Vascular space

The pathophysiologic mechanisms of portal hypertension and of cirrhosis itself are entwined with the mechanisms of ascites (Fig. 19-3). Cirrhotic changes and the subsequent decrease in synthetic function lead to a decrease in production of albumin (hypoalbuminemia). Albumin is the major intravascular protein involved in maintaining oncotic pressure in the vascular system low serum albumin levels and increased capillary permeability allow fluid to leak from the vascular space into body tissues. This can result in peripheral edema, ascites, and fluid in the pulmonary system. The obstruction of hepatic sinusoids and... 

Detumescence occurs with sympathetic discharge after ejaculation. Sympathetic activity induces smooth muscle contraction of arterioles and vascular spaces leading to a reduction in blood inflow, decompression of the sinusoidal spaces, and enhanced outflow. 

Psychogenic dysfunction occurs if a patient does not respond to psychic arousal. It occurs in up to 30% of all cases of ED. Common causes include performance anxiety, strained relationships, lack of sexual arousability, and overt psychiatric disorders such as depression and schizophrenia.5 It is postulated that the anxious or nervous man will have excessive stimulation of the sympathetic system, leading to smooth muscle contraction of arterioles and vascular spaces within erectile tissue.6 O Many patients may initially have organic dysfunction, but develop a psychogenic component as they try to cope with their inability to achieve an erection. It has been estimated that up to 80% of ED cases have an organic cause, with many having a psychogenic component as well.1... 

Cetuximab is a human/mouse antibody that binds to the epidermal growth factor receptor to block its stimulation. The pharmacokinetics of cetuximab demonstrate a volume of distribution that approximates the vascular space and a terminal half-life of 70 to 100 hours. Cetuximab has shown clinical activity in the treatment of colorectal cancer. An acnelike rash may appear on the face and upper torso 1 to 3 weeks after the start of therapy. Other side effects include hypersensitivity reactions, interstitial lung disease, fever, malaise, diarrhea, abdominal pain, and nausea and vomiting. 

Compartment 1 represents the vascular space of the tissue and can be identified as either a blood, plasma, or serum space. Compartment 2 is the interstitial space, and compartment 3 the intracellular tissue volume. Assuming first-order or linear membrane transport for the drug, the flux terms can be expanded as... 

Distribution - The distribution of darbepoetin in adult CRF patients is predominantly confined to the vascular space (approximately 60 mL/kg). With once-weekly dosing, steady-state serum levels are achieved within 4 weeks with a less than 2-fold increase in peak concentration when compared with the initial dose. 

Therapeutic irradiation is known to have multiple interactions with the vasculature of the irradiated tissue (12). Radiation has direct cytotoxic effects on the vascular endothelium, likely due to induction of oxidative injury. Radiation-induced injury stimulates inflammation and influx of inflammatory cells in addition to creating aprocoagulant state in the vascular space by the transcriptional induction of tissue factor with the subsequent activation of coagulation factors as well as von Willebrand factor and platelets. Experimental evidence suggests that the mechanism by which radiation initiates these responses is in part through the induction of cell-adhesion molecules including ICAM-1, E-selectin, and P-selectin and in part through local cytokine production and release (13). 

The fact that the microbubbles are restricted to the vascular space makes them ideal for contrast echocardiography and vascular imaging. Echocardiography is used extensively to assess ischemic heart disease. Contrast-enhanced echocardiography improves visualization of the cavities of the heart, the lumen of arteries and veins, and small vessels within solid organs and perfused tissues. Effective endocardial border delineation allows assessment of global heart function and the detection of coronary insufficiency (Fig. 12). 

Figure 19.1 Physiological pharmacokinetic model for evaluating in vivo disposition of a macromolecular drug. (A) A multi-compartment model in which every tissue compartment is connected with the plasma pool by blood flow. (B) Tissue uptake of a drug from vascular space to tissue parenchyma.

Preston et al. [66] have shown that BBB permeability to the nonmetabolizable, but slowly BBB penetrant, tracer mannitol (182 Da), is between 0.19 and 0.22 pL/g/min in the brain of rats of 1 week of age and this permeability is identical to that of adult rats. The vascular space occupied by the tracer mannitol (the initial volume of distribution Fj) falls from 1.23 mL, at 1 week of age, to 0.75 mL per 100 g brain in the adult rat [66], indicating either a larger vascular volume, resulting from a greater capillary density or capillary diameter in the neonatal rat, or to a significant degree of internalization of the mannitol by the endothelium, possibly by fluid-phase endocytosis into the cerebral capillary endothelial cells in the newborn, compared to the adult. 

After IV application, peptides and proteins usually follow a biexponential plasma concentration-time profile that can best be described by a two-compart-ment pharmacokinetic model [13]. The central compartment in this model represents primarily the vascular space and the interstitial space of well-perfused organs with permeable capillary walls, especially fiver and kidneys, while the peripheral compartment comprises the interstitial space of poorly perfused tissues such as skin and (inactive) muscle [4]. 

Values for mean volume of distribution at steady state (Vss) appeared to be independent of dose, and ranged from 1.99 to 2.88 L/m2 after the first dose of 20 to 500 mg/m2 of cetuximab (Fig. 14.5). These volumes are consistent with that of the vascular space, and in agreement with values of other IgGl-derived monoclonal antibodies. 

In mild cases of hyponatremia, treatment typically focuses on water restriction (< 800 mL/day) however this approach suffers from poor patient compliance due to thirst brought on by increasing serum osmolality.1,10 In cases of extreme hyponatremia, infusions of hypertonic saline are used to elevate serum sodium concentrations. Loop diuretics (e.g., furosemide) are often used as an adjunct to such treatment to offset potential volume overload.1 Hypertonic saline therapy is also suboptimal, as it carries a risk of overly rapid adjustment of plasma sodium levels, which can result in the rapid shift of water from brain tissue to the vascular space, triggering neural demyelination that can result in seizures, coma, quadriplegia, and even death.1... 

Connective tissue is a term applied to a conglomeration of substances that constitute the extracellular non vascular space in various tissues of the organism. It serves to bind the cells together, to provide resiliency to tissues, and sometimes... 

The liver does not synthesise enough albumin and does not metabolise aldosterone. A lack of albumin in the vascular space reduces colloid oncotic pressure and water flows out of the blood vessels to form tissue oedema or ascites (oedema in the peritoneal cavity). Water oozing from the pulmonary arteries causes pulmonary oedema. 

Figure 15.2. Location of xenobiotic transporters in selected barrier and excretory tissues. For simplicity, the tissues are arranged along a structure representing the vascular space. Arrows indicated direction of transport under normal conditions. This figure is not meant to be comprehensive not all transporters expressed in a tissue are shown. Transporters driven by ATP pump substrates out of cells (efflux). Other transporters are capable of supporting substrate uptake or efflux. Which of these processes predominates depends on available driving forces—for example, substrate concentration gradient and the capability to couple transport to sources of potential energy.

The reverse flux of fluid from the interstitial to the vascular space (14) is caused by increased interstitial fluid pressure (12) and increased plasma protein concentration (oncotic pressure), hyperosmotemia, or both depending upon the intensity (above or below 50 -peak capacity) and duration of the exercise. Increased interstitial hydrostatic pressure and increased plasma osmotic pressures retard the fluid shift from plasma to the interstitium. Equilibrium is reached when interstitial pressure balances capillary filtration pressure (24). After cessation of exercise, restitution of plasma volume takes 40-60 minutes (21,22) unless significant dehydration is present. The immediate post-exercise hyperosmotemia, the relative hyperproteinemia, and the reduction in systemic blood pressure contribute to the restoration of plasma volume. The reduction in blood pressure, which produces a fall in local hydrostatic pressure within the capillaries of the previously active muscle, is probably the single most important factor. 

Selectively permeable membranes keep plasma proteins and charged substances within the vasculature. It is estimated that 93% of plasma proteins are retained in the vascular space, which create an osmotic driving force in the venous capillaries for the return of fluid to the blood (Kimelberg, 2004). However, due to the presence of the BBB, water flow occurs differently in the CNS, maintaining a stable and unique microenvironment for the normal function of neurons and other cells. 

The issue of inadequate sampling time is exemplified by monoclonal antibodies. As shown in Table 32.12/ the Vi and Vss are similar and are similar in size to a vascular space of 2-3 L/m. It is also important to note that for the most part/ in the studies submitted to support New Drug Application (NDA) approval/ Vgs was determined with methods assuming linear/ first-order kineticS/ and clearly this is not the case for the majority of the monoclonal antibodies currently marketed/ such as cetuximab (Erbitux). In fact/ the use of noncompartmental methods to describe the pharmacokinetics of mABs oversimplifies their complex properties. 

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