A Relapsing Meningeal Acute Myeloid Leukaemia FLT3-ITD+ Responding to Gilteritinib.

A patient with a therapy-related acute myeloid leukaemia (AML), NPM1mut, and FLT3-ITD+ was treated with induction and consolidation with CPX-351, obtaining a complete response (CR) but minimal residual disease persisted positive. Later, she complained progressive burning leg pain, weakening of the right hand and leg muscles, associated with absence of osteotendinous leg reflexes. Examination of cerebrospinal fluid (CSF) showed a meningeal relapse of AML. Moreover, a magnetic resonance imaging (MRI) showed 2 right meningeal implants of myeloid sarcoma and bone marrow revealed haematologic relapse of disease. She was treated with medicated lumbar punctures (LPs) followed by an FLA-Ida scheme, and she achieved a 2nd CR. Unfortunately, the patient developed hyperleucocytosis and reappearance of meningeal myeloid sarcoma at MRI. For this reason, a monotherapy with gilteritinib (an FLT3 inhibitor) was started: after 3 months of therapy, central nervous system (CNS)-disease shrunken and then faded, while AML in the bone marrow achieved only a partial response. This is the 1st report of a positive biological effect of gilteritinib on CNS (meningeal) myeloid sarcoma. There are no studies of gilteritinib concentration into CSF and penetration of gilteritinib into the blood-brain barrier should be further studied, given the paucity of drugs active on CNS relapse of AML. In patients receiving CPX-351 only, diagnostic LP should be considered after induction.

Validation of a method for the determination of AMG 579 in cerebrospinal fluid with a focus on sample collection procedures for clinical trials.

Analysis of pharmaceutical compounds in cerebrospinal fluid (CSF) may present challenges due to the combination of the low protein content in this matrix and relatively low drug concentrations, often corresponding to free drug concentrations in plasma, typically found in CSF. A 30% loss of AMG 579 was observed during preparation of quality control samples and further investigation determined that this loss was likely due to binding to collection tubes. This observation also highlighted the possibility of additional losses of AMG 579 that could occur during collection of clinical samples, such as binding to catheters used in the collection of CSF. Loss of AMG 579 in QC samples was reduced from 30% to 5% when the volume of CSF stored in 1.5 mL vials was increased from 0.06 mL to 1 mL. Modest but unavoidable losses of about 20% of AMG 579 were also found following perfusion through both silicone and polypropylene (Pharmed(®) BPT) collection catheters. Silicone tubing was used for CSF collection based on clinical site preference. An LC-MS/MS method was validated to quantify AMG 579 in human CSF to support clinical testing. The original range of the assay was 1-1000 ng/mL but the LLOQ was subsequently lowered to 0.1 ng/mL to better meet project requirements. Interday bias (% RE) and precision (% CV) were -4.2% and 12.3% at the LLOQ, and less than ± 0.9% and 8.3% for higher concentrations, respectively. The compound was stable in human CSF for at least 5h at room temperature, 55 days at -70 °C (-60 to -80 °C range), and through three freeze-thaw cycles. Careful selection of assay conditions and materials minimized losses of the compound during sample collection and storage. While these losses could not be entirely eliminated, practical sample collection and storage conditions were established to allow for analysis of AMG 579 in human clinical trials.

Brain microdialysate, CSF and plasma pharmacokinetics of ligustrazine hydrochloride in rats after intranasal and intravenous administration.

The aim of this work was to investigate the pharmacokinetics of ligustrazine hydrochloride (LZH) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal (10 mg/kg) or intravenous administration (10 mg/kg) in male Sprague-Dawley rats. Plasma, CSF and cerebral cortex microdialysates were collected at timed intervals for the measurement of LZH by a quick and sensitive HPLC-UV method. LZH entered the brain quickly following both routes of administration. No significant difference was observed between the AUCCSF or cortex /AUCplasma ratio of LZH after intranasal administration (38.4%, 17.4%) and that after intravenous injection (45.9%, 19.9%). The drug targeting index (DTI) was 0.85 and 0.91 in the CSF and cortex, respectively. In conclusion, LZH is rapidly absorbed into the systemic circulation following intranasal administration. There is no direct pathway for LZH transport from the nasal cavity to the brain. The rapidity and magnitude of LZH penetration into the brain indicate that intranasal administration of this agent is a promising alternative to intravenous administration.

[Determination of tetramethylpyrazine in animal serum and cerebrospinal fluid by high performance liquid chromatography].

A reversed-phase high performance liquid chromatographic (RP-HPLC) method for the determination of the tetramethylpyrazine(TMP) in Chuanxiong extract, the animal(mouse) serum and cerebrospinal fluid has been developed. The TMP was separated on an ODS column Zorbax SB-C18(4.6 mm i.d. x 250 mm, 5 microns) at room temperature and detected by using UV detector at 270 nm. The mobile phase was methanol-water (50:50, V/V) containing 0.2 mmol/L of NH4H2PO4 flowing at a rate of 0.8 mL/min and 20 microL samples were injected. The detection limit of TMP was 1 mg/L and the calibration curve is linear between 5 and 500 mg/L with a correlation coefficient (r) of 0.999. The recovery of TMP ranged 98%-103%. The extract of Chuanxiong and pretreated serum and cerebrospinal fluid sample are stable for a week at room temperature.