Tissue treatment volume

TABLE 9.2 Tissue Treatment Volume as a Function of Tissue Elimination Half-Life... 

Tissue treatment volumes of the substance being infused are a strong function of the tissue elimination half-life, which reflects the sum of both metabolic and micro vascular tissue clearances. Table 9.2 summarizes how this treatment volume and associated penetration distance varies with the characteristic tissue elimination half-life of the infused species. Various elimination half-lives were used for these simulations and an infusion rate of 3 pL/min into brain for 12 hours was assumed. For the extreme case of a macromolecule undergoing no metabolism, the treatment volume is 27 cm, with a penetration distance of 1.9 cm. For a more realistic tissue elimination half-life, as might be encountered with weakly binding monoclonal antibodies or stabilized analogs of somatostatin or enkephalin peptides, this volume and the distance, respectively, decrease only to 14 cm and 1.5 cm. 

When the elimination half-life drops to 1 hour, as is characteristic of the rates encountered with nerve growth factor or stabilized analogs of substance P peptide or glucocerebrosidase enzyme, the treatment volume decreases to 2.7 cm, with a penetration distance of 0.9 cm. In a rapid metabolism situation, when the elimination half-life decreases to just 10 minutes, as expected for substances such as native somatostatin, enkephalin, and substance P, the treatment volume diminishes to only 0.5 cm. However, the penetration distance is still 0.5 cm and still in excess of the penetration distances encountered with modes of delivery depending on diffusional transport across tissue interfaces. Finally, it should be noted that these penetration distances, computed here for a volumetric infusion rate of 3 pL/min, will decrease with decreases in the flow rate only as the cube root of the reduction factor (cf. Equation 9.24). For example, there will be only a 30% decrease in penetration distance for a 3-fold drop in flow rate to 1 pL/ min. 

Ideal Treatment Volume and Temperature Distribution. Heating pattern or specific absorption rate (SAR) induced by external devices is defined as the heat energy deposited in the tissue or tumor per second per unit mass or volume of tissue. In optimal treatment planning, it is the temperature rather than the SAR distribution that is optimized in the treatment plan. The maximum temperature generally occurs in the tissue region with heat deposition. However, one should note that SAR and temperature distribution may not have the same profile, since temperature distribution can also be affected by the environment or imposed boundary conditions. 

Fig. 6. Spatial distribution of net osmoticum deposition rate per mm of tissue water in the apical 10 mm of maize primary roots growing at various vemiculite water contents (see Fig. 3). The data were obtained by dividing rates per mm length (Fig. 5) by the volume of water in each segment. The inset shows root diameter as a function of distance from the apex in the different treatments. Points are means s.d. ( = 5-6). Modified from Sharp et al. (1988, 1989).

Finasteride has been clinically proved to reduce the median volume of the prostate in patients and is currently prescribed for the treatment of BPH. The compound also has demonstrated efficacy in the treatment of male pattern baldness and is prescribed for this indication as well. Subsequent to the discovery of finasteride, it was found that there are two isoforms of steroid 5a-reductase in mammals, type 1 and type 2. The type 2 isoform is primarily active in reproductive tissue, while the type 1 isoform contributes to DHT formation in the skin, liver, and reproductive tissue. Finasteride inhibits both isozymes in rats, but selectively inhibits the type 2 isozyme only in humans. It is hypothesized that dual inhibition of both isoforms of steroid 5a-reductase might prove more effective in treating BPH. Hence the GlaxoSmithKline group identified and developed dutasteride (Figure 8.18C). Dutasteride inactivates both human isoforms of steroid 5a-reductase by a mechanism similar to that described for finasteride (Bramson et al., 1997 see also the Web site www.avodart.com). Both finasteride and dutasteride have demonstrated clinical efficacy and are currently used in the treatment of BPH. 

Procedure Cholinesterase activity in analyzed tissue or the matrix (biotest with immobilized AChE) is determined in the incubation media [consisting of substrate ATCh - 34 mmol maleate buffer 0.1 M, pH = 6.0- 6.5 ml sodium citrate 0.1 M - 0.5 ml CuS045H20 0.03M -1.0 ml distilled H20 (or inhibitor in variant with toxin analyzed) -1.0 ml potassium ferricyanide 0.005 M -1 ml.] Volume of incubation media in one test - 400 mcl. As a blank (control sample), a treatment of the exposure without the substrate is used. If inhibitory effects of allelochemical (or any toxin) are analyzed, before the substrate addition the sample was preliminary exposed to allelochemical inhibitor. Two methods for the AChE-biotests may be recommended (i) in microcells ( stationary conditions ) and (ii) in flowing columns-reactors ( dynamic conditions ). 

The tissues were fixed in 0.05 M cacodylate buffer containing 2.5% glutaraldehyde and 1.5% formaldehyde (pH 7.0) for 16 h. The ZIO mixture was prepared as follows 3 g zinc (powder) and 1 g resublimed iodine crystals were dissolved in 20 mL distilled water. After stirring for 5 min, the zinc was filtered off. The filtered solution was mixed with an equal volume of 2% 0s04 solution and the solution used immediately. Treatment with the ZIO mixture was carried out for 4 h at room temperature. 

The earliest detectable human cancers usually have a volume of at least 1 cc and contain 10 (1 billion) cells. This number reflects the result of at least 30 cycles of cell division, or cell doublings, and represents a kineti-cally advanced stage in the tumor s growth. Most patients actually have tumor burdens that are greater than 10 . Since the major limiting factor in chemotherapy is cytotoxicity to normal tissues, only a limited log cell kill can be expected with each individual treatment. 

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