Use of taurine for treating or preventing ischaemic injury

Abstract: The invention relates to methods for inducing analgesia (or even anesthesia) and for prevention or amelioration of damage caused by injury of tissues in general, but especially neural, for the central nervous system being the most vulnerable of all tissues, by the systemic administration of a therapeutically effective amount of primarily taurine, and secondarily homotaurine and/or methionine for a sufficient period of time (several hours to a few days, depending on the severity of the injury, and timing when therapy is initiated from the time of injury) to allow recovery from the original insult or from phenomena that follow the initial injury.

Description: BACKGROUND ART Field of the Invention This invention is applicable in all fields of medicine, but more particularly, in the specialties of anesthesiology, neurology, neurosurgery, internal medicine, pediatrics, oncology, obstetrics, neo-natology, cardiology, cardiac surgery, radiology, critical care medicine and transplantation in general. It relates to the use of exogenous taurine to protect organs in general and particularly the central nervous system (CNS) in patients (in-vivo conditions), or explanted donor organs (including the liver, pancreas, small bowel, lungs, kidneys or the heart) (in vitro conditions) to be used for transplantation from the ravaging effects of hypoxia or ischemia (lack of or decreased oxygenation or blood flow) caused by vascular severance, such as during organ harvesting for transplantation, primary or secondary intra-vascular obstructions (such as in stroke) or extra-vascular factors accompanying trauma to the tissue (head trauma or during neurosurgical procedures). Conventional Art CNS ischemia is characterized by a complex cascade of hemodynamic, electrophysiological and biochemical processes with many interwoven vicious circles. The decrease of CNS blood flow below a critical threshold results in energy failure, tissue acidosis, disturbed ion homeostasis characterized by enhanced cellular K + efflux and Na + and Ca ++ influx, membrane depolarization and cytotoxic edema (Choi, 1990; Rudolphi, 1992; Wieloch, 1982). These basic biochemical processes of ischemia might be quantitatively different in various organs but are qualitatively common to practically all tissues, and therefore general principles aimed to prevent or ameliorate them could be extended to organs other than the CNS. In the CNS it has been reported that extracellular or interstitial levels of the excitatory aminoacids (EAAs) as well as inhibitory and potentially protective aminoacids such as taurine increase 4-20 fold during or shortly after ischemic injury (Benveniste, 1984; Hillered, 1989; Simpson, 1992) or head trauma (Nilsson, 1990; Persson, 1992); likewise there is a similar outpour of adenosine (Nilsson, 1990; Van Wylen, 1986). The flooding of the extracellular space with EAAs results in indiscriminate and continuous activation of postsynaptic EAAs receptors (phenomenon known as excitotoxicity) such as those for NMDA (N-methyl-D-aspartate, activated by glutamate and aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and KA (kainate) which may result in ultimate cell death, an occurrence that may be delayed for 2 or 3 days or even longer. This elevation of (interstitial) extracellular EAAs levels is thought to be part of the periphenomena of most acute CNS injury events leading to cell damage (Choi, 1990; DeLeo, 1987; Rothman, 1986). Even though the exact physiopathologic role glycine plays is not fully known, for NMDA receptors to become fully activated seems to require the presence of glycine in addition to the EAAs (glutamate or aspartate) (Johnson, 1987). The role and importance of adenosine receptors in general and particularly in the CNS have been recently reviewed by Fredholm (1995) and Jacobson (1995). The neuroprotective role of adenosine in cerebral ischemia have been summarized by Choi (1990), Rudolphi (1992) and Schubert (1993). Purinergic compounds which may interact with these adenosine receptors include the naturally present adenosine and adenosine tri-phosphate (ATP) or the synthetic adenosine analogues, and are well known to exert multiple functions in almost every tissue of the body, but are particularly conspicuous and therefore have been extensively studied in the brain where general antinociceptive (analgesic or even anesthetic), antiepileptic and tissue protective effects are well documented. Even though all the mechanisms of action of adenosine are not completely elucidated, the general consensus, as has been reviewed and summarized by Fredholm (1995) is that the effects are mediated by receptors of mainly the A1 (considered to be sensitive to µmolar concentrations of adenosine and functionally to produce hyperpolarization of membranes and inhibition of the release of EAAs) and A2 types, (sensitive to mmolar concentrations, and functionally characterized to produce release rather than inhibition of EAAs on one hand but particularly dilatation of the vasculature) located in cell membranes on the cell surface. In the CNS, although there are areas rich in A2 type receptors, A1 are predominant (Fredholm, 1995; Jacobson, 1995), and consequently their activation induce mostly widespread inhibition of the release of EAAs. Pharmacological manipulation of these adenosine effects has been described as adenosinergic approach, and may include the administration of adenosine itself or ATP, or metabolically stable synthetic adenosine analogues, or therapy directed to increasing tissular adenosine concentration either by inhibiting its reuptake by the cells, or by inhibiting the destruction of the endogenously formed adenosine, or by the administration of precursors or prodrugs of adenosine to enhance its endogenous production. The exogenous administration of purinergic compounds (adenosine or its analogues and ATP) that act on the adenosine receptors or pharmacological agents that alter the tissue levels of endogenous adenosine have been proven to have important antinociceptive: sedative, analgesic (Fukunaga, 1995; Sollevi, 1992), antiepileptic and/or neuroprotective activities (Fredholm, 1995; Rudolphi, 1992, Schubert, 1993). Because the extent of protection obtained with adenosinergic approaches in experimentally induced ischemia conditions of the CNS and other tissues, seems to be dose-dependent (Goldberg, 1988), in seeking significant A1 receptors effects, the administration of sufficient adenosinergic agents will almost always result in A2 receptors activation (dangerous levels of hypotension) and these consequent cardiovascular effects have hindered the acceptance of the adenosinergic approach at any clinical level (anesthesia, neurology or transplantation field) (Rudolphi, 1992). In spite of the extensive work and considerable knowledge gained on the physiology and pharmacology of the various adenosine receptors as well as the adenosine analogues which were developed with the idea of selectively activating A1 receptors at small adenosine concentrations, to avoid the cardiovascular (vasodilating) hypotensive effects, which are mainly the result of A2 receptors activation that occurs at greater concentrations, many of the adenosinergic approaches affect both types of the ubiquitous and widely distributed adenosine receptors (throughout the entire body). Consequently their use has been hampered mainly by the undesirable cardiovascular effects, i.e., severe and dangerous decrease of blood pressure (hypotension) when dosages sufficient to attain adequate tissue levels at the target organ are used. Until now, the beneficial CNS effects of adenosine and adenosinergic approaches in regards to antinociception and neuroprotection have been explained on the basis of the general effects of hyperpolarization of membranes and inhibition of the release of EAAs, effects that are thought to be mediated mainly by A1 type Adenosine receptors, but the inventors have further uncovered the heretofore non-described effect that adenosine releases in a dose-dependent manner various inhibitory aminoacids but mainly taurine, regardless of the area of the brain, whether rich in A1 or A2 receptors and therefore suggesting that such effects might not be mediated by the classic Adenosine receptors. Although how taurine functions is not fully understood as yet, taurine is particularly abundant in the retina (where light promotes oxidation) and the brain (where oxidation might destroy the CNS function). Taurine is known to be a naturally present aminoacid with important anticalcic, antioxidant and protective features (Huxtable, 1980; Lehmann A, 1984; Wright CE 1986). Indeed, exogenously administered taurine in cats (van Gelder, 1972,a; 1976,b) as well as homotaurine in rats (Fariello, 1982) were reported previously to have antiepileptic effects but never found their way to be used as therapeutic agents. The common denominator of a number of protective pharmacological agents including barbiturates, benzodiazepines, isoflurane (all with anesthetic and anticonvulsant properties) and anticonvulsants (such as MK 801) is precisely the anticonvulsant action when used in therapeutically effective doses, and typically they induce marked EEG quiescence or functional depression (Kato, 1990; McDonald, 1990; Michenfelder [a], 1988). The inventors have further demonstrated that exogeneously administered taurine could mimic many if not all of the effects elicited by systemic administration of purinergic compounds, including those of anti-nociception with minimal or no cardiovascular effects. The role of adenosine in pain perception as anti-nociceptive was summarized by Fredholm (1995). Of particular interest is the fact that the analgesic effects of morphine and morphine-like narcotics seem to be exerted via stimulation of adenosine release (Stone, 1981), and those of benzodiazepines via inhibition of adenosine uptake mechanisms. The administration of intravenous adenosine (Sollevi, 1992) or ATP (which is degraded to adenosine at the tissue level) proved to markedly decrease the requirements for anesthetic agents (Fukunaga, 1994) transoperatively, and notably the requirements for postoperative analgesics (Sollevi, 1992) Hornfeldt et al., Life Sciences, 50 (1992) 1925 - 1934, and Smullin et al., Pain, 42 (1990) 93 - 101, describe the antinociceptive effects of the intrathecal injection of taurine. Schurr et al. in Pharmacology of Cerebral Ischemia, Ed. J. Krieglstein, Elsevier Science Publishers B.V., 1986, 363 - 370, reports that taurine protects the guinea pig heart against hypoxic and reoxygenation damage and attenuates Ca 2+ influx during ischemia in the rabbit brain. Beyer et al., Pharmacol. Biochem. Behav., 34 (1989) 491 - 495, and Beyer et al., Pharmacol. Biochem. Behav., 29 (1988) 73 - 78, describe an analgetic or anaestetic effect and an anticonvulsant action of taurine, respectively, when administered in high concentrations. SUMMARY OF THE INVENTION This invention is therefore aimed at solving the above-mentioned shortcoming of adenosinergic approaches, while obtaining protective effects, thus providing similar or even greater beneficial effects than adenosinergic approaches without the troublesome hypotension. Exogenous purinergic compounds delivered directly in the brain tissue via microdialysis probes (thus avoiding hypotension that plagues systemic administration) (a well known technique for those skilled in the art of drug delivery for pharmacological studies and analysis of interstitial fluid levels of various substances including aminoacids) induces the release of a number of inhibitory aminoacids but especially taurine into the CNS interstitial space. Therefore the logical conclusion is that some of the beneficial effects so far ascribed to adenosine could be actually due to this taurine, which is known to have important inhibitory, anticalcic and antioxidant activities, for which it has been described as the natural protective substance (Huxtable, 1980; Wright, 1986). Ischemic injury involves Ca ++ overload of cells and subsequent oxidation of lipid membrane and cytoskeleton structures; this phenomenon is particularly conspicuous in the excitable CNS tissue (Wieloch, 1982). The anticalcic and antioxidant effects of taurine have been shown in the retina and various neural preparations (cultures, slices, synaptosomes) as well as in cardiac tissue, thus establishing the grounds for extending the protective effects to tissues other than the CNS as well, for the treatment or prevention of ischemic injury of a variety of organs. For metabolic reasons (Lloyd, 1988; Schrader, 1991) the combined use of taurine with homotaurine or with methionine should result in mutually potentiating effects. The simultaneous use of small amounts of purinergic compounds (not enough to produce significant hypotension) and taurine alone or taurine + homotaurine and/or with methionine are likewise supplementary and are expected to further potentiate mutually their protective effects. According to the invention, there is provided the use of taurine in the manufacture of a pharmaceutical formulation for treating or preventing ischemic injury of mammalian tissues, including human tissues said formulation comprising a hypertonic solution of taurine at 7-10% in an amount to be administered intravenously at 10 mmol/Kg bodyweight of taurine. According to a further aspect of the invention, there is provided a pharmaceutical formulation for treating or preventing ischemic injury of tissues in general in a mammal including the human, comprising a therapeutically effective amount for treating or preventing the ischemic injury of taurine, at 7-10% in an amount to be administered intravenously at 10 mmol/kg bodyweight either alone or may comprise another supplementing agent (generally an anesthetic or anticonvulsant). BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing brain cortical interstitial fluid levels of taurine which are related logarithmically to the dose of taurine given intravenously. Figs 3 to 6 are illustrations of the power spectrum of the electroencephalogram (EEG) in a non-ischemic rabbit obtained during the administration of incremental amounts of taurine. Fig. 7 is a graph showing the protective effect afforded by taurine in spinal cord ischemia model in rabbits. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, a therapeutically effective amount of exogenous taurine is administered to a mammal including the human to mimic the keenly sought beneficial effects of adenosinergic approaches without the undesirable cardiovascular side-effects. The issue of when and for how long taurine ought to be given for tissue protection, will depend on the severity of the ischemia producing cause and the feasibility of specifically eliminating the cause of ischemia itself, but it must be made available to the target tissue as early as possible. Ideally it should be started before or shortly after the initiation of the ischemia and continued preferably beyond the time normal or close to normal blood flow is restored, since many of the injurious events occur at the time blood flow is restored, i.e., reperfusion to the already Ca ++ loaded ischemic tissue. Taurine, by preventing further Ca ++ loading and oxidation of lipids should minimize not only events occurring during ischemia but also many of such reperfusion events. A loading IV dose of taurine with 10 mmol/kg of body weight (enough to obtain a functionally quiet CNS by EEG criteria) followed by a maintenance continuous IV drip or periodic IV boluses are recommended. Since these beneficial effects are not limited to the CNS but are effects observable in other tissues as well, the indications for protective effects can be extended to many target organs, either in situ such as for resuscitation, or during cardiac, liver, renal or pancreatic surgery or in explanted organs such as for harvesting and preserving of donor organs for transplantation, for which perfusion solutions containing at least 1 or 2 mmol/L or more, are recommended. In regards to method of delivery, the parenteral intravenous route is the preferred route, given as an initial loading bolus and then either repeated periodically or preferably as a continuous drip using any of the commonly available delivery devices. Whatever the method, it is necessary to attain interstitial concentrations of taurine sufficient to obtain a quiescent EEG and to maintain these concentrations of taurine in the brain extracellular fluid for an extended period of time, preferably over 8 hours, and still more preferably greater than the length thought to be under the danger of excitotoxicity, which might be 48 to 72 hours. The inventors have proven in preliminary experiments that exogenously administered taurine alone mimics many, if not all the effects sought with purinergic compounds in the CNS or elsewhere, and hence the potential use of taurine, either alone or in combination with methionine or small amounts of purinergic compounds as therapeutic agent(s) in a/or for a wide variety of conditions (anesthetic, neurologic and non-neurologic such as cardiac protection in patients suffering from myocardial ischemic episodes or infarction or during heart surgery, or for donor organ preservation in transplantation of various organs), oriented to protect the organ from the potentially devastating effects of ischemia. Taurine, is a naturally present aminoacid in practically every tissue. Taurine is especially well known to be used normally as a detoxifying substrate by the liver. Although toxicological studies have not been made, it is most likely that taurine, is devoid of toxic effects when used at the therapeutically useful dosages or at least will have wide margins of safety which is a highly desirable feature for any substance to be used as a therapeutic agent. Because, in various ischemic models, the required amounts of purinergic compounds to get only the desirable inhibition of the release of EAAs are reportedly to be small, on one hand, and the beneficial effects of taurine are dose dependent on the other, the combination of small amounts of the former and whatever is necessary of the latter is rational, and might avoid having to use large amounts of purinergic compounds that would have to be used if all the sought effects were to be obtained with purinergic compounds only with the consequent undesirable and unavoidable cardiovascular (hypotensive) effects. Potential combinations of taurine, may contain a number of other already available drugs [including but not limited to adenine nucleosides (adenosine or adenosine analogues) and nucleotides (ATP or ATP analogues), mannitol, vitamin C, glutathione, vitamin E and related compounds, magnesium, dantrolene, corticosteroids, promazine and related compounds, nicholin, 21-amino steroids, non-steroidal anti-inflammatory agents, other anti-inflammatory agents, calcium antagonists (nifedipine, diltiazim, nicardipine, etc), openers of K ATP channels in general with representatives such as pinacidil, nicorandil, chromakalim, among others or physical means such as hypothermia to mutually potentiate their protective effect. REFERENCE Example 1 Dose-response of occipital cortical taurine concentration levels were measured by micro-dialysis technique, and EEG (frontal leads) were observed in a non-ischemic rabbit. The exogenously administered intravenous bolus of methionine (0.5 mmol/kg) induced tendency, though minimal, of elevation of the endogenous taurine levels, but produced typical and unequivocal EEG changes characterized by wide amplitude, relatively slow waves that are characteristic of stage II-Ill of EEG depth of anesthesia (Table 1, periods 4-6, Fig 2), as compared to that of basal anesthesia condition (Table 1, periods 1-3, Fig 2; EEG stage I, obtained with isoflurane 1.5 % and mixture of N 2 O/O 2 at 65:30 %) prior to the administration of taurine. Incremental doses (intravenous bolus) of taurine (0.5 mmol/kg every 3 cortical interstitial fluid-dialysate collection periods of 22 minutes each period) starting at 0.5 mmol/kg, without changing other anesthetic conditions, resulted in EEG evidence of further deepening of the anesthesia level (periods 7-18, Figs 1 and 3-6), which can be summarized by the left and downward shift of the EEG spectrum (Figs 3-6) expressed in terms of Fourier transform power spectrum (FFT of one minute epochs of EEG taken at the end of each collection period). These EEG changes paralleled the logarithmic increases of the interstitial taurine cortical concentrations reflected in the dialysate taurine contents (Table 1, Fig 1), and for example after the dose of 2.0 mmol/kg of taurine (periods 16-21) the EEG reached stage IV-V (burst suppression) consistent and persistently. Dose-Response Sample No. Cortical Concentration (pmol/30 uL Dialysate) EEG pmol Log EEG Stage I-VI FFT Power Spectrum Control 1 87.8 1.9435 I Fig 2 2 82 1.9138 I 3 87.8 1.9435 I M:0.5 mmol/kg 4 94.8 1.9768 II Fig 2 5 118 2.0719 III 6 96 1.9823 III Fig 2 T:0.5 mmol/kg 7 453 2.6551 III Fig 3 8 976 2.9894 III Fig 3 9 798 2.9021 III-IV Fig 3 T:1.0 mmol/kg 10 1151 3.0607 III-IV Fig 4 11 1164 3.0645 III-IV Fig 4 12 1105 3.0414 III-IV Fig 4 T:1.5 mmol/kg 13 1982 3.2967 IV Fig 5 14 2347 3.3711 IV Fig 5 15 2074 3.3161 IV Fig 5 T:2.0 mmol/kg 16 2848 3.4548 IV-V Fig 6 17 3430 3.5353 V Fig 6 18 3628 3.5599 V Fig 6 Methionine (M) or Taurine (T) was administered as an IV bolus over a 3 minute period at the beginning of the corresponding fraction period (). EEG=Electroencephalogram; FFT=Fourier transform or EEG power spectrum of one minute EEG epoch; EEG anesthesia stage I-VI (see text). Example 2 The protection afforded by taurine was examined in the well known spinal cord ischemia model in the rabbit (reversible clamping of the abdominal aorta below the renal artery) of one hour duration. The protective effects were compared against what is considered the golden standard of the protective methods: hypothermia, which is well characterized by the increasing protective efficacy, within a certain range, with the degree of hypothermia established at the time ischemia occurs. In one group of animals (○) sufficient degree of hypothermia (mean esophageal temperature of 29.38°C) to obtain adequate protection (the rabbit would recover normal spinal cord function within 6 hours of establishing spinal cord reperfusion following one hour of ischemia) was determined; in another group (x) the degree of hypothermia induced was slightly less (esophageal temperature being 29.9°C or 0.52°C higher than the former group) so that animals would not recover cord function, and in a third group () 10 mmols/kg of body weight of taurine prepared as a 10% solution was administrated: one third of it at the time of induction of anesthesia, one third during the induction of hypothermia (which turned out to be 30.58°C or 1.2°C higher than the first (○) group, and 0.68°C higher than the second (x) group), and the remaining one third 5 minutes prior to establishing reperfusion of the spinal cord (declamping of the aorta). As depicted in the Figure 7, animals receiving taurine were all adequately protected at temperatures that hypothermia alone failed to achieve, functional recovery being persistent 24 hours later, indicating that the spinal cord was indeed adequately protected during the one hour of blood perfusion deprivation, with no evidence of gross delayed untoward phenomena at least for 24 hours. In addition, pilot experiments with isotonic taurine solution was found to be less effective than the 10% (hypertonic) solution of taurine. The protective effects of taurine could further be potentiated with a number of other medications aimed to reduce the production of free radicals such as mannitol, deferoxamine and vitamin C, or to prevent the increase of intracellular Na or Ca such as Mg and dantrolene, or inhibitors of phospholipase C such as chlorpromazine and nicholin leading to the conclusion that when taurine is used with one or more other medication(s) with protective properties on their own, even though the protective effects might not be an algebraic summation of the activity of each one of the components the net resulting effect would be a greater protective efficacy than the individual component given separately (potentiation). The therapeutically effective taurine doses for clinical use is 10 mmol/kg of body weight, when administered as a hypertonic solution. The more concentrated the better (to be able to give the same dosage of taurine in the least volume), but considering the physical properties of solubility of taurine (13% at room temperature of 23°C) a 7% to 10% solution would probably be the most workable concentration, taking into account also the volume tolerance when given within a short period of time. REFERENCE Example 3 Since many substances with protective effects exert the protection by promoting blood flow to the affected area in addition to the specific mechanism by which exert the protective action, the blood flow effects of topical taurine solution to the dorsal aspect of the toes were examined by measuring skin temperature with an infra-red camera in a patient with frostbite of the left foot (4th toe), without and with iced cold water immersion challenge for 5 seconds. The skin temperature reflects the blood flow to the area, the warmer the greater blood flow. How fast the skin temperature returns to normal after a short period of immersion into iced-water is a commonly used clinical test to evaluate the blood flow to the area and its neurogenic control. The non-specific protective vasodilating effect exerted by the topically absorbed taurine will be manifested as increase of temperature, over the basal temperature or by accelerating the recovery of the basal temperature after iced-water immersion. Accordingly as can be seen on the tables 2 and 3, topical taurine increases the temperature of the toes where it was applied, whether it is applied without or with prior challenge of exposure to cold. The maximal effects are seen between 15 to 20 minutes after its topical application in both situations. Previous studies of spinal cord ischemia have shown the most protective effects of hypertonic solutions as compared to isotonic or hypotonic solutions, and similar correlation is predicted for the vascular effects, though only a 10% solution was tested. Although of slightly lesser magnitude and not tabulated, similar response is observed when applied to normal subjects, not only on feet, but also on hands and the forehead. The implication being that it should be especially effective when applied to patients who have various degrees of neurovascular disorders. No Iced Water Challenge Room Temp. :27.5°C Toe-Skin Temperature Evaluation-Side Contra-Lateral Side Average 4* Toes 3rd Average 4* Toes (1,2,4,5)* 3rd (1,2,4,5)* % of Max Change Baseline 32.25°C -- 31.4°C 31.85°C 31.5°C 0 min Topical Taurine -- Nothing Topical Water Nothing 5 mins 33.02°C 81.05% 32°C 31.67°C 31.9°C 10 mins 32.7°C 47.37% 31.8°C 31.2°C 31.1°C 15 mins 32.9°C 68.4% 32.3°C 31.37°C 31.8°C 20 mins 33.2°C 100% 32.1°C 31.85°C 31.7°C 25 mins 33.02°C 81.05% 32.1°C 31.37°C 31.7°C 30 mins 32.87°C 65.26% 31.9°C 31.6°C 31.9°C Iced Water Challenge Room Temp. :27.7°C Toe Skin Temperature Average 5 Toes Evaluation Side % Recovery Average 5 Toes Contra-Lateral Side % Recovery Baseline 32.62°C -- 31.92°C -- Iced Water (5 seconds) 24.2°C -- 21.56°C -- 0 min Topical Taurine -- Topical Water -- 5 mins 29.38°C 61.52% 26.58°C 48.65% 10 mins 31.42°C 85.75% 28.16°C 63.71% 15 mins 31.66°C 88.6% 28.6°C 67.95% 20 mins 30.92°C 79.81% 28.06°C 62.74% 25 mins 31.5°C 86.7% 28.16°C 63.71% 30 mins 31.04°C 79.81% 27.46°C 56.95% References: Benveniste H, Drejer J, Schousboe A, Diemer NH (1984): Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. 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Claims: Use of taurine for the manufacture of a pharmaceutical formulation for treating or preventing ischemic injury of mammalian tissues, including human tissues, wherein the pharmaceutical formulation is for intravenous administration and comprises a hypertonic solution of taurine at 7-10 % in an amount to be administered intravenously at 10 mmol/kg bodyweight. The use according to claim 1, wherein said ischemic injury is of the central nervous system.

Inventors: MIYAMOTO KOHO, MIYAMOTO TADAOMI, MIYAMOTO, KOHO, MIYAMOTO, TADAOMI
Applicants: MEDDISS INC, MEDDISS, INC.
Application year: 1997
Main classification: A61K31
IPC codes: A61P25, A61K31, A61K9, A61P9, A61K45