Lung bioavailability of hydrofluoroalkane fluticasone in young children when delivered by an antistatic chamber/mask

OBJECTIVE: To determine whether an antistatic valved holding chamber/mask improves lung bioavailability of hydrofluoroalkane (HFA) fluticasone in young children. STUDY DESIGN: Twelve patients, age 1 to 6 years, with well-controlled asthma were treated with an HFA fluticasone metered-dose inhaler (Flovent HFA) twice daily (440 microg/day). The drug was delivered by tidal breathing through conventional (AeroChamber Plus) and antistatic (AeroChamber MAX) valved holding chambers (VHCs) with masks in a randomized, crossover manner, each for 3 to 7 days. When adherence was 100% at home, blood was collected for measurement of steady-state fluticasone plasma concentration (FPC) 1 hour after the last dose was administered in the clinic. FPC indicates systemic exposure directly and airway delivery indirectly. It was measured by liquid chromatography-mass spectrometry. Data were analyzed by regression analysis. RESULTS: The mean +/- SD FPC was 107 +/- 30 pg/mL after conventional VHC and 186 +/- 134 pg/mL after the antistatic VHC (P = .03). In 5 patients (40%), the antistatic VHC increased FPC by >/= 100%, to potentially excessive levels in 4 of them; it had little effect in 7 patients. CONCLUSIONS: HFA fluticasone was delivered to the airways by both devices even though the patients could not inhale deeply and breath hold. The antistatic VHC variably increased lung bioavailability. To reduce systemic exposure, the dose should be weaned to the minimum required to maintain asthma control.     

First-Line management of CML: a state of the art review

With the advent of imatinib, an inhibitor of the fusion Bcl-Abl tyrosine kinase that is responsible for the disease phenotype, first-line treatment of chronic myelogenous leukemia (CML) has undergone rapid changes. As a consequence of the success of imatinib, allogeneic stem cell transplantation (allo-SCT) has moved from the first-line indication to an option that is usually considered for patients without optimal response to imatinib or those for whom treatment with imatinib has failed. First-line use of interferon-alpha (IFN-alpha), with or without cytarabine or hydroxyurea, is now rarely considered. Most patients with newly diagnosed chronic-phase CML experience complete cytogenetic responses during imatinib treatment, but continued treatment is necessary to prevent cytogenetic or molecular relapse. Cumulative evidence with imatinib and IFN-alpha show that experiencing early and deep responses is important in preventing progression to more advanced phases of the disease. These features emphasize the need to carefully monitor patients for residual disease and provide guidance on treatment options in the event of imatinib intolerance or failure. This article reviews the current role of allo-SCT, imatinib, and IFN-alpha in treating newly diagnosed chronic-phase CML, highlighting the benefits and challenges of long-term patient management, and discusses emerging trends.     

Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.      

Measurement of piperacillin plasma concentrations in cancer patients with suspected infection

Background

Piperacillin (PIP) in combination with tazobactam is commonly used for anti-infective treatment in cancer patients. PIP exerts a time-dependent killing. Thus, the maintenance of plasma concentrations above a pre-defined target concentration for a pre-defined time may be relevant for optimal efficacy. It is assumed that PIP-plasma concentrations above the clinical breakpoint of the target pathogen [Pseudomonas aeruginosa, clinical breakpoint at minimal inhibitory concentration (MIC) 16 mg/L] should be reached for 100% of the dosing interval or >4xMIC (64 mg/L) for 50% of the dosing interval. Whereas studies in the intensive-care setting have shown underdosing in patients with sepsis, little is known about PIP-plasma concentrations in cancer patients.

Methods

Data of 56 cancer patients who received piperacillin/tazobactam (PIP/TAZ, 4.5 g three times daily) as empiric therapy for suspected infection were analysed at baseline and 4 h after the infusion.

Results

Median trough concentrations in steady state [median 3 days (IQR 3–5) after start of PIP/TAZ] were 4.6 mg/L (95% CI 0.3–136.3) and median PIP-plasma concentrations 4 h after infusion were 46.2 mg/L (95% CI 10.1–285.6). A second evaluation 5 days (IQR 4–7) after start of PIP/TAZ confirmed these results: trough concentrations were 2.7 mg/L (95% CI 0.5–6.3), concentrations after 4 h 28.0 mg/L (95% CI 1.7–47.3). A good renal function was associated with lower plasma concentrations (r = ?0.388, p < 0.003). Detailed pharmacokinetic measurements in six patients showed low maximum plasma concentration (median 165 mg/L) and a rapid decline of plasma concentrations (median plasma half time 1.38 h).

Conclusion

In conclusion, piperacillin plasma concentrations in cancer patients are below target levels warranting prospective trials to investigate therapeutic drug monitoring.

     

Metabolism of dynorphin A(1-13)

Dynorphin A(1-13), a tridecapeptide of the endogenous opioid peptides, has modest effects in reducing mild opiate withdrawal in humans. Previous studies revealed that dynorphin also potentiates the analgesic effect of morphine in morphine-tolerant rats and mice. The therapeutic potential of dynorphin A(1-13) is limited due to extensive metabolism by human metabolic enzymes resulting in an in vivo half-life of less than one minute. Chemical modifications of dynorphin A(1-13), such as N-methylation of Tyr1 and amidation of the C-terminus have been shown to be effective in protecting against the proteolytic enzymes in human plasma. This article is a general review of the metabolism of dynorphin A(1-13) in human plasma and CSF.     

Identification of Stabilized Dynorphin Derivatives for Suppressing Tolerance in Morphine-Dependent Rats

PURPOSE: Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained. METHODS: The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats. RESULTS: Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity. CONCLUSIONS: [N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.