Kathleen E. Heppert

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies

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. Am. J. Hematol. 89:363–368, 2014.

Evaluation of an osmotic pump for microdialysis sampling in an awake and untethered rat

The feasibility of using an osmotic pump in place of a syringe pump for microdialysis sampling in rat brain was investigated. The use of an osmotic pump permits the rat to be free from the constraints of the standard tethered system. The in vitro flow rates of a microdialysis syringe pump (set at 10.80 microl/h) and the osmotic pump (pump specifications were 11.35 microl/h) with no probe attached were compared, yielding results of 10.87 microl/h+/-1.7% and 10.95 microl/h+/-8.0%, respectively. The average of four flow rate experiments in vivo yielded R.S.D.s less than 10% and an average flow rate of 11.1 microl/h. Following the flow rate studies, in vivo sampling of neurotransmitters was accomplished with the osmotic pump coupled to a microdialysis probe implanted in the brain. Finally, after determination of basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) in the rats, the rats were dosed with benserazide followed by l-3,4-dihydroxyphenylalanine (l-DOPA). The results from the dosing study showed at least a 10-fold increase in compounds in the l-DOPA metabolic pathway (DOPAC and HVA) and a slight or no increase in 5-HIAA (serotonin metabolic pathway.) These results indicate that the osmotic pump is a viable alternative to the syringe pump for use in microdialysis sampling.

Using a microdialysis shunt probe to monitor phenolphthalein glucuronide in rats with intact and diverted bile flow

Abstract This study is undertaken to demonstrate that the shunt microdialysis probe is a valuable tool for profiling analytes in the rat bile duct while preserving enterohepatic circulation (EHC). Phenolphthalein (PT) is well known to be efficiently converted to its glucuronide adduct and enterohepatically cycled. Phenolphthalein glucuronide (PTG) has been used as marker to study both liver function and EHC. Using a microdialysis shunt probe, the concentration of PTG in the bile can be monitored. In this study, the PTG profiles were obtained in anesthetized rats with the bile flow either diverted or intact. Characterization of the PTG extraction efficiency (EE) using microdialysis showed that the in vitro EE of PTG was affected by the presence of bile salts, whereas the bile salts have no effect on the EE of caffeine. In addition, it was shown that the bile salt concentration must be balanced on both sides of the membrane in order to obtain the expected flow rate through the perfusion channel of the probe. A 2% solution of bile salts in Ringers (BSR) was sufficient as the perfusate against rat bile in the shunt. With BSR as the perfusate, consistent in vitro EE results (by both recovery and delivery experiments) for PTG were obtained. These in vitro results compared favorably with EE values determined in vivo.

Nucleotide hydrolysis in the presence of μ-hydroxo-bridged-cobalt(III) complexes

Abstract Two cobalt(III) complexes with tridentate ligands, the acyclic diethylenetriamine and macrocyclic 1,4,7-triazacyclononane, were examined as potential catalysts for the hydrolysis of adenosine 5′-triphosphate (ATP). Studies were performed primarily at pH 4.5, where the two complexes were in the binuclear di-μ-hydroxo forms. For both complexes, a rapid initial hydrolysis with first order dependence on the concentration of ATP was observed, kobs of approximately 0.20 min−1, followed by very slow hydrolysis. Deuterium isotope studies done in D2O showed a normal isotope effect with kH/kD = 1.8. Spectral investigations and 59Co NMR studies indicated that the biphasic nature of the hydrolysis reaction may be due to the formation of a complex in which inorganic phosphate is coordinated to the cobalt, effectively poisoning the catalyst.