NOXIOUS FLUIDS

[0001] This application is a Continuation-in-Part of, and claims priority under 35 U.S.C. § 120 to, U.S. App. No. 15/656,418, filed 21 July 2017 by the inventor hereof, which claims priority under 35 U.S.C. § 119 to U.S. Provisional App. Nos. 62/365,676, filed 22 July 2016, and 62/377,011, filed 19 August 2016, the entireties of which are incorporated by reference herein.

BACKGROUND

Field of Endeavor

[0002] The present invention relates to devices, systems, and processes useful as medical therapies for tumors, primary and metastatic, benign or malignant.

Brief Description of the Related Art

[0003] Loco-regional treatment of cancer has predominately focused on liver cancer and includes several different therapies, including ablation by local deposition of electromagnetic radiation, ablation by local injection of absolute ethanol or acetic acid, or trans-arterial treatment like embolization using particles, chemotherapy, liquid embolic agents, radioactive particles, or combinations thereof. In the case of localized primary liver cancer, these treatments can be curative. In multifocal primary or metastatic liver cancer, multiple randomized clinical trials have shown improvement in survival by embolization techniques. Treatment of other cancers outside of the liver is possible, for example by local deposition of electromagnetic energy or injection of alcohol or acetic acid, but intra-arterial embolization is limited outside of the liver because of the risk of infarction of the organ being treated if feeding arteries are occluded, as is typical of embolization procedures. In the liver, normal liver cells are mostly spared during embolization because of perfusion by the portal vein.

[0004] However, even for those with liver cancer there is an unmet need for those with large malignant liver tumors, or those with multifocal malignant liver tumors. First, ablation techniques are only effective for single tumors with maximum diameter of 3-5 cm. While embolization techniques can be helpful for larger tumors, or tumors that are multifocal, most embolization techniques partially or totally block arterial blood flow to the liver, which can make repeat treatment difficult. Since such treatments are rarely curative with large or multifocal malignant liver tumors, the ability to perform repeat trans-arterial treatment would be useful. Also, treatment of other solid tumors outside of the liver, such as brain tumors for example, is not done using intra-arterial transcatheter therapy because of the risk that embolization, or intentional artery occlusion, poses to the organ at large.

[0005] Infusion of chemotherapy drugs directly into the hepatic artery has been tried in the past using implantable ports and pumps, with catheters exiting the ports and entering the hepatic arterial circulation. However, such treatment is associated with similar toxicity as intravenous infusion, without any demonstrable improvement in survival compared with systemic administration.

[0006] Another infusion therapy for liver cancer involves the use of 3-bromopyruvate. It currently appears that 3-bromopyruvate disrupts a cellular metabolic process, namely, it appears to disrupt glycolysis and is thus "suspected to be a Warburg-effect play against tumor cell metabolism" (see blogs.sciencemag.org/pipeline/archives/2016/08/17/3-bromopyr uvate- what-a-mess). Thus, 3-bromopyruvate disrupts the ability of tumor cells to generate ATP or energy; it does not appear to kill cells by disrupting the cellular membranes or denaturing cellular proteins.

SUMMARY

[0007] According to a first aspect of the invention, a method of treating a tumor in an organ of a patient and at least one blood vessel which supplies blood to said organ and said tumor comprises infusing a fluid comprising at least one substance into the at least one blood vessel at a concentration and rate of said at least one substance sufficient to kill cells of said tumor by direct toxicity, said direct toxicity being mediated through direct disruption of cells, including rupturing cell membranes or denaturing cellular proteins, and not mediated through disruption of biochemical processes of said cells, said concentration and rate being insufficient to kill nontumorous organ cells.

[0008] According to another aspect of the present invention, a method of treating a tumor in an organ of a patient having feeding blood vessel which provided blood to said organ and to said tumor comprises infusing a fluid having a temperature above 104 degrees Fahrenheit into the feeding blood vessel at a rate sufficient to kill cells of said tumor, said rate being insufficient to kill nontumorous organ cells.

[0009] According to yet another aspect of the present invention, a method of treating a tumor in an organ of a patient and feeding blood vessel supplying blood to said organ and to said tumor comprises infusing a fluid having a temperature below 85 degrees Fahrenheit into the feeding blood vessel at a rate sufficient to kill cells of said liver tumor, said rate being insufficient to kill nontumorous liver cells.

[0010] According to another aspect of the present invention, a method of treating a tumor in an organ of a patient with a feeding blood vessel supplying blood to said organ and to said tumor comprises infusing a toxic or poisonous substance; a substance is toxic or poisonous herein because it can kill said patient at relatively low concentrations in the blood (e.g., <=10 mg/kg blood concentration), and is not a medication because it has no known therapeutic use when administered systemically or through the body. Infusing is performed at a concentration and rate into said organ or tumor sufficient to kill said organ or tumor while below the concentration and rate that would result in systemic toxicity or death to the patient.

[0011] Still other aspects, features, and attendant advantages of the present invention will become apparent to those skilled in the art from a reading of the following detailed description of embodiments constructed in accordance therewith, taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The inventions of the present application will now be described in more detail with reference to exemplary embodiments of the apparatus and method, given only by way of example, and with reference to the accompanying drawing(s), in which:

[0013] FIG. 1 illustrates the arterial and portal venous circulation of the liver with an exemplary infusion device; and

[0014] FIG. 2 illustrates an alternative infusion route.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS [0015] Referring to the drawing figures, like reference numerals designate identical or corresponding elements throughout the several figures.

[0016] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes reference to one or more of such solvents, and reference to "the dispersant" includes reference to one or more of such dispersants.

[0017] Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0018] For example, a range of 1 to 5 should be interpreted to include not only the explicitly recited limits of 1 and 5, but also to include individual values such as 2, 2.7, 3.6, 4.2, and sub-ranges such as 1-2.5, 1.8-3.2, 2.6-4.9, etc. This interpretation should apply regardless of the breadth of the range or the characteristic being described, and also applies to open-ended ranges reciting only one end point, such as "greater than 25," or "less than 10."

[0019] Fig. 1 is a schematic illustration showing the arterial and venous circulation of the liver including:

[0020] 11 Liver

[0021] 12 Hepatic Artery

[0022] 13 Portal Vein

[0023] 14 Hepatic Vein

[0024] 15 Vena Cava

[0025] 16 Aorta

[0026] In this exemplary method, a method of medical treatment for tumors involves placing a catheter 20 with its tip 22 in a feeding blood vessel, in this example the hepatic artery 12, and infusing or injecting one or more substance(s) at a concentration and rate that is directly toxic to tumor cells but tolerated by normal cells. Another example of a way to administer the treatment is by infusing in the portal vein 13. Yet another example of a way to administer the treatment is by infusing in both the hepatic artery 12 and the portal vein 13, which can be performed simultaneously, serially, alternatingly, and at the same or different infusion rates and/or duty cycles. Importantly, the administration does not cause an

"embolization", i.e., it does not result in thrombosis or occlusion of the feeding blood vessel being infused. Thus, the infusion is not clinically toxic to non-cancerous liver cells in that it doesn't result in organ failure or death of the patient.

[0027] The methods described herein include prolonged calibrated infusion of noxious or toxic fluid solutions into the liver or other organ, containing elements that do not exert a medication-type effect on a target enzyme or molecule, such as interfering with cellular metabolic processes through interference with intracellular biochemical reactions, nor do they exert their oncolytic effect by ischemia, but rather that are directly toxic by mechanisms such as rupturing cell membranes, binding and disabling cellular structures critical to cell viability, or denaturing cellular proteins. As used herein, in addition to the foregoing, the term "medication" means that the solute in the solution, if any, is not known to exert therapeutic effects to treat any disease by interfering or altering any biochemical or molecular process at the in the body. The administration is calibrated to result in death of tumor cells but not normal cells and also to result in death of tumor cells by mechanisms other than ischemia, and without thrombosis or occlusion of the artery being used for administration of the noxious substances.

[0028] Without being restricted to a particular theory, it is believed that the methods described herein kill tumor cells by "direct toxicity", essentially burning or freezing them with temperature, or with an acidic or basic substance, or 'drowning' them (over- hydration which swells and bursts the cells), or binding and interfering with organelles or intra-cellular components whose function is critical to cell viability, or increasing their metabolic demands beyond their ability, and similar mechanisms for other substances described herein.

[0029] The therapy described herein would be most amenable to use in the liver, although tumors in other organs, such as the lung or brain, can also be similarly treated. The liver has dual blood supply, being perfused by the hepatic artery and by the portal vein. Although ¾ of the normal liver's blood supply is via the portal vein, liver tumors, either primary or metastatic, have a strong preference for blood flow from the hepatic artery, and obtain the vast majority of their blood flow from the hepatic artery. By administering noxious substances in liquid form, for example, into the hepatic artery at the properly calibrated rate and concentration, it is possible to achieve a toxic effect in liver tumor cells while only a sub- lethal amount is delivered to nontumorous liver cells. Alternatively, noxious fluids could be administered into the portal vein to achieve oncolysis. These treatments are dependent on achieving controlled and calibrated rates of infusion that are tuned to toxicity to the tumor and organ, and create a "toxic penumbra" or "toxicity gradient" that favors death of tumor cells and preservation of normal cells. Furthermore, these therapies don't create and thus do not rely on blood vessel occlusion, and can therefore be repeated indefinitely. Similar therapy may be possible for other solid tumors in organs such as the prostate, brain, and the lung. Another way to achieve this treatment is to inject short-acting biodegradable particles of a size and shape that occlude the artery temporarily and leech out noxious substances as they degrade while degrading rapidly enough to preserve patency of the blood vessel.

[0030] With continued reference to the liver and tumors thereof as only an exemplary embodiment, the methods described herein include as one method titration of the infusion rate of a toxic solution so that the cumulative dose administered into the feeding blood vessel is not enough to cause toxicity resulting in organ failure or death in the person, because of dilution of the toxic solution in the vascular system of the entire body after the solution has passed out of the liver, and therefore the concentration of the toxic substance in circulating systemic blood is below the critical toxic threshold concentration. However, since the toxic substance is infused directly into the feeding blood vessel, the concentration in the liver is higher than in the systemic circulating blood.

[0031] One exemplary methodology is to start with a known toxic dose of a substance, for example, the "LD-50" dose (i.e., the dose of a substance that, if administered

systemically, kills 50% of the organisms). The LD-50 dose may be in the form of a blood concentration, or in the form of a total dose. If the LD-50 is in the form of a total dose, a calculation of the blood concentration in mg/dl would be done using the following formula:

(0.006012 x Height )+(14.6 x Weight)+604, using height in inches and weight in pounds (Gibon E, Courpied JP, Hamadoucne M. Total joint re-placement and blood loss: what is the best equation, Int Orthop. 201 Apr; 37(4): 735-739). Then, this concentration would be reduced by a known amount, e.g., cut in half, one-third, two-thirds, etc., in order to start the infusion with an adequate safety margin. In order to determine the infusion rate, a contrast study of the feeding blood vessel can be done and injection rates of contrast varied so that the entire vessel is opacified on the injection but there is little reflux of contrast upstream in the artery of the injection site. By way of example, the hepatic artery may for example be found to flow at a rate of 5 ml/sec, as estimated by that method at the time of treatment of a particular patient. The initial infusion starts at a reduced (e.g., half) concentration of the estimated LD-50 concentration, in this example at a rate of 2.5 ml/sec. This initial infusion is run at that rate until a very

conservative total dose had been administered, starting for example at 1/lOOth the total systemic LD-50 dose. Then, after the infusion is discontinued, the patient is observed for systemic and organ toxicity for up to two weeks. If none is observed, the patient returns for another treatment, this time increasing the total dose administered to a designated factor, e.g., double, triple, etc., of the prior dose (l/50th of the LD-50 cumulative systemic dose).

Alternatively, local effects within the organ, such as temperature, pH, or osmolarity changes could be monitored for example with a probe or other means inserted directly within the liver through the skin, or within a draining vein. If the given dose does not show significant change in the parameter by direct measurement, then the dose could be escalated at the same procedural sitting. These exemplary processes are repeated until: a) tumors are killed; or b) organ or systemic toxicity is observed. That would represent a treatment cycle. Treatment cycles could be repeated if tumors initially shrink but then subsequently begin to grow.

[0032] Another exemplary method would be infusion of a standard medical fluid, such as a normal saline solution or Ringer' s lactate solution, for example, that has been heated to a temperature where the cells are intolerant of prolonged infusion, but not hot enough to coagulate or occlude the hepatic artery. Such a fluid could be heated, for example, to 95° centigrade and infused at half of the calculated arterial flow rate, and the toxicity measured by measuring levels of organ enzymes and the temperature of the patient. Infusion of such liquids that have been cooled to near freezing, for example, could be used in a similar fashion. Other medical fluids, like iodinated contrast, or noxious fluids, could also be used after heating or cooling in this way.

[0033] The methods described herein are a type of loco-regional therapy. Local infusion via the hepatic artery of chemo-therapy drugs is well-known; however, chemotherapy drugs are designed for systemic administration, and usually exert their effect in killing tumor cells on interfering with cellular division or mitosis, rather than direct rupture of cell membranes, denaturing cell membranes, coagulative necrosis, or other directly toxic effects. [0034] Some examples of compounds that could be used in the methods described herein, alone or in combination with any other such compounds, including many with known LD- 50' s, are:

LDso LD ₅ o : g/kg

Animal, Referenc

Substance {LCso} {LCso : g L}

Route e standardized

aq.

{0.059 mg/L

invertebrates, {0.000059}

imm. }

Caffeine rat, oral 192 mg/kg 0.192 [37]

185-

Arsenic trisulfide rat, oral 0.185-6.4 [38]

6,400 mg/kg

Sodium nitrite rat, oral 180 mg/kg 0.18 [39]

Uranyl acetate dihydrate mouse, oral 136 mg/kg 0.136 [41]

Dichlorodiphenyltrichloroet

hane mouse, oral 135 mg/kg 0.135 [42]

(DDT)

Bisoprolol mouse, oral 100 mg/kg 0.1 [43]

Pentaborane human, oral <50 mg/kg <0.05 [49]

Chlorotoxin (CTX,

mice 4.3 mg/kg 0.0043 [62] from scorpions)

Cantharidin (from blister

human, oral 500 μ _§ ^ _§ 0.0005

beetles)

Aflatoxin

Bl (from Aspergillus rat, oral 480 μg/kg 0.00048 [65] flavus mold)

Amatoxin (from Amanita 300- rat 0.0007 [67] phalloides mushrooms) 700 μ _§ ^ _§

Tetrodotoxin (TTX,

mice, oral 334 0.000334 [68] from blue-ringed octopus)

Bufotoxin (from Bufo toads cat,

300 μ _§ ^ _§ 0.0003 [69] ) intravenous

Robustoxin (from Sydney

mice 150 μ _§ ^ _§ 0.00015 [70] funnel-web spider)

Venom of the Brazilian rat,

134 0.000134 [71] wandering spider subcutaneous

LDso LD ₅ o : g/kg

Animal, Referenc

Substance {LCso} {LCso : g L}

Route e standardized

Hypotonic saline solution

(<0.8% NaCl)

Diphtheria toxin i mice 10 ng/kg 0.00000001 [83]

Shiga

! mice 2 ng/kg 0.000000002 [84] toxin (from dysentery)

(see, e.g., en.wikipedia.org/wiki/Median_lethal_dose, the entirety of which is incorporated by reference herein)

For a subset of the foregoing, there are not published "lethal doses", because they are technically not poisons (sulfuric acid, phosphoric acid, carbonic acid, acetic acid, citric acid, sodium hydroxide, sodium bicarbonate, potassium hydroxide, calcium hydroxide, magnesium hydroxide, 3% saline solution, hypertonic saline solution, saline solution with osmolarity >300 mg/dl, distilled water, hypotonic saline solution. For these and similar substances, it is known that, in high enough amounts, which may be expressed as a volume or flow rate to which tissue is exposed, the substance can be toxic; for example, hyperhydration (i.e., "water intoxication" or "water poisoning") is well known to result from the consumption of too much water within a period of time, which results in an imbalance of electrolytes which in turn has noxious effects on cells. Similarly, substances which are not technically poisons are thus useful in the methods described herein by exposing tumor cells to sufficient quantities, including high enough flow rates, within a short enough time period for the tumor cells to die, but the flow of the chosen substance(s) is restricted to blood vessels that supply blood to the tumor(s) and is not a systemic infusion. Following the same methodology described elsewhere herein, the organ, or portion thereof which includes the tumor of interest, is infused with the substance (which is, again, technically not a poison) at a lower infusion rate and time than would be known to be toxic to cells, monitoring the patient over time, and infusing again at an increased rate until a) tumors are killed, or b) organ or systemic toxicity is observed.

[0035] Note that administration of noxious substances could be done other than by dissolving them and administering the resulting solution. For example, noxious substances could be incorporated into biodegradable or permanent microspheres and then injected into blood vessels supplying organs that contain tumors, configured in such a way that they either do not occlude the blood vessel or that they occlude it briefly so that its patency long-term is not compromised, said noxious substances leeching out into the blood or tissue at a dose that is tolerable to the person but not to the tumors.

[0036] Either therapy by infusion or injection of microspheres that leech noxious substances could be used not only to selectively kill tumors, but if done at high enough rates also to ablate or kill organs or segments of organs that contain tumors.

[0037] From among the foregoing, the following are preferred: ethanol, acetic acid, hydrochloric acid, sulfuric acid, sodium hydroxide, sodium bicarbonate, hypertonic saline, hypotonic saline, and distilled water (which is a type of hypotonic saline).

[0038] While the invention has been described in detail with reference to exemplary embodiments thereof, it will be apparent to one skilled in the art that various changes can be made, and equivalents employed, without departing from the scope of the invention. The foregoing description of the preferred embodiments of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. The embodiments were chosen and described in order to explain the principles of the invention and its practical application to enable one skilled in the art to utilize the invention in various embodiments as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended hereto, and their equivalents. The entirety of each of the aforementioned documents is incorporated by reference herein.

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