Blood Flow Clearance Research Articles

Design and characterization of a microfabricated hydrogen clearance blood flow sensor

BackgroundModern cerebral blood flow (CBF) detection favors the use of either optical technologies that are limited to cortical brain regions, or expensive magnetic resonance. Decades ago, inhalation gas clearance was the choice method of quantifying CBF, but this suffered from poor temporal resolution. Electrolytic H2 clearance (EHC) generates and collects gas in situ at an electrode pair, which improves temporal resolution, but the probe size has prohibited meaningful subcortical use. New methodWe microfabricated EHC electrodes to an order of magnitude smaller than those existing, on the scale of 100μm, to permit use deep within the brain. ResultsNovel EHC probes were fabricated. The devices offered exceptional signal-to-noise, achieved high collection efficiencies (40–50%) in vitro, and agreed with theoretical modeling. An in vitro chemical reaction model was used to confirm that our devices detected flow rates higher than those expected physiologically. Computational modeling that incorporated realistic noise levels demonstrated devices would be sensitive to physiological CBF rates. Comparison with existing methodThe reduced size of our arrays makes them suitable for subcortical EHC measurements, as opposed to the larger, existing EHC electrodes that would cause substantial tissue damage. Our array can collect multiple CBF measurements per minute, and can thus resolve physiological changes occurring on a shorter timescale than existing gas clearance measurements. ConclusionWe present and characterize microfabricated EHC electrodes and an accompanying theoretical model to interpret acquired data. Microfabrication allows for the high-throughput production of reproducible devices that are capable of monitoring deep brain CBF with sub-minute resolution.

Revisiting the well-stirred model of hepatic clearance: QH, CLHand F changing in the same direction

This tutorial examines the relationship between CL, F, and hepatic blood flow (QH) quantitatively at oral and i.v. administration as an answer to the quiz set for KSCPT members. In case of oral dosing, when hepatic blood flow increases, the hepatic clearance (CL) and bioavailability (F) increases in high-extraction ratio drugs according to the well-stirred model equations for hepatic clearance: CLH = QH·ER = QH∙fu∙CLint/(QH+fu∙CLint) and F = 1 − ER Despite such a clear relationship, many students may feel it rather paradoxical that the increased CL (thus decreasing the AUC) causes increased F and thus the AUC (F∙Dose/CLH) remains unchanged. This tutorial clarifies that the degree to which CL increase fails to match that of the QH increase, and thus the decreased ER (= CL/QH) that results in the increased F. Contemplating this simple, but seemingly paradoxical phenomenon may help students gain a deeper understanding of the first-pass effect.

Design and characterization of a microfabricated hydrogen clearance blood flow sensor

Design and characterization of a microfabricated hydrogen clearance blood flow sensor

Predictability of intranasal pharmacokinetics in man using pre-clinical pharmacokinetic data with a dopamine 3 receptor agonist, PF-219061

(R)-3-(4-propylmorpholin-2-yl) phenol (PF-219061) is a potent, selective agonist of the dopamine 3 receptor for the treatment of female sexual dysfunction.In vivo, PF-219061 exhibits liver blood flow clearance in both rat and dog. Oral bioavailability was 0.7% in dog and less than 5% in rat.Intranasal dosing was investigated to improve bioavailability. Pre-clinical assessments in rat and dog demonstrated intranasal bioavailabilities of 16–38% in rat and 54–61% in dog with very rapid absorption. It was predicted that an intranasal dose in man would give approximately 25–50% bioavailability.The clinical data verified the preclinical predictions demonstrating rapid absorption and approximately dose-proportional increases in exposure. The intranasal bioavailability in man was estimated to be 26–38%.These findings indicate the potential utility of intranasal dosing as a route that circumvents the first-pass effects for PF-219061 resulting in high exposures.

In vitro/in vivo Difference in Enhanced Skin Permeation of Nicardipine Hydrochloride by the 1-Menthol-Ethanol System

The in vitro/in vivo difference in enhanced skin permeation of nicardipine hydrochloride (NC) by simultaneous use of 1-menthol and ethanol (MEW system, 1-menthol:ethanol:water = 5:40:55) was investigated in hairless rats. First, the cutaneous blood flow clearance (clearance from skin to blood flow) of NC per unit area of skin (CLCB/A), which was comparable to the permeability coefficient across skin (PC), was calculated from intracutaneous and intravenous injection data using the deconvolution method; the value was 1.67 microliters/h/cm2. Two formulations containing NC and the MEW system, solution (SOL) and 15% hydroxypropyl cellulose gel (GEL), were used for in vitro and in vivo permeation experiments. The in vitro PC of NC via excised skin from SOL (23.3 microliters/h/cm2) was significantly higher than CLCB/A, and that from GEL (1.48 microliters/h/cm2) was similar to CLCB/A. Consequently, the steady-state concentration of NC in skin during in vivo application of SOL was 6.6 times higher than corresponding in vitro data. In vivo PCs from SOL and GEL were however significantly lower than CLCB/A. These results may be explained by the findings, using a laser Doppler flowmeter, that cutaneous blood flow was decreased by the application of MEW.

Mathematical modeling of hydgogen clearance blood flow measurements in peripheral nerve

The hydrogen clearance technique of blood flow measurement often yields biexponential washout curves. In peripheral nerve, arteriovenous shunt vessels may clear hydrogen gas, causing the fast component of a biexponential curve. We simulated the washout of hydrogen from nerve tissue in the vicinity of a large shunt vessel by modeling the diffusion of hydrogen through tissue to the vessel and its removal by a network of capillaries. We then determined the fast and slow clearance rates and the relative weights or contributions of the fast and slow components and found that they are affected by all of the model parameters.

Thermal clearance blood flow sensor—sensitivity, linearity and flow depth discrimination

A thermal clearance blood flow sensor has been designed which incorporates four separate sensing elements, permitting flow changes at four differing depths to be measured. Static and dynamic laboratory tests have confirmed the differing flow depth response of the sensor and demonstrated a linear response to flow over the physiological skin blood flow range. Flow depth response has been shown to be dependent upon sensor geometry. Response should also in theory be dependent on the thermal conductivity of the sensor body material. However, using conventional encapsulation materials, it does not seem possible to obtain a depth sensitivity of less than 0.2 mm.

Blood flow clearance changes in pig skin after single doses of X rays

Early and late changes in the functional vascularity of pig skin have been evaluated after X-irradiation. These changes were assessed using a quantitative isotopic clearance technique. Two waves of radiation-induced changes in isotopic clearance were demonstrated. The first wave, observed after an interval of three weeks, was characterized by the faster clearance of the tracer from areas of irradiated skin. The second wave, which reached a peak after 12 weeks, was denoted by a slowing of the clearance rate relative to normal skin. The modification in vascular function observed at 12 weeks was transient, function returning to normal as late radiation damage developed. The changes observed in the pig have many similarities with those recorded in man but are markedly different from those found in rodents. These differences are discussed with respect to the vascular structure of the skin of the animal species investigated.