TWI278327B - An apparatus for treating disorders by altering ion flux across cell membranes with electric fields - Google Patents

Abstract

The invention relates to methods and devices for treating disorders with electric current or electric field therapy. The invention uses applied electric current or current induced by an external electric field to manipulate movement of ions across cell membranes and to alter ionic concentrations. The invention is useful, for example, for treating hyperproliferative and cardiovascular disorders and for ameliorating the effects of stress.

Description

1278327 玖, invention description: L inventor's technical field] Cross-reference related application This application was filed on December 14, 2001 and announced on December 5, 2005. Part of the US application No. 10/017, 105 continuation of the application. This application also claims the benefit of U.S. Provisional Application Serial No. 60/433,766, filed on December 17, 2002, and U.S. Provisional Application Serial No. 60/399,249, filed on July 30, 2002. The entire contents of all of the aforementioned applications are incorporated herein by reference. ο [Background] A variety of electrical therapy devices are known. Typically, the electrodes of a device contact a patient, in which case the electrotherapy device employs an applied current and can be referred to as an electric cwrr (9) i therapy device. Examples include TENS or PENS (Ghoname, Ε·Α·, et al., Anesth. Analg., 88:841-46 (1999); Lee, RC, et al., J Burn Care Rehabil., 14:319-335 (1993)).

If the electrode is not in contact with the patient, the electrotherapy device induces current in the patient by means of an external electric field 20 (hereinafter referred to as "EF"), which may be referred to as an electric field or potential (electric therapy device. EF produces surface charge in all conductive bodies (including animals or human bodies). When EF is applied, positive and negative charges will appear on the opposite side of the body. When the electric field alternates, the charge will In the position, I paid 1278327 for 'in the body, I became a sputum, a graded electricity (see Hara, H., et al., Niigata Med., 75:265-73 (1961)). In 1972, the Ministry of Health and Welfare of Japan (japan, s Ministry of Health and Welfare) approved an electrical stimulation device (approval number 5 147〇〇BZZ〇〇904). In 1978, the USFDA approved electrical stimulation to treat bone disease. However, the treatment literature reported a wide variety of For the biological response of electrical stimulation, such as 'extenial sim s〇 idal alternating fields' (ac EF) has been shown to change cell type in other organisms, in fibroblasts Protein synthesis, redistribution of the invasive membrane 10 protein, DNA synthesis in chondrocytes, intracellular 4 edge: elongation, microfilament structure in human hepatoma cells And the level of electrolytes in the blood (Kim, γ.ν., et al., Bioelectromagnetics, 19:366-376 (1998); Cho, MR, et al., FASEB J·, 13:677-682 ( 1999); Hara, H., Niigata Med., 15 75:265_73 (1961). Some researchers believe that many of the observed effects are not directly due to EF' but are EF in primary cellular structures such as membranes. - Secondary effects of the effects of membrane-receptor complexes and ion-transport channels. Although the biological utility of induced current has been studied in the last 25 20 years Most of the research was motivated by the safety of people exposed to strong electrical or magnetic fields from high transmission power lines and associated electrical devices. For example, utility company staff are routinely exposed to Electric field of 50-500 kV/m and such as 5 G-like high magnetic field, and the general public is usually exposed to an electric field of 1 -1 〇kV / m and a magnetic field of up to 2 G (portiei, 1278327 CJ & Wolfe, MS (eds.) Assessment of Health Effects from Exposure To Power-line Frequency Electric and Magnetic Fields, NIEHS Publ. No. 98^3981 (National Institute of Environmental Health Sciences, 1998)). Previous techniques lacked sufficient research into the efficacy of low ground and weak electric fields. In addition, conventional EF therapy devices employ high voltages and do not account for differences in EF intensity across different regions of the body. In a nutshell, the prior art is not intended to be a combination of appropriate and effective electrical parameters for 10 for truly effective electrical therapy. Previous prior art devices have generally been very high, as indicated by Sperer, U.S. Patent No. 5,387,231. Operating at a voltage or very high current, both of which produce a diathermy effect in the tissue being treated. In many cases, the prior art may refer to one of various electrical parameters or The other, but neglecting the importance of other parameters.” 15 Because previous techniques show completely different biological responses, and rely on inaccurate measurements and focus on high voltage and high current efficacy. There is still a need to identify specific parameters for use in electrotherapy, particularly electrotherapy using relatively low voltages and currents. SUMMARY OF THE INVENTION 3 20 SUMMARY OF THE INVENTION The inventors have determined the parameter values of the successful treatment of a particular disorder and the applied current. These parameters include, for example, frequency in Hwtz, voltage (in volts), induced current density (in mA/m2), applied current density (in mA/m2), individual continuous 1278327 Time (in minutes, hours, and days), and all: between roads (heat is based on the total sum of a continuous exposure cycle). Jian,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Or its - part, or its cells, the average area of the cell Γ area. For example, if there is a human being and the interested part is the whole hand of the human, the average fatality is the value of the (4) κ for the entire hand-neighboring cell. The average current density is the sum of the current densities of the various parts of the hand divided by their area. The special formula and technique (4) described here are used to estimate the external current density and the average induced current density. Unless otherwise specified (4) organisms, the term includes both humans and other organisms. 15 - The specific example of the invention relies on the applied current (appHed electric c_t). Decrease the ground, the density of the external application is about 2, within the scope of the scope. Another specific example of this invention relies on a particularly low amount of induced current to control the movement of ions across the cell membrane. In order to treat a disorder caused by or caused by an abnormal ion concentration in an organism cell, a specific example of the induced current includes subjecting the organism to an external electric field, the external electric field generating an approximation 0.001 mA/m2 to approximately 15 mA/m2^. The mA/m' is preferably from about 0.001 mA/m2 to about H) mW, more preferably from about 〇1 W1 mW to about 2 cents per cell membrane. The average (mean) induced current density. In a preferred embodiment, the external electric 1278327 field (E) is measured by the term in the equation E = i / e 〇 coS, where S is a % of electricity: a section of the measurement sensor (section), εο is a Uuetion rate in a vacuum, I is a current, ω is 2πί, and f is a frequency. Also preferably, the induced current (J) is measured by the term in the formula = ι / Β 5, where I is a measured current and B is a circular area expressed as B = Α 2 / 4π (circle area), A is a circle denoted as A = 2πΓ, and r is a radius. In an additional preferred embodiment of the invention, the induced current density is generated over a continuous period of time from about 10 minutes to about 240 minutes throughout the cell membrane. In the repeated 10 implementation (in reappiicati〇n), the average induced current density is preferably generated for a continuous period of from about 30 minutes to about 90 minutes, preferably resulting in a total exposure of less than about 1,500 minutes. time. Two specific examples of the application of current and induced current in the present invention can be applied to an entire body or only a part of the body. A portion of the body may include a limb, an organ, a defined body tissue, a part of the body (such as a 'lie down'), a body system, or a subsection of the temple. A trained individual can determine/special obstacles to be applied to an entire body or a portion of the body in accordance with the present invention. The invention may further comprise providing a calcium supplement, a one-dimensional 20 vitamin D supplement, a phytohemagglutinin Oectin supplement, or a combination of such supplements to the organism. Preferably, the phytohemagglutinin supplement comprises concanavalin A or wheat germ agglutinin. In a preferred embodiment, the invention alters or affects the I bow 10 in a different manner. 1278327 or other cationic or multivalent cations (including cation electrolytes and proteins that play an important role in the activation of electro-sensitive calcium receptors (CaR) associated with Ca++ uptake in extracellular fluids) flow. 10 15 An alternative embodiment of the invention relates to a device for use as an EF therapy. A preferred EF therapy device is an electric field therapy device comprising: a main electrode and a counter electrode; a voltage for applying a voltage to the electrodes a voltage generator; an induced current generator that controls an external electric field by changing a voltage or a distance between the opposite electrode and the living body or a portion thereof; and a driving source for generating the voltage Power supply. Preferably, the package pressure is generated to have a booster coil (b〇〇ster(3) mountain and the voltage generator is grounded at an intermediate point or one end of the booster coil. More preferably in one of the present inventions In an EF therapy device, it has a primary electrode and a counter electrode disposed adjacent to the head, shoulder, abdomen, waist or buttocks of the human body, and between the opposing electrode and the torso of the human individual The distance between the surfaces is about e25 cm, and the other is t1 to 15 em. In an alternative aspect, the opposite electrode is a ceiling, a thin wall, a floor, furniture, or other objects or surfaces in the phase (10). The case involves determining the optimal parameters for the fine 7 or external current therapy, the best parameters of the therapy = two =, _ recognized - to be induced in the living organism: two ==; (11) Screening or measuring an average of 1 on the cell membrane of a tissue sample or culture of the organism or derivation

• The m field produces a measured or measured induced current density at a specific distance from the organism, sample or culture; (iv) screening or measurement _ used to produce screens or Measured induced current density for a continuous period of time; (7) applying 5 of the screened or measured electric field to the organism, sample or culture to produce the screened or measured induced current density on the cell membranes for the duration a continuous time period that is screened or measured; (10) determining the extent to which the desired biological response occurs; (vii) selectively repeating any of steps (9) through (10); and/or (vϋ〇 confirming optimal induction The desired biological response is φ Η) the value of the induced current density that is screened or measured, the value of the external electric field that is screened or measured, or the continuous time period that is selected or measured. The value. With regard to this specific example, "measurement," the term encompasses situations in which the experimenter unconsciously, deliberately, or pre-selects parameter values at first. For example, "measurement," the term contains an EF device that produces a random or initial unknown. The average induced current density of 15 quantities and then the researcher directly or indirectly determines the number of cases. The invention is further illustrated by the following figures and detailed description. β [Embodiment] 2 详细 Detailed Description of the Preferred Embodiment Method Method for Modulating Ion Flux Across Cell Membranes An ion imbalance may originate from a disorder or condition, or may Is a side effect of a medical treatment or supplement. The present invention alters the flow of ions across the cell membrane by generating a current through the cell membrane of 12 1278327. The invention also affects the composition of the cell membrane (such as its transmembrane protein). The present invention restores or balances the cellular i〇nic homeostasis or changes the membrane potential of the cell membrane. Therefore, the present invention is applicable to prevention or treatment related to cell or cell 5 ion concentration, such as concentration of (Ca2+), magnesium (Mg2+), sodium (Na+), potassium (K+), and chlorine (cr). obstacle. In order to treat disorders associated with serum calcium concentration, the average induced current density generated throughout the cell membrane is preferably from about 0.3 mA/m2 to about 0.6 mA/m2, more preferably from about 44 mA/m2 to about 0.5 mA/ M2, optimally about 0.42 mA/m2. The applied current is used to treat a disorder associated with serum calcium concentration. The average applied current density is preferably from about 60 mA/m2 to about 2,000 mA/m2, and the average applied current density is generated throughout the cell membrane. A continuous period of from 1 minute to about 20 minutes, more preferably from about 2 to about 10 minutes. Tissues that can be administered by the methods of the invention include, for example, musculo-skeletal tissues, tissues or the central nervous system, gastrointestinal system tissues, Reproductive system tissues (both male and female), pulmonary system tissues, cardiovascular system tissues, endocrine system tissues, immune system tissues, Lymphatic system tissues, and urogenital system tissues. Biofilms of eukaryotic cells, such as plasma membranes, are selectively permeable to these ion systems. The choice of permeability allows for the creation of 13 1278327. Cells use this membrane potential to transport molecules across the raft. Many ions associated with generating a membrane potential perform life functions. For example, a threshold concentration of calcium ions in muscle cells initiates the acceptance of Ifg in the pancreatic system (pancreatic §) of the exocrine cell 5 threshold / temperament word salty seeds trigger digestive enzymes ) secretion. Similarly, different concentrations of sodium and potassium ions are necessary for the conduction of dectric impulses via axons of nerve axons. A protein family, widely referred to as voltage-gate ion channels (v〇ltage_gated i〇n 10 Channels), maintains ion concentration and membrane potential. The voltage-gate mother-scorpion channel is a transmembrane protein containing ion-selective pores, and the ion-selective pores allow the ions to pass through the biofilm through the configuration of the side channel (c〇nf〇rmati〇nai state). . The configuration of the channel is affected by a voltage-sensitive portion comprising 15 charged amino acids that are reactive with the membrane potential. The channel is either conductive (on/activated) or non-conductive (off/non-activated). Since special ions (i.e., Ca2+) are involved in cardiovascular health, the present invention is useful for the prevention and treatment of cardiovascular disorders. These disorders include, for example, cardiomyopathy, dUated congestive cardiomyopathy, hypertr〇phic cardiomyopathy, angina, variant angina (variant angina) ), unstable angina, atherosclerosis, aneurysms, abdominal aortic aneurysm 14 1278327 (abdominal aortic aneurysms), peripheral arterial disease (peripherai arterial disease), blood pressure disorder ( Such as hypotension and hypertension), orthostatic hypotension, chronic pericarditis, arrhythmias, atriai 5 fibrillation and flutter, heart disease (heart disease), left ventricular hypertrophy, right ventricular hypertrophy, tachycardia, atrial tachycardia, ventricuiar tachycardia, And hypertension (hypertension)10 The invention may also be used to prevent or treat blood disorders. These blood disorders include, but are not limited to, hyponatremia, hypernatremia, hypokalemi, hyperkalemia, hypoPalemia ), hypercalcemia, hypophosphatemia, hyperPerPh〇sphatemia, hypomagnesemia and hyperpenginsemia, and blood sugar Regulatory disorders (such as diabetes, adult diabetes, and juvenile diabetes). In one embodiment of the invention, a lectin and coenzyme are co-applied to enhance Ca2+ flow across the cell membrane. The plant lectin which can be used in the present invention includes, for example, Concanavalin A and wheat germ agglutinin (wheat germin

Agglutinin). In another embodiment, the ion current caused by the present invention is produced simultaneously with a calcium supplement. In another embodiment, the ion current caused by the present invention is produced simultaneously with a vitamin D supplement or with a calcium supplement and a vitamin D 1278327 supplement. The vitamin D supplement of the present invention includes, for example, vitamin 52 and vitamin & Likewise, the method of the present invention can be performed with the same supplemental light source that is applied to the surface of the biological sample or patient. The light source emits a wavelength in the range of about 225 nm to about 100 nm. The light source of the present invention, which is co-administered with the method of the present invention, emits a wavelength in the range of from about 230 nm to about 313 nm. In an additional embodiment of the invention, another molecule can be transferred across a cell membrane simultaneously with a stream of ions produced by the invention. The additional molecules that can be transferred simultaneously with the stream of ions 10 can be naturally produced by the body, or alternatively can be provided by supplementation (e.g., via a vitamin or the like). For example, cellular glucose uptake can be enhanced by the flow of calcium ions across a cell membrane. Additional molecules that can be transferred across a cell membrane simultaneously with a stream of ions produced by the present invention include nutraceuticals (eg, a nutritional supplement designed to aid in the prevention or treatment of a disorder and/or condition). . Further, the method of the present invention can be used in conjunction with hyperalimentatkm treatment (e.g., administration of nutrients beyond normal needs to treat disorders such as coma or severe burns or gastrointestinal disorders). The 1-60 Hz electric field upregulates the cytosolic calcium (Ca2+) position in the mouse spleen cells stimulated by the lectin 20. The EF exposure system used in this experiment is composed of four parts. Composition: Electric field exposure vessel made of polycarbonate; function generator (SG-4101, IWATSU Co. Ltd., Tokyo, Japan); digital multimeter (digital 16) 1278327 multi-meter) (VOAC-7411 IWATSU, Tokyo, Japan); and controller (Hakuju Co. Ltd., Tokyo, Japan). Figure 1 shows an electric field exposure jhl in an EF exposure system. The electric field exposure consists of a cover (Hd), a and a doughnut-shaped insert (internal diameter: 5 12 mm). An EF between two circular platinum electrodes (cell culture spaces) is generated via the function generator and is carefully adjusted by using the controller and the digital multimeter. The field strength of the 60 Hz electric field is detected by measuring the current density in the cell culture space where the electric field is exposed to the solitary cell. 10 The current density is calculated by the equation · current density = Ι / S, where "the sputum is the supplied current (pA) and the S system is the cell culture space (0 · 36 π) Area (cm2). Therefore, the current density can be calculated by current density = 885 Ι [μΑΛ: ιη2], approximately 1.7 ml of analysis buffer (137 mM 15 NaCl, 5 before EF exposure). mM KC1, 1 mM Na2HP〇4, 5 mM glucose, 1 mM CaCl2, 0.5 mM MgCl2, 0.1% (w/v) BSA, and 10 mM HEPES pH 7.4) were poured into the electrode chamber. To avoid cell and underlayer Contact with the electrode, a polycarbonate membrane (isopore, MILLIPORE, MA USA) was placed between the dish and the insert. Approximately 1 ml of the cell suspension was inverted into the well/interval and was Covered with a lid. Cell preparation Female BALB/c mice housed in a traditional animal room equipped with a clean air filter (4-7 weeks old, available from CLEA (Tokyo, Japan) The spleen was removed under anesthesia (Spienect〇mize(j), and the cell suspension of the spleen fine 17 1278327 was made In order to test the cell viability, the cells were cultured in Dulbecco's modified Eagle's medium (Dulbecco's modified Eagle's medium supplemented with 1% fetal bovine serum (5) bovine serum, FSB). SIGMA, M〇, USA)) 5. During the [Ca-+]e assay, the cells were maintained in Hanks' Balanced Salt Solution (HBSS) (SIGMA, MO, USA), which [Ca2+]i The assay was performed within 4 hours after cell preparation. Cells were stored prior to use. Determining the viability of cells exposed by EF The mouse spleen cells (5 X 106 cells/ml) were exposed to 60 Hz. , 6 μΑ/cm2 10 or 6〇4 8/〇1112 ugly, at 37. (:, 5% <:02 for 3 minutes and 24 hours. Simulated (sham) cells are left exposed to electric field The time of 3 minutes and 24 hours of Alex, but not exposed to EF. At the end of 30 minutes and 24 hours of exposure, the cell suspension collected from the exposed field of the electric field at 4 under 2.5 Mg / ml of brominated The ingot (pr〇pidiumiodide) was stained for 30 minutes, and the percentage of 15 dead cells was via flow cytometry. Calculated. For the analysis of cell preparation and phytohemagglutinin of spleen cells (106 cells/ml) at 37 ° C with fluoro-3-acetylindole oxymethyl group containing 2.5 μM Flux-3-acetoxylmethyl) (Molecular Probes, USA) 20 [Vandenberghe et al., 1990] HBSS was incubated for 20 minutes. The cell suspension was then diluted 5 times with HBSS containing 1% FBS, incubated at 37 C for 4 minutes, washed 3 times with assay buffer, and the cells were suspended in the assay buffer. The concentration in the liquid becomes a concentration of 1X l〇6/ml. These cell suspensions were gently mixed by light 18 1278327 throughout the cell preparation. Considering the synergistic interaction between EMF and mitogen (Walleczek and Liburdy, 1990) (Synergistic interaction) 'Concanavanin A (c〇nA) (Seikagaku Co., Tokyo, 5 Japan ) is used with phytohemagglutinin (pha) (SIGma, MO, USA). The experimental design used to determine the effect of 60 Hi [6 μΑ/cm2) EF on the production of high [Ca2+]Jm cells is based on the early analysis of the viability test results of exposed murine splenocytes. 'We chose to use the best culture. The following five experiments were performed with exposure conditions (60 Hz, 6 10 kA/cm2 EF): (1) Cells suspended in HEPES-buffered solution (BS) + 1 mM CaCl2 were exposed to EF for a total of 40 minutes and exposed. 12.5 pg/ml of Con-A was added after the first 8 minutes. The control group consisted of cells exposed to EF without c〇n-A and cells exposed by EF without Con-A. High 15 [Ca2+]cjs percentages were examined at defined exposure time points; (2) Cells in HEPES-BS + 1 mM CaCl2 were exposed for a total of 12 minutes' and different concentrations (1 ng - 12.5 pg/ml) of Con -A was added after the first 4 minutes of exposure. The control group was essentially the same as the experimental group but no EF exposure; 20 (3) Cells in HEPES-BS + 1 mM CaCl2 were exposed for a total of 8 minutes, and 5 pg/ml of PHA was after the first 4 minutes of exposure. Add to. The control group consisted of cells not exposed to EF containing PHA and cells exposed by EF without PHA; (4) cells suspended in HEPES-BS without CaCl2 were exposed for a total of 19 1278327 for 12 minutes, and different Concentrations (1 ng _ 5 tons/mail ‧ were added after the first 4 minutes of exposure. The control group was essentially the same as the experimental group but without EF exposure; and (5) in order to assess the sustained utility of EF exposure, suspension Cells in HEPES_BS + 5 1 mlCaCl2 were exposed for a total of 4 minutes, then Con-A at different concentrations (0.025 -12. 5 pg/ml) were added, and then there was no 8 minute 'high [Ca^] for liver exposure. The production of e cells was followed by flow cytometry. The control group was essentially the same as the experimental group but did not have any EF exposure. Statistical Analysis 10 Statistical analysis of cell viability was performed using the Studden's t test. (Student's t test) was determined. As EF exposed between groups [Caljj: data used by ANOVA (ANalysis Of VAriance between groups), Stutton's t test and paired t test (paired T test) All calculations for statistical analysis of the 15 MS-EXCEL® Japanese version (Microsoft Office software: Ver · 9.0.1,

It was carried out in Microsoft Japan Inc. Tokyo, Japan). Results Figure 2 shows the percentage of viable cells after EF exposure. In all three replicates, more than 98% of the cell lines were viable after exposure to 6 μΑ/cm 2 or 60 μΑ/cm 2 . The number of high [Ca2+]c cells was significantly increased in both EF exposed and unexposed cell suspensions containing 12.5 pg/ml Con-A (Fig. 3). In Fig. 3, a circle indicates a suspension without Con-A, a triangle indicates a suspension with Con-A exposed to EF, and a square indicates a suspension with Con-A not exposed to 20 1278327 to EF. . The high [Ca2+]c cells in the cell suspension exposed without the Con-A remain essentially unchanged. The c〇n A-induced response was immediately noted and reached a saturation point within 5-8 minutes after the addition of mitogens (eg, such as Di(1). Cells induced by EF exposure and uncontaminated 5 Con-A The difference between the two is not significant (insignificant) & P &gt; 0. 〇 5). Figures 4A and 4B summarize the results of EF exposed cell cultures containing different concentrations of Con_A with and without ImM CaCh. The fourth insult shows the results of a culture containing 1 mM CaCh. In Figure 4A, the culture exposed to face Ερ 10 (black bars) and the culture not exposed to EF (white bars) contained 1 mM CaCl2 and different concentrations of Con-A (0.01 gg/ Ml to 5 pg/ml). In the presence of CaCl2 (Fig. 4A), EF significantly enhanced Con-A-dependent [Ca2+]c (P&lt;0.01: ANOVA). Although the increase in high [Ca2+]c cells in the 0.675-5.0 pg/ml Con-A-stimulated group was more than 15 parenchymal, only 1.25 b/1111 and 2.5 08/1111 (^〇11-eight induced The cells showed significant differences (Ρ&lt;〇·〇5: paired t test). In Figure 4B, EF exposed cultures (black bars) and control cultures that were not exposed to EF ( White straight strips) Both contain different concentrations of Con-A, but do not contain CaCl2 〇 in the control group and EF exposed to the two secluded _ groups, in the absence of 〇 2+ 20 cells (Fig. 43) (: 〇11-eight-dependent [〇32+](: the ascending system is minute. To determine whether EF-dependent [Ca2+]c upregulation is restricted to Con-A, PHA-stimulated Cells were also analyzed. Both EF exposed and unexposed cells containing PHA showed a significant increase in high 21 1278327 [Ca2+]c cells (Fig. 5). However, compared to the unexposed population The increase in EF-exposed cells was significant (P <0.05: paired t-test) compared to those stimulated with 0.025 pg/ml Con-A Add 5 3·125_12·5 Kg/ml of Con-A to the cell suspension (either unexposed or initially exposed to EF for 4 minutes) on high [0&2+] (: cells) Shows an increase in page selection (Fig. 6). Cells stimulated to 3.125 and 6.25 48/1111 (1!〇11-eight cells in high [Ca2+]c cells (which are approximately 8 minutes after C〇nA stimulation) ) showed a sustained increase, whereas cell cultures stimulated with a higher concentration of 10 Con-A (12.5 pg/ml) showed on high [Ca2+] Js cells approximately 4 minutes after Con-A stimulation. A debilitating effect. The enhanced utility of EF exposure was only significantly verifiable at 2-4 minutes in the presence of 6.2 pg/ml Con-A (Ρ &lt;0·05: paired t test). Example 2 - Effect of low frequency electric field on Vasoactive Substance-Inducecn intracellular calcium (Ca2+) response in human [5 Vascular Endothelial cells]. To assess EF in human vascular endothelium The effect on cells (hereinafter referred to as HUVEC), intracellular calcium levels were detected by HUVEC in the form of ATP and histamine. EF estimated utility in the HUVEC, HUVEC 20 is exposed to a 50 Hz (30,000 V / m), 3,000 volts EF. The EF induced current density on the HUVEC was estimated to be 0.42 mA/m2. HUVEC was exposed to these test parameters for 24 hours. After exposure, the cytosolic free Ca2+ concentration was determined by a fluo3 flow cytometer. A change in the image intensity of fliK &gt; 3 was confirmed by instant exposure of a total of 22 1278327 real-exposure confocal laser microscopy. The results confirmed that EF increased the calcium concentration in HUVEC. B. The treatment of proliferative cell disorders (pr〇iiferative cei 〖 disorders) is the treatment of proliferative cell disorders, especially those involving differentiated fibroblast cells, which are generated throughout the cell membrane. The density is preferably from about 1 mA/m 2 to about 2 mA/m 2 'more preferably from about 2 mA/m 2 to about L 2 mA/m 2 , and still more preferably from about 0·29 mA/m 2 to About 1.12 mA/m2. With an applied current, the average applied current density generated throughout the cell membrane is preferably from about 10 mA/m2 to about 1 〇〇 10 mA/m2. The fibroblast cell line is a cell type derived from embryonic mesoderm tissue. Fibroblasts are capable of being cultured in vitro and secrete matrix pr〇teins such as laminin, fibronectin, and 15 collagen. Cultured fibroblasts usually do not differentiate like tissue fibroblasts. However, with appropriate stimulation, fibroblasts have the ability to differentiate into many cell types such as, for example, fat cells, connective tissue cells, muscle cells, collagen fibers (c〇llagenfibers) and the like. Specific fibroblasts can differentiate into many cell types associated with connective tissue and the muscle 20 musculoskeletal system. Methods for controlling the growth of undifferentiated fibroblasts in vivo or in vitro can be applied to control derived from Growth of differentiated cells of fibroblasts. For example, hyperpr〇liferaUve disorders of the musculoskeletal tissue can be controlled or prevented by the method of preventing fibroblast growth. We determined that an applied current density of about 10, 50 or 100 mA/m2 was produced throughout the cell membrane for a period of about 24 hours/day for at least about 7 days to inhibit the growth of cultured fibroblasts in a current density dependent manner. . 5 hyperproliferative disorders include, for example, association with connective and musculoskeletal

Organize related neoplasms such as fibrosarcoma, rhabdomyosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, and lipid Sarcoma 10 (liposarcoma). Additional hyperproliferative disorders that can be prevented, ameliorated, or treated using the methods of the invention include, for example, progression of malignancies and/or sputum, including such as: abdomen ( The abdomen), bone, brain, breast, colon, digestive system, endocrine gland (adrenal gland, accessory sacral gland, pituitary gland, 15 sputum, ovary, thymus, thyroid), eyes, head and neck, liver, lymph System, nervous system (central and peripheral), pancreas, pelvis, peritoneum, skin, soft tissue, spleen, chest, and urogenital tract tumor, leukemias [ Including acute promyelocytic, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic , myelomonocytic, monocytic, erythrocytic leukemia (eryt) Hroleukemia)], lymphoma (lymphomas) [including He Jiejin 24 1278327

(Hodgkins) and non-Hodgkins lymphomas, multiple myeloma, colon carcinoma, prostate cancer, lung cancer, small cells Small cell lung carcinoma, bronchogenic carcinoma, testicular cancer, cervical cancer, ovarian cancer, breast cancer, angiosarcoma, Lymphatic sarcoma (lymphangiosarcoma), endotheliosarcoma, lymphatic endothelial sarcoma (lymphangioendotheliosarcoma), synovial tumor 10 (synovioma), mesothelioma, Ewing's sarcoma, leiomyosarcoma ( Leiomyosarcoma), squamous cell carcinoma, basal cell carcinoma, pancreatic cancer, renal cell carcinoma, Wilm's tumor, liver cancer 15 (hepatoma), bile duct carcinoma, adenocarcinoma, epithelial cell carcinoma ( Epithelial carcinoma), melanoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, neuro 20 glioma ), astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma Acoustic neuroma, oligodendroglioma, menangioma, neuroblast 25 1278327 cell tumor, retinoblastoma, bladder carcinoma, class Embryonal carcinoma, cystadedenocaixinoma, medullary carcinoma, choriocarcinoma, and seminaloma 〇 Example & EF exposure to murine spleen cells The effect of Ca2+ concentration in fish 31^/eight 31 fibroblasts on murine spleen cells EF Effect on murine splenocytes calcium concentration, a special field EF of 6〇 Hz 10 is applied to the exposed spleen cells of mice. The mice were excised from the spleen under anesthesia. In a 60 mm dish, the spleen was injected with PBS (containing 0.083% NH/l phosphate buffer). The cells were resuspended and maintained in Hanks' Balanced Salt Solution (HBSS) (SIGMA, MO, USA) during the [Ca]e assay, which was tested for 4 hours after 15 days of cell preparation. It is carried out inside. Cells were stored at 4 °C prior to use. Application of a 60 Hz EF produced 6,20, 60, and 200 μΑ/cm2 of applied current density on splenocytes. Splenocytes were exposed to these conditions for 4 minutes, and after these exposures, the splenocyte samples were stimulated with concanavalin A (ConA). After spleen cells were stimulated with (^(10)8, the cell 20 free Ca2+ concentration was determined by flowocytometry. This experiment confirmed that ConA increased the calcium concentration in splenocytes. The calcium ion concentration was due to a 6-200 μΑ /cm2 increases with the application of EF. More importantly, the increase in calcium ion concentration depends on the current density (see Figure 7, where the Y-axis shows the calcium concentration and the X-axis shows the time in minutes.) 26 1278327 Effect of BALB 3T3 To determine the effect of EF on calcium ion concentration in murine 3T3/A31 fibroblasts, these 3T3 cells were introduced to an EF at 60 Hz. The 3T3 cell line was obtained from the Japan International Center for Protozoal Diseases. The cell bank of the Japanese National Research Center for Protozoan Disease and grown in DMEM containing 5% FCS and 10 mM HEPES at 37 ° C. EF produces a 200 μΑ/cm 2 application of cells throughout the cell. Current Density. After 2 minutes of exposure, the cytosolic free Ca2+ concentration was measured by a fluo3 flow cytometer, and the fluo3 flow cytometer showed an increase in the bow concentration in these cells. A change in the intensity of the fluo3 image was confirmed by a conjugated focal laser microscope. i Example 4 - Effect of Ionophore 舆 EF on membrane potential in BALB 3T3 15 Figure 8 shows that the ionophore changes the BALB of the mouse. Membrane potential of 3T3/A31 fibroblast/embryonic cells. Figure 8 shows the time course of DiBAC intensity in BALB 3T3 cells stimulated to a final concentration of 0.4 mM A23187. A23187 is an extract from Sfre/A (Aarire) (9) is also a monocarboxylic acid (monocarboxylic acid) which is a movable carrier of about 20 channels. DiBAC is a fluorescent dye which enters the cell membrane when the potential of the cell membrane changes. Therefore, when these BALB 3T3 cells When the cell membrane is depolarized, DiBAC enters those cell membranes, thereby increasing the intensity of the DiBAC signal (Y-axis) in the BALB 3T3 cells. Figure 9 shows an electric field (EF) at 100 Hz for BALB 3T3 27 1278327 Effect of membrane potential, the electric field produces a current density of approximately 200 mA/cm 12. The change in membrane potential is measured by flow cytometry. The methodology for flow cytometry is as follows In DMEM culture is supplemented with 5% FCS 10mM HEPES. And be departing from the (de-touched) at 0.02% trypsin and 5% EDTA its connection. It was then resuspended in HEPES buffer (137 mM NaCl, 5 mM KC1, 1 mM Na2HP04, 5 mM glucose, 1 mM CaC12, 0.5 mM MgC12, 0.1% (w/v) BSA and 10 mM HEPES pH 7.4) in. It was then loaded with a final concentration of 200 nM of DiBAC4 (3). It was incubated 10 at 37 ° C for > 5 minutes. Next, flow cytometry measurements are performed. Figure 10 also shows the effect of an electric field (EF) at 100 Hz on the membrane potential in BALB 3T3, which produces a current density of approximately 2 mA/cm2. Example 5 - Extracellular current changes in synovial cells of viviparous cells (Svmwial 28 1 丄5 ti匕AblagL sputum main cell gap junction Communication,). We examined the effect of low quasi-current on the intercellular gap junction (GHC) regulated by c〇imexin43 protein. The single-cell 2 〇 layer of synovial fibroblasts (HIG-82) and neuroblastoma cells (5 Y) merged into a bath solution, 0-75 mA/m2 (0 -56 mV/m' 60 Hz) ' and single channel conductance (singie_channei con (juctance), cell membrane current _ volt (IV) curve, and Ca2+ influx (influx) using nystatin double-ami single_patch The conductance of the closed and open states of the gap-junction channel in HIG-82 cells in cells 1278327 exposed to 20 mA/m2 (in 〇·76ρΑ and 0.39 pA, respectively) Each was significantly reduced; no effect occurred on the conductance of the gap junction channel between 5Y cells. A low current density of 10 mA/m2 significantly increased the Ca2+ influx in HIG-82 cells, but for 5Y fine 5 The cell has no effect. The IV curve of the plasma membrane of these two types of cells does not rely on 60-Hz, 0-75 mA/m2 current, indicating that the 60-Hz current is not a function of GJIC in HIG-82 cells. Regulated by a change in membrane potential. The conclusion is low Quasi-extracellular currents can alter GJIC in synoviocytes via a mechanism that does not depend on membrane 10 potential, but may rely on Ca2+ influx. The results indicate GJIC-regulatory responses in synoviocytes (eg, they are for the anterior - The secretory response of pro~inflammatory cytokines can be antagonized by the application of extracellular low frequency currents. C. Method of Reducing Stress 15 The present invention can be applied to prevention or treatment. Stress and stress-related disorders such as reduced immune-system function, infection, hypertension, atherosclerosis (10), and insulin-resistant dyslipidemia syndrome. For treatment of stress, immunosuppressive disorders 20 and to reduce the level of ACTH or cortisol, the average induced current density generated throughout the cell membrane is preferably from about 0.03 mA/m2 to about 12 mA/m2. More preferably, it is from 0.035 mA/m2 to about 11.1 mA/m2. With an applied current, the average applied current density is preferably from about 60 mA/m2 to about 600 mA/m2. 29 1278327 Stress is associated with many health disorders, including hypertension, atherosclerosis, insulin-resistant blood fat abnormalities, and established immune dysfunction (Vanitallie TB·, m, 51:40-5 (2002) )). Researchers have found that stress can affect the normal homeostasis of adrenocortical 5 hormones such as cortisol and corticosterone. The corticosterone is produced by the adrenal gland and its alteration is a common indicator of stress. In a report involving mice exposed to an electric field of up to 50 kV/m, 60 Hz, a decrease in plasma corticosterone concentration was observed, but only at the beginning of the exposure period (Hackman, RM 10 & Graves, Η· Β·, Price/ιαν· Price·〇/· 32:201-213 (1981)). Similarly, Poitet and Cabanes reported that lower cortisol levels were found in the adrenal gland when rabbits and rats were exposed to 50 kV/m at 50 Hz, but cortisol concentrations in the blood were not detected. (P〇rtet, R. & Cabanes, J., Bioelectromagnetics 9:95-104 (1988)) ° 15 ACTH is a peptide represented by the pituitary gland and is almost exclusively specialized. Control the secretion of cortisol. The ACTH level is a powerful indicator of body function in terms of physical function, primarily because A C T Η acts to control the secretion of cortisol, a major anti-inflammatory molecule that is important for stress responses such as traumatic events. Interestingly, the researchers have found no increase in the ACTH level after 30-120 days of exposure to electric fields (Free, M.J., et al., Bioelectromagnetics 2:105-121 (1981)). In one study, when rats were exposed to 100 kV/m, 60 Hz for 1-3 hours, no changes were found in plasma ACTH (Quinlan, WJ, et al, Bioelectromagnetics 6:381-389 30). 1278327 (1985)). When the mice were exposed to i〇kV/m, 50 Hz, the serum ACTH concentration ratio was ft?, the group in the group (deBruyn, L. & deJager, L., Environ. Res 65: 149- 160 (1994)). Lipid staining in the adrenal cortex is elevated, but only in males. The authors infer that the electric field is a pressure source 5 (stre de yr). The altered blood ACTH concentration was also found in rats exposed to a 15 kV/m '60 Hz electric field for 30 days (Marino, Α·Α·, et al., Physiol. Chem· Phys· 9: 433-441 (1977)) Conversely, we have confirmed that applying an electric field under a particular parameter to a test animal causes a pressure-induced decrease in ACTH concentration. 10 For example, applying an electric field of 17500 V/m (50 Hz), a voltage of 7,000 V, and an induced current density of about 0.035-0.5 mA/m2 lasting a period of 60 minutes caused pressure in the test animals. The induced serum ACTH level is reduced. Example 6 - Effect of a 50 Hz electric field on blood flow ACTH, 15 glucose, lactic acid, and pyruvic acid in rats that were about to walk. Electric field exposure system The EF exposure system used in this example was composed of the following three The main part is composed of a high voltage generator (HealthtronTM, maximum output voltage: 9,000 V; Hakuju Institute for Health Science 20 Co. Ltd., Tokyo, Japan), a constant voltage power supply (TOKYO SEIDEN, Tokyo, Japan). And EF exposed cages. The exposed cages consist of a cylindrical plastic cage (φ: 400 mm, height: 400 mm) and two electrodes (1,200 X 1,200 mm) made of stainless steel placed above and below the cylindrical cage. Composition. In order to form EF (50 Hz; 17,500 31 1278327 V/m) in the cage, a stable alternating current (50 Hz; 7,000 V) was applied to the upper electrode. Experimental animal female, 7-week-old Wistai* rat weighing 300-350 g was purchased from Charies River Japan, Inc. (Tokyo, Japan) and housed in a traditional animal equipped with an air purification filter. In the room. Restraint Stress Rats were restricted by placing each package in a thin polycarbonate sheet and placed over the lower electrode for 3 minutes. The design of the EF design for the restraint pressure is determined as described below. To evaluate the constraining method using thin polycarbonate sheets, six rats were divided into two groups: only constraint and constraint plus diazepine treatment. To detect the effects of exposure to EF, we used normal and ovariectomized rats. Normal rats were divided into two groups, Constraint and Constraint plus EF. In addition, 15 ovariectomized rats were also divided into four subgroups: simulated £17 exposure (A1), simulated EF exposure plus constraint (A2), EF exposure plus constraint (A3) 'mode (four) EF Exposure plus nitrozapine treatment and restraint (A4). _ Ovariectomy was performed 4 weeks before the experiment. The EF exposure and approximations used in this study are as follows: Rats were exposed to 5 Hz, 20 Wm EF for a total of epochs! hour. Rats were restrained with thin polycarbonate plates for the second half of the EF exposure period. The experimental design of the control group was identical to the experimental group except that there was no EF exposure. Collection of blood samples 1 ml of blood was collected from the subclavian vein (10) as (10) (10) 32 1278327 vein before the experiment was performed, and plasma was prepared by centrifugation at 1,500 xg for 10 minutes at 4 ° C. Gold paste was stored at _80 ° C prior to hormone measurement. After the experiment, 3 ml of whole blood from each rat was collected under anesthesia by cardiac puncture (cardiac 5 puncture) into a glass tube containing 9 mg of EDTA. 1 ml of blood was used to analyze blood status. The other 2 ml was centrifuged (at 4 C for 10 minutes at 1,500 X g) and the supernatant was stored at _80. c until the measurement of hormones, glucose, lactic acid and pyruvic acid. Blood analysis 10 Hematology analysis including red and white blood cell counts, platelet counts, hematocrit, and hemoglobin levels was performed using an automatic multi-hemocytometer (Sysmec CC-78, Sysmec inc ·, Tokyo, Japan). Plasma glucose, lactic acid, and pyruvate levels were measured using an automated analyzer (7170 15 Hitachi, Hitachi Co. ltd. Tokyo, Japan). The ACTH level was determined by using an ACTH radioimmunoassay kit (ACTH IRMA, MITSUBISHI CHEMICAL) Co. Ltd.) was combined with a gramma counter (Auto-Gamma 5530 Gamma Counting System, Packard Instrument Co. ltd.). The plasma corticosterone 20 was used in a commercial kit (ImmuChem). Double Antibody Corticosterone kit, ICN Biomedicals Inc.). Statistical analysis results are expressed as mean ± standard error of the mean (SE·) or as median, 25th percentile, 75^ percentile The 1278327 data set of the minimum and maximum values. The statistical significance of difference between the paired groups was calculated by the Stoneman's t test, and the significant difference was defined as / &quot;&lt;0.05. All calculations for statistical analysis are in MS-EXCEL® 曰 version (Microsoft Office 5 software: Ver·9·0·1, Microsoft Jap An Inc. Tokyo, Japan) was performed. The result was a change in plasma ACTli level induced by restraint stress. 10 Figure 11 shows the effect of pressure on the plasma ACTH level. Rats were intraperitoneally 1 mg/kg BW of diazepam (closed round) or saline (open squares) was administered. These rats were constrained to elicit a stress response 3 minutes after the administration of diazipine was performed. Figure 11 shows the ACTH levels of individual rats 30 minutes after the start of the constraint. In this only constrained 15 group, the values before and after the constraint period (mean ± 3 j··) are 231 135 and 1177 ± 325 pg/ml, compared to 358 ± 73 and 810 ± 121 pg/m in the constrained plus diazapine group. ACTH levels before and after restraint pressure in each cohort The 30-minute restriction increased the plasma ACTH levels by 51-fold and 20-fold-fold higher in the group with only the constraint and the constraint + diazapine, respectively. The effect of EF exposure on the change of plasma ACTH level induced by restraint Figures 12A and 12B show exposure to EF for normal (A) and ie nesting Effect of (B) in the rat plasma ACTH level of. All rats were constrained for the second half of the EF exposure period. In the following groups, plasma eight (: Ding 34 3478327 quasi-measured in EF and after 6 min: untreated (n=6), only constrained (imaginary, n=6) Constraint at EF (EF, n=6) and constrained with diazapine at the simulated EF (simulated vs. diazapine, n=6). Addition of diazapine occurs during the first 3 minutes of the EF period The data is represented as boxes 5, in which it is not possible to divide the main four squares into two small four-square horizontal lines | the median [the horizontal line that forms the bottom side of each major four-square box) Representing the 25η percentile, the horizontal line forming the top side of each major quad box represents the 75th percentile, shown as the horizontal line above each major quad box representing the maximum, and the display as 10 in each major The horizontal line below the four boxes represents the minimum value. The pre-constraint values (Pre values) are not displayed. p&lt;〇〇5 comes from the value before the constraint. t· Ρ&lt;〇·〇5 comes from the unprocessed group. In the ovariectomized rats, the plasma ACTH level of the unconstrained group was 60 minutes. No changes were shown during the period. In the other three groups of 15 groups, the ACTH level was increased during the constraint period (Fig. 12B). Comparison between before and after the period, in "only constraints,,," Constrained and EF,,, and plasma levels in the Constrained and Diazapine group increased by 186, 13.4, and 13·7 times, respectively. Figure 13 shows EF exposure for plasma ACTH in normal rats (η=6). 20-bit quasi-impact. Data are expressed as a median, 25th percentile, 75th percentile, minimum, and maximum. Figures 12A and 13 show ACTH and corticosterone in normal rats. Changes in plasma levels. In this "constrained only, the ACTH levels in the "Constraint and EF" group were 1595 ± 365 and 1152 ± 183 (pg/ml), respectively, while the corticosterone level 845 ± 48 and 786 35 1278327 ± 24 (ng/ml), respectively. Effect of EF exposure on plasma parameters Figures 14A and 14B show EF exposure for normal (A) and ovariectomized (B The effect of plasma glucose level changes induced by restraint in rats. Those levels are in the period of 60 minutes. (n=6) was detected later. The number of samples in all groups was 6. The data was expressed as a median, 2 51 h percentile, 75 &amp; percentile, minimum, and maximum *: corpse &lt; 〇〇 5 from untreated group. In ovariectomized rats, the constraint increases plasma glucose level _ 10 (Ρ &lt;〇·〇5:史徒登氏 test), while EF Or diazepine has a tendency to suppress these increases (Fig. 14B). However, the tendency to suppress blood glucose levels in this EF cohort was not found in normal rats that did not undergo an ovariectum (my) (Fig. 14A). Panels 15A and 15B show the effect of EF exposure on the level of plasma lactate induced by normal (a) and (I) resected (B) rats. The levels were measured after a period of 60 minutes (n=6). Data are expressed as a median, 25th percentile, 75* percentile, minimum, and repaired maximum. *: Corpse &lt; 0.05 from untreated groups. From the simulated group. In the ovariectomized rats, the plasma lactic acid level in the only constrained group did not show a significant difference compared to the untreated group (Fig. 15B). The plasma lactate level of the group exposed to EF and diazapine was significantly lower than those in the only constrained group (/&gt;&lt;〇·〇5:史斯特登氏 test) (Fig. 15B). In normal rats, the plasma lactate level (average soil S.E.) was 28.6±3·6 and 38.1±3.7 36 1278327 (mg/dl)' with or without EF (Fig. 15A). As shown by a statistical analysis, the lactic acid level of the animals exposed to EF was significantly lower than those of the only constrained group (Ρ &lt;0·05: The Stuart's t test). Figure 16 shows the effect of EF exposure on the level of plasma pyruvate induced by the 5 in ovariectomized rats. The levels were measured after a 60 minute period (n=6). Data are expressed as a median, 25th percentile, 75thi quantile, minimum, and maximum. *: Corpse &lt;〇〇5 from a group that has not been processed. In ovariectomized rats, the plasma pyruvate level of only the constrained cohort was not significantly different from those of the untreated cohort 10, but tends to decrease due to constraints. The system in the group exposed to EF or administered to diazepine was significantly lower than those in the simulated group of exposures (Ρ&lt;0·05: Storchen t test) 16 figure). Figure 17 shows the effect of EF exposure on the white blood cell count (WBC) count induced by restriction in ovariectomized rats. The levels were measured after a period of 60 15 minutes (n=6). Data are represented as a median, 25 percentile, 75^ percentile, minimum, and maximum. *·· The corpse &lt;0·05 comes from; there are also groups that are processed. In general, the observed constraint-dependent changes are related to the number of white blood cells (WBCs). The WBc 20 counts in the group without treatment, restriction, exposure to EF, and administration of biszapine showed 78, 99, 96, and 85 (x 1 〇 2 cells/μΐ), (Fig. 17) . As shown by a statistical analysis, in the ovariectomized rats, the WBC level in the constrained animals was significantly higher than that in the untreated group (corporate &lt;〇〇5··斯斯特登氏t test Those in the ). The WBC level in the group exposed by ef or administered zilaprazine was higher than that of the untreated group and lower than the group with only 37 1278327 constraint. Implementation of Electroencephalogram Studies Six rats were exposed to an electric field estimated at 17,500 V/m for 15 minutes a day for a total of 7 days. The devices used to expose the animals were a Category 5 Healthtron exposed cage (as previously described). Six rats were used as a control group (simulated exposure). The following parameters (endpoints endpoims) were observed: brain wave abnormalities detection; each EEG stage group (awake, rest, slow wave sleep sleep (sl〇w wave light sleep), slow wave depth The percentage of si〇w wave deep sleep and fast wave sleep; and the EEG power spectrum of the frontal cortex (1-3.875 Hz) - θ (4-15.875 Hz) &gt; a (8-12 Hz) - β 1 (12.125-15.875 Hz), as a percentage of /3 2 (16-25 Hz). At repeated exposures of 7,000 V (17,500 V/m) for 15 minutes, an increase in a significant slow-wave sleep sleep phase on the first day was observed to last for 15 hours in a 1–2 hour period. On day 7, a significant reduction in rest and wake-up periods was observed 0-30 minutes after exposure. A significant decrease in the awake period and a significant increase in the slow-wave sleep period were observed during the period after exposure for a period of time ranging from 5 to 1 hour. A significant decrease in the awake period and an increase in the slow wave bead sleep period were observed during the period after the change in exposure from the time of 20 hours. In addition, a significant increase in the slow-wave shallow sleep period was observed during the period after exposure for a period ranging from 2 to 4 hours. No spontaneous EEG wave type or behavioral abnormalities were observed. There were no indications in the &amp; study that repeated exposure to 1 field presented any neurological relationship to the frequency analysis of the leaf 32. D. The additional disorder or condition is the treatment of electrolyte imbalance, and the average induced current density generated throughout the cell membrane is preferably from about 44 mA/m2 to about 5 6.0 mA/m2'. From 4 mA/m2 to about 5 6 it is 2, and still more preferably about 0.43 mA/m2 to about 5.55 mA/m2. For the treatment of arthritis, the average induced current density generated throughout the cell membrane is about 0.02 mA/m to about 〇·4 mA/m2, more preferably about 25 mA/nr to about 〇·35 mA/m2. Most preferably about ο.· mA/m2 to about 0.32 · 10 mA/m2. For treatment of overweight, the average induced current density generated throughout the cell membrane is preferably from about 0.02 mA/m2 to about 1.25 mA/m2, more preferably from about 〇·〇2 mA/m to about 1.2 mA/m2' Most preferably from about 0.024 mA/m2 to about 1.12 mA/m2 ° 15 The invention is also applicable to the prevention or treatment of musculoskeletal and connective tissue disorders. Such disorders include, for example, osteoporosis (including aging, secondary, and juvenile idiopathic), bone-thinning disorders, celiac disease, and tropical Proper treatment of tropical sprue, bursitis, scleroderma, 20 CREST syndrome, Charcot, s joints, fracture bones, and Proper repair of ligaments and cartilage tears. The present invention is also applicable to rheumatoid arthritis, immunosuppression disorders, neuralgia, insomnia 39 1278327

(insomnia), headache, facial paralysis, neurosis, arthritis, joint pain, allergic rhinitis, stress, chronic pancreatitis ), DiGeorge abnormalities, endometriosis 5 (endometriosis), urinary tract obstructions, pseudogout (pseudogout), thyroid disorders, parathyroid disorders, hypopituitarism, gallstones Gallstones), peptic ulcers, salivary gland disorders, appetite disorders, heart, vomiting, thirst, excessive urine production, vertigo ), benign paroxysmal positional vertigo, achalasia and other neurological disorders, acute kidney failure, chronic kidney failure, diffuse esophagus痉挛 (diffuse esophageal spasms), and transient cerebral ischemia 15 (transient Ischemic attacks, TIAs). The invention can also be applied to treatment

It includes permeability, additional renal disorders that it maintains, and conditions or disorders that include an osmolar imbalance. E. EF Therapy Device The EF device is designed to produce an electric field in which an individual is placed. 20 As illustrated in Figure 18, the electric field can encompass the entire individual. Alternatively, the electric field may enclose only a particular part or organ of the individual. Fig. 19 is a view showing a high voltage generating device (1) showing a specific example of the present invention. That is, the potential therapy placement (1) includes a potential therapy device (2), a high voltage generating device (3), and 40 1278327: ::=4). The potential treatment device (2) comprises a chair (7) having an armrest (6); a head electrode (8) attached to the chair p() as a counter electrode; and a phase above the top end of the head (3) : for the electrode, the individual (7) places his/her leg on the second electric: == 彳 is the head electrode (8), which is the opposite electrode of the face electrode, which can be another ceiling, two : Board, cookware or other interior items in the room ~ I'm dry. The south voltage produces a voltage of one thousand and one thousand to the head electrode (8) and the second electrode (9). The high w generating device (3) is usually mounted on the chair (7) - eight, t between the legs and on the floor, or in the vicinity of the scorpion (7). (8):: 6 The distance between the hai or the head electrode (8) and the tip of the patient's head. To be changed. An insulating material (1 Iati〇_eri·wound around the 15=electrode (8) and the second electrode (9). The second electrode (9) is broken by a wire to a high voltage output of the high voltage generating device (3) End (10). The high voltage output terminal (10) is also provided to apply a voltage to the head electrode (8) and the second electrode (9). Further, the chair (7) and the second electrode (9) include insulators (12), (12) at a position in contact with the floor. This distance (6) between the surface of the human body and the first electrode (four) can be easily changed by placing mats of different thicknesses on the bed base (9) 20. - A potential treatment device (2C) still provided with another configuration has a type shown in a perspective view [perspective view] and a 20th view (a side view), which exemplifies that the edge individual (5) and each are drawn The positional relationship between the black electrodes is sorrowful. The ram (7a) is provided with a front open cover body (34) covering the individual (5). The covering body (34) is provided with a first electrode (8c) as a counter electrode for accommodating the head of the individual (5); a second electrode (9c) is a calendar of the main electrode The electrode, and the other first electrode (80c) disposed at a position from the shoulder to the waist in a sitting position, serves as an opposite electrode disposed at the waist of the upper portion of the body. The other first electrode (80c) has a plurality of side electrodes (8〇c,) to cover the body of the individual (5) from the side. Preferably, the first electrode (8c) is arranged along the head of the human body, and the other first electrode (8〇c) is arranged in several layers from the shoulder to the waist in the longitudinal direction. These first electrodes φ 1 〇 (8C), the other first electrode (80c), the side electrodes (80c,), and the second electrode (9c) are arranged in an insulating material (35). A detachable cushion member made of an insulator is attached to the covering body (34). Therefore, the adhesion of a mat component can be varied, and the distance between the body surface and the first electrode (8c), (8〇c), (8〇c,) can be changed and/or As mentioned above, in such a potential therapeutic device (10), the inductive current control member can be applied to the first electrode (10), (paper), _, as an opposite electrode, and the second The electrode (9e) is externally applied, and the distance (4) between the first electrodes (8c), (80c), (80c,) and the dry surface of the person is variable. Or by controlling the applied _electrode ((10), (敝), ((10).)) and the second electrode (9c), and further, by changing the first The distance (4) between the electrodes (8c), (8〇c), (8〇c') and the surface of the human body controls the electric field of the body surface and flows a very small amount in various areas in which the human body lies. Inductive current 42 1278327 A potential therapy device (2A) provided with another configuration is shown in Fig. 21A [perspective view] and Fig. 21B [side view The potentiometric device (2A) has a bed type. A box (32) for accommodating the individual (5) is disposed on a bed base (31). Each electrode is disposed in the box (32) In short, 5 is provided with a first electrode (8a) as an opposite electrode and a second electrode (9a) as a main electrode placed on a leg of the human body. The first electrode (8a) Is placed on the head, shoulders, abdomen, legs, and buttocks or other areas of a human body. And preferably, the first electrode (8a) has a shape that is approximately equal to the head, shoulders, abdomen, and buttocks of a human body. Width and area. The blank areas in the illustrations of Figure 10 indicate that no electrodes are provided. The electrodes are placed in an insulator (33). A mat made of an insulator (not shown) is placed On the respective electrodes of the bed base (31), mats of different thicknesses are prepared. In the above-mentioned 19th figure, the head electrodes (8) above the head and 15 the humans of the individual (5) The distance (d) between the body torso surfaces is set at about 1 to 25 (^, in the second (^ picture, in the The distance between the first electrode (8〇:), (8), (80c') and the surface of the human body torso of the individual (5) is approximately 1 to 25 cm, preferably About 4 to 25 cm, and in Fig. 21A, the distance (d) between the first electrodes (8a), (8b) and the human body torso surface 20 of the individual (5) is set at about 1 to 25 cm, preferably about 3 to 25 cm. As described in an electronic configuration block diagram in Fig. 22 below, the high voltage generating device (3) has one of the commercial power sources The voltage 100V AC is increased to, for example, a booster transformer of 15 00 volts (13 trans trans transformer) (1), and a current 1278327 for controlling the current flowing to the respective electrodes. eurrem limitation resistors (R) , (R),. The high dust generating device (3) has a configuration in which an intermediate point (8) of a booster coil (τ) is grounded and the ground voltage (gr_d v〇ltage) is set to a boosted voltage half. A point (s') can be grounded as shown by the illustrated temporary line (pr〇vis〇ry line). Here, as shown in the block diagram of FIG. 22, a high voltage (the high voltage side intermediate point (8) is grounded by the booster voltage transformer (τ)) is supplied from a loov AC power source via Obtained by a voltage controller (13) of the high voltage generating device (3), and furthermore, 'each south voltage passes through the current limiting resistors (R), (r, ) is connected to the head electrodes (8),

15 20 Like (tea see below), with these second electrodes (9), (5) or similar (see below). In addition, the electric tilting device (1) is provided with a current control component. The inductive current control member can cause a very small amount of flow to flow to the various regions of the human body peak that make up the individual (7), the external application pressure applied to the head electrode (8) and the second electrode (9), and - the distance between the head electrode (8) and the surface of the human body (4), or the applied voltage of the second electrode (9) by the control device, or the read-by-change by the change The electrode (8) disc is spaced from the surface of the torso of the human body to control the body's torso electric field. Between the surface of the human body and the first pole (8-shaped distance (4) can be placed on the bed base (9) by a mat of different thicknesses (4)

Easily changing the state of the potentiometric device (1) by increasing the induced current even if a high voltage is applied to the lower-vehicle, the therapeutic effect can be obtained 44!278327: 'Even if the duration is in the conventional method The same time period. In addition, the /α therapy can be completed in a shorter time than before. Further, in order to achieve the same therapeutic effect, the inductive packet flow of the same value as the prior art can be obtained at a lower voltage and at the same 5 treatment times as before. The potential therapy device (1) of this class is designed to be as free from high-output buns, high-level radio frequency noise, and strong magnetic fields. In order to reduce the influence of the electromagnetic field on the potential therapy device (1), it is preferable to use a drive mechanical switch, a relay (rela &gt; 7) and an electric motor or electric timing device or other electrical components more than electronic components, Semiconductors, power components (such as thyrist〇r, bidirectionally controlled rectifiers (such as from)) tweezers. A sacred or EMI sensing microcomputer is used for its design and manufacture. However, such as an electronic functional component, the electronic continuous exchange switch $ (eiectronic serial bus switching) is effective as a 15 optical emitter diode power supply system, and the optical emission diode is effective. Used as a source of light to inform the individual or operator of the active or inactive state of the potential therapy device of the present invention. As discussed above, a simulated human body (h) can be used to measure The EF and the induced current are measured as shown in Figures 23A, 23B and 23C. This simulated human body (h) is made of PVC and its surface is coated with a mixed solution of silver and silver chloride. This causes the resistance (1 Κ Ω or less) to be equivalent to the resistance of a real human body. The simulated human body (h) is well known as a nursing nursing simulator, and its size 1278327 is similar to the average human body size, for example, it is 174 cm high. These dimensions are further described in Table 1.

46 1278327 Table 1: Measurement of the current density in the human body. Section of Area (mm) Cross Sectional Area (m2) Eye 550 0.02407 Nose 475 0.01795 Neck 328 0.00856 Chest 770 0.04718 Upper abdomen 710 0.04012 Arm 242 0.00466 Wrist 170 0.00230 Torso 660 0.03466 Thigh 450 0.01611 Knee 309 0.00760 Ankle 205 0.00334 Body surface electric field is attached to a measurement area of the simulated human body (h) by attaching a disc-shaped electric field measuring sensor (e) It was measured. These measurements occur at 115 V/60 Hz and 120 V/60 Hz. A method of measuring an induced current and a device for this purpose are shown in Fig. 24. In the induced current measuring device (20), as shown in Figs. 23A and 23B, the simulated human body (h) is placed on the chair in a normal sitting position (7). The head electrode (8) above the head, which is a counter electrode, is adjusted and mounted 11 cm from a head of the simulated human body (h). The measurements are performed by measuring various portions (such as, for example, the k-k' line portion illustrated in Fig. 24), transferring the induced current waveform through optical transfer, and at the induced current measuring device ( 20) The ground side is observed by observing this waveform. Here, the applied voltage is 15,000 V. In this measurement method, a current induced in portions of each of the 15 regions of the simulated human body (h) is measured by using two leads to generate a short circuit that flows a current across the portion of the simulated human body (h). 1278327 (short-circuii) (22) [not shown] obtains the induced current. The measured induced current is converted into a voltage signal via an I/V converter (23) (Fig. 24). This voltage signal is then converted into an optical signal via an optical analog data link on the transfer side. 5 These optical signals are transferred via an optical fiber cable (25) to an optical analog data link (26) on the receiving side and converted into a voltage signal. This voltage signal is then processed by a frequency analyzer (27) for frequency analysis by a waveform observation and analysis recorder. A buffer and a 10 adder are disposed between the I/V converter (23) and the optical analog data link (24) on the transfer side [not shown]. Therefore, the electric field values and induced currents measured at 115 v/60 Hz and 120 V/60 Hz at various positions of the simulated human body (h) are shown in Table 2. If the electric field value is different from that of Table 2, it is known that the value of the induced current passing there is also 15 different. Therefore, it is assumed that the effective induced current for each region of a true human body torso can be obtained by changing the electric field of each region involved. 48 1278327 Table 2: Relationship between electric field value and induced current value Area part @115V/50Hz @120Y/60Hz Electric field value (kY/m) Induced current (//A) Electric field value (kY/m) Induced current (/ /A) Head top surface 182 0.72 190 0.90 Head front 81 0.32 84 0.40 Head behind 113 0.44 118 0.55 Neck side 16 0.06 16 0.08 Shoulder 37 0.15 38 0.18 Chest 19 0.08 20 0.10 Arm 29 0.11 30 0.14 Elbow 33 0.14 34 0.17 Back 52 0.20 54 0.25 Hand back 21 0.08 22 0.10 Caudal bone 42 0.17 43 0.21 Knee 11 0.05 12 0.06 Tibia 21 0.08 22 0.10 Foot tip 3.4 0.01 3.5 0.02 Foot bottom 348 1.37 363 1.72

The body surface electric field E can be obtained by using the following equation, by the induced current value of each region obtained by the measurement method of the induced current in each region of the figure 24. That is, E = I/eocoS. Here, S system 5 is the surface of the electric field measuring sensor, εο is an induction rate in a vacuum, I is an induced current, ω is 2πί and f is frequency. When the induced current of each region is obtained by the above method, an induced current density J of each region can be obtained using the following formula. That is, A = 2Tir, B = Tir2, B = Α2/4π, J = I/B, where A is 10 circumference, B is a circular area, r is a radius, and I is a measurement. The current is measured, and the J is an induced current density. When the potential therapy is performed by controlling the voltage of the head electrode (8) and the applied voltage applied to the second electrode (9), the above-mentioned induced current control members may cause a very A small amount of induced current flows to 15 - various areas of the human body torso. 49 1278327

Table 3 shows the relationship between (1) induced current in the nose, neck and torso (//A); (2) induced current density (mA/m2) in the nose, neck and torso; And the applied voltage (KV) at 120V/60HZ. At the same applied voltage, the current density tends to be highest in the neck, the second highest in the torso 5 and lowest in the nose. It is noted that the induced current density in Table 3 is less than 10 mA/m2, and the current density of 10 mA/m2 or less has been passed by the International Commission on Non Ionizing Radiation Protection. Established as safe. Table 3: Applied voltage and induced current applied voltage [kV] Induced current value (//A) Induced current density (mA/m勹 head (nose) Neck torso head (nose) Neck torso 0 0 0 0 0.0 0.0 0.0 5 10 11 30 0.6 1.3 0.9 10 20 23 61 1.1 2.6 1.7 15 30 34 91 1.7 3.9 2.6 20 40 45 121 2.2 5.2 3.5 25 50 57 152 2.8 6.6 4.4 30 60 68 182 3.3 7.9 5.2 10 Figure 25 also shows the relationship between the applied voltage (KV) and the induced current (//A) in the nose, neck and torso. As apparent in Figure 25, the applied voltage is The induced currents Φ are proportional to each other. Table 4 shows a change in induced current and induced current density in a human neck as the distance between the head electrode (8) and the tip of the head ( A function of d) 50 1278327 Table 4: Variation of induced current as a function of distance from the electrode Distance between the first electrode and the tip of the head Induced current value Induced current density distance (cm) (βΑ) (mA/m2 ) 4.3 50 5.8 5.4 46 5.4 6.3 43 5.0 6.9 40 4.7 8.3 39 4.5 9 38 4.4 9.9 35 4.1 11 34 3.9 12 34 3.9 13 33 3.8 14 31 3.7 15 30 3.5 16.1 30 3.5 17.2 30 3.5 Table 4 indicates that the induced current is stable at 30 μΑ at a distance of 15 cm or more. Therefore, in order to change the distance by changing the distance Inductive current, the distance should be 15 cm or less. Figure 26 also shows the induced current change due to distance (d) 5. In an experiment involving about 300 cases of low back pain, we determined EF is effective in the treatment of low back pain. We have also determined the following optimal doses and parameters. In short, the optimal dose is generated by controlling the flow of induced currents through the area that constitutes a human body lying down. Obtained with 10 flow times of the induced current. In addition, it is obtained by controlling the generation of the sum of the voltages of the first electrode voltage and the second electrode voltage, and the application time thereof. For low back pain, EF The therapeutic effect is optimized by applying it at a voltage of from about 10 KV to about 30 KV (preferably about 15 KV) for about 30 minutes. In other words, from about 300 KV/min to about 900 KV/min, Preferably 15 about 450 KV/min Here, Table 5 shows the induced current values measured at 115 V/50 Hz in the 1278327 domain portion of each zone constituting the torso of the simulated human body (h), and taking into account the simulated human body in Table 1. The induced current density obtained from the calculation of the induced current value at the size. From Table 5, the measured values of the induced current (μΑ) and the induced current density 5 (mA/m2) in the various regions constituting the trunk of the human body are as follows: Eye: 18/0.8; Nose: 24/1.3 Neck · 27/3.1; chest: 44/0.9; pit of the stomach: 8.6/1.6; and torso: 91/2.8. Table 5: Area, induced current value, and induced current density area Partial induced current @115V/50Hz (//A) Induced current density @115V/50Hz (mA/m2) Eye 18 0.8 Nose 24 1.3 Neck 27 3.1 Chest 44 0.9 Stomach cavities 65 1.6 Arm Arm 8.6 1.8 Wrist 3.1 1.3 Torso 73 2.1 Thigh Thigh 46 2.8 Knee Knee 52 6.8 Ankle 58 17 In addition, based on the aforementioned induced current and induced current density, at 12〇10 V/60 Hz The induced current and the induced current density are calculated according to the following equation 式 and Equation 2. Equation 1: Inductive current: I(60Hz)=I(50Hz)x60/50x 120/115 15 Equation 2: Inductive current density: J(60Hz)=J(50Hz)x60/50xl20/115 52 1278327 Table 6 shows The calculation results of the induced current and the induced current density in various regions of the human body trunk at 12〇v/60 Hz. From Table 6, the measured values of the induced current (μΑ) and the induced current density (mA/m2) in the respective regions constituting the trunk of the human body are as follows: ····················· 5 JO/1·7; neck: 34/3.9; chest · · 55/1.2; stomach pits: 11/2.3; and torso: 114/3.6. Area, induction flow value, and sense current in the skin-sensitive area @120V/60Hz (UA) ϋ屯&quot;IL and induced current density @120V/60Hz (mA/m2) Eye 23 0.9 Nose 30 1.7 — Neck Part 34 3.9 Chest 55 1.2 One stomach depression 81 2.0 Arm 1 11 2.3 Wrist 3.9 1.7 Torso 91 2.6 Thigh 57 3.6 Knee 64 8.5 Foot 72 22 When the distance between the electrode and the human body area is fixed, the above mentioned And the flow-through voltage of the body torso of the human body is proportional to the 10 induction current system. Therefore, when a human body is treated with a chair, the optimal dose can be obtained by controlling the generation of the applied voltage and the time of administration, because if the distance between the electrode and the human body is - most The method of good common factor (co-(10) gamma frost) is determined by the electric field strength of each region of the 'then-human 4 body is determined by the voltage applied by the outer 15 . A red-over-exposure individual will understand that the amount of applied voltage and current density can be controlled using a suitable - electric field' device (such as a test h_53 1278327 HES-30 device (Hakuju Co.)). For example, the induced current generated in a biological sample can be increased by applying a voltage to increase the potential of the electrode. Other suitable devices are known to trained individuals and include, but are not limited to, 〇〇298 device 5 (Ha_U Co·), HEF-K 9000 device (Hakuju Co.), HES-15A device (Hakuju Co.), HES-30 device (Hakuju Co.), AC/DC generator (Sankyo, Inc.), and function generator SG4101 (lwatsu, Inc). The features of some exemplary devices are presented in Table 7 along with the specifications of those devices. An additional electric field device that can be used in conjunction with the method of the present invention includes an electric field generating device as disclosed in U.S. Patent No. 4, the disclosure of which is incorporated herein by reference. The treatment device is capable of directly transmitting an electric field to a desired portion of a patient lying on the device. Others of the present invention are disclosed in U.S. Patent No. 4, the disclosure of which is incorporated herein by reference. The table provides a special specification of the Ef device that has been selected for use with the method of the present invention. 1278327

Weight high voltage group 彳% 40 kg body 41kg 130 kg 240 kg insulation pad (N treatment chair with power off switch box 15 kg 00 chair 15.8 kg rppr CA i control switch each JH2- m Μ pq 4 &lt; automatic timer time 30 minutes +/- 10% 30 minutes with Bu 2, 4, 6 and 8 hours Unlimited unlimited output voltage Charging Footrest 7500 V +/- 10%, 60 Hz AC charging footrest 0-3,500 V 0-15,000 V 0-30,000 V AC: 0-3,500 V; DC: 0-3,500V AC: 0-3,500 V; DC: 0-3,500V Upper Electrode 7500 V +/- 10%, 60 Hz AC upper electrode 0-3,500 V power 18 VA+/-15% 10W 100 VA 200 VA 25 W 25 W rated power supply frequency 60 Hz 50 or 60 Hz 50 or 60 Hz 50 or 60 Hz 50 or 60 Hz 50 or 60 Hz Rated power supply voltage 115 V AC 100 V AC 100 V AC 100 V AC 100 V AC 100 V AC Unit type 00298 HEF-K 9000 HES-15A HES-30 AC/DC Generator Function Generator: SG410I

1278327

The current-density distribution induced by the 60-Hz electric field in a homogeneous but irregular human model uses a two-stage finite-difference procedure (Hart, FX, β/Sink) · "11:213-228 (1990)) was calculated. For the case of an ungrounded human model exposed to a 10 kV/m electric field, the induced current density system in the plane passing through the lower back of the torso It is 1·14 mA/m2 (Fig. 27). The current density at other locations is in the range of 0·8-3.5 mA/m2. The correct value depends on the coupling between the model and the ground. However, a reasonable coupling condition is such that the calculated current density is less than a factor of 2. The similar results are found by others (Gandhi, OP &amp; Chen, JY, Bioelectromagnetics Suppl. 1:43-60 (1992); King, RWP, / five five five, Tranx price omM. five sighs 45:520-530 (1998)) o

The fhiite-difference tiine-domain method is used by 15 to calculate the induced current in the anatomical basis model of the human body (Furse, CM &amp; Gandhi, OP·, Bioelectromagnetics 19:293-299 ( 1998)). This calculation is performed in a supercomputer to allow for a much larger amount of parsing than previously possible. The results obtained from the current densities induced in the particular organization of the model are shown in Table 8. Comparable results are used by others including fat-muscle (Chuang, H.-R· &amp; Chen, K, M·, / 5, 5, 5 TV (2/w· J5沁md 36: 628-634 (1989)) And a bone-brain (Hart, FX· &amp; Marino, Α·Α·, J5k/·5ng· Comp· 24:105-108 (1986)) mixed tissue model was found. 56 1278327 Table 8· Current density induced by a specific tissue of human individuals exposed to a 60 Hz, 10 kV/m electric field. Tissue induced current density (mA/m2) Small intestine 1.3 Spleen 1.4 Pancreas-dirty 1.5 Liver 1.4 Kidney 2.8 Lung 0.6 Bladder 1.9 Heart 2.2 Stomach 1.2 Testicular 0.7 Prostate 1.0 Eye water (Eye humor) 5.6 Cerebrospinal fluid 4.8 Pineal gland 1.4 Pituitary gland 3.5 Brain 1.9 Example 8 - Exposure to electric field (EF): It is slow for some clinical symptoms in human patients. And Palliative Effect 〇5 Electric field exposure device, Healthtron (Model HES 30, Hakuju

The Institute for Health Sciences Co., Ltd., Tokyo, Japan) was used. The Healthtron includes a step-up transformer (a device used to control the voltage in the circuit), a seat, and an electrode. It applies a high voltage to one of the two opposing electrodes to produce a constant potential difference ίο and form an EF in the space between the two electrodes. The user sits comfortably and is allowed to read a book or sleep during the exposed time. In order to avoid accidental electric shocks due to the formation of electrical current, 57 1278327 these individuals do not allow any form of contact with the floor and the body of any person (operator and other persons exposed to electricity) during treatment. The insulator-covered electrodes are placed on the floor that allows the feet to be placed on the top of the patient's head. 30, the initial power supply of volts (50 or 60 Hz ELF) is applied to the electrodes placed on the foot to produce an EF between the foot and the head electrode. Each exposure to electricity lasts for 3 minutes and the frequency of exposure varies from parent to mother to mother.

The efficacy of Healthtrori is based on the direct supervision of Dr. Ylliehi Ishikawa's Tiger Gate in the port area of Tokyo, Tokyo (τ(10)n〇m〇n Qi also 10 Mil withdrawal (Bu, Tokyo, Japan) from August 1, 1994 to The results obtained from the questionnaire submitted on June 30, 1997 were evaluated. A total of 1,253 patients (489 males, 764 females) were executed with the instrument, of which 505 (208 males) 297 women) visit the clinic and use the Healthtron device and implement the instrument at least twice. Others can use the device more than twice. In order to reduce the subjective level of participants in the questionnaire, Healthtron's assessment of mitigation effectiveness is limited. In these 5〇5 patients, each Healthtron user was taken care of by a doctor and interviewed about the palliative utility of the instrument during previous visits. The interview included major medical discomfort symptoms, past medical history and Inquiries regarding treatment, Healthtron's frequency of use, and post-use perception (including its palliative utility and the personal health of the user). The severity of the symptoms of the first hospital visit was 5 疋 at a special level of '3' and the severity after Healthtron therapy was divided into 5 levels, namely: very good (5), good (4), No change (3), deterioration (2) ' and high deterioration (1). Very good and good is distinguished as "moderate 58 1278327" regardless of the frequency/interval of Gonggong, and the time of easing (in days) is recorded as well. The patient's age is distributed between 20 and 90 years old. Among them, 85.3% consisted of > age group 5 (Table 9). There were 208 (41%) males and 297 (59%) females. 55 different symptoms were indeed forbeared. And the proportion of those patients whose symptoms were reported to have been alleviated by Healthtron therapy is summarized in Table 9. "1 should be in Table 101. Symptoms confirmed by at least 1 patient include cold in the limbs (cold Feeling), fatigue, headache, high blood pressure, insomnia, 10 pain, lower back pain, pain in the extremities, pruritus cutaneous, itching in the limbs, shoulder/neck pain and stiffness. The mitigation effect of Healthtron therapy is as follows The system is significant: no headache associated with fever, organ therapy (organotherapy X such as subarachnoid or cerebral hemorrhage (Cerebral Hemorrhage)), or inflammation (91.7%), joint pain (66.7%), lower back pain 15 ( 57.3%), shoulder/neck pain and stiffness (56. 0-57.8%), and the reduction of fatigue (55.0%). Interestingly, the palliative effect on pain-related symptoms that affect locomotorial organs (heads, joints, shoulders, neck, limbs, and abdomen) There were 175 (58.5%) of the 299 cases recorded. These pain-related symptoms were not caused by trauma. After the first treatment of 20, 1 of the patients with itchy skin had 4 of them The claim has been alleviated and the clinical manifestations of one patient have deteriorated. 1278327 Table 9: Healthtron users age range and gender distribution age range of users Male: Female ~ 20 2 2:0 21-30 38 15:23 31 ~40 34 10:24 41 ~50 81 29:52 51 ~60 147 59:88 61 ~70 143 69:74 71 ~80 50 20:30 81 ~90 10 4:6 Total 505 208 ( 41%): 297 (59%) Table 10 shows the palliation rate of 55 clinical symptoms confirmed in 505 patients. Table 10 - The mitigation rate of 55 clinical symptoms in 505 patients. Number of patients with symptomatic number of patients (%) bloating (abdominal fullne Ss) 1 0 (0) Abdominal pain 2 1 (50) Allergic constitution 7 3 (42.9) Baldness (alopecia) 3 3 (100) Arrhythmia 2 1 (50) Back pain (back pain) 5 3 (60) blurred vision 5 2 (40) chest pain 1 1 (〇) cold feeling in the extremities 14 6 (42.9) constipation 5 3 (60) cough 5 3 (60) deafness 2 1 (50) diarrhea 3 3 (100) dizziness 5 3 (60) ear ringing 7 1 (14.3 ) ( ( ( ( ( ( ( ( ( ( 2 〇(〇) facial paralysis 1 1 (100) facial stiffness 1 〇 (〇) fatigue (fatigue) 20 11 (55) generalized muscle stiffness 1 〇(〇) gingival pain 1 0(0) Glycosuria 7 4 (57.1) Headache 12 11 (91.7) The body feels heavy (Heavy f Eeling in the body) 4 2(50) Head feeling in the head 1 〇(〇) Heavy feeling in the legs 1 1 (100) The stomach feels heavy (Heavy Stomach feeling) 1 〇(〇) Hypertension 10 4 (40) Insomnia 17 8 (47.1) Yellow jaundice 1 1 (100) Joint pain 45 30 (66.7) Loss of appetite 1 〇(〇) Loss of grip 1 〇(〇) lower back pain 89 51 (57.3) menstrual irregularity 1 〇(〇) limbs Pain in the extremities 31 10 (32.3) Palpitation 1 1 (100) Paralysis in the extremities 3 〇(〇) Plantar edema 4 2(50) Frequent urination (Pollakiuria) ) 1 1 (100) pruritus cutaneous 10 4 (40)

61 1278327 rigidity of the arms 1 1 (100) sensation of numbness in the extremities 29 11 (38.0) separation of the calx epidermis 1 1 (100) shoulder or neck pain (shoulder or neck pain 25 14 (56) shoulder or neck stiffness 90 52 (57.8) throat throat i (sore throat) 2 1 (50) stomachache (stomachache) 5 4 (80) joint swelling of joints 2 2 (100) Trembling of the extremities 1 1 (100) Urinary incontinence 1 〇 (〇) Total 505 268 (53.1) Figure 28 shows the frequency/interval without considering Healthtron therapy In the case, the average mitigation time for each of the 505 patients. Considering the small sample size of many of the identified symptoms, in the inherent limitations of this study, the researchers rely solely on data from the questionnaire, and we believe that the continuation of treatment mitigation is only Symptoms confirmed by patients who show at least 10% of the >50% mitigation rate can be properly described. The relaxation of fatigue lasted for about 50 days; the joints, lower back, and shoulder/neck stiffness were alleviated for less than 100 days. The longer average mitigation time indicated in many other symptoms may be a true measure of sample size rather than treatment. F. Method of Optimizing Electrotherapy Parameters The selection and control of the parameter range of the present invention while avoiding unnecessary side effects that may be caused by the use of EF 62 1278327 enables the use of EF as a therapeutic tool. Thus, the present invention provides parameters and their range of use to enable a trained individual to use EF as a therapeutic tool to achieve a particular biological outcome and avoid unnecessary side effects. 5 A preferred method for determining the optimal parameters of EF therapy comprises the steps of: (1) identifying a desired biological response to be induced in a living organism; (ii) selecting or measuring a person in the organism. Or an average induced current of 10 degrees on the membrane of a tissue sample or culture derived from the organism; (iii) selecting or measuring an external electric field that is away from the organism, sample or culture The selected current density is selected or measured at a particular distance; (iv) selecting or measuring a continuous time period for generating a selected or measured induced current density on the cells; (v) applying the Selecting or measuring an electric field to the organism, sample or culture to produce the selected or measured induced current density on the membranes of the cells for a continuous period of time selected or measured; (vi) determining The extent to which the desired biological response occurs; (vii) selectively repeating any of steps (ii) through (vi); and (viii) confirming that the desired biological response is optimally induced Selection or measurement Induced current density, or the selected external electric field or the measured or measured values during the selected continuous time 20 amount. Preferably, the method further comprises, prior to step (viii), generating a dose-response curve as the selected or measured induced current density, the selected or measured external electric field, or A function of any of the selected or measured continuous time periods. Still more preferably, the method further comprises, prior to step (viii) 1278327, selecting or measuring the following: the number of times step (v) is repeated, the time interval between steps (V), and the selected Or the measured induced current density is generated throughout the period of the film. More preferred embodiments include one or more of the following features: The selected 5 or measured induced current density is from about 0.001 mA/m2 to about 15 mA/m2; the induced current density is measured by flow through An induced current of a specific region of a living body or a portion thereof converts the detected current into a voltage signal, converts the voltage signal into an optical signal, and then converts the optical signal into a voltage signal, and The waveform and frequency are analyzed and selected or measured; and/or the external electric field (E) is selected or measured by the term in the equation E = I/eocoS, where S is an electric field measuring sensor (measurement sensor) section (secti〇n), ε〇 is a induction rate in a vacuum 'I is a current, and £〇C〇S is the description of the ω system 1, and f is the frequency. 15 A preferred method for determining optimal parameters for external current therapy comprises the steps of: (1) identifying a desired biological response to be induced in a living organism; (ii) selecting or measuring a The average induced current on the membrane of the organism or a tissue sample or culture derived from the organism is 20 degrees, wherein the average applied current density is from about 10 mA/m2 to about 2,000 mA/m2; (iii) selecting or measuring a current that will produce the selected or measured applied current density; (iv) selecting or measuring a continuous period of time to produce the selected or measured applied current density; Applying the selected or measured current to generate the selected or measured applied current density for a selected or measured continuous time period; (vi) determining what the desired biological inverse 64 1278327 should occur Degree (Vii) repeating any of steps (ii) through (vi) to generate a dose-response curve as the selected or measured current, the selected or measured applied current density, or the Selection or measurement a function during the time; and (viii) confirming that the selected or measured current that best induces the desired biological inverse, the selected or measured applied current density, or the selected or measured The value during continuous time. Preferably, the method further comprises, prior to step (viii), selecting or measuring the following: the number of times step (v) is repeated, the time interval between repetitions of step (v), and the applied current density It is produced throughout the period of the film. Book 0 The inventors have determined the parameters that best treat a particular disorder. In general, the EF voltage (exogenous) can be applied in a range between about 5 〇 v and about 30 kV. The induced current density can be generated in a range from about 〇 〇〇 1 to about 15 mA/m 2 . Preferably, the EF induced current density is produced in the range of from about 〇12 to about ll.lmA/m2, more preferably from about 0.026 to about 5.55 mA/m2. 5 The applied current can be used in a range between about 10 and about 2, 〇〇〇 mA/m2. In another embodiment of the invention, the applied current is generated in a range between about 50 to about 600 mA/m2. In a specific embodiment of the present invention, the EF applied current is generated in a range between about 6 Torr and about 1 Torr () mA/m2. | Table 11 provides a preferred set of parameters for the treatment of disorders and conditions. Table 2 provides a particular disorder, condition, organ or system to which the parameter set is administered. Table 11 also provides specific parameter values, however it is to be understood that the values are approximate and equivalent ranges are contemplated by the present invention. 65 1278327 Exposure time 4 minutes 2 minutes 24 hours / day, lasts 7 days 2 and 24 Xiaori Temple / day 2 hours / day, lasts 56 days 24 hours 30 minutes and 24 hours applied current density (in mA / m2 60, 200, 600, or 2,000 2000 10, 50, and 100 60 or 600 ξ ^ _ 笮 9 d 0.026-0.32 d Ο ρη ^ 5 WW _ 2000 3000 EF frequency (in Hertz) 8 8 50 (30 kV/m) 1 50(30 kV/m) S Obstacle, condition, organ or system U Definitive: ητ^ U ε Barriers associated with fibroblast proliferation U e Rheumatoid arthritis End U meal Tn^? Cup r U €: Μ Parameter group ^-H (Ν inch vn \〇卜1278327 pier piercing H&lt; Bu φ (Ν r—H 寸 inch 〇 Ν Ν Η Η Η 24 小 小 小 小Ο 〇〇〇^〇Ο — ν〇'W Ο ¥-Η 0.035-0.5 0.42 7000 3000 Bu S Γ&gt; s ο rH, χ&gt; 〇乂\〇o &gt; Pin · To be a spider, iron, + ( N cd + (N a + (N Λ + &lt;N Λ + CN c3 禳u U ♦ UU u ε heat · down Driving a thin ffiCJ 禳 4 t!: •I鮏$瓌J, tb J, ti: 4 〇3? Zhu Forget Zhuke 00 〇\ 〇^-H (N m inch 1278327 30 minutes and 24 hours 12 1 hour/day, 7 times for 72 or 100 days, 7 times to 7000 V; 23 times for 30,000 V 2 or 3 times for 30 minutes period/week, each patient has a total of 5 periods, each period lasting 30 minutes. 60 or 600 0.0001 -0.42 2.3-11.1 7.5-11.1 50 and 15000 (AC, DC+, DC-) 9000 or 30000 30000 8 8 Increase the induction of ConA by immune system cells Increase the barriers associated with the induction of ConA by immune system cells and electrolyte imbalance Arthralgia, Severe Stress, Chronic Insomnia and Chronic Allergy Fatigue VO 00 〇 \ 1278327

2 hours 30 minutes / period, every other day, lasts 14 days 30-120 minutes / day, lasts 28 days 30-120 minutes / day, lasts 56 days 0.08-1.12 3.75-5.55 (N rH 1 Ο 卜 d 0.024-1.12 8000 15000 40000 ο (Ν ^ Ο Ο 〇 〇 可? (Ν ^ 〇Ο Μ 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 有关 有关 有关 有关 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 体重 Ν (N 1278327 The present invention is also directed to a method of determining a desired set of parameters (such as EF characteristics, induced current density, applied current density, and exposure time) whereby the 'maximum desired utility' is in biological testing. In a preferred embodiment of the invention, the method of optimization comprises the steps of: • identifying a desired biological effect to be induced in an organism or part thereof (eg 'in Intramuscular cells cause a flow of calcium ions in one direction; a value is selected as an average applied current density or an induced current density in the cell membrane of the organism or a part thereof, wherein the applied current is applied In other words, the value preferably falls within the range of about 1 〇 mA/m 2 to about 2, 〇〇〇 mA / m 2 'and falls about 〇〇〇 lm A / m 2 to about 15 mA in terms of induced current. Within the range of m2; determine the value of the applied current or EF (such as frequency and EF voltage) that will produce the selected current density; select a discontinuous time period

15 20 to produce the applied current density, wherein the period falls within a range of about 2 minutes to a sentence or a discontinuous guar; the applied current or E is used to generate the selected current density; The extent to which the desired biological effect month occurs; and the repetition of those steps. Preferably, the step of optimizing is also accompanied by the generation of a dose-response curve as a function of the value of (4). In another age, it is W 丨丄 具 具 中 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' It was measured. In the specific examples of the present invention, the parameters used to regulate the ion flow of the &amp; cell membrane in vivo are not illustrated by the combination presented in Table 12. In other specific examples of the invention, the silk is in vitro! The parameters of the lang over the cellular ion current are exemplified by the group 4 presented in the buckle.

70 25 1278327 Table 12 - Model parameters for regulating ion current in vivo Parameter group EF voltage (in volts) EF frequency (in Hz) Induced current density (in mA/m2) Applied current density (in mA/m2) Exposure time 1 2,000 50 0.026-0.32 2 hours/day for 7 days 2 2,000 50 0.026-0.32 2 hours/day, 56 days 3 7,000 50 (17.5 KV/m) 0.035-0.5 60 minutes 4 30,000 60 7.5-11.1 30 minutes 5 7,700 50 0.015-0.22 2 hours / day, 6 days / week, duration. 15 weeks 6 15,000 60 3.8-5.6 20 minutes / day, 4 times per period, lasts 15 days 7 50 50 0.0001-0.42 72 days 8 15,000 50 0.0001-0.42 100 days 9 3,000 60 0.006-0.08 35 days 10 10,000 60 0.05-0.7 15 minutes / day, lasted 91 days 11 7,000 60 (17.5 KV / m) 0.035-0.5 15 Minutes/day, lasts 7 days 12 8,000 40 KV/m 2 hours 13 15,000 50 3.75-5.55 30 minutes/period, every other day, lasts 2 weeks 14 10,000 -30,000 50 2.5-11.1 30 minutes 15 30,000 50 7.5-11.1 15 Minutes/day, 3 times/week, lasts 2 weeks 16 30,000 50 7.5-11.1 30 minutes/day 17 30,000 60 7.5-11.1 30 minutes/day 71 1278327 18 2,400 50 (6 KV/m) 0.012-0.17 19 8,000 50 (40 KV/m) 0.08-1.12 2 hours 20 1,200 50 (6 KV/m) 0.012-0.17 1 hour/day, 7 days 21 50 (12-40 KV/m) 0.024-1.12 3CM20 minutes/day, lasting 4 weeks 22 50 (12-40 KV/m) 0.024-1.12 30-120 minutes/day, duration 8 weeks 23 2,400 50 (6 KV/m) 0.012-0.17 30 minutes 24 2,400 50 (6 KV/m) 0.012-0.17 120 minutes 25 10,000 ' 20,000 or 30,000 2.5-11.1 20 minutes 26 10,000 2.5-3.7 10 minutes / day 3 times/week for 5 weeks 72 1278327 Table 13 - Model parameters for adjusting ion current in vitro Parameter group EF voltage (in volts) EF frequency (in Hz) Induced current density (in mA/ M2 (units) Applied current density (in mA/m2) Exposure time 1 60 60 4 minutes 2 60 200 4 minutes 3 60 600 4 minutes 4 60 2000 4 minutes 5 60 2000 4 minutes 6 60 10 24 hours/day , lasted 7 days 7 60 50 24 hours / day, lasted 7 days 8 60 100 24 hours / day, lasted 7 days 9 50 (30 KV / m) 0.42 2 hours 10 50 (30 KV/m) 0.42 24 hours 11 50 (30 KV/m) 0.42 24 hours 12 60 60 or 600 30 minutes 13 60 60 or 600 24 hours 14 60 60 12 minutes 15 60 60 4 minutes 16 3,000 50 ( 30 KV/m) 0.42 24 hours 17 50 100-1000 18 50 10 7 days 19 50 50 7 days 20 50 100 7 days 21 15,000 60 22 1,000 50 (150 KV/m) 3.9 48 hours 23 1,000 50 (10 KV/ m) 0.26-0.34 48 hours 24 50 (8.3 KV/m) 0.28 48 hours 73 1278327 In an alternative embodiment, the invention can be used as a diagnostic tool to determine if a body is suffering a particular disorder or Symptoms. Specific parameters related to prevention, improvement, and treatment may be used to detect the presence of the same disorder or condition. These parameters can be applied as a diagnosis and are used to monitor for monitoring. If the patient does not respond to a given parameter set (which is related to the disease), then a lack of response implies a side patient; there are also party-specific disorders or conditions. Alternatively, if the patient responds to a given set of parameters (which is associated with the disease), then a response indicates a presence of a particular disorder and/or condition. Specific examples of the diagnosis of the present invention can be used for each disorder and/or condition (for each, a specific EF parameter set has been determined). It will be clearly understood that the present invention can be applied differently than the methods specifically described in the foregoing description and examples. Many modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims. The entire disclosure of the various documents (including patents, patent applications, journal articles, excerpts, laboratory manuals, books, or other disclosures) cited in the background, detailed description, and examples of the invention is herein Incorporate this case as a reference. 2 A sputum-cut electrotherapy device and a method of applying an electric field are disclosed in the U.S. Patent Application Serial No. 1/〇17,1,5, filed on December 14, 2001, The whole is incorporated herein by reference. 74 1278327 [Fig. 1 shows a field exposure dish in an EF exposure system; Figure 2 shows the percentage of viable cells after EF exposure; 5 3 The figure shows a significant increase in the number of high [Ca2+]c cells in both EF exposed and unexposed cell suspensions containing 12.5 pg/ml Con-A;

Figures 4A and 4B summarize the results of cell cultures (ceii cuitures) containing different concentrations of c〇nA with and without ImM CaCl2; 10 Figure 5 shows the presence of phytohemaglutinin (phytohemaglutinin, PHA) showed significant increase in high [Ca2+]jm cells in both EF exposed and unexposed cells; Figure 6 shows that when supplemented with 3.125-12.5 pg/ml of Con-A, Cells that were exposed or unexposed by EF had a significant increase in high [Ca2+]js cells compared to those stimulated with 15 0.025 pg/ml Con-A.

Figure 7 shows an example of an increase in the concentration of ConA induced by ConA in spleen cells (Spien0Cyte cells); Figure 8 shows a 2 〇 BALB 3Τ3 mouse embryonic cell stimulated with a final concentration of Μ·4 μΜ A23187 Time-history variation of the intensity of DiBAC in the middle; Figure 9 shows the effect of an electric field (EF) producing a current density of about 2〇〇μΑ/cm2 at 1〇〇HZ on the membrane potential in BALB 3T3; Shows the effect of an electric field (EF) at a current density of about 200 μΑ/cm2 at 1 Hz on the membrane potential in BALB 3T3: 75 1278327 Figure 11 shows the pressure for plasma adrenocorticotropic hormone (hereinafter referred to as " Effect of ACTH") level; Figures 12A and 12B show the effect of exposure to EF on plasma ACTH levels in normal (A) and ovariectomized (B) rats; Figure 13 shows Effect of EF exposure on blood-filled ACTH levels in normal rats (n==6); Figures 14A and 14B show EF exposure for normal (A) and nesting

In addition to (B) rats constrained the effect of "restraLinduced" plasma glucose level changes; 10 Figures 15A and 15B show EF exposure for restraint in normal (A) and ovariectomized (B) rats - Induction of plasma lactate level imaging; Figure 16 shows the effect of EF exposure on constrained-induced plasma pyruvate levels in ovariectomized rats; Figure 17 shows EF exposure for Constrained _ 15 induced white blood cell (WBC) counts in the nematode-treated rats;

Figure 18 illustrates an example of an electric field generated by the use of a therapeutic device (in this case, a Bi〇niTr〇n chair from the Baige Health Sciences Association); Figure 19 Figure 20A and 20B of a preferred EF therapy device of one of the inventions shows another preferred EF therapy device; Figures 21A and 21B show another preferred EF therapy device'; Figure 22 is a diagram showing a preferred electronic configuration of an EF therapy escort system; 76 1278 Jiang% 135644 patent application specification revision page July 2006, section 23A For a front view of an irritated human body, Figure 23B is a perspective view, and Figure 23C is a diagram showing an EF measurement sensor attached to the body neck. Figure 24 shows a device for measuring the sensed current generated by the EF therapy device; Figure 25 shows the relationship between an applied voltage and an induced current;

Figure 26 shows the relationship between the position of a head electrode and the current induced at the neck, 10 Figure 27 illustrates the induced current density (mA/m2) at different locations of an ungrounded human individual. And Figure 28 shows the efficiencies of EF exposure for different symptoms in humans. [The main components of the figure represent the symbol table] d.. Distance 2A··potentiometric device e.. electric field measurement sensor 2C.. potential therapy device h.·simulation of human body 3..high voltage generating device k-k' ··Line 4.. Commercial power supply R.. Current limiting resistor 5. Individual R'.. Current limiting resistor 6.. Armrest S.. Intermediate point 7.. Chair S'··Point 7a.. Chair T .. supercharger coil 8. head electrode 1. potentiometric device 8a. · first electrode 2. potential treatment device 8c · first electrode. 77 1278327 9.. second electrode 9a. Electrode 9c.. second electrode 10: high voltage output terminal 11.. wire 12: insulator 12'.. insulator 13.. voltage controller 23.. 1. V inverter 24.. optical analog data link 25. Optical fiber cable 26: Optical analog data link 27. Frequency analyzer 31.. Bed base 32.. Box 33.. Insulator 34.. Cover 35.. Insulation material 80c.. First electrode 80c'. Side electrode 78

Claims (1)

1278327 资年丨丨月修 (more) 正本, patent application scope · Patent application No. 92135644 胄 Patent application scope revision 2(10)(4) 1. A potential treatment device for treating or preventing a disorder, the obstacle causing - biological The abnormal ion concentration 5 in the cell or part of the cell is caused by the abnormal ion concentration, and the device comprises: (a) a main electrode and an opposite electrode; (b) - for applying a voltage a voltage generator to the electrodes; (4) an induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (4) Driving the voltage to generate a power source of 10 &amp; and the treatment or ribbing comprises restoring the cells to a normal ion concentration, including applying an external electric field to the organism or portion, the external electric field to the cells An average induced current density of from about 0.001 mA/m2 to about i5 mA/m2 is produced on the cell membrane. 2_ The potential therapeutic device of claim 1, wherein the plasma 15 comprises calcium ions. 3. If applying for a potential treatment device for full-time sub-item i, the step further comprises providing a dance supplement, a vitamin D supplement, a plant lectin supplement, or such supplement to the organism or part thereof. One combination of products. 4. The potential therapeutic device of claim 3, wherein the plant coagulant supplement is provided, and the plant lectin supplement comprises concanavalin A or wheat germ agglutinin. 5. If you apply for a patent scope! The potential treatment device of any one of the four items, wherein the average induced current density is about 〇〇1 mA/m2 to about 2 mA/m2 〇1278327. 6. The potential treatment device according to claim 5, wherein The biological system is a human and the electric field produces the average induced current density over the cell membrane of the human cell for a continuous period of from about 10 minutes to about 240 minutes. 5. The potential treatment device of claim 6, further comprising the additional continuous application of the external electric field to the human or a portion thereof and repeated generation of the average induced current density for an additional continuous period of from about 30 minutes to about 90 minutes. period. 8. The potential therapeutic device of claim 1, wherein the primary electrode 10 does not contact the organism or a portion thereof. 9. A potential therapeutic apparatus for treating a proliferative cell disorder, wherein the apparatus comprises: (a) a primary electrode and an opposite electrode; (b) a voltage generator for applying a voltage to the electrodes (c) an induced current generator that controls the external electric field by varying the voltage or a distance between the opposing electrode and the living body 15 or a portion thereof; and (d) - driving the voltage a power source of the generator, and wherein the treatment system comprises an ion current that changes a cell membrane across a living organism or a portion thereof, and includes applying an external electric field to the living body or portion, the external electric field generating an amount on the cell membranes. · Average inductive 20 flow density from 1 mA/m2 to approximately 2 mA/m2. 10. The potential therapeutic device of claim 9, wherein the average inductive current density is from about 0.2 mA/m2 to about 1.2 mA/m2. 11. The potentiometric device of claim 10, wherein the average induced current density is from about 0.29 mA/m2 to about 1.12 mA/m2. 2 1278327 12. The potential therapeutic device of claim 10, wherein the plasma comprises an ion. 13. The potential therapeutic device of claim 9, further comprising providing a calcium supplement, a vitamin D supplement 5, a plant lectin supplement, or the supplement to the organism or a portion thereof A combination. 14. The potential therapeutic device of claim 13, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 15. The potential therapeutic device of claim 10, wherein the proliferating cell disorder involves a differentiated fibroblast. 16. The potential therapeutic device of claim 10, wherein the biological system is a human, and the electric field produces the average induced current density on the membrane of the human cell for a period of about 10 minutes to about A continuous period of 240 minutes. 15. The potential therapeutic device of claim 16, further comprising an additional continuous period of subsequently applying the electric field to the human or a portion thereof and repeatedly generating the average induced current density for a period of from about 30 minutes to about 90 minutes. . 18. The potential treatment device of claim 17, wherein the human 20 is arranged in a bed of a hospital or clinic. 19. The potential therapeutic device of claim 9, wherein the primary electrode does not contact the organism or a portion thereof. 20. A potential therapy device for treating electrolyte imbalance, wherein the device comprises: (a) - a primary electrode and an opposite electrode; (b) - a voltage generator for applying 1278327 plus a voltage to the electrodes (C) an induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) - driving the voltage generation The power source of the device, and the treatment system includes ion flow that changes the cell membrane across a lifetime of 5 objects or portions thereof, including applying an external electric field to the organism or portion, the external electric field producing approximately 0.4 mA on the cell membranes Average induced current density from /m2 to approximately 6.0 mA/m2. 21. The potential therapeutic device of claim 20, wherein the average induced current density is from about 0.4 mA/m2 to about 5.6 mA/m2. 10. 22. The potential therapeutic device of claim 21, wherein the average induced current density is from about 0.43 mA/m2 to about 5.55 mA/m2. 23. The potential therapeutic device of claim 21, wherein the plasma comprises an ion. 24. The potential therapeutic device of claim 20, further comprising a calcium supplement, a vitamin D supplement, a lectin supplement, or the supplement for the organism or a portion thereof One combination. 25. The potential therapeutic device of claim 24, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 20. The potential therapeutic device of claim 21, wherein the biological system is a human, and the electric field produces the average induced current density on the membrane of the human cell for about 10 minutes. A continuous period of approximately 240 minutes. 27. The potential therapeutic device of claim 26, further comprising 1278327 comprising an additional continuous application of the electric field to the human or a portion thereof and repeated generation of the average induced current density for an additional period of from about 30 minutes to about 90 minutes. period. 28. The potential treatment device of claim 27, wherein the human 5 is arranged in a bed of a hospital or clinic. 29. The potential therapeutic device of claim 20, wherein the primary electrode is not in contact with the organism or a portion thereof. 30. A potential therapeutic apparatus for treating a disorder associated with serum calcium concentration, wherein the apparatus comprises: (a) a primary electrode and an opposite electrode; (b) 10 for applying a voltage to the electrodes a voltage generator; (c) an induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) one for driving The power source of the voltage generator, and wherein the treatment system comprises a flow of calcium ions that alters a cell membrane across a living organism or a portion thereof, and the package 15 includes applying an external electric field to the organism or portion, the external electric field on the cell membranes An average induced current density of from about 0.3 mA/m2 to about 0.6 mA/m2 is produced. 31. The potential therapeutic device of claim 30, wherein the average induced current density is from about 0.4 mA/m2 to about 0.5 mA/m2. 20 32. The potential therapeutic device of claim 31, wherein the average induced current density is about 0.42 mA/m2. 33. The potential therapeutic device of claim 30, further comprising providing a calcium supplement, a vitamin D supplement, a lectin supplement, or one of the supplements to the organism or a portion thereof combination. 3 ^\· A potential therapeutic apparatus according to claim 33, wherein the plant singularity supplement is provided, and the phytohemagglutinin supplement comprises a globulin globulin or a wheat germ agglutinin. 35. The potential therapeutic device of claim 31, wherein the biological system is - human, and the electric field produces the average induced current density on the cell membrane of the human cell for about 1 minute to A continuous period of approximately 240 minutes. 36. The potential therapeutic device of claim 35, further comprising the additional continuous application of the electric field to the human or a portion thereof and repeated generation of the average induced current density for an additional continuation of from about 3 minutes to about 9 minutes. period. 37. The potential treatment device of claim 36, wherein the human being is placed in a hospital or clinic bed. 38. If the potential of the third item of the application is also placed, the main electrode does not touch the organism or part thereof. 39. A potential treatment device for reducing the level of adrenoceptor or serotonin (9), the device comprising: (a) a primary electrode and an opposite electrode; (9) - for applying - electrospinning the electrodes a voltage generator; (c)-induced current generating H, which is controlled by a voltage or a distance between the opposite electrode and the living body or a portion thereof; and (4) - for driving the The power source of the voltage generator, and wherein the reduction comprises altering the ion current across the cell membrane of a living organism or a portion thereof, including applying an external electric field to the organism or portion, the external electric field being on the fine drum The average induced current density from about G q3 to about 12 1278327 mA/m2. 40. The potential therapeutic device of claim 39, wherein the average induced current density is from about 0.035 mA/m2 to about 11 _1 mA/m2. 41. The potential therapeutic device of claim 40, wherein the average 5 induced current density is from about 0.035 to about 0.5 mA/m2. 42. The potential therapeutic device of claim 39, wherein the plasma comprises calcium ions, and the potential therapeutic device further comprises providing a calcium supplement, a vitamin D supplement, a plant agglutination to the organism or a portion thereof. A supplement, or a combination of such supplements. The potential treatment device of claim 42, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 44. The potential therapeutic device of claim 40 or 42, wherein the biological system is a human, and the electric field produces the average induced current density on the membrane 15 of the human cell for about 10 minutes. A continuous period of approximately 240 minutes. 45. The potential therapeutic device of claim 44, further comprising the subsequent application of the electric field to the human or a portion thereof repeatedly and repeatedly generating the average induced current density for a period of from about 30 minutes to about 90 minutes. period. 46. The potential treatment device of claim 45, wherein the human is placed in a hospital or clinic bed. 47. The potential therapeutic device of claim 39, wherein the primary electrode is not in contact with the organism or a portion thereof. 1278327 48. A potential therapy device for treating pressure, the device comprising: (a) a primary electrode and an opposite electrode; (b) a voltage generator for applying a voltage to the electrodes; (c) An induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) - a power source for driving the voltage generator And the treatment system comprises ion flow that alters a cell membrane across an organism or a portion thereof, and includes applying an external electric field to the organism or portion, the external electric field producing an amount of about 〇.〇3 mA/ on the cell membranes. Average induced current density from m2 to approximately 12 mA/m2. 10 49. The potential therapeutic device of claim 48, wherein the average induced current density is from about 0.035 mA/m2 to about 11.1 mA/m2. 50. The potential therapeutic device of claim 49, wherein the ion comprises an ion. 51. The potential therapeutic device of claim 48, further comprising a calcium supplement, a vitamin D supplement, a lectin supplement, or the supplement for the organism or part thereof One combination. 52. The potential therapeutic device of claim 51, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. The potential treatment device of claim 49, wherein the biological system is a human, and the electric field generates the average induced current density on the membrane of the human cell for about 10 minutes. A continuous period of approximately 240 minutes. 54. The potential therapeutic device of claim 53, wherein the further package 1278327 comprises an additional continuous application of the electric field to the human or a portion thereof and repeated generation of the average induced current density for an additional period of from about 30 minutes to about 90 minutes. period. 55. The potential treatment device of claim 54, wherein the human 5 is arranged in a hospital or clinic bed. 56. The potential therapeutic device of claim 48, wherein the primary electrode is not in contact with the organism or a portion thereof. 57. A potential therapy device for treating arthritis, the device comprising: (a) a primary electrode and an opposite electrode; (b) - a voltage generator for applying a voltage to the 10 electrodes; An induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) - a power source for driving the voltage generator And the treatment comprising altering the flow of ions across a cell membrane of an organism or a portion thereof, comprising applying an external 15 electric field to the organism or portion, the external electric field producing an amount of about 0.02 mA/m2 on the cell membranes to An average induced current density of approximately 0.4 mA/m2. 58. The potential therapeutic device of claim 57, wherein the average induced current density is from about 0.025 mA/m2 to about 0.35 mA/m2. 59. The potential therapeutic device of claim 58 wherein the average 20 induced current density is from about 0.026 mA/m2 to about 0.32 mA/m2. 60. The potential therapeutic device of claim 58 wherein the ion comprises an ion. 61. The potential therapeutic device of claim 57, further comprising providing a calcium supplement to the organism or a portion thereof, a vitamin D 1278327 supplement, a lectin supplement, or the supplement A combination. 62. The potential therapeutic device of claim 61, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 5. The potential treatment device of claim 58 or 61, wherein the biological system is a human, and the electric field produces the average induced current density on the membrane of the human cell for about 10 minutes. A continuous period of approximately 240 minutes. 64. The potential therapeutic device of claim 63, wherein the further package 10 comprises an additional continuous application of the electric field to the human or a portion thereof and repeated generation of the average induced current density for an additional period of from about 30 minutes to about 90 minutes. period. 65. The potential treatment device of claim 64, wherein the human is placed in a hospital or clinic bed. The potential treatment device of claim 57, wherein the primary electrode is not in contact with the organism or a portion thereof. 67. A potential therapy device for treating overweight, the device comprising: (a) - a primary electrode and an opposite electrode; (b) - a voltage generator for applying a voltage to the electrodes; (c) An induced current generator 20 that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) a power source for driving the voltage generator And the treatment system comprising an ion current that changes a cell membrane across an organism or a portion thereof, comprising applying an external electric field to the organism or portion, the external electric field producing a signal on the cell membrane of 10 1278327 about 0.02 mA / M2 to about degrees. The mouth is spread, wherein the average 5 induced current density is about (10) times 2 to about 2 mW. Applying for a potential treatment device of 68 (4), wherein the average induced current density is 24 mA/m2 to about 〖i2 mW. Patent application (4) Potential therapy device of 68, wherein the ion contains calcium ions. 10 The potential therapeutic device of claim 67, wherein the step further comprises providing the raw side or part thereof with a supplement, a vitamin d supplement, a plant lectin supplement, or a combination of the supplements. . 7^ The potential treatment device of claim 71, wherein the plant political agglutination supplement is provided, and the plant (four) element comprises a concanavalin A or a wheat germ agglutinin. An average inductive current of 15 mA/m2. 73. A potential therapeutic device according to claim 67 or 7 wherein the biological system is a human and the electric field produces the average induced current on the cell membrane of the human cell. The density duration is a continuous period of from about 1 minute to about 240 minutes. 74. The potential therapeutic device of claim 73, further comprising repeatedly applying the electric field to the human or a portion thereof after P and repeatedly generating the average induced current density for an additional period of from about 30 minutes to about 9 minutes. Continuous period. 75. The potential treatment device of claim 74, wherein the human is placed in a hospital or clinic bed. 1278327 76. The potential therapeutic device of claim 67, wherein the primary electrode is not in contact with the organism or a portion thereof. 10 15 20 77. A potential therapy device for determining an optimal parameter for treating an electric field exposure outside a disorder, the device comprising: (a) a primary electrode and an opposite electrode; (b) - for applying a voltage generator to the electrodes; (c) an induced current generator that controls the external electric field by varying the voltage or a distance between the opposing electrode and the living organism or a portion thereof; (d) - a power source for driving the voltage generator, and wherein the decision comprises: (i) identifying a desired biological response to be induced in a living organism; (ii) selecting or measuring a The average induced current density at the cell membrane of the organism or a tissue sample or culture derived from the organism; (iii) selecting or measuring an external electric field that is away from the organism, sample Or a certain distance from the culture produces an induced current density that is screened or measured; (iv) selecting or measuring a continuous time period for producing a screened or measured induced current density on the membranes; Apply The selected or measured electric field to the organism, sample or culture, to produce the selected or measured induced current density on the cell membranes for the continuous time period selected or measured; 12 1278327 (vi) determination The extent to which the desired biological response occurs; (vii) selectively repeating any of steps (ii) through (vi); and/or (viii) confirming that the desired biological response is optimally induced As the value of the selected or measured induced current density, as the value of the selected 5 or measured external electric field or as the value of the selected or measured continuous time period. 78. The potential therapeutic device of claim 77, further comprising, prior to step (viii), generating a dose-response curve as the selected or measured induced current density, the selected or measured external electric field 10 Or one of the continuous time periods that are selected or measured. 79. The potential therapeutic device of claim 77, further comprising, prior to step (viii), selecting or measuring the following: the number of times of the repeated step (v); between the repetition of step (v) Time interval; and 15 the selected or measured induced current density is generated over the entire period of the cell membrane. 80. The potential therapeutic device of claim 77, wherein the selected or measured induced current density is from about 0.001 mA/m2 to about 15 mA/m2. The electrical potential treatment device of claim 77, wherein the cells are in a culture. 82. The potentiometric device of claim 81, wherein the cell lines in the culture are human cells. 83. The potential therapeutic device of claim 77, wherein the fine 13 1278327 cell line is in a living organism or a part thereof. 84. The potential therapeutic device of claim 83, wherein the living system is a human. 85. The potential treatment device of claim 77, wherein the inductive 5 current density is measured by measuring an induced current flowing in a given region of the living organism or a portion thereof. The current is converted into a voltage signal, which is selected or measured by converting the voltage signal into an optical signal, and then converting the optical signal into a voltage signal and analyzing the waveform and frequency. 10 86. The potential therapeutic device of claim 77, wherein the induced current density is represented by J, and the J system is represented by J = I/B. 87. The potential therapeutic device of claim 77, further comprising providing a calcium supplement, a vitamin D supplement, a lectin supplement, or the supplement to the organism, sample or culture. One of the 15 combinations. 88. The potential therapeutic device of claim 87, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 89. The potential therapeutic device of claim 77, wherein the primary 20 electrode is not in contact with the organism or a portion thereof. 90. A potential therapy device for treating a proliferative cell disorder, the device comprising: (a) a primary electrode and an opposite electrode; (b) a voltage generator for applying a voltage to the electrodes; (c) an induced current generator that controls the external electric field by varying the voltage or a distance between the opposing electrode and a portion of the living body or 14 1278327; and (d) - driving the voltage a power source for the generator, and wherein the treatment system comprises ion flow that changes a cell membrane across an organism or a portion thereof, including contacting the organism or portion with an electrical current that produces a 5 of about 10 on the cell membrane Average applied current density from mA/m2 to approximately 100 mA/m2. 91. The potential therapeutic device of claim 90, wherein the plasma comprises calcium ions and the average applied current density is generated on the cell membranes for a continuous period of substantially at least about 7 days. 10 92. The potential therapeutic device of claim 90, further comprising providing a calcium supplement, a vitamin D supplement, a lectin supplement, or the supplement to the organism or a portion thereof A combination. 93. The potential therapeutic device of claim 92, wherein the lectin supplement is provided, and the lectin supplement comprises a pea 15 or a wheat germ agglutinin. 94. A potential therapeutic device according to claim 90, 91 or 92, wherein the biological system is a human. 95. A potential therapy device for treating a stress-related disorder or symptom, the device comprising: (a) a primary electrode and an opposite electrode; (b)-20 a voltage for applying a voltage to the electrodes a generator (C) an induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) - for driving the a power source for the voltage generator, and wherein the treatment system comprises ion flow that changes a cell membrane across an organism or a portion thereof, including causing 15 1278327 the organism or portion to contact with a generating $w' that current is generated on the cell membranes It is a current density of approximately 60 mA/m2. The average of the large ', spoon 600 mW 96. If the scope of the patent application section contains the mother ion. And a therapeutic device, wherein the plasma 97 is a potential therapeutic device according to the scope of the patent application, further supplemented with a 0-plug/partially providing a supplement, a vitamin D 98, a rectal lectin supplement, or A combination of ones such as supplements. 10 15 20 . The potential treatment turtle of claim 97, wherein the plant coagulant supplement is provided, and the lectin reduction product comprises concanavalin A or wheat germ agglutinin. 9 9 . The potential treatment device according to claim 9 or claim 7, wherein the biological system is a human. Just--the treatment of the potential-related obstacles related to the concentration of serum dance, the device contains the main electrode and - the opposite electrode; (8) ^ ^ force. a voltage generator (10) for inducing a current generator, wherein the external electric field is changed by changing the voltage or between the opposite electrode and the living body or a portion thereof; and (4) a power source of the voltage generator, and a flow of the mother ion in the cell membrane of the i object or a portion thereof, including contacting the organism or portion with a current that is generated on the cell membrane - an average applied current density of from about 6 G mA/m2 to about 2 mAW. For example, the potential treatment device of claim 1 GG of the patent, wherein the 16 1278327 plasma contains calcium ions. 102. The potential therapeutic device of claim 100, further comprising providing a calcium supplement, a vitamin D supplement, a lectin supplement, or one of the supplements to the organism or a portion thereof Group 5 in combination. 103. The potential therapeutic device of claim 102, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 104. The potential therapeutic device of claim 100 or 102, wherein the biological system is a human. 105. The potential therapeutic device of claim 100, wherein the current produces the average applied current density on the cell membranes for a continuous period of from about 1 minute to about 20 minutes. 106. The potential therapeutic device of claim 105, wherein the 15 current produces the average applied current density on the cell membranes for a continuous period of from about 2 minutes to about 10 minutes. 107. A potential therapy device for determining an optimal parameter for treating a current exposure of a disorder, the device comprising: (a) a primary electrode and an opposite electrode; (b) - for applying a voltage to the The voltage of the electrode generates 20; (c) an induced current generator that controls the external electric field by changing the voltage or a distance between the opposite electrode and the living body or a portion thereof; and (d) - a power source for driving the voltage generator, and wherein the treatment system comprises: (i) identifying a desired biological inverse 17 1278327 to be induced in a living organism; (ii) selecting or measuring a bit An average induced current density on the cell membrane of the organism or a tissue sample or culture derived from the organism, wherein the average applied current density is from about 10 5 mA/m2 to about 2,000 mA/m2; (iii) selecting or measuring a current that will produce the selected or measured applied current density; (iv) selecting or measuring a continuous time period for generating the selected or measured applied current density; 10 15 20 (v) Adding the selected or measured current to generate the selected or measured applied current density for the selected or measured continuous time period; (vi) determining the extent to which the desired biological response occurs; (vii) Repeating any of steps (ii) through (vi) to generate a dose-response curve as the selected or measured current, the selected or measured applied current density, or the selected or measured a function of a continuous time period; and (viii) confirming the selected or measured current that best induces the desired biological response, the selected or measured applied current density, or the selected or measured continuous The value during the time. 108. The potential therapeutic device of claim 107, further comprising, prior to step (viii), selecting or measuring the following: the number of times of the repeated step (v); between the repetition of step (v) Time interval; and 18 1278327 The selected or measured induced current density is generated over the entire period of the cell membrane. 109. The potential therapeutic device of claim 108, wherein the cell lines are in a culture. 5 110. The potential therapeutic device of claim 109, wherein the cell lines in the culture are human cells. 111. The potential therapeutic device of claim 108, wherein the cell line is in a living organism or a part thereof. 112. The potential therapeutic device of claim 111, wherein the living system is a human. 113. The potential treatment device of claim 108, further comprising providing a calcium supplement, a vitamin D supplement, a lectin supplement, or the supplement to the organism, sample or culture. One combination. 15 114. The potential therapeutic device of claim 113, wherein the lectin supplement is provided, and the lectin supplement comprises concanavalin A or wheat germ agglutinin. 19 1278327 Fresh July 0 repair (more) original 1 exposed fiber Qingtongtong Abdominal distension, abdominal pain, allergic constitution, baldness, arrhythmia, back pain, blurred vision, chest pain, cold, constipation, cough, ear diarrhea, dizziness, dizziness, rash, eye fatigue, facial edema, facial paralysis, facial nerve, unilateral stiffness, fatigue, systemic muscle stiffness, silver pain, diabetes, headache The body feels heavy, the head feels heavy, the legs feel heavy, the stomach feels heavy and bloody. Insomnia plague, joint pain, loss of appetite, lack of grip, loss of back pain, menstrual irregularity*^ limb pain, palpitations, paralysis of the limbs, edema, frequent edema, skin, painful arm Straight limbs feel the peeling of the epidermis of the epidermis, shoulder or neck pain, shoulder or neck stiffness, pain, stomach pain, joint swelling, limb fibrillation, urinary incontinence 12783 No 92135644 Patent Application Manual Amendment Page July 2006 柒, designated representative map: (1) The representative representative of the case is: (1). (2) A brief description of the symbol of the symbol of the representative figure: None. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: