EXTH-35. STEADY STATE BRAIN EXTRACELLULAR FLUID AND PLASMA PHARMACOKINETICS OF LETROZOLE IN SPRAGUE DAWLEY RATS: GENDER DIFFERENCES AND PROJECTIONS FOR TUMORAL DRUG LEVELS

To evaluate the regulation of (H+) and (HCO3 minus) in brain extracellular fluid during respiratory acidosis, the changes in cisternal and lumbar CSF acid-base state were assessed in six anteshetized, paralyzed, mechanically ventilated dogs rendered hypercapnic by increase in FIco2. Arterial (HCO3 minus) was held constant. The electrochemical potential difference (mu) between CSF and blood for H+ and HCO3 minus was calculated from values for (H+) and (HCO3 minus) in CSF and arterial plasma and the simultaneously measured CSF/plasma DC potential difference. Measurements were made at pHa equal to 7.40, after stable arterial values of pHa of about 7.2 were attained and 3, 4.5, and 6 h thereafter. A steady state for ion distribution was attained by 4.5 h. Values of mu for H+ and HCO3 minus at 6 h had returned to +0.7 and minus 0.7 mV of control for cisternal CSF and +1.3 and minus 0.6 mV of control for lumbar CSF. The attainment of steady-state values for mu close to control is comparable with passive distribution of these ions between CSF and blood.

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Distribution of H+ and HCO3 minus between CSF and blood during metabolic alkalosis in dogs

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1975.228.4.1141 ◽

1975 ◽

Vol 228 (4) ◽

pp. 1141-1144 ◽

Cited By ~ 15

Author(s):

EG Pavlin ◽

ttf Hornbein

Keyword(s):

Cerebrospinal Fluid ◽

Steady State ◽

Metabolic Alkalosis ◽

Extracellular Fluid ◽

Ion Distribution ◽

Brain Extracellular Fluid ◽

Dc Potential ◽

Arterial Plasma ◽

Lumbar Cerebrospinal Fluid

In anesthetized, paralyzed dogs ventilated to maintain a normal PaCO2, metabolic alkalosis was induced and held constant over 6 h by infusion of sodium bicarbonate. Determination of pH, PCO2, (HCO3 minus), and (lactate) in cisternal and lumbar cerebrospinal fluid (CSF) and in arterial plasma together with measurement of the CSF/plasma DC potential differences permitted calculation of the electrochemical potential difference (mu) for H+ and HCO3 minus; measurements were made prior to induction of metabolic alkalosis at pHa equal to 7.40, as soon after induction as stable arterial values were achieved and 3, 4.5, and 6 h thereafter. A steady state for ion distribution was reached by 4.5 h. Values of mu for H+ and HCO3 minus returned to +0.1 and +0.9 mV of control at 6 h for cisternal CSF and +0.6 and minus 0.4 mV for lumbar CSF. This return of muH+ and muHCO3 minus close to control in the steady state is compatible with passive distribution of these ions between brain extracellular fluid and blood.

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Subchronic Toxicity of S-111-S-WB in Sprague Dawley Rats

International Journal of Toxicology ◽

10.1177/1091581810370372 ◽

2010 ◽

Vol 29 (4) ◽

pp. 358-371 ◽

Cited By ~ 6

Author(s):

Jozef J. W. M. Mertens ◽

Daniel W. Sved ◽

Gary B. Marit ◽

Nichole R. Myers ◽

Phil L. Stetson ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Steady State ◽

Ammonium Salts ◽

Serum Concentrations ◽

Sprague Dawley ◽

Subchronic Toxicity ◽

Lower Serum ◽

Sprague Dawley Rats ◽

Steady State Serum ◽

Effect Level

S-111-S-WB, a mixture of perfluoro fatty acid ammonium salts (C6-C13), was administered orally to Crl:CD (SD)IGS-BR rats. Higher hepatic β-oxidation and liver weights with hepatocellular hypertrophy were present at the 0.125 and 0.6 mg/kg/d dosage. The 0.6 mg/kg/d males developed hepatocellular degeneration and necrosis. Lower serum protein and higher bilirubin and BUN were seen in the 0.6 mg/kg/d males and lower globulin and higher alkaline phosphatase in the 0.125 mg/kg/d males and 0.6 mg/kg/d animals. After 2 weeks, serum concentrations of pentadecafluorooctanoic acid (C8), heptadecafluorononanoic acid (C9), perfluoroundecanoic acid (C11), and perfluorotridecanoic acid (C13) were constant for at least 8 hours. After 90 days, only C9 in the 0.025 mg/kg/d females had reached steady state. Serum C8 and C9 concentrations in the males were 10-fold higher than in the females, whereas C11 and C13 were similar for both genders. The main elimination was via the urine for C8 (males) and C9 (females), and via the feces for C11 and C13. The no-observed-effect level (NOEL) was 0.025 mg/kg/d for the males and 0.125 mg/kg/d for the females.

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Development of Risperidone PLGA Microspheres

Journal of Drug Delivery ◽

10.1155/2014/620464 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Susan D’Souza ◽

Jabar A. Faraj ◽

Stefano Giovagnoli ◽

Patrick P. DeLuca

Keyword(s):

Steady State ◽

Sustained Release ◽

Sustained Delivery ◽

Plga Microspheres ◽

Sprague Dawley ◽

Multiple Dosing ◽

Duration Of Action ◽

Sprague Dawley Rats

The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug.

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Zidovudine Concentration in Brain Extracellular Fluid Measured by Microdialysis: Steady-State and Transient Results in Rhesus Monkey

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.301.3.1003 ◽

2002 ◽

Vol 301 (3) ◽

pp. 1003-1011 ◽

Cited By ~ 29

Author(s):

Elizabeth Fox ◽

Peter M. Bungay ◽

John Bacher ◽

Cynthia L. McCully ◽

Robert L. Dedrick ◽

...

Keyword(s):

Steady State ◽

Rhesus Monkey ◽

Extracellular Fluid ◽

Brain Extracellular Fluid

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The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid

Journal of Pharmacokinetics and Pharmacodynamics ◽

10.1007/s10928-013-9314-4 ◽

2013 ◽

Vol 40 (3) ◽

pp. 327-342 ◽

Cited By ~ 32

Author(s):

Joost Westerhout ◽

Jean Smeets ◽

Meindert Danhof ◽

Elizabeth C. M. de Lange

Keyword(s):

Steady State ◽

Extracellular Fluid ◽

Brain Extracellular Fluid ◽

The Impact

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Plasticity of rat motoneuron rhythmic firing properties with varying levels of afferent and descending inputs

Journal of Neurophysiology ◽

10.1152/jn.00122.2011 ◽

2012 ◽

Vol 107 (1) ◽

pp. 265-272 ◽

Cited By ~ 14

Author(s):

C. W. MacDonell ◽

D. C. Button ◽

E. Beaumont ◽

B. Cormery ◽

P. F. Gardiner

Keyword(s):

Steady State ◽

Initial Segment ◽

Interspike Interval ◽

Discharge Rate ◽

Sprague Dawley ◽

Descending Pathways ◽

Sprague Dawley Rats ◽

Rhythmic Firing ◽

Firing Properties ◽

Frequency Current

Hindlimb motoneuron excitability was compared among exercise-trained (E), sedentary (S), and spinal cord transected (T) Sprague-Dawley rats by examining the slope of the frequency-current (F/I) relationship with standard intracellular recording techniques in rats anesthetized with ketamine-xylazine. The T group included spinal transected and spinal isolated rats; the E animals were either spontaneously active (exercise wheel) or treadmill trained; and rats in the S group were housed in pairs. An analysis of motoneuron initial [1st interspike interval (ISI)], early (mean of 1st three ISIs), and steady-state (mean of last 3 ISIs) discharge rate slopes resulting from increasing and decreasing 500-ms injected square-wave depolarizing current pulses was used to describe rhythmic motoneuron properties. The steepest slope occurred in the S group (55.3 ± 22.2 Hz/nA), followed by the T group (35.5 ± 15.3 Hz/nA), while the flattest slope was found in the E group (25.4 ± 10.9 Hz/nA). The steepest steady-state slope occurred in the S group but was found to be similar between the T and E groups. Furthermore, a spike-frequency adaptation (SFA) index revealed a slower adaptation in motoneurons of the E animals only (∼40% lower). Finally, evidence for a secondary range of firing existed more frequently in the T group (41%) compared with the S (12%) and E (31%) groups. The lower F/I slope and lower SFA index of motoneurons for E rats may be a result of an increase in Na+ conductance at the initial segment. The results show that motoneuronal rhythmic firing behavior is plastic, depending on the volume of daily activation and on intact descending pathways.

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