ABSTRACT
A 78-year-old woman was diagnosed with herpes zoster in the first branch of the trigeminal nerve and was treated with amenamevir. Subsequently, she was hospitalized for postherpetic neuralgia. Fever and unconsciousness were observed, and a diagnosis of varicella-zoster virus meningoencephalitis and vasculitis was made. In addition to the antithrombotic therapy, she was treated with intravenous acyclovir and steroid pulse therapy; however, her unconsciousness persisted. Amenamevir was not transferrable to the spinal fluid and resulted in an incomplete treatment of herpes zoster in the cerebral nerve region, suggesting that this case may be related to the severe course of the disease.
Subject(s)
Acyclovir/administration & dosage , Antiviral Agents/therapeutic use , Herpes Zoster/complications , Herpes Zoster/drug therapy , Meningoencephalitis/drug therapy , Meningoencephalitis/etiology , Oxadiazoles/therapeutic use , Trigeminal Nerve , Vasculitis/drug therapy , Vasculitis/etiology , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/cerebrospinal fluid , Female , Humans , Infusions, Intravenous , Magnetic Resonance Imaging , Meningoencephalitis/diagnosis , Meningoencephalitis/virology , Methylprednisolone/administration & dosage , Oxadiazoles/adverse effects , Oxadiazoles/cerebrospinal fluid , Pulse Therapy, Drug , Severity of Illness Index , Vasculitis/diagnosis , Vasculitis/virologyABSTRACT
BACKGROUND: The concentration of amyloid ß (Aß) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aß concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. METHODS: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. RESULTS: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aß(1-38), Aß(1-40) and Aß(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. CONCLUSION: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aß concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/cerebrospinal fluid , Enzyme Inhibitors/administration & dosage , Oxadiazoles/administration & dosage , Sulfonamides/administration & dosage , Administration, Oral , Adult , Amyloid Precursor Protein Secretases/metabolism , Area Under Curve , Biomarkers/cerebrospinal fluid , Double-Blind Method , Down-Regulation , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Enzyme Inhibitors/cerebrospinal fluid , Enzyme Inhibitors/pharmacokinetics , Humans , Male , Oxadiazoles/adverse effects , Oxadiazoles/blood , Oxadiazoles/cerebrospinal fluid , Oxadiazoles/pharmacokinetics , Peptide Fragments/cerebrospinal fluid , Sulfonamides/adverse effects , Sulfonamides/blood , Sulfonamides/cerebrospinal fluid , Sulfonamides/pharmacokineticsABSTRACT
BMS-708163 is a gamma-secretase inhibitor that is being developed for the treatment of Alzheimer's disease. Several LC-MS/MS methods have been developed for the determination of BMS-708163 in both plasma and cerebrospinal fluid in support of dog, rat, mouse and human studies. To support non-clinical studies, an LC-MS/MS method with a lower limit of quantitation (LLOQ) of 5 ng/mL, was developed and validated in dog, rat, and mouse plasma by using the deprotonated ion as the precursor ion. To support clinical studies, an LC-MS/MS method with LLOQ of 0.1 ng/mL, was developed and validated in human plasma by using the formate adduct as the precursor ion. Formic acid (0.01%) in water and acetonitrile was found to be the most favorable mobile phases for both deprotonated and formate adduct ions in negative electrospray ionization mode. A combination of a 3M Empore C18 plate for SPE and a Waters Atlantis dC18 analytical column for separation was used to achieve a highly selective solid phase extraction and chromatographic procedure from plasma without dry down and reconstitution steps. In the development of an assay for BMS-708163 in cerebral spinal fluid (CSF), significant non-specific binding of BMS-708163 was observed and resolved with pre- or post-spike of 0.2% Tween 20 into CSF samples. A dilute-and-shoot LC-MS/MS method with LLOQ of 0.1 ng/mL was developed and validated to assess BMS-708163 exposure in human CSF.
