therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Ciclopirox , Female , Gastrointestinal Diseases/chemically induced , Gene Expression Regulation, Neoplastic/drug effects , Half-Life , Hematologic Neoplasms/blood , Hematologic Neoplasms/pathology , Humans , Inactivation, Metabolic , Inhibitor of Apoptosis Proteins/genetics , Iron Chelating Agents/administration & dosage , Iron Chelating Agents/adverse effects , Iron Chelating Agents/metabolism , Iron Chelating Agents/pharmacokinetics , Male , Middle Aged , Neoplasm Proteins/genetics , Pyridones/adverse effects , Pyridones/blood , Pyridones/pharmacokinetics , RNA, Messenger/blood , RNA, Neoplasm/blood , Survivin , Treatment Outcome
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