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Uwe Spannagel - One of the best experts on this subject based on the ideXlab platform.
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Treatment of Deep Vein Thrombosis in the Pelvis and Leg: Variability of the Intravascular Space
Deutsches Arzteblatt international, 2008Co-Authors: Uwe SpannagelAbstract:I would like to point out a number of errors and make a few comments. In table 1, the approved low-molecular-weight heparins (LMWH) are listed; in the adjacent column, it is stated that LMWH should be given in doses adapted to the patient’s body weight. This is not true of all LMWH, however: certoparin is approved for the treatment of deep vein thrombosis in a dosage of 8000 IU anti-Xa b.i.d., independently of body weight. In general, it seems to me that the authors fail to address the issue of body-weight-adjusted administration of LMWH in a critical manner. This type of administration is often inappropriate from the pharmacological point of view. The authors do, indeed, write that an abnormal body weight should be taken into account, among other factors, but they do not explain why. The reason can be stated simply enough: LMWH are strongly hydrophilic substances that are distributed exclusively in the Intravascular Space once they are absorbed after subcutaneous injection. The size of the Intravascular Space, which is the smallest distributive Space in the body, depends only in part on body weight. It indeed increases with increasing muscle and organ mass, but not with an increase in body weight due to fatty tissue. Thus, two patients of identical weight, but different heights, can have Intravascular Spaces of very different sizes. It follows that, despite the relatively wide therapeutic window of LMWH, dosing them exclusively on the basis of the patient’s body weight would lead to overdosing of short but markedly overweight patients, which would then be likely to produce hemorrhagic complications. This risk of overdose can be avoided by basing the LMWH dose not on the patient’s body weight per se, but rather on his or her normal weight – or else by using an LMWH preparation that can be given in a dose that is independent of body weight. This is not a new idea, by the way; I read it for the first time in 1983, in my pharmacology textbook (1).
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correspondence letter to the editor variability of the Intravascular Space
Deutsches Arzteblatt International, 2008Co-Authors: Uwe SpannagelAbstract:I would like to point out a number of errors and make a few comments. In table 1, the approved low-molecular-weight heparins (LMWH) are listed; in the adjacent column, it is stated that LMWH should be given in doses adapted to the patient’s body weight. This is not true of all LMWH, however: certoparin is approved for the treatment of deep vein thrombosis in a dosage of 8000 IU anti-Xa b.i.d., independently of body weight. In general, it seems to me that the authors fail to address the issue of body-weight-adjusted administration of LMWH in a critical manner. This type of administration is often inappropriate from the pharmacological point of view. The authors do, indeed, write that an abnormal body weight should be taken into account, among other factors, but they do not explain why. The reason can be stated simply enough: LMWH are strongly hydrophilic substances that are distributed exclusively in the Intravascular Space once they are absorbed after subcutaneous injection. The size of the Intravascular Space, which is the smallest distributive Space in the body, depends only in part on body weight. It indeed increases with increasing muscle and organ mass, but not with an increase in body weight due to fatty tissue. Thus, two patients of identical weight, but different heights, can have Intravascular Spaces of very different sizes. It follows that, despite the relatively wide therapeutic window of LMWH, dosing them exclusively on the basis of the patient’s body weight would lead to overdosing of short but markedly overweight patients, which would then be likely to produce hemorrhagic complications. This risk of overdose can be avoided by basing the LMWH dose not on the patient’s body weight per se, but rather on his or her normal weight – or else by using an LMWH preparation that can be given in a dose that is independent of body weight. This is not a new idea, by the way; I read it for the first time in 1983, in my pharmacology textbook (1).
Arthur J Atkinson - One of the best experts on this subject based on the ideXlab platform.
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chapter 3 compartmental analysis of drug distribution
Principles of Clinical Pharmacology (Second Edition), 2007Co-Authors: Arthur J AtkinsonAbstract:Publisher Summary This chapter discusses the compartmental analysis of drug distribution. Drug distribution can be defined as the postabsorptive transfer of a drug from one location in the body to another. Drug transfer between compartments is characterized by “intercompartmental clearance,” a term to describe the volume-independent parameter that quantifies the rate of analyte transfer between the compartments of a kinetic model. The central compartment of a pharmacokinetic (PK) model usually is the only one that is directly accessible to sampling. When attempting to identify this compartment as Intravascular Space, the erythrocyte/plasma partition ratio must be incorporated in comparisons of central compartment volume with expected blood volume if plasma levels, rather than whole blood levels are used for PK analysis. The physiological basis for the transfer of drugs and other compounds among compartments can only be inferred for mammillary systems in which the central compartment represents Intravascular Space and intercompartmental clearance can be equated with transcapillary exchange. The mechanism of transcapillary exchange is elaborated in the chapter.
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CHAPTER 3 – Compartmental Analysis of Drug Distribution
Principles of Clinical Pharmacology, 2007Co-Authors: Arthur J AtkinsonAbstract:Publisher Summary This chapter discusses the compartmental analysis of drug distribution. Drug distribution can be defined as the postabsorptive transfer of a drug from one location in the body to another. Drug transfer between compartments is characterized by “intercompartmental clearance,” a term to describe the volume-independent parameter that quantifies the rate of analyte transfer between the compartments of a kinetic model. The central compartment of a pharmacokinetic (PK) model usually is the only one that is directly accessible to sampling. When attempting to identify this compartment as Intravascular Space, the erythrocyte/plasma partition ratio must be incorporated in comparisons of central compartment volume with expected blood volume if plasma levels, rather than whole blood levels are used for PK analysis. The physiological basis for the transfer of drugs and other compounds among compartments can only be inferred for mammillary systems in which the central compartment represents Intravascular Space and intercompartmental clearance can be equated with transcapillary exchange. The mechanism of transcapillary exchange is elaborated in the chapter.
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Simultaneous analysis of inulin and 15N2‐urea kinetics in humans
Clinical pharmacology and therapeutics, 1993Co-Authors: Yaseen K Odeh, Zhao Wang, Tsuen Ih Ruo, Theodore Wang, Marilynn C. Frederiksen, Peter A Pospisil, Arthur J AtkinsonAbstract:To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to Intravascular Space. The mean distribution volumes of 0.164 ± 0.009 L/kg (± SD) for inulin and of 0.670 ± 0.143 L/kg for urea were similar to expected values for extracellular Space and total body water, respectively. Distribution from Intravascular Space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 ± 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 ± 0.40 L/min). Clinical Pharmacology and Therapeutics (1993) 53, 419–425; doi:10.1038/clpt.1993.45
Donald Hodge - One of the best experts on this subject based on the ideXlab platform.
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Calciphylaxis, proteases, and purpura: An alternative hypothesis for the severe shock, rash, and hypocalcemia associated with meningococcal septicemia
Critical care medicine, 2002Co-Authors: Philip Holland, Douglas Thompson, Stephen W Hancock, Donald HodgeAbstract:The hallmarks of severe meningococcal sepsis include the rapid onset of shock, purpuric rash, and metabolic derangement, in particular, hypocalcemia. The severe ecchymoses and purpura associated with meningococcal sepsis are usually attributed to acute thrombotic episodes, attributable to the associated procoagulation disorder. An alternative explanation for the rash is a sudden extravasation of calcium from the Intravascular Space into the tissues. We will argue that in meningococcal sepsis, cleavage of albumin into fragments by protease(s) occurs and these fragments, along with calcium, cross the endothelium into the interstitium. The fragmentation of albumin and its loss through the endothelium would also provide a more rational explanation for the rapidity of the shock and the hypocalcemia that is so characteristic of the disease.
G Mitchell - One of the best experts on this subject based on the ideXlab platform.
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Effects of dehydration and rehydration on the Intravascular Space in horses
Comparative biochemistry and physiology. Comparative physiology, 1992Co-Authors: Jennifer C. Sneddon, J.p. Van Der Walt, G MitchellAbstract:Abstract 1. 1. The resistance of sub-tropical horses, and desert-dwelling horses to 72 hr dehydration/24 hr rehydration was investigated via changes in red cell parameters and plasma protein concentration. 2. 2. Red cell count, haemoglobin and haematocrit increased up to 48 hr dehydration. Between 48 and 72 hr dehydration these parameters decreased, implying a fluid shift onto the Intravascular Space from the interstitium/hindgut. Most parameters had regained baseline values by 24 hr rehydration. 3. 3. Mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration and total plasma protein were not significantly different between breeds at, or between most stages of hydration. 4. 4. Protection of plasma volume during dehydration/rehydration was aided by maintaining Intravascular protein (especially albumin) levels. Red cells were transiently dehydrated and overhydrated but resisted osmolysis.
John P. Atkinson - One of the best experts on this subject based on the ideXlab platform.
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Evolution of the complement system: from defense of the single cell to guardian of the Intravascular Space.
Immunological reviews, 2016Co-Authors: Michelle Elvington, M. Kathryn Liszewski, John P. AtkinsonAbstract:The complement system is an evolutionarily ancient component of immunity that revolves around the central component C3. With the recent description of intracellular C3 stores in many types of human cells, our view of the complement system has expanded. In this article, we hypothesize that a primitive version of C3 comprised the first element of the original complement system and initially functioned intracellularly and on the membrane of single-celled organisms. With increasing specialization and multicellularity, C3 evolved a secretory capacity that allowed it to play a protective role in the interstitial Space. Upon development of a pumped circulatory system, C3 was synthesized in large amounts and secreted by the liver to protect the Intravascular Space. Recent discoveries of intracellular C3 activation, a C3-based recycling pathway and C3 being a driver and programmer of cell metabolism suggest that the complement system utilizes C3 to guard not only extracellular but also the intracellular environment. We predict that the major functions of C3 in all four locations (i.e. intracellular, membrane, interstitium and circulation) are similar: opsonization, membrane perturbation, triggering inflammation, and metabolic reprogramming.