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PubMed1987

Medium viscosity regulates the activity of membrane-bound and soluble phospholipase A2.

Medium viscosity is a regulator of very low density lipoprotein production by cultured hepatocytes; their secretion and synthesis are inversely proportional to the extracellular fluid viscosity. The possibility that the mechanism of this extracellular effect on cell function involves modulation of cell membrane component(s) was considered. Along with this assumption, we studied the effect of medium viscosity on the activity of phospholipase A2 (PLA2), an enzyme present in the cell surface membrane, and the activity has been correlated with cellular secretion. We have found that culture medium viscosity inhibits the activity of PLA2 in the plasma membrane of cultured liver cells, concomitantly with the inhibition of lysosomal enzyme and lipoprotein secretion. It was also found that the degradation of liposomal phosphatidylcholine by soluble snake venom PLA2 is inversely proportional to the solvent viscosity. The possibility that the effect of medium viscosity on the enzymatic reaction involves the modulation of dynamic properties of membrane phospholipids was then considered. This hypothesis was examined by monitoring the fluorescence depolarization of fluorophores incorporated into phospholipid vesicles. No significant effect of the solvent viscosity on the phospholipid bilayer was observed. It is proposed that the regulation of cellular secretion by extracellular fluid viscosity involves modulation of the cell membrane PLA2 activity.

Animals↗

PubMed1988

Influence of right atrial stretch and atrial natriuretic factor on rat intestinal fluid content.

1. Studies were made on the effects of right atrial stretch and atrial natriuretic factor (ANF) infusion on fluid movement into the intestinal tract. 2. Stimulation of the atrial volume receptors by inflation of an intracardiac balloon in the conscious, unrestrained rat did not change intestinal fluid content under normovolaemic conditions. 3. When the rat was rendered hypovolaemic by peritoneal dialysis (34% deficit in extracellular fluid volume), right atrial stretch significantly increased intestinal fluid content. Under these conditions, inflation of the balloon restored large intestinal fluid content to the pre-dialysis state, i.e. right atrial stretch completely abolished that component of fluid absorption attributable to the extracellular fluid volume deficit. 4. These data suggest that stimulation of the right atrial receptors inhibits intestinal fluid reabsorption but probably does not initiate fluid secretion. 5. There was no evidence that this might be mediated by ANF since rat ANF (twenty-eight residue peptide, Ser-99-Tyr-126), infused for 1 h at doses of 0, 0.05, 0.1 and 0.5 microgram/min, did not cause any detectable changes in the fluid content of the large or small intestine of similarly prepared hypovolaemic rats.

Animals↗

PubMed1996

Endocrine, renal, and circulatory influences on fluid and electrolyte homeostasis during weightlessness: a joint Russian-U.S. project.

Microgravity is known to have a substantial effect on fluid homeostasis. The research described here was planned as part of the first joint Russian-U.S. science program carried out during a Shuttle flight. The aim of the program was to study the nature of the changes in fluid homeostasis induced by microgravity, as well as to determine the possible mechanisms underlying the regulation of fluid balance under conditions of spaceflight. To determine the effects of spaceflight on the homeostasis of fluid and electrolytes, measurements were taken of total body water, extracellular fluid plasma volumes, levels of regulatory hormones, and nutrient consumption before, during, and after a nine-day flight. Changes in renal function were studied before and after the flight. In these 2 subjects, weightlessness was not associated with a decreased extracellular fluid volume. However, there were the characteristic decreases in plasma atrial natriuretic peptide concentrations, and increases in plasma and urinary cortisol. Results indicated decreased urine volume, even through the first 48 hours of flight. Fluid volumes and glomerular filtration rate were increased after landing, probably related to the saline-loading countermeasure used by Shuttle crewmembers. The information obtained as a result of this research will facilitate the development of future research programs, as well as preventive measures for future long-duration spaceflights.

Body Water↗

PubMed1979

Cerebral vessels have the capacity to transport sodium and potassium.

The activity of Na+, K+-activated adenosinetriphosphatase and the uptake of a potassium analog, rubidium, were found to be similar in cerebral microvessels and choroid plexus when measured in vitro. This similarity suggests that sodium and potassium concentrations in the nascent brain extracellular fluid are determined by the same active process that regulates their concentration in nascent cerebrospinal fluid. The brain microvessels may thereby play on active role in brain potassium homeostasis and brain extracellular fluid formation.

Animals↗

PubMed2001

Influence of actin cytoskeleton on intra-articular and interstitial fluid pressures in synovial joints.

Fibroblast microfilamentous actin (F-actin) influences interstitial fluid pressure via linkages to collagen in rat skin (Berg et al., 2001). The present aims were to determine whether the actin cytoskeleton of synovial endothelium, fibroblasts, and synoviocytes influences in vivo (i) fluid exchange between a joint cavity and synovial microcirculation and (ii) extracellular fluid pressures in joints. Rabbit knee joints were treated intra-articularly with the F-actin disrupting drugs cytochalasin D and latrunculin B while joint fluid pressure P(j) was recorded. In joints injected with small volumes of control solution, P(j) fell with time (-0.05 +/- 0.01 cm H2O x min(-1), mean +/- SEM, n = 9, equivalent drainage rate 3.9 microl x min(-1)). Cytochalasin or latrunculin reversed this in approximately 4 min in vivo; P(j) increased with time, e.g., +0.12 +/- 0.04 cm H2O x min(-1) at 200 microM cytochalasin (equivalent filtration rate into joint 6.6-12.5 microl x min(-1), n = 4), with a cytochalasin EC50 of 45 microM. Plasma gamma-globulin clearance into the joint cavity was also increased. Post mortem, cytochalasin did not reverse dP(j)/dt and had no more effect on P(j) than did control solution. Also, when synovial interstitial fluid pressures were measured by servonull micropipette post mortem (control -0.95 +/- 0.37 cmH2O, n = 18) cytochalasin had no significant effect on interstitial pressure over 60 min, even at 1 mM. It was concluded that synovial endothelial F-actin has an important role in the normal synovial microvascular resistance to fluid filtration and plasma gamma-globulin permeation and is thus a potential link between pro-inflammatory mediators and arthritic joint effusions. The results provided no support for the hypothesis that synoviocyte F-actin influences the swelling tendency of synovial matrix and hence extracellular fluid pressures, in contrast to the findings of Berg et al. (2001) in rat dermis.

Actins↗

PubMed2005

Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus.

In the rat dorsomedial hypothalamus (DMH), serotonin (5-HT) concentrations are altered rapidly in response to acute stressors. The mechanism for rapid changes in 5-HT concentrations in the DMH is not clear. We hypothesize that the mechanism involves corticosteroid-induced alterations in the uptake of 5-HT from extracellular fluid through the action of corticosterone-sensitive organic cation transporters (OCTs). To determine if OCTs affect the clearance of 5-HT from the extracellular fluid compartment within the medial hypothalamus (MH), the OCT blocker, decynium 22 (0, 10, 30, or 100 microM), was perfused into the MH via a microdialysis probe, and dialysate 5-HT concentrations were measured at 20 min intervals. In addition, home cage behavior was measured both before and after drug administration. Inhibition of OCTs in the MH resulted in a reversible dose-dependent increase in extracellular 5-HT concentration. Increases in extracellular 5-HT concentrations were associated with increases in grooming behavior in rats treated with the highest concentration of decynium 22. No other behavioral responses were observed following administration of any concentration of decynium 22. These findings are consistent with the hypothesis that OCTs in the MH play an important role in the regulation of serotonergic neurotransmission and specific behavioral responses. Because the MH plays an important role in the neuroendocrine, autonomic, and behavioral responses to stress-related stimuli, these data lead to new questions regarding the role of interactions between corticosterone and corticosterone-sensitive OCTs in stress-induced 5-HT accumulation within the MH as well as the physiological and behavioral consequences of these interactions.

Analysis of Variance↗

PubMed2004

Capillary leakage in cardiac surgery with cardiopulmonary bypass.

Cardiopulmonary bypass causes a systemic inflammatory response, which can lead to capillary leak syndrome. In 15 adults undergoing elective cardiac surgery with cardiopulmonary bypass, we determined the volume and peak time of capillary leakage from the measurements of extracellular fluid volume and circulating blood volume taken preoperatively, at various intervals up to 24 hours after surgery, and on the 7th postoperative day. Extracellular fluid volume rose from 15.5 +/- 2.7 L preoperatively to a peak 4 hours after surgery of 18.3 +/- 3.2 L and remained elevated at 24 hours. Circulating blood volume fell from 4.10 +/- 0.68 L preoperatively to 3.20 +/- 0.58 L at the end of surgery. Fluid administered intraoperatively did not raise the circulating blood volume. Intraoperative fluid balance was positive at 2.62 +/- 0.72 L but negative at all time points postoperatively. There was significant postoperative capillary leakage, increasing from 4.7% +/- 2.3% of body weight at the end of surgery to a peak 4 hours later of 5.4% +/- 2.0% and falling to 2.8% +/- 3.3% at 24 hours. This knowledge of the pattern of change in capillary leakage after cardiac surgery with cardiopulmonary bypass might serve as a valuable guide for postoperative management.

Adult↗

PubMed1997

[The effect of wuto granules on the levels of excitatory amino acids in extracellullar fluid of rat hippocampus following cerebral ischemia].

We observed the changes of excitatory amino acids (EAA) in extracellular fluid (ECLF) in rat hippocampus in case of cerebral ischemia after giving Wuto Granule compring the test groups with the control groups by microdialysis method. Results showed that there was no effect on EAA in extrcellular fluid by the drug before cerebral ischemia, but there existed staistical singnifcant changes of EAA in extracellular fluid one hour after cerebral ischemia comparing the test groups Glu and Asp with the control groups (P < 0.01). We found that there is a decrease of release of release of EAA in ECLF in case of ischemia by Wuto Granule. It could be deduced that Wuto Granule can penetrate the brain-blood barrier and this can protect the brain incse of ischemia. The application of intracerebral micrdialysis has provided a new method for the research work of pharmacology.

Animals↗

PubMed1989

Differences in the synthesis and kinetics of release of interleukin 1 alpha, interleukin 1 beta and tumor necrosis factor from human mononuclear cells.

Cell-associated and secreted interleukin 1 alpha (IL 1 alpha), IL 1 beta and tumor necrosis factor alpha (TNF-alpha), produced by human mononuclear cells (MNC) in vitro in response to lipopolysaccharide, were measured by radioimmunoassay. After 18 h of incubation, total production of IL 1 alpha in medium containing 1% heat-inactivated serum was two-to-three times higher than IL 1 beta. However, in the presence of 1% serum and 5% fresh plasma, IL 1 alpha and IL 1 beta were produced in similar amounts. Independent of the culture conditions, 90% of the IL 1 alpha remained cell associated whereas 80% of IL 1 beta was extracellular. The kinetics of production and release of IL 1 alpha, beta and TNF-alpha were also studied. IL 1 alpha and TNF-alpha reached maximal levels within 6 h of stimulation, whereas IL 1 beta reached maximal levels between 12 and 16 h. IL 1 alpha remained primarily cell associated (80%) for the first 24 h. After 48 h, extracellular IL 1 alpha exceeded cell-associated levels. IL 1 beta was primarily secreted (80%), appearing in the extracellular fluid within 6 h. TNF-alpha appeared in the extracellular fluid within 1 h of incubation, with less than 10% cell associated at any time during the 48 h of incubation. Although the three cytokines share many biological activities, this study provides evidence that MNC IL 1 alpha is predominantly a cell-associated cytokine acting on a cell-cell basis, whereas IL 1 beta and TNF-alpha are secreted as paracrine mediators.

Cells, Cultured↗

PubMed2000

Biochemical and microscopic evidence for the internalization of drug-containing mast cell granules by macrophages and smooth muscle cells.

During mast cell degranulation the soluble component of the granule is released into extracellular fluid, whereas two neutral proteases and heparin proteoglycans form the extracellular granule remnants. These structures are negatively charged and bind with high affinity LDL and other basic molecules. In this study we show that granule remnants expelled into extracellular fluid are able to bind the aminoglycoside antibiotic gentamicin and the anticancer agent doxorubicin in a dose-dependent manner. In addition, granule remnants loaded with the two basic substances are subsequently phagocytosed by macrophages. Indeed, when cells are incubated for 24 h with 1 mg/ml gentamicin, the intracellular concentration of the drug, which in basal conditions is extremely low, increases significantly in the presence of degranulating mast cells (from 5.1 +/- 1.0 to 25.4 +/- 2.5 microg/mg protein) and a good correlation between histamine release and gentamicin uptake is evident. The antineoplastic agent doxorubicin can penetrate cells by passive diffusion; however, when mast cells are added to macrophage monolayer, incubated for 30 min with 50 microM of the antineoplastic agent, a significant increase in intracellular doxorubicin concentration is observed (from 3.5 +/- 0.2 to 4.7 +/- 0.2 microg/mg protein). Internalization of granule remnants carrying gentamicin or doxorubicin is also evident in smooth muscle cells of the synthetic phenotype. In particular, when smooth muscle cells are incubated for 24 h with 1 mg/ml gentamicin, addition of isolated granules increases the uptake from 2.4 +/- 0.2 to 4.8 +/- 0.4 microg/mg protein. Similar results are obtained in smooth muscle cells incubated for 4 h with doxorubicin 50 microM (from 3.3 +/- 0.2 to 4.8 +/- 0.5 microg/mg protein). Data are confirmed by microscopic experiments by means of fluorescence microscopy and electron microscopic studies. The study demonstrates that basic substances can enter phagocytic cells when loaded to granule remnants. The phenomenon can be of particular interest for substances like the aminoglycosides that do not cross biological membranes; indeed, the storage of these antibiotics in phagocytic cells could have important consequences on their antibacterial activity in vivo. Macrophages and smooth muscle cells can also act as a reservoir for doxorubicin. High concentrations of the antineoplastic agent in these cells could be responsible for toxicity, as well as play an important role in the transport of the drug to tumor cells.

Animals↗

PubMed1993

Protective effect of coronary sinus obstruction from primary ischemia-induced ventricular fibrillation in the dog.

We examined whether partial coronary sinus obstruction affects the latency of the early ventricular fibrillation (VF) of acute ischemia. During baseline trials 15 of 19 open-chest dogs fibrillated repeatedly and predictably within 2 to 5 minutes (251.6 +/- 64 seconds) after reversible, double coronary artery occlusion without developing profound hemodynamic deterioration. The effect of partial coronary sinus obstruction sufficient to increase coronary sinus pressure to 40 mm Hg could be adequately tested in 11 dogs. Coronary sinus obstruction consistently prevented VF in five dogs, significantly prolonged the VF latency in three (p < 0.01 to p < 0.001), and had no clear effect in another three. The overall effect was significant at the p < 0.01 level. VF latency prolongation/prevention was also positively correlated to the residual coronary sinus pressure at the time of VF (r = 0.76; p < 0.008), as well as the baseline VF latency (r = 0.75; (p < 0.008). The protective effect of coronary venous hypertension most likely reflects preservation of adequate extracellular fluid in the ischemic region after the perfusion arrest. This extracellular fluid may constitute a key component in the prevention of early ischemic arrhythmias by preserving interstitial hydraulic continuity and tissue homogeneity through enhanced dilution and diffusion of solutes.

Animals↗

PubMed1994

Factors affecting nerve excitability and conduction as a basis for desensitizing dentine.

Nerve excitability is principally determined by the state of membrane sodium channels, which can be influenced by factors such as drugs or the ionic composition of the extracellular fluids. The excitability of isolated nerves is increased by lowered extracellular calcium and hydrogen ion concentrations, and similar effects are seen on intradental nerve excitability. This is of interest as some agents used to desensitize hypersensitive dentine are believed to act by reducing intradental nerve excitability. A variety of ions, including potassium and divalent cations, have been shown to reduce intradental nerve excitability when applied in relatively high concentrations to dentine close to the pulp. However, these conditions do not mimic the clinical situation, where agents are applied to outer dentine, up to 2 mm from the pulp. Also, when agents are applied to dentine it is difficult to quantify the precise changes in extracellular fluid composition, and there is the additional complication of possible interactions between the agents and dentine. These problems can be minimized by using isolated nerves, which allow better control over the conditions and ionic concentrations necessary to achieve nerve conduction block. Such methods can provide a convenient way to screen potential desensitizing agents before evaluation in vivo or in clinical trials.

Action Potentials↗

PubMed2005

Bone as an ion exchange organ: evidence for instantaneous cell-dependent calcium efflux from bone not due to resorption.

The current study tests the hypothesis that basal level and minute-by-minute correction of plasma Ca2+ by outward and inward Ca2+ fluxes from and into an exchangeable ionic pool in bone is controlled by an active partition system without contributions from the bone remodeling system. Direct real-time measurements of Ca2+ fluxes were made using the scanning ion-selective electrode technique (SIET) on living bones maintained ex vivo in physiological conditions. SIET three-dimensional measurements of the local Ca2+ concentration gradient (10 microm spatial resolution) were performed on metatarsal bones of weanling mice after drilling a 100-mum hole through the cortex to expose the internal bone extracellular fluid (BECF) to the bathing solution, whose composition mimicked the extracellular fluid (ECF). Influxes of Ca2+ towards the center of the cortical hole (15.1+/-4.2 pmol cm-2 s-1) were found in the ECF and were reversed to effluxes (7.4+/-2.9 pmol cm-2 s-1) when calcium was depleted from the ECF, mimicking a plasma demand. The reversal from influx to efflux and vice versa was immediate and fluxes in both directions were steady throughout the experimental time (>or=2 h, n=14). Only the efflux was nullified within 10 min by the addition of 10 mM/L Na-Cyanide (n=7), demonstrating its cell dependence. The timeframes of the exchanges and the stability of the Ca2+ fluxes over time suggest the existence of an exchangeable calcium pool in bone. The calcium efflux dependency on viable cells suggests that an active partition system might play a central role in the short-term error correction of plasma calcium without the contribution of bone remodeling.

Animals↗

PubMed2006

Aldosterone--a hormone of cardiovascular adaptation and maladaptation.

Aldosterone stimulates reabsorption of sodium, sustaining blood volume and pressure in the face of salt deprivation or extracellular fluid depletion. The steroid also stimulates excretion of potassium, protecting extracellular fluid from excessive levels of that ion. These two actions are relatively rapid and clearly adaptive when appropriately initiated and terminated, but maladaptive when prolonged or excessive, causing hypertension and electrolyte imbalance. Aldosterone and other mineralocorticoids exert slower, direct effects on cells in the heart, kidneys, and vessels, leading to hypertrophy, fibrosis, and dysfunction contributing to degenerative cardiovascular diseases. The maladaptive actions of aldosterone are exacerbated by sodium chloride, angiotensin, endothelin, and certain growth factors. Damage can be minimized by antagonists of aldosterone receptors, inhibitors of the renin system, depletion of salt, and repletion of potassium and magnesium. Specific inhibitors of fibrosis and hypertrophy, and more effective inhibitors of the renin system should be useful in the future.

Aldosterone↗

PubMed1980

Effect of carbonic anhydrase inhibitors and acidosis in choroid plexus epithelial cell sodium and potassium.

To elucidate the mechanism by which carbonic anhydrase inhibitors block fluid production by the choroid plexus (CP), Na-K transport by the rat choroidal epithelium was investigated by measuring acetazolamide- and benzolamide-induced changes in cell [K] and [Na]. Although plasma and cerebrospinal fluid [K] and [Na] were not significantly altered after 1 hr of drug treatment, both acetazolamide (20 mg/kg) and benzolamide (40 mg/kg) decreased in vivo CP cell [Na] by 11 to 18 mmol/kg of cell H2O and substantially increased cell [K] by 25 to 35 mmol. Compensatory artificial respiration to control blood pH blocked the drug-induced effects of cell electrolytes. Furthermore, acetazolamide (5 x 10(-5) and 5 x 10(-4) M) did not significantly alter cell [Na] or [K] in in vitro incubations of CP, although cell [K] tended to decrease in a drug concentration-dependent manner. Thus, carbonic anhydrase inhibitors have no direct effect on the gradient for Na or K between choroid cell fluid and surrounding extracellular fluid. It is proposed that the carbonic anhydrase inhibitors reduced Na entry into the choroid epithelium across the basolateral membrane concurrent with a decrease in the rate of the apical membrane Na-K pump. To investigate whether the drug-induced extracellular acidosis changed cell electrolyte levels directly or indirectly, in vitro CP tissue incubations were performed in which the pH of the artificial cerebrospinal fluid was varied from 7.24 to 7.44. CP cell [K] increased by 20 mmol/kg of H2O and cell [Na] fell by 10 when bathing medium pH was lowered from 7.39 to 7.24. We postulate that the lowered blood pH directly stimulates K uptake and Na efflux from the CP cell, although an indirect effect of acidosis, either through an alteration of levels of circulatory hormones or of autonomic input to the CP, cannot be excluded.

Acetazolamide↗

PubMedDate not supplied

Calcitonin and the bone fluid compartment: effect of calcitonin and/or parathyroid hormone on plasma radiocalcium changes.

Changes in plasma calcium and 45Ca concentrations were followed after injection of calcitonin or a combination of calcitonin (CT) and parathyroid hormone (PTH) into thyroparathyroidectomized rats maintained on thyroxine. Comparison was made between rats injected with the hormone(s) after a recent feeding and after an overnight fast. Also cor (18 hr 45Ca) before, and more than 6 days (greater than 6 day 45Ca) prior to hormone administration. The following results were obtained: The action of CT predominated over that of PTH for the first few hours after injection. However, the effects of PTH were eventually manifested even when additional CT was administered. In the "greater than 6 day" 45Ca groups, PTH normally produced an increase in plasma 45Ca specific activity. However, in fasted rats, plasms 45Ca fell with total calcium with no change in specific activity following CT injection. In fed rats CT injection was followed by a decrease in plasma 45Ca specific activity. When both hormones were administered plasma 45Ca specific activity changes mimicked those produced by CT alone even after PTH plasma effects were manifested. In the "18 hr" 45Ca groups, CT produced first a drop in plasma 45Ca, followed by a reduction in the rate of its removal from plasma. It is concluded that the data can best be explained by the postulate that plasma calcium concentrations are maintained by the control of fluxes between bone fluid in the osteocyte-lining cell bone unit and the extracellular fluid. PTH increases the efflux from this bone fluid compartment while CT restricuts the source of calcium and, therefore, the efflux. Plasma 45Ca changes are due to a combination of changes in flux rates and mixing processes between the extracellular fluid compartment and the bone fluid compartment.

Animals↗

PubMed1983

In vitro amino acid transport by renal tubules of prenatally protein-deprived fetal rats.

Amino acid transport in the renal tubules of 21-day fetal offspring of protein-deprived (4% casein diet) and adequately fed (24% casein diet) rats was studied by measuring the in vitro accumulation of glycine and the amino acid analog, alpha-aminoisobutyric acid (AIB). The prenatally protein-deprived (PPD) fetuses were smaller than the controls with a mean weight of 3.8 g compared to 5.5 g, and their kidneys were 0.4% of body weight, compared to 0.5% of body weight in the control group. Assessment of the renal proximal tubule transport mechanisms indicated that they were capable of transporting glycine and AIB at day 21 of gestation. There were no differences between the two groups in total water content or extracellular fluid content of the renal cortical tissue slices. The samples from PPD fetuses were able to accumulate concentrations of amino acids equal to or greater than those of control fetuses. The accumulation of AIB per gram of tissue was almost twice as great in the PPD tissue slices as in the control slices, whereas the accumulation of glycine per gram of tissue was equal in the two groups. Comparison of the fluid content and extracellular space of the PPD and control tissues suggests that this difference in uptake was not due to changes in the fluid distribution. It is proposed that the increase in AIB absorption by PPD renal tissue is related to retardation in maturation of the tissue. Transport of glycine, which matures later in development, may be immature in both groups. The greater amino acid uptake may conserve amino acids and thus have survival value in PPD young.

Amino Acids↗

PubMedDate not supplied

Clinical pharmacokinetics during plasma exchange.

Drug removal during plasma exchange (PE) is a complex phenomenon that is defined by the molecule pharmacokinetic characteristics. Plasma-protein binding and the volume of distribution (Vd) are two kinetic parameters that strongly affect the efficiency of drug removal by PE. The effect of PE on drug kinetics has been specifically studied with antivirals, cardiotonic agents, antibiotics, corticosteroids, antalgics, anti-epileptic agents and non-steroidal anti-inflammatory drugs. This effect can be evaluated using different parameters: extracorporeal clearance, half-life, amount eliminated, and fraction of the drug removed. The estimated fraction eliminated (Fe) from the body by PE is the best parameter to evaluate the effectiveness of the exchange procedure; it can account for 0.5-30 per cent. Results reported in the literature showed that PE most influences drugs with a low Vd, regardless of the extent of protein binding. We established that, during PE, there is a linear relationship between Fe and the fraction of the drug in extracellular fluids. The fraction eliminated during PE is approximately one-seventh of the fraction of the drug in extracellular fluids. We propose to use this extracellular fraction as a predictive index: when < 20, extraction is low; the amount eliminated becomes consequential only when the index > 20. Dosage supplementation may be needed to maintain an adequate drug concentration in the body. Practically, for drugs with a low Vd (< 0.3 l/kg), it seems necessary to adjust the dosage.

Algorithms↗