973 results match your criteria csf pharmacokinetic

Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, translation from animal to human in a rare genetic disease.

Clin Transl Sci 2021 Jun 2. Epub 2021 Jun 2.

BioMarin Pharmaceutical Inc., Novato, California, USA.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an ultra-rare pediatric neurodegenerative disorder characterized by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). In the absence of adequate TPP1, lysosomal storage material accumulation occurs in the central nervous system (CNS) accompanied by neurodegeneration and neurological decline that culminates in childhood death. Cerliponase alfa is a recombinant human TPP1 enzyme replacement therapy administered via intracerebroventricular infusion and approved for the treatment of CLN2 disease. Read More

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A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.

Alzheimers Res Ther 2021 05 27;13(1):106. Epub 2021 May 27.

Alzheimer Center, Department of Neurology, Amsterdam UMC, Amsterdam, The Netherlands.

Background: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.

Methods: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Read More

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A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration.

J Pharmacokinet Pharmacodyn 2021 May 15. Epub 2021 May 15.

Clinical Pharmacology and Pharmacometrics, Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA.

Antisense oligonucleotides (ASOs) are promising therapeutic agents for a variety of neurodegenerative and neuromuscular disorders, e.g., Alzheimer's, Parkinson's and Huntington's diseases, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), caused by genetic abnormalities or increased protein accumulation. Read More

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Population Pharmacokinetic-Pharmacodynamic Modeling and Covariate Analyses of Neutropenia and Thrombocytopenia in Patients With Solid Tumors Treated With Lurbinectedin.

J Clin Pharmacol 2021 Apr 29. Epub 2021 Apr 29.

Pharma Mar, Madrid, Spain.

Lurbinectedin is a selective inhibitor of oncogenic transcription. Reversible myelosuppression is its most relevant toxicity. Pharmacokinetic-pharmacodynamic analyses were conducted to characterize the time course of absolute neutrophil count and platelet count recovery and to detect and quantify the effect of relevant covariates in patients with advanced solid tumors treated with lurbinectedin. Read More

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IV and oral fosfomycin pharmacokinetics in neonates with suspected clinical sepsis.

J Antimicrob Chemother 2021 Jun;76(7):1855-1864

Infection, Immunity and Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK.

Background: Fosfomycin has the potential to be re-purposed as part of a combination therapy to treat neonatal sepsis where resistance to current standard of care (SOC) is common. Limited data exist on neonatal fosfomycin pharmacokinetics and estimates of bioavailability and CSF/plasma ratio in this vulnerable population are lacking.

Objectives: To generate data informing the appropriate dosing of IV and oral fosfomycin in neonates using a population pharmacokinetic analysis of plasma and CSF data. Read More

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Widespread and sustained target engagement in Huntington's disease minipigs upon intrastriatal microRNA-based gene therapy.

Sci Transl Med 2021 Apr;13(588)

Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands.

Huntingtin (HTT)-lowering therapies hold promise to slow down neurodegeneration in Huntington's disease (HD). Here, we assessed the translatability and long-term durability of recombinant adeno-associated viral vector serotype 5 expressing a microRNA targeting human (rAAV5-miHTT) administered by magnetic resonance imaging-guided convention-enhanced delivery in transgenic HD minipigs. rAAV5-miHTT (1. Read More

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A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers.

Mult Scler Relat Disord 2021 Feb 24;51:102861. Epub 2021 Feb 24.

Biogen, Cambridge, MA, USA.

Background: Biomarkers are a useful and reliable measure of disease activity in many fields of medicine. Axonal and glial biomarkers in multiple sclerosis (MS) are being applied more often as technology is improving and becoming increasingly reliable. Nonclinical studies have shown dimethyl fumarate (DMF) to have cytoprotective and anti-inflammatory effects. Read More

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February 2021

Antimicrobial use in central nervous system infections.

Curr Opin Infect Dis 2021 Jun;34(3):255-263

Cleveland Clinic, Cleveland, Ohio, USA.

Purpose Of Review: Central nervous system (CNS) infections are associated with high rates of morbidity and mortality. The purpose of this review is to summarize current antimicrobial therapies, as well as, updates in the management of community-acquired meningitis and healthcare-associated meningitis and ventriculitis.

Recent Findings: Due to the increasing rates of multidrug resistant and extensively-drug resistant organisms, available antimicrobials are limited. Read More

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Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues.

Adv Drug Deliv Rev 2021 06 9;173:20-59. Epub 2021 Mar 9.

AbbVie Inc., 1 N Waukegan Road, North Chicago, IL 60064, USA. Electronic address:

Initially thought to be useful only to reach tissues in the immediate vicinity of the CSF circulatory system, CSF circulation is now increasingly viewed as a viable pathway to deliver certain therapeutics deeper into brain tissues. There is emerging evidence that this goal is achievable in the case of large therapeutic proteins, provided conditions are met that are described herein. We show how fluid dynamic modeling helps predict infusion rate and duration to overcome high CSF turnover. Read More

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High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial.

Clin Infect Dis 2021 Mar 8. Epub 2021 Mar 8.

Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, MN, USA.

Background: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Read More

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Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children.

PLoS Comput Biol 2021 Mar 4;17(3):e1008786. Epub 2021 Mar 4.

Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. Read More

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Phase I dose-escalation, safety, and CNS pharmacokinetic study of dexanabinol in patients with brain cancer.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab006. Epub 2021 Feb 15.

Moores Cancer Center, UC San Diego, La Jolla, California, USA.

Background: Dexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose. Read More

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February 2021

Ampicillin Pharmacokinetics During First Week of Life in Preterm and Term Neonates.

Pediatr Infect Dis J 2021 May;40(5):464-472

Department of Microbiology.

Background And Aims: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid.

Methods: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. Read More

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A validated LC-MS/MS method for the simultaneous quantification of the novel combination antibiotic, ceftolozane-tazobactam, in plasma (total and unbound), CSF, urine and renal replacement therapy effluent: application to pilot pharmacokinetic studies.

Clin Chem Lab Med 2021 Apr 25;59(5):921-933. Epub 2020 Nov 25.

UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia.

Objectives: Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane-tazobactam is a novel cephalosporin-beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography - tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine. Read More

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Antigen Mass May Influence Trastuzumab Concentrations in Cerebrospinal Fluid After Intrathecal Administration.

Clin Pharmacol Ther 2021 Feb 5. Epub 2021 Feb 5.

EA 4245 Transplantation, Immunologie, Inflammation, Université de Tours, Tours, France.

Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro-oncology, especially in leptomeningeal carcinomatosis of HER2-overexpressing breast cancer. Case reports of i.t. Read More

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February 2021

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study.

Clin Cancer Res 2021 May 5;27(9):2442-2451. Epub 2021 Feb 5.

Pediatric Neuro-Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.

Patients And Methods: Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Read More

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Pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor in children with acute leukaemia.

Br J Clin Pharmacol 2021 Jan 28. Epub 2021 Jan 28.

Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.

Aims: This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia.

Methods: PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. Read More

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January 2021

Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration alone in intracranial infections.

Int J Antimicrob Agents 2021 Mar 16;57(3):106281. Epub 2021 Jan 16.

Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. Electronic address:

The aim of this study was to investigate the pharmacokinetics of colistin in cerebrospinal fluid (CSF) after intraventricular (IVT) administration of colistin methanesulfonate (CMS) for central nervous system (CNS) infections caused by multidrug-resistant Gram-negative bacteria. Ten patients with CNS infection were treated with CMS (active substance colistin equivalent to 100 000 units, every 24 h) by IVT administration. After 3 days of treatment, the concentration of colistin in the CSF was determined by selective ultra-performance liquid chromatography (UPLC) at 2, 4, 6, 8, 12 and 24 h after CMS administration. Read More

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A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys.

Stem Cell Res Ther 2021 Jan 7;12(1):17. Epub 2021 Jan 7.

School of Life Sciences, Tsinghua University, Beijing, China.

Background: Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. Read More

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January 2021

Bifunctional GM-CSF-derived peptides as tools for O-glycoengineering and protein tagging.

J Biotechnol 2021 Feb 30;327:18-27. Epub 2020 Dec 30.

UNL, CONICET, FBCB (School of Biochemistry and Biological Sciences), CBL (Biotechnological Center of Litoral), Ciudad Universitaria, Ruta Nacional 168, Km 472.4, C.C. 242, S3000ZAA, Santa Fe, Argentina. Electronic address:

Rapid development of effective biotherapeutics has been a concern during the last couple decades. In our work we designed two novel peptide tags, GMOP and mGMOP, derived from the N-terminal region of human granulocyte and macrophage colony stimulating factor (hGM-CSF), which contain four and six potential O-glycosylation sites, respectively. These peptide tags were fused to the N-terminus of human interferon-α2b (hIFN-α2b), a therapeutic antiviral and antiproliferative protein rapidly cleared from circulation. Read More

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February 2021

Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.

JAMA Neurol 2021 Mar;78(3):312-320

Steven's Institute of Technology, Marlboro, New Jersey.

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD).

Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Read More

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Nanocapsules containing Saussurea lappa essential oil: Formulation, characterization, antidiabetic, anti-cholinesterase and anti-inflammatory potentials.

Int J Pharm 2021 Jan 3;593:120138. Epub 2020 Dec 3.

Univ Lyon, Université Claude Bernard Lyon-1, CNRS, LAGEPP UMR 5007, F-69622 Lyon, France. Electronic address:

Plant-based remedies have been widely used for the management of variable diseases due to their safety and less side effects. In the present study, we investigated Saussurea lappa CB. Clarke. Read More

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January 2021

Glymphatic Cerebrospinal Fluid and Solute Transport Quantified by MRI and PET Imaging.

Neuroscience 2020 Nov 26. Epub 2020 Nov 26.

Laboratory for Neuroimaging, NIAAA, Bethesda, MD, United States.

Over the past decade there has been an enormous progress in our understanding of fluid and solute transport in the central nervous system (CNS). This is due to a number of factors, including important developments in whole brain imaging technology and computational fluid dynamics analysis employed for the elucidation of glymphatic transport function in the live animal and human brain. In this paper, we review the technical aspects of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in combination with administration of Gd-based tracers into the cerebrospinal fluid (CSF) for tracking glymphatic solute and fluid transport in the CNS as well as lymphatic drainage. Read More

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November 2020

Population pharmacokinetics of vancomycin in patients with external ventricular drain-associated ventriculitis.

Br J Clin Pharmacol 2021 Jun 13;87(6):2502-2510. Epub 2020 Dec 13.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Muenster, Germany.

Background: To determine the distribution of vancomycin into the cerebrospinal fluid (CSF) in patients with external ventricular drain (EVD)-associated ventriculitis, the pharmacokinetics of vancomycin were evaluated and covariate relationships explored.

Methods: For the population pharmacokinetic model patients were recruited in a neurocritical care unit at the University Hospital of Muenster in the period between January 2014 and June 2015. All patients had a clinical evidence of EVD-associated ventriculitis. Read More

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Population Pharmacokinetics of Intraventricular Vancomycin in Neonatal Ventriculitis, A Preterm Pilot Study.

Eur J Pharm Sci 2021 Mar 12;158:105643. Epub 2020 Nov 12.

Neonatal Intensive Care Unit, Southmead Hospital, Southmead Road, Bristol, United Kingdom, BS10 5NB; Neonatal Neurology Group, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom, BS8 1TH.

Aim: Intraventricular vancomycin is an effective treatment for neonatal ventriculitis, as the cerebrospinal fluid (CSF) vancomycin levels reach adequate concentrations to achieve microbiological cure. There is no robust data on intraventricular vancomycin pharmacokinetics in the preterm population. This pilot population pharmacokinetic modelling study examines the pharmacokinetic behaviour of intraventricular vancomycin in the preterm population of < 28 weeks gestation, to inform the feasibility of future prospective studies. Read More

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[Pharmacokinetics and pharmacodynamics of pegylated recombinant human granulocyte colony-stimulating factor in children with acute lymphoblastic leukemia: a prospective control trial].

Zhongguo Dang Dai Er Ke Za Zhi 2020 Nov;22(11):1172-1177

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

Objective: To study the pharmacokinetic characteristics, clinical effect, and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in children with acute lymphoblastic leukemia (ALL).

Methods: A prospective study was performed on children with ALL who cyclophosphamide, cytarabine, and 6-mercaptopurine were used for consolidation therapy. PEG-rhG-CSF (PEG-rhG-CSF group) or rhG-CSF (rhG-CSF group) was injected after chemotherapy. Read More

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November 2020

Local Targeting of Lung-Tumor-Associated Macrophages with Pulmonary Delivery of a CSF-1R Inhibitor for the Treatment of Breast Cancer Lung Metastases.

Mol Pharm 2020 12 10;17(12):4691-4703. Epub 2020 Nov 10.

Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.

The lungs are major sites of metastases for several cancer types, including breast cancer (BC). Prognosis and quality of life of BC patients that develop pulmonary metastases are negatively impacted. The development of strategies to slow the growth and relieve the symptoms of BC lung metastases (BCLM) is thus an important goal in the management of BC. Read More

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December 2020

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Read More

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December 2020

Pharmacologic approaches to HIV-associated neurocognitive disorders.

Curr Opin Pharmacol 2020 10 10;54:102-108. Epub 2020 Oct 10.

Antiviral Pharmacology Laboratory, UNMC Center for Drug Discovery, Omaha, NE, United States. Electronic address:

Antiretroviral therapy in people living with HIV can achieve potent, long-term suppression of HIV plasma viremia and has increased life expectancy. The central nervous system is infected early after virus acquisition and remains a reservoir for HIV. HIV-associated neurocognitive disorders (HAND) are an end-organ manifestation of HIV infection. Read More

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October 2020

IntraOmmaya compartmental radioimmunotherapy using I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

Eur J Nucl Med Mol Imaging 2021 04 13;48(4):1166-1177. Epub 2020 Oct 13.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases. Read More

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