scholarly journals Pharmacodynamics of Isavuconazole in a Rabbit Model of Cryptococcal Meningoencephalitis

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Laura L. Kovanda ◽  
Charles Giamberardino ◽  
Laura McEntee ◽  
Dena L. Toffaletti ◽  
Kelly S. Franke ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fungal Pathogens ◽  
Rabbit Model ◽  
Response Relationship ◽  
Fungal Burden ◽  
Cryptococcal Meningoencephalitis ◽  
Exposure Response ◽  
Dose Dependent ◽  
The Brain ◽  
Over Time

ABSTRACT Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.

scholarly journals Cerebrospinal Fluid and Plasma (1→3)-β-d-Glucan as Surrogate Markers for Detection and Monitoring of Therapeutic Response in Experimental Hematogenous Candida Meningoencephalitis

2008 ◽  
Vol 52 (11) ◽  
pp. 4121-4129 ◽  
Author(s):  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
William W. Hope ◽  
Diana Mickiene ◽  
Amy M. Kelaher ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Amphotericin B ◽  
Therapeutic Response ◽  
Rabbit Model ◽  
Vitreous Humor ◽  
Therapeutic Monitoring ◽  
Treatment Groups ◽  
Dose Dependent ◽  
Established Infection

ABSTRACT The treatment, diagnosis and therapeutic monitoring of hematogenous Candida meningoencephalitis (HCME) are not well understood. We therefore studied the expression of (1→3)-β-d-glucan (β-glucan) in cerebrospinal fluid (CSF) and plasma in a nonneutropenic rabbit model of experimental HCME treated with micafungin and amphotericin B. Groups studied consisted of micafungin (0.5 to 32 mg/kg) and amphotericin B (1 mg/kg) treatment groups and the untreated controls (UC). Despite well-established infection in the cerebrum, cerebellum, choroid, vitreous humor (102 to 103 CFU/ml), spinal cord, and meninges (10 to 102 CFU/g), only 8.1% of UC CSF cultures were positive. By comparison, all 25 UC CSF samples tested for β-glucan were positive (755 to 7,750 pg/ml) (P < 0.001). The therapeutic response in CNS tissue was site dependent, with significant decreases of the fungal burden in the cerebrum and cerebellum starting at 8 mg/kg, in the meninges at 2 mg/kg, and in the vitreous humor at 4 mg/kg. A dosage of 24 mg/kg was required to achieve a significant effect in the spinal cord and choroid. Clearance of Candida albicans from blood cultures was not predictive of eradication of organisms from the CNS; conversely, β-glucan levels in CSF were predictive of the therapeutic response. A significant decrease of β-glucan concentrations in CSF, in comparison to that for UC, started at 0.5 mg/kg (P < 0.001). Levels of plasma β-glucan were lower than levels in simultaneously obtained CSF (P < 0.05). CSF β-glucan levels correlated in a dose-dependent pattern with therapeutic responses and with Candida infection in cerebral tissue (r = 0.842). Micafungin demonstrated dose-dependent and site-dependent activity against HCME. CSF β-glucan may be a useful biomarker for detection and monitoring of therapeutic response in HCME.

scholarly journals Evaluation of the Mtb72F Polyprotein Vaccine in a Rabbit Model of Tuberculous Meningitis

2006 ◽  
Vol 74 (4) ◽  
pp. 2392-2401 ◽  
Author(s):  
Liana Tsenova ◽  
Ryhor Harbacheuski ◽  
Andre L. Moreira ◽  
Evette Ellison ◽  
Wilfried Dalemans ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Weight Loss ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Mycobacterium Tuberculosis ◽  
Tuberculous Meningitis ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Cns Infection ◽  
The Brain

ABSTRACT Using a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F+AS02A) or Mtb72F formulated in AS01B (Mtb72F+AS01B) was protective against central nervous system (CNS) challenge with Mycobacterium tuberculosis H37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F+AS02A-vaccinated rabbits. In addition, protection against M. tuberculosis H37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F+AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.

Fibrinolytic Activity of Cerebro-Spinal Fluid and the Development of Artificial Cerebral Haematomas in Dogs

1969 ◽  
Vol 21 (02) ◽  
pp. 294-303 ◽  
Author(s):  
H Mihara ◽  
T Fujii ◽  
S Okamoto
Keyword(s):  
Cerebrospinal Fluid ◽  
Carboxylic Acid ◽  
Fibrinolytic Activity ◽  
Clinical Implications ◽  
Trans Form ◽  
Plate Method ◽  
Blood Samples ◽  
Fibrin Plate ◽  
The Brain

SummaryBlood was injected into the brains of dogs to produce artificial haematomas, and paraffin injected to produce intracerebral paraffin masses. Cerebrospinal fluid (CSF) and peripheral blood samples were withdrawn at regular intervals and their fibrinolytic activities estimated by the fibrin plate method. Trans-form aminomethylcyclohexane-carboxylic acid (t-AMCHA) was administered to some individuals. Genera] relationships were found between changes in CSF fibrinolytic activity, area of tissue damage and survival time. t-AMCHA was clearly beneficial to those animals given a programme of administration. Tissue activator was extracted from the brain tissue after death or sacrifice for haematoma examination. The possible role of tissue activator in relation to haematoma development, and clinical implications of the results, are discussed.

Vasopressin enhances the clearance of β-endorphin immunoreactivity from rat cerebrospinal fluid

1990 ◽  
Vol 122 (2) ◽  
pp. 191-200 ◽  
Author(s):  
C. G. J. Sweep ◽  
Margreet D. Boomkamp ◽  
István Barna ◽  
A. Willeke Logtenberg ◽  
Victor M. Wiegant
Keyword(s):  
Cerebrospinal Fluid ◽  
Receptor Antagonist ◽  
Short Duration ◽  
Lateral Ventricle ◽  
Underlying Mechanism ◽  
Terminal Phase ◽  
Intracerebroventricular Injection ◽  
Intracerebroventricular Administration ◽  
Biphasic Pattern ◽  
The Brain

Abstract The effect of intracerebroventricular (lateral ventricle) administration of arginine8-vasopressin (AVP) on the concentration of β-endorphin immunoreactivity in the cerebrospinal fluid obtained from the cisterna magna was studied in rats. A decrease was observed 5 min following injection of 0.9 fmol AVP. No statistically significant changes were found 5 min after intracerebroventricular treatment of rats with 0.09 or 9 fmol. The decrease induced by 0.9 fmol AVP was of short duration and was found 5 min after treatment but not 10 and 20 min. Desglycinamide9-AVP (0.97 fmol), [pGlu4, Cyt6]-AVP-(4–9) (1.44 fmol), Nα-acetyl-AVP (0.88 fmol), lysine8-vasopressin (0.94 fmol) and oxytocin (1 fmol) when intracerebroventricularly injected did not affect the levels of β-endorphin immunoreactivity in the cerebrospinal fluid 5 min later. This suggests that the intact AVP-(1–9) molecule is required for this effect. Intracerebroventricular pretreatment of rats with the vasopressin V1-receptor antagonist d(CH2)5Tyr(Me)AVP (8.63 fmol) completely blocked the effect of AVP (0.9 fmol). In order to investigate further the underlying mechanism, the effect of AVP on the disappearance from the cerebrospinal fluid of exogenously applied β-endorphin was determined. Following intracerebroventricular injection of 1.46 pmol camel β-endorphin-(1–31), the β-endorphin immunoreactivity levels in the cisternal cerebrospinal fluid increased rapidly, and reached peak values at 10 min. The disappearance of β-endorphin immunoreactivity from the cerebrospinal fluid then followed a biphasic pattern with calculated half-lifes of 28 and 131 min for the initial and the terminal phase, respectively. Treatment of rats with AVP (0.9 fmol; icv) during either phase (10, 30, 55 min following intracerebroventricular administration of 1.46 pmol β-endorphin-(1–31)) significantly enhanced the disappearance of β-endorphin immunoreactivity from the cerebrospinal fluid. The data suggest that vasopressin plays a role in the regulation of β-endorphin levels in the cerebrospinal fluid by modulating clearance mechanisms via V1-receptors in the brain.

Cerebrospinal fluid microscopy as an index for predicting the prognosis of cryptococcal meningitis patients with and without HIV

2020 ◽  
Vol 15 (17) ◽  
pp. 1645-1652
Author(s):  
Keming Zhang ◽  
Hang Li ◽  
Lei Zhang ◽  
Wanqing Liao ◽  
Liyan Ling ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Clinical Data ◽  
Cryptococcal Meningitis ◽  
Fungal Burden ◽  
Hospital Patients ◽  
Patient Prognosis ◽  
Worse Prognosis ◽  
Fluid Test

Aim: To evaluate the clinical data and quantitative cerebrospinal fluid for associations with the outcome of cryptococcal meningitis (CM) patients in the hospital. Patients & methods: We retrospectively analyzed a total of 139 CM patients comprising 108 without HIV and 31 with HIV admitted in a Jiang Xi hospital. Resμlts: We found that CM patients with the high fungal burden (≥10 yeasts/μl) (26.3%) had a worse prognosis than those with the low fungal burden (<10 yeasts/μl). (4.9%) (p = 0.0007 <0.05). Conclusion: In CM patients, a fungal burden of 10 yeasts/μl in the first cerebrospinal fluid test may be used as an indicator of patient prognosis, and we can personalize patients’ treatment based on the fungal burden to improve prognosis.

Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro

2001 ◽  
Vol 91 (6) ◽  
pp. 2703-2712 ◽  
Author(s):  
Stephen M. Johnson ◽  
Julia E. R. Wilkerson ◽  
Daniel R. Henderson ◽  
Michael R. Wenninger ◽  
Gordon S. Mitchell
Keyword(s):  
Brain Stem ◽  
Respiratory Activity ◽  
Dependent Manner ◽  
Frequency Increase ◽  
Burst Frequency ◽  
Bath Application ◽  
Burst Amplitude ◽  
Dose Dependent ◽  
The Brain

Brain stem preparations from adult turtles were used to determine how bath-applied serotonin (5-HT) alters respiration-related hypoglossal activity in a mature vertebrate. 5-HT (5–20 μM) reversibly decreased integrated burst amplitude by ∼45% ( P < 0.05); burst frequency decreased in a dose-dependent manner with 20 μM abolishing bursts in 9 of 13 preparations ( P < 0.05). These 5-HT-dependent effects were mimicked by application of a 5-HT1A agonist, but not a 5-HT1B agonist, and were abolished by the broad-spectrum 5-HT antagonist, methiothepin. During 5-HT (20 μM) washout, frequency rebounded to levels above the original baseline for 40 min ( P < 0.05) and remained above baseline for 2 h. A 5-HT3 antagonist (tropesitron) blocked the post-5-HT rebound and persistent frequency increase. A 5-HT3 agonist (phenylbiguanide) increased frequency during and after bath application ( P < 0.05). When phenylbiguanide was applied to the brain stem of brain stem/spinal cord preparations, there was a persistent frequency increase ( P < 0.05), but neither spinal-expiratory nor -inspiratory burst amplitude were altered. The 5-HT3receptor-dependent persistent frequency increase represents a unique model of plasticity in vertebrate rhythm generation.

scholarly journals The Effect of an Alternative Definition of “Percent Highly Annoyed” on the Exposure–Response Relationship: Comparison of Noise Annoyance Responses Measured by ICBEN 5-Point Verbal and 11-Point Numerical Scales

2021 ◽  
Vol 18 (12) ◽  
pp. 6258
Author(s):  
Makoto Morinaga ◽  
Thu Lan Nguyen ◽  
Shigenori Yokoshima ◽  
Koji Shimoyama ◽  
Takashi Morihara ◽  
...  
Keyword(s):  
Sound Pressure ◽  
Response Relationship ◽  
Alternative Definition ◽  
Exposure Response ◽  
Noise Annoyance ◽  
Numerical Scale ◽  
Verbal Scale ◽  
Sound Pressure Levels ◽  
Acoustic Surveys ◽  
Definition Of

Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5–point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day–evening–night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.

scholarly journals Safety of Catheter Embolization of Pulmonary Arteriovenous Malformations—Evaluation of Possible Cerebrovascular Embolism after Catheter Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia/Osler Disease by Pre- and Post-Interventional DWI

2021 ◽  
Vol 10 (4) ◽  
pp. 887
Author(s):  
Guenther Schneider ◽  
Alexander Massmann ◽  
Peter Fries ◽  
Felix Frenzel ◽  
Arno Buecker ◽  
...  
Keyword(s):  
Arteriovenous Malformations ◽  
Pulmonary Arteriovenous Malformations ◽  
B Values ◽  
Safe Method ◽  
Embolization Therapy ◽  
Catheter Embolization ◽  
Contrast Enhanced ◽  
Previously Treated ◽  
The Brain ◽  
Over Time

Background. This paper aimed to prospectively evaluate the safety of embolization therapy of pulmonary arteriovenous malformations (PAVMs) for the detection of cerebral infarctions by pre- and post-interventional MRI. Method One hundred and five patients (male/female = 44/61; mean age 48.6+/−15.8; range 5–86) with pre-diagnosed PAVMs on contrast-enhanced MRA underwent embolization therapy. The number of PAVMs treated in each patient ranged from 1–8 PAVMs. Depending on the size and localization of the feeding arteries, either Nester-Coils or Amplatzer vascular plugs were used for embolization therapy. cMRI was performed immediately before, and at the 4 h and 3-month post-embolization therapy. Detection of peri-interventional cerebral emboli was performed via T2w and DWI sequences using three different b-values, with calculation of ADC maps. Results Embolization did not show any post-/peri-interventional, newly developed ischemic lesions in the brain. Only one patient who underwent re-embolization and was previously treated with tungsten coils that corroded over time showed newly developed, small, diffuse emboli in the post-interventional DWI sequence. This patient already had several episodes of brain emboli before re-treatment due to the corroded coils, and during treatment, when passing the corroded coils, experienced additional small, clinically inconspicuous brain emboli. However, this complication was anticipated but accepted, since the vessel had to be occluded distally. Conclusion Catheter-based embolization of PAVMs is a safe method for treatment and does not result in clinically inconspicuous cerebral ischemia, which was not demonstrated previously.

Exposure–Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus

Rheumatology ◽  
2021 ◽  
Author(s):  
Yen Lin Chia ◽  
Linda Santiago ◽  
Bing Wang ◽  
Denison Kuruvilla ◽  
Shiliang Wang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Drug Clearance ◽  
Optimal Dosage ◽  
Type I ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Phase 3 ◽  
Optimal Dosage Regimen ◽  
Exposure Response ◽  
Selection Of

Abstract Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFN test–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses &lt;300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor–mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

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