scholarly journals Sensitive LC-MS/MS Methods for Amphotericin B Analysis in Cerebrospinal Fluid, Plasma, Plasma Ultrafiltrate, and Urine: Application to Clinical Pharmacokinetics

2021 ◽  
Vol 9 ◽  
Author(s):  
Leandro Francisco Pippa ◽  
Maria Paula Marques ◽  
Anna Christina Tojal da Silva ◽  
Fernando Crivelenti Vilar ◽  
Tissiana Marques de Haes ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amphotericin B ◽  
Inflammatory Diseases ◽  
Total Concentration ◽  
Pharmacokinetic Parameters ◽  
Lipid Complex ◽  
Clinical Pharmacokinetics ◽  
The Central Nervous System ◽  
In The Beginning ◽  
Plasma Ultrafiltrate

Neurocryptococcosis, a meningoencephalitis caused by Cryptococcus spp, is treated with amphotericin B (AmB) combined with fluconazole. The integrity of the brain-blood barrier and the composition of the cerebrospinal fluid (CSF) may change due to infectious and/or inflammatory diseases such as neurocryptococcosis allowing for the penetration of AmB into the central nervous system. The present study aimed to develop LC-MS/MS methods capable of quantifying AmB in CSF at any given time of the treatment in addition to plasma, plasma ultrafiltrate, with sensitivity compatible with the low concentrations of AmB reported in the CSF. The methods were successfully validated in the four matrices (25 μl, 5–1,000 ng ml−1 for plasma or urine; 100 μl, 0.625–250 ng ml−1 for plasma ultrafiltrate; 100 μl, 0.1–250 ng ml−1 for CSF) using protein precipitation. The methods were applied to investigate the pharmacokinetics of AmB following infusions of 100 mg every 24 h for 16 days administered as a lipid complex throughout the treatment of a neurocryptococcosis male patient. The methods allowed for a detailed description of the pharmacokinetic parameters in the assessed patient in the beginning (4th day) and end of the treatment with AmB (16th day), with total clearances of 7.21 and 4.25 L h−1, hepatic clearances of 7.15 and 4.22 L h−1, volumes of distribution of 302.94 and 206.89 L, and unbound fractions in plasma ranging from 2.26 to 3.25%. AmB was quantified in two CSF samples collected throughout the treatment with concentrations of 12.26 and 18.45 ng ml−1 on the 8th and 15th days of the treatment, respectively. The total concentration of AmB in plasma was 31 and 20 times higher than in CSF. The unbound concentration in plasma accounted for 77 and 44% of the respective concentrations in CSF. In conclusion, the present study described the most complete and sensitive method for AmB analysis in plasma, plasma ultrafiltrate, urine, and CSF applied to a clinical pharmacokinetic study following the administration of the drug as a lipid complex in one patient with neurocryptococcosis. The method can be applied to investigate the pharmacokinetics of AmB in CSF at any given time of the treatment.

Serial MRI and CSF Analysis in a Dog Treated with Intrathecal Amphotericin B for Protothecosis

2012 ◽  
Vol 48 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Martin Young ◽  
William Bush ◽  
Melissa Sanchez ◽  
Pat Gavin ◽  
Mathew Williams
Keyword(s):  
Cerebrospinal Fluid ◽  
Amphotericin B ◽  
Head Tilt ◽  
Mri Findings ◽  
Lipid Complex ◽  
Fluid Analysis ◽  
Csf Analysis ◽  
Transient Improvement ◽  
The Right ◽  
The Brain

A 3 yr old female spayed English setter mixed-breed dog presented with diarrhea, weight loss, side stepping to the right, and a right head tilt. Rectal and cerebrospinal fluid cytology and culture confirmed a diagnosis of Prototheca zopfii. MRI of the brain showed inflammation of the brain and meninges, ventriculomegaly, and syringomyelia. Treatment with prednisone, itraconazole, and amphotericin B lipid complex administered intrathecally yielded transient improvement. Progressive brainstem signs were noted, and a repeat MRI and cerebrospinal fluid analysis documented persistent disease. This is the first description of the MRI findings and treatment with intrathecal amphoteracin B lipid complex for protothecosis of the central nervous system. Protothecosis should be considered in dogs with chronic diarrhea and compatible MRI findings.

scholarly journals An update on meningoencephalomyelitis of unknown aetiology in dogs

2017 ◽  
Vol 64 (2) ◽  
pp. 131
Author(s):  
M. CHARALAMBOUS (Μ. ΧΑΡΑΛΑΜΠΟΥΣ) ◽  
T. DANOURDIS (Τ. ΔΑΝΟΥΡΔΗΣ) ◽  
A. HATZIS (Α. ΧΑΤΖΗΣ) ◽  
Z. S. POLIZOPOULOU (Ζ. ΠΟΛΥΖΟΠΟΥΛΟΥ)
Keyword(s):  
Computed Tomography ◽  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Inflammatory Diseases ◽  
Histopathological Examination ◽  
Unknown Aetiology ◽  
Cerebrospinal Fluid Analysis ◽  
Fluid Analysis ◽  
The Central Nervous System

Inflammatory diseases of the central nervous system are common causes of neurological dysfunction in the dog and can be grouped into two broad categories; those of infectious and those of unknown aetiology. Μeningoencephalomyelitis of unknown aetiology include non-infectious inflammatory central nervous system diseases in which abnormal findings on magnetic resonance imaging and cerebrospinal fluid analysis indicate inflammatory central nervous system disease, but for which histopathological confirmation has not been reached. Meningoencephalomyelitis of unknown aetiology describes a group of non-infectious inflammatory diseases of the central nervous system. These include the granulomatous meningoencephalomyelitis and the necrotising encephalitis, the latter can be further distinguished into two subtypes: necrotising meningoencephalitis and necrotising leucoencephalitis. Steroid-responsive meningitis-arteritis may be also included to this category and, usually, does not present signs of encephalitis or/and myelitis (except in the chronic form) and is easier diagnosed even without histopathological examination. In most cases of meningoencephalomyelitis of unknown aetiology, a presumptive diagnosis can be achieved by the assessment of case presentation, theneurologic signs, cerebrospinal fluid testing, cross-sectional imaging of the central nervous system and appropriate microbiological tests.Definite diagnosis is achieved with histopathological examination. The underlying cause for these diseases is unknown. The clinical signs in meningoencephalomyelitis of unknown aetiology is variable and depends on which area of the central nervous sytem is affected. Meningoencephalomyelitis is acute in onset, progressive in nature and associated with multifocal to diffuse neuroanatomic localization. Extraneural signs are less common and these usually include pyrexia and peripheral neutrophilia. The differential diagnosis for dogs presented for an acute onset of multifocal central nervous system signs includes genetic abnormalities, metabolic disorders, infectious meningoencephalitis, toxin exposure, stroke and neoplasia.The diagnostic approach includes a complete blood count, a comprehensive chemistry panel, urinalysis, survey radiographs of the thorax plus abdominal ultrasound to rule out systematic disease and metastatic neoplasia, computed-tomography or magnetic reso meningitisnance imaging, cerebrospinal fluid analysis and microbiological tests.When neoplasia is suspected, computed-tomography-guided brain biopsy may be required for the differentiation. Meningoencephalomyelitis of unknown aetiology responds more or less to immunosuppressive therapies, but the prognosis should be guarded to poor with the exception of steroid-responsive meningitisarteritis, for which it is good. Treatment protocols are based on prednisolone, but new immunosuppressive agents have now been added in those to control the diseases and they seem to be effective. However, gold standard protocols have yet to be established.

scholarly journals Compartmentalized Intrapulmonary Pharmacokinetics of Amphotericin B and Its Lipid Formulations

2006 ◽  
Vol 50 (10) ◽  
pp. 3418-3423 ◽  
Author(s):  
Andreas H. Groll ◽  
Caron A. Lyman ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Derek Armstrong ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Lung Tissue ◽  
Colloidal Dispersion ◽  
Pharmacokinetic Parameters ◽  
Dilution Method ◽  
Lipid Complex ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Lipid Formulations

ABSTRACT We investigated the compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations in healthy rabbits. Cohorts of three to seven noninfected, catheterized rabbits received 1 mg of amphotericin B deoxycholate (DAMB) per kg of body weight or 5 mg of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), or liposomal amphotericin B (LAMB) per kg once daily for a total of 8 days. Following sparse serial plasma sampling, rabbits were sacrificed 24 h after the last dose, and epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and lung tissue were obtained. Pharmacokinetic parameters in plasma were derived by model-independent techniques, and concentrations in ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Mean amphotericin B concentrations ± standard deviations (SD) in lung tissue and PAM were highest in ABLC-treated animals, exceeding concurrent plasma levels by 70- and 375-fold, respectively (in lung tissue, 16.24 ± 1.62 versus 2.71 ± 1.22, 6.29 ± 1.17, and 6.32 ± 0.57 μg/g for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0029]; in PAM, 89.1 ± 37.0 versus 8.92 ± 2.89, 5.43 ± 1.75, and 7.52 ± 2.50 μg/ml for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0246]). By comparison, drug concentrations in ELF were much lower than those achieved in lung tissue and PAM. Among the different cohorts, the highest ELF concentrations were found in LAMB-treated animals (2.28 ± 1.43 versus 0.44 ± 0.13, 0.68 ± 0.27, and 0.90 ± 0.28 μg/ml in DAMB-, ABCD-, and ABLC-treated animals, respectively [P = 0.0070]). In conclusion, amphotericin B and its lipid formulations displayed strikingly different patterns of disposition in lungs 24 h after dosing. Whereas the disposition of ABCD was overall not fundamentally different from that of DAMB, ABLC showed prominent accumulation in lung tissue and PAM, while LAMB achieved the highest concentrations in ELF.

scholarly journals NMR metabolomics of cerebrospinal fluid differentiates inflammatory diseases of the central nervous system

2018 ◽  
Vol 12 (12) ◽  
pp. e0007045 ◽  
Author(s):  
Caitlin D. French ◽  
Rodney E. Willoughby ◽  
Amy Pan ◽  
Susan J. Wong ◽  
John F. Foley ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Inflammatory Diseases ◽  
Nmr Metabolomics ◽  
The Central Nervous System

Diagnostic relevance of CSF interleukin-6

2016 ◽  
Vol 39 (6) ◽  
Author(s):  
Sylvia Gruber ◽  
Philipp Werner ◽  
Reinhard Germann ◽  
Peter Fraunberger
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
B Cells ◽  
Interleukin 6 ◽  
Inflammatory Diseases ◽  
Diagnostic Significance ◽  
Glia Cells ◽  
Chronic Inflammatory Diseases ◽  
The Central Nervous System ◽  
Stimulatory Factor

Abstract:In 1985 interleukin 6 (IL-6) was first identified as a differentiation factor for B-cells (B-cell stimulatory factor 2) which caused B-cells to mature and produce antibodies. Numerous studies now demonstrate the pleiotropic character of IL-6, which has been shown to possess important functions in the immune system, the regulation of hematopoesis, inflammation and oncogenesis. In the central nervous system (CNS), IL-6 is involved in neurogenesis and the response of neurons and glia-cells to various injuries. CNS infections, cerebral ischaemia, CNS traumata or chronic inflammatory diseases with CNS manifestations such as neuro-lupus or neuro-sarcoidosis are associated with increased IL-6 levels in the cerebrospinal fluid (CSF). Thus, the use of IL-6 as a diagnostic and prognostic tool in these diseases is being investigated. In this review we aim to provide an overview of current studies and evaluate the diagnostic significance of CSF-IL-6.

scholarly journals Collection of cerebrospinal fluid in 50 adult healthy donkeys (Equus asinus): clinical complications, and cytological and biochemical constituents

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Mohammed A. H. Abdelhakiem ◽  
Hussein Awad Hussein
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Inflammatory Diseases ◽  
Sodium Concentration ◽  
Biochemical Constituents ◽  
Clinical Complications ◽  
Cell Counts ◽  
Equus Asinus ◽  
The Central Nervous System

Abstract Background Diseases of the central nervous system are a well-recognized cause of morbidity and mortality in equine. Collection and analysis of cerebrospinal fluid (CSF) give information about the type and stage of degenerative and inflammatory diseases in central nervous system (CNS). The present research aimed to assess the clinical complications of CSF collections and to establish range values of cytological and biochemical parameters of CSF in adult healthy donkeys (Equus asinus). The CSF samples were collected from fifty healthy donkeys at the lumbosacral (LS) and atlanto-occipital (AO) sites. Results Hypothermia, tachycardia, ataxia and recumbency may develop post-puncture. Erythrocytes were noticed in 35 of 50 CSF samples. Total nucleated cell counts ranged from 0 to 6 cells/μL, and lymphocytes predominated the cells (61%). The concentration of glucose (1.2 to 5.3 mmol/L) was lower than that of serum (P < 0.05). The CSF sodium concentration (123 to 160 mmol/L) was approximately like that of serum, but potassium (1.5–3 mmol/L) was lower than that of serum (P < 0.01). Urea concentrations (1.1–2.9 mmol/L) were markedly lower than serum (P < 0.001). Concentrations of CSF total proteins, and albumin ranged from 0.1 to 0.6 g/dL, and from 0.002 to 0.013 g/dL, respectively. The albumin quotient ranged from 0.06 to 0.56. Conclusions Transient hypothermia, tachycardia, ataxia and recumbency may develop as clinical complications of CSF puncture procedures. The collection site has no impact on the constituents in CSF. Furthermore, this study presented the range values for normal cytological and biochemical constituents of CSF in donkeys (Equus asinus) that can provide a basis in comparison when evaluating CSF from donkeys with neurologic diseases.

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