WO2022047545A1 - Nouvelles utilisations d'agents anti-infectieux et/ou d'agents emboliques dans des procédures minimalement invasives - Google Patents

Nouvelles utilisations d'agents anti-infectieux et/ou d'agents emboliques dans des procédures minimalement invasives Download PDF

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WO2022047545A1
WO2022047545A1 PCT/AU2021/051029 AU2021051029W WO2022047545A1 WO 2022047545 A1 WO2022047545 A1 WO 2022047545A1 AU 2021051029 W AU2021051029 W AU 2021051029W WO 2022047545 A1 WO2022047545 A1 WO 2022047545A1
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blood vessel
target
agent
bodily tissue
afferent
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PCT/AU2021/051029
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English (en)
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Steven Landers
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IP Cornerstone Pty Ltd
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    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
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    • A61M25/00—Catheters; Hollow probes
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    • A—HUMAN NECESSITIES
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    • A61B5/4538—Evaluating a particular part of the muscoloskeletal system or a particular medical condition

Definitions

  • the present invention relates generally to the treatment or prevention of osteoarthritis, and other conditions such as cancer in mammalian subjects.
  • Musculoskeletal conditions remain significant causes for long-term pain and disability in humans. Under the rubric of musculoskeletal conditions, osteoarthritis is a chronic and progressive joint disease typically affecting the hands, spine, hips, knees and ankles. It is the most common form of arthritis affecting well over 200 million individuals globally.
  • Osteoarthritis may arise from mechanical stress on joints, there being also an accompanied deficiency in the ability of joint tissues to repair damage.
  • the mechanical stress may arise from misalignment of bones, injury, forces placed on the joint by excessive body weight, a loss of strength in muscles supporting a joint, and impairment of peripheral nerves.
  • osteoarthritis include thickening of joint ligaments, wearing or detachment of menisci, formation of osteophytes about the joints, increase in subchondral bone volume and hypomineralization. Pain associated with osteoarthritis is thought to originate from the thickened synovium and subchondral bone lesions.
  • osteoarthritis There is no cure for osteoarthritis, with treatment options being chiefly directed to physical therapy to maintain joint mobility and flexibility as best as possible, and managing pain with oral analgesics and other pharmaceutical agents. It is a problem in the art that some pharmaceutical agents have low therapeutic indices, and therefore present issues of toxicity or side-effects when used at therapeutic levels.
  • destruction in the hostile environment of the gastrointestinal tract can be limiting.
  • first-pass degradation by the liver can limit therapeutic levels of the agent at a target site.
  • intra-articular administration of hyaluronic acid to supplement levels in the synovial fluid is helpful in regaining the natural lubricating effect of the fluid.
  • Administration of a therapeutic via the intra-articular route is painful, and can lead to infection of the joint.
  • the newly deposited hyaluronic acid eventually degrades and is not replaced by the body leading to a return of pain and dysfunction in the joint.
  • Intra-articular administration of a pharmacologically active agent may be ineffective where pain originates in intra-osseous or peri-articular tissues.
  • Arthroplasty is an option for severely degraded joints. This type of surgery is economically burdensome, and carries the risk of infection and the formation of blood clots. More over the artificial joint materials implanted in an arthroplasty can wear or loosen overtime and require later replacement.
  • the present invention provides a method of treating and/or preventing a musculoskeletal condition or cancer in a subject in need thereof, the method comprising the step of introducing an anti-infective agent and/or embolic agent into an afferent blood vessel of a target bodily tissue associated with a musculoskeletal condition or cancer or is liable to be associated with a musculoskeletal condition or cancer, and causing or allowing the anti-infective agent and/or embolic agent to pass via the afferent blood vessel to the target bodily tissue.
  • the method of claim 1 comprising the steps of: identifying a target afferent blood vessel supplying blood to a target bodily tissue, introducing an anti-infective agent and/or embolic agent into the target afferent blood vessel, and causing or allowing the anti-infective agent and/or embolic agent to pass via the target afferent blood vessel to the target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it supplies the target bodily tissue, and/or a tissue region proximal thereto from which a blood vessel may be recruited to supply the target bodily tissue.
  • the method comprises the step of assessing the image to determine whether or not the candidate afferent blood vessel supplies nontarget bodily tissue.
  • the candidate afferent blood vessel is not considered or is less likely to be considered a target afferent blood vessel if it does not supply the target bodily tissue.
  • the method comprises the step of assessing the image to decide whether or not the candidate afferent blood vessel preferentially supplies the target bodily tissue over a non-target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it preferentially supplies the target bodily tissue over a non-target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it preferentially supplies the target bodily tissue over a non-target bodily tissue by a multiple of at least about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the target afferent blood vessel supplies a network of abnormal neovessels or a normal collateral vessel which supply the target bodily tissue.
  • the method comprises assessing the image to decide whether or not blood vessels supplied by the candidate afferent blood vessel forms a network of abnormal neovessels which supplies the target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if blood vessels supplied by the candidate afferent blood vessel forms a network of abnormal neovessels which supplies the target bodily tissue.
  • the method comprises the step of occluding a non-target afferent blood vessel so as to prevent, inhibit or limit introduction of the anti- infective agent and/or embolic agent into the non-target afferent blood vessel.
  • the musculoskeletal condition is osteoarthritis.
  • the target bodily tissue is a component of a joint, or is functionally related to a joint.
  • the musculoskeletal condition target is at least partially causative of inflammation, pain or malfunction of the target bodily tissue, or is at least partially caused by inflammation or malfunction of the bodily tissue.
  • the target bodily tissue is a tissue having a neoplasm, or a tissue associated with a neoplasm.
  • the neoplasm is malignant.
  • the anti-infective agent lacks or substantially lacks any one or more of: vascularization activity, anti -angiogenic activity, vasodilator activity, vasoconstriction activity, embolization activity, blood vessel occlusion activity, thrombolytic activity, anti-neoplastic activity, anti-inflammatory activity, or immunomodulatory activity.
  • the anti-infective agent has one or more activities other than an anti-infective activity, however anti-infective activity is the primary activity.
  • the anti-infective agent is an antibiotic.
  • the method comprises the step of identifying an infectious agent that is pathological or is likely to the pathological for the musculoskeletal condition or cancer.
  • the method comprises the step of identifying an infectious agent that is causative or is likely to be causative of a sign or a symptom associated with the musculoskeletal condition or cancer.
  • the step of identification comprises the step of taking a biological sample from the subject. [040]. In one embodiment of the first aspect, the anti-infective agent is chosen according to the identified infectious agent.
  • the anti -infective agent and/or embolic agent is substantially solubilised in a solvent.
  • the anti-infective agent and/or embolic agent is present in the form of an aqueous solution.
  • the anti -infective agent and/or embolic agent is devoid or substantially devoid of a particle or other solid.
  • the present invention provides a composition comprising an anti-infective agent and/or embolic agent, the composition formulated or presented so as to facilitate administration into an afferent blood vessel of a target bodily tissue.
  • the administration is via an image-guided method whereby the anti-infective agent and/or embolic agent is introduced into an identified afferent target blood vessel by a minimally invasive method.
  • the composition is used in a method whereby the anti-infective agent and/or embolic agent is introduced into an identified afferent target blood vessel of a target bodily tissue.
  • the identified target afferent blood vessel is identified by an image guided method.
  • the anti-infective and/or embolic composition comprises an imaging agent.
  • the anti -infective composition is present in the form of a reservoir of anti-infective agent and/or embolic agent configured to be locatable in an afferent blood vessel supplying a target bodily tissue by a minimally invasive visually-guided method, and configured to release the anti-infective agent and/or embolic agent into blood passing through the afferent blood vessel over a time period so as to expose the target bodily tissue to the anti-infective agent and/or embolic agent over the time period.
  • the reservoir is a drug-eluting depot or functional equivalent thereof.
  • the present invention provides a method of treating and/or preventing an inflammation in a subject in need thereof, the method comprising the step of introducing an anti-infective agent and/or embolic agent into an afferent blood vessel of a target bodily tissue that is inflamed or is liable to become inflamed, and causing or allowing the anti-infective agent and/or embolic agent to pass via the afferent blood vessel to the target bodily tissue.
  • the method comprises the steps of: identifying a target afferent blood vessel supplying blood to a target bodily tissue, introducing an anti-infective agent and/or embolic agent into the target afferent blood vessel, and causing or allowing the anti-infective agent and/or embolic agent to pass via the target afferent blood vessel to the target bodily tissue.
  • the step of identifying a target afferent blood vessel supplying blood to an inflamed bodily tissue comprises the steps of: identifying a candidate afferent blood vessel, introducing an imaging agent into the candidate afferent blood vessel, causing or allowing the imaging agent to pass via the candidate afferent blood vessel into surrounding tissue, generating an image of afferent blood vessels and/or a tissue region by way of detecting the presence or absence of the imaging agent, and assessing the image to determine whether or not the candidate afferent blood vessel supplies the target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it supplies the target bodily tissue, and/or a tissue region proximal thereto from which a blood vessel may be recruited to supply the target bodily tissue.
  • the method comprises the step of assessing the image to determine whether or not the candidate afferent blood vessel supplies nontarget bodily tissue.
  • the candidate afferent blood vessel is not considered or is less likely to be considered a target afferent blood vessel if it does not supply the target bodily tissue.
  • the method comprises the step of assessing the image to decide whether or not the candidate afferent blood vessel preferentially supplies the target bodily tissue over a non-target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it preferentially supplies the target bodily tissue over a non-target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if it preferentially supplies the target bodily tissue over a non-target bodily tissue by a multiple of at least about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the target afferent blood vessel supplies a network of abnormal neovessels or a normal collateral vessel which supply the target bodily tissue.
  • the method comprises assessing the image to decide whether or not blood vessels supplied by the candidate afferent blood vessel forms a network of abnormal neovessels which supplies the target bodily tissue.
  • the candidate afferent blood vessel is considered or is more likely to be considered a target afferent blood vessel if blood vessels supplied by the candidate afferent blood vessel forms a network of abnormal neovessels which supplies the target bodily tissue.
  • the method comprises the step of occluding a non-target afferent blood vessel so as to prevent, inhibit or limit introduction of the anti- infective agent and/or embolic agent into the non-target afferent blood vessel.
  • the anti-infective agent and/or embolic agent lacks or substantially lacks any one or more of: vascularization activity, anti-angiogenic activity, vasodilator activity, vasoconstriction activity, embolization activity, blood vessel occlusion activity, thrombolytic activity, anti-neoplastic activity, anti-inflammatory activity, or immunomodulatory activity.
  • the anti -infective agent and/or embolic agent has one or more activities other than an anti-infective activity, however anti-infective activity is the primary activity.
  • the anti-infective agent and/or embolic agent is an antibiotic.
  • the method comprises the step of identifying an infectious agent that is pathological or is likely to the pathological for the inflammation.
  • the method comprises the step of identifying an infectious agent that is causative or is likely to be causative of a sign or a symptom associated with the musculoskeletal condition or cancer.
  • the step of identification comprises the step of taking a biological sample from the subject.
  • the anti-infective agent is chosen according to the identified infectious agent.
  • the anti -infective agent and/or embolic agent is substantially solubilised in a solvent.
  • the anti-infective agent and/or embolic agent is present in the form of an aqueous solution.
  • the anti -infective agent and/or embolic agent is devoid or substantially devoid of a particle or other solid.
  • FIG. 1 shows tabulated results from the trial described in Example 2.
  • FIG. 2 shows KOOS pain score results from the trial described in Example 2.
  • the present invention provides a method of treating and/or preventing a musculoskeletal condition or cancer in a subject in need thereof, the method comprising the step of introducing an anti-infective agent and/or embolic agent into an afferent blood vessel of a target bodily tissue associated with a muscoloskeletal condition or cancer or is liable to be associated with a muscoloskeletal condition or cancer, and causing or allowing the anti-infective agent and/or embolic agent to pass via the afferent blood vessel to the target bodily tissue.
  • infection is of clinical importance in the origin of inflammation and/or pain and/or associated dysfunction of musculoskeletal conditions such as osteoarthritis, tendinopathies and the like.
  • the local administration of an anti-infective agent and/or embolic agent into an afferent artery supplying infected tissue via interventional radiological means is useful in the prevention and/or treatment of a musculoskeletal condition or an associated sign or symptom.
  • treatment of infection by localized administration of an anti-infective agent and/or embolic agent via interventional radiological means is useful in the prevention or treatment of cancer or an associated sign or symptom.
  • the target bodily tissue may not be infected, or is not apparently infected, or has a very low level of infection and in which case the anti-infective agent and/or embolic agent nevertheless exerts an anti-inflammatory effect.
  • the sign or symptom associated with osteoarthritis or cancer may be any one or more of pain, discomfort, swelling, and function (including reduction of joint mobility).
  • the anti-infective agent and/or embolic agent directly or indirectly affects the pathological basis of the osteoarthritis or cancer and leads to a reversal (or at least a partial reversal) of the disease, or a halting (or at least a slowing) of disease progression.
  • the term “anti-infective agent and/or embolic agent” is intended to include any agent that is capable of killing or at least inhibiting an infectious agent. The agent may be efficacious against any one of more of a bacteria, a virus, a fungus, a unicellular parasite, a multicellular parasite, and a mycoplasma,
  • the present invention may be predicated at least in part on the recognition of the role of infectious agents in osteoarthritis and/or cancer, and furthermore the use of minimally invasive techniques to administer anti-infective agent and/or embolic agents in a targeted manner to tissues involved in the pathophysiology or symptomology of arthritis and/or cancer.
  • the invention may be predicated at least in part on the recognition of the role of anti-infectives in the treatment of osteoarthritis and/or cancer where there is no infection, or no apparent infection, or only very low level infection.
  • Interventional radiological methods allow for the highly targeted delivery of anti- infective agent and/or embolic agents at relatively high levels (and in some cases up to saturation or near saturation levels), without toxicities or other adverse effects that would normally be noted at such levels of the agent.
  • the present methods may allow for levels of anti-infective to be provided at a target tissue that are simply not physically possible by way or oral, parenteral, topical, intraarticular, intramuscular or subcutaneous administration of an agent.
  • the use of a visually-guided method such as fluoroscopy using a contrast medium
  • identify an afferent blood vessel that supplies a suspected inflamed tissue allows for the anti-infective agent and/or embolic agent to be delivered to a relatively small volume of tissue.
  • the anti-infective agent and/or embolic agent may be introduced via a catheter into the femoral artery.
  • the femoral artery supplies many tissues of the lower leg selective administration of the agent to the knee will not be achieved.
  • Injection of a contrast agent into the popliteal artery allows for visualisation of the descending genicular artery which specifically supplies blood to the knee.
  • the catheter may be further advanced (under fluoroscopic guidance) to branches and sub-branches of the genicular artery in order to provide for more highly targeted administration.
  • the catheter tip may be still further advanced into finer vessels to very precisely target an inflamed tissue. Indeed, even neovessels associated with an inflamed tissue may be identified and flooded with an anti-infective agent and/or embolic agent via the catheter. Without wishing to be limited by theory in any way, it is contemplated that exposure of infected tissues to high levels of anti-infective agent and/or embolic agent, even for only a short period of time, may significantly disrupt an established infection or to prevent escalation of an infection leading to a therapeutic effect. Without wishing to be limited by theory in any way, it is proposed that the inflammation in osteoarthritis is caused at least in part by the presence of an infective agent.
  • bacteria or their associated products can trigger or upregulate inflammatory pathways in osteoarthritic joint tissue.
  • the bacteria may therefore cause or contribute to disease pathology, or at least a sign or symptom of the disease.
  • the bacteria cause a negative effect not by way of any inflammatory pathway, but instead by damaging cells or tissue organization, or by disrupting normal cellular function.
  • an infection may trigger an immune response not only to the infectious agent, but which also attacks a host tissue.
  • the tissue under treatment may be exposed for no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 minutes, however in that time period sufficient anti-infective agent and/or embolic agent may contact any infectious agent present so as to inhibit or kill at least some of the infectious agents in or about the tissue.
  • the infection or an associated pathological response in osteoarthritis or cancer may be sufficiently attenuated so as to give a therapeutic benefit well after exposure to the agent.
  • the level of anti-infective agent and/or embolic agent is present about the target tissue at a multiple of the level normally achievable where the agent is administered orally or parenterally.
  • the multiple may be about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the absolute level will be dependent at least in part on the species of anti- infective agent and/or embolic agent used.
  • the level of anti-infective agent and/or embolic agent achievable at the target tissue may be considered by reference to a saturation level of the agent (i.e. the level where no further agent can be added to the extracellular compartment before the agent starts to leave solution).
  • the level of anti-infective agent and/or embolic agent achievable at the target tissue may be at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the saturation level for the agent concerned.
  • the concentration of the anti-infective agent and/or embolic agent solution is preferably relatively high, and possibly even at or close to saturation with respect to the solvent concerned.
  • the agent when introduced at the target site the agent is at a very high concentration and therefore potentially capable of flooding the site with the agent.
  • the anti-infective agent is the antibiotic amoxycillin
  • a saturated or even supersaturated solution may be prepared.
  • the molecule has a solubility of about 3.4 mg/ml in water at 25 degrees Celsius, and so concentration about this value, or 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% that value may be introduced in the relevant afferent blood vessel.
  • the anti-infective agent and/or embolic agent is introduced into the target afferent blood vessel in an extended release form, such as a depot form.
  • an extended release form such as a depot form.
  • This form may allow for the slow release of agent over a period of hours, days, weeks or months.
  • the concentration of agent about the target tissue may not be unusually high, however the ongoing exposure of the tissue to the agent may be sufficient so as to disrupt the pathological infection of the tissue.
  • Extended release may be achieved by the use of a gel or similar comprising the anti-infective agent and/or embolic agent within a matrix. Dissolution of the matrix over time at the target site may release agent in a controlled manner until exhausted.
  • a biodegradable stent which is coated with an anti-infective agent and/or embolic agent (possibly in the form a slow-release matrix) may be introduced into the afferent blood vessel.
  • compositions of the present invention may be art-accepted or formulated for use with the present methods.
  • an organ or tissue is targeted for treatment, with a flexible catheter being introduced into a large vessel of the body via a small incision.
  • a small incision in the groin, wrist, arm, ankle or neck may be used to introduce an angiographic catheter via an introducer sheath into a large diameter blood vessel of the body.
  • the catheter is manually urged through the introducer sheath into the large blood vessel, the catheter tip being advanced toward the target site.
  • the catheter is manually steerable to assist in directing the tip into a desired branch blood vessel.
  • An imaging medium (typically a contrast agent being a solution of a radio-opaque material) is introduced into the blood vessel so as to allow the radiologist to visualize downstream vasculature and guide the catheter tip progressively through a series of blood vessel branches to arrive at or near the target site.
  • fluoroscopy is used to present an image of the vasculature on a screen to the medical specialist [098].
  • the catheter tip will be guided by the radiologist according to known vascular landmarks as revealed by the contrast agent.
  • the operator may guide the vasculature tip not by any known landmark but instead by the presence of abnormal vessels (such as neovessels) or other anatomical feature as revealed by the contrast agent.
  • abnormal vessels such as neovessels
  • other anatomical feature as revealed by the contrast agent.
  • a target afferent blood vessel which supplies blood to a target tissue may be identified, such as a tissue of an osteoarthritic joint.
  • an anti- infective agent and/or embolic agent may be introduced into the identified target afferent blood vessel via a catheter and normal blood circulation used to carry the agent in the anterograde direction to the supplied inflamed tissue.
  • the target afferent blood vessel is known before commencement of the present method, in which case an image -guided method is implemented to guide the catheter to the known blood vessel.
  • the known vessel may be the genicular artery and the anti-infective is introduced via a catheter into that artery.
  • the catheter tip will be guided to a branch, sub-branch, sub-sub branch or further finer branch of the known artery to identify a blood vessel that more specifically supplies the target tissue.
  • particularly high concentrations of anti-infective agent and/or embolic agent may be delivered to the target tissue whilst sparing non-target tissue from exposure to the agent.
  • a candidate afferent blood vessel is identified as a potential vessel that supplies the target bodily tissue.
  • the candidate vessel may be identified by reference to a known vascular landmark.
  • the princips pollicis artery supplies the thumb and accordingly that artery may be selected as a candidate artery for delivery of an anti-infective agent and/or embolic agent to a joint of the thumb.
  • a more highly targeted treatment may be given where the catheter is advanced to a branch or sub-branch of the princips pollicis artery.
  • the catheter tip may be advanced to a branch or a sub-branch as a candidate vessel (or even finer vessel), with contrast medium being introduced at that point in the vasculature.
  • the contrast medium enters the target tissue and/or shows neovessels then the vessel into which that contrast medium was introduced is considered to be the target vessel.
  • a candidate vessel that is shown to supply (and preferably specifically supply) a target tissue is in accordance with the present methods considered a target afferent blood vessel.
  • more than one candidate afferent blood vessel may exist for any given target tissue.
  • more than one target afferent blood vessel may exist for any given target tissue.
  • the some clinical judgement may be required to select a vessel that is most helpful (or least harmful) in the general aim of targeting delivery of an anti-infective agent and/or embolic agent to an inflamed tissue.
  • the method will be most efficacious where most, substantially all, or all the afferent blood vessels that supply blood to the target tissue are used to introduce anti- infective agent and/or embolic agent. In this way, little or none of the target tissue is spared from exposure to the agent thereby ensuring maximal diminution of the infected state of the tissue.
  • the target afferent blood vessel may be selected so as to limit exposure of a nontarget bodily tissue.
  • target vessel may be a part of the microvasculature that supplies the target tissue, or may be a vessel that selectively supplies the microvasculature that supplies the target tissue.
  • it may be necessary to implement microangiography to introduce contrast medium and anti- infective agent and/or embolic agent into vessels of diameter 200 pm and under.
  • the skilled person has familiarity with microangiographic techniques and having the benefit of the present specification is enabled practice the present methods in smaller diameter blood vessels.
  • the target afferent blood vessel is identified by determining that the vessel supplies, or is part of, pathological neovasculature.
  • Abnormal neovessels may appear as a tumor blush-type enhancement in the arterial phase of a digital subtraction angiogram.
  • a medical practitioner having a specialty in imaging (such as an interventional radiologist) will generally be capable of visually determining the presence of a neovessel, and having the benefit of the present specification may introduce anti-infective agent and/or embolic agent into the neovessels according to the present methods.
  • the afferent blood vessel may be a collateral blood vessel that is normally present or may have formed to shunt blood around a blockage so as to supply the target bodily tissue.
  • any determination, judgement or decision executed in a method may be made by a human (typically an interventional radiologist).
  • the determination, judgement or decision may be made non-human means such as algorithmic means or by artificial intelligence means.
  • the non-human means may comprise software -based image analysis means whereby an electronic image of blood vessels highlighted by a contrast agent is analyzed to determine a particular image pattern.
  • the image analysis means may comprise software configured to identify a network of neovessels.
  • Neovessels may be treated by means of embolization or ablation are used to prevent the flow of blood therethrough. Some embodiments of the present methods require patency of neovessels which are exploited to deliver the anti-infective agent and/or embolic agent to the target tissue.
  • the determination may be made according to the radiologist’s knowledge of the condition to be treated, the anatomy of the general target site and the tissues which are likely to be inflamed and require treatment.
  • the presence of neovessels having an abnormal radiological appearance may allow the radiologist to make a reasonable assumption as to the usefulness of those neovessels to deliver an anti-infective agent and/or embolic agent.
  • the radiologist may combine two or more of aspects of anatomical knowledge, knowledge of the pathophysiology of the relevant condition, the image of the vasculature provided by the present method, the kinetics of flow of contrast agent through the vasculature, images of other bodily structures of the subject available to the radiologist, and the like. In any event, the radiologist may conclude only a likelihood of a candidate vessel being a useful target vessel.
  • the anti-infective agent and/or embolic agent used in the present method may be any agent presently known to have anti-infective activity, or any agent that is synthesized or isolated or becomes known to have anti-infective activity.
  • the agent may be an element, an ion, a compound, a polymer or a more complex species.
  • the agent is not necessarily homogenous, with a heterogeneous mixture of two or more species being considered to be an anti-infective agent and/or embolic agent in the context of the present invention.
  • the anti -infective agent and/or embolic agent may be selected in light of a known or suspected infectious agent present in or about the target tissue.
  • a sample of the tissue or an associated tissue fluid such as extracelluar fluid, blood, lymph, bile, synovial fluid, and cerebrospinal fluid
  • a proxy for an infectious agent such as a metabolite, enzyme, degradation product, DNA, RNA and a biochemical marker.
  • the organism may be subject to a sensitivity assay to identify an agent having a useful level of efficacy against the isolated organism.
  • an antibiotic sensitivity assay may be used where a suspected causal bacterium is isolated from a clinical sample.
  • the anti-infective agent may be selected without any testing of a clinical sample, and instead on the basis of clinical or scientific judgement given the factual circumstances of the subject. For example, a body of knowledge may accumulate over time suggesting that a certain microorganism or a marker of a certain microorganism is abnormally present in the synovial fluid of many osteoarthritis patients. The antibiotic sensitivity of that microorganism may be known allowing the clinician to select an appropriate antibiotic for localized delivery to the target issue.
  • the anti-infective agent is an antibiotic agent or a combination of antibiotic agents.
  • the antibiotic may be a beta-lactam (including aminopenicillins, antipseudomonal penicillins, beta-lactamase inhibitors, natural penicillins, and the penicillinase resistant penicillins; common types being amoxixillin +/- clavulante, ampicillin; representative commercial forms including AmoxilTM, AugmentinTM, UnasynTM); a tetracycline (including demeclocycline, doxycycline, eravacycline, minocycline, omadacycline, tetracycline, representative commercial forms including DeclomycinTM, AdoxaTM, DoryxTM, Doxy 100TM, OraceaTM XeravaTM, DynamycinTM, MinocinTM, SolodynTM, NuzyraTM, PanmycinTM, SumycinTM); a cephalosporin (including cefotaxime, ceftaidime, cefuroxime; representative commercial forms being ClaforanTM, AvycazTM, FortazTM, Ta
  • the antibiotic is a carbapenem, or an imipenem, or a cilastin. In other embodiments of the method, the antibiotic is not a carbapenem, or is not an imipenem, or is not a cilastin.
  • the present invention may allow for the use of an anti -infective agent that is otherwise contraindicated by reason of low bioavailability or toxicity.
  • the present methods involve targeted and localized delivery of drug to a tissue in need thereof and accordingly such issues may be lessened or even obviated.
  • the anti-infective agent and/or embolic agent is delivered in combination with an anti-inflammatory agent, such as a non-steroidal anti- infective drug (NSAID).
  • NSAID non-steroidal anti- infective drug
  • This class of drug include members known to inhibit the enzymes COX-1 and/or COX-2 to attenuate prostaglandin production in a bodily tissue.
  • NSAIDs include aspirin, celecoxib (CelebrexTM), diclofenac (VoltarenTM), diflunisal (DolobidTM), etodolac (LodineTM), ibuprofen (AdvilTM), indomethacin (IndocinTM), ketoprofen (OridisTM), ketorolac (ToradolTM), nabumetone (RelafenTM), naproxen (NaprosynTM), oxaprozin (DayproTM), piroicam (FeldeneTM), salsalate (AmgesicTM), sulindac (ClinorilTM) and tolmetin (TolectinTM).
  • the anti-inflammatory agent may be a corticosteroid.
  • This class of drug includes the glucocorticoids such as hydrocortisone (CortefTM), cortisone, ethamethasoneb (CelestoneTM), prednisone (IntensolTM), prednisolone (OrapredTM), triamcinolone (AristospanTM) Methylprednisolone (MedrolTM), and dexamethasone (IntensolTM).
  • the corticosteroid may be a mineralocorticoid such as Fludrocortisone (FlorinefTM).
  • the anti-inflammatory agent may be an antileukotriene, a class of drugs which typically function as leukotriene -related enzyme inhibitors (arachidonate 5 -lipoxygenase) or leukotriene receptor antagonists (cysteinyl leukotriene receptors) thereby disrupting the function of these inflammatory mediators.
  • exemplary forms of this class of drug include zileuton and meclofenamate sodium.
  • the anti-inflammatory agent may be a disease modifying agent, as distinct from an agent that merely targets inflammatory pathways.
  • a disease modifying drug may act to indirectly act to reduce or prevent inflammation be altering the course of the disease underlying the inflammation.
  • the anti-inflammatory agent may be a biologic, such as a TNF- a inhibitor.
  • TNF- a inhibitors block tumor necrosis factor, a cytokine involved in inflammation.
  • Exemplary TNF-a inhibitors include: adalimumab (HumiraTM), certolizumab (CimziaTM), etanercept (EnbrelTM), golimumab (SimponiTM), and infliximab (RemicadeTM). These drugs may increase the risk of fungal infections and tuberculosis when administered systemically by infusion. However, targeted delivery to the biologic to a site of inflammation as provided by the present methods may lessen the occurrence or severity of adverse events.
  • interleukin inhibitors include interleukin inhibitors, including inhibitors of IE-1, IE-6, IL-12, and IL-13 activity.
  • Drugs in this class include anakinra (KineretTM), tocilizumab (ActemraTM), canakinumab (HarisTM), secukinumab (CosentyxTM) and ustekinumab (StelaraTM).
  • Patients receiving interleukin inhibitors may suffer bowel perforation when systemically infused. The present method may avoid the need to flood the systemic circulation with agent causing gastrointestinal problems.
  • a useful biologic may be a peptide or polypeptide such as calcitonin, being a 32- amino acid polypeptide hormone of thyroid origin.
  • An exemplary calcitonin product is salmon calcitonin produced by recombinant DNA technology (MiacalcinTM), which is typically (in the prior art) administered parenterally.
  • MoacalcinTM recombinant DNA technology
  • cartilage and subchondral bone act as a functional unit, in both the normal and pathological state. Vascular pathology and the loss of mineral density in subchondral bone have been found to be important in the initiation and progression of osteoarthritis.
  • Calcitonin acts to conserve or increase bone density, or improve fracture healing, and may therefore provide advantage in arthritis treatment and/or prevention.
  • a biologic used as an anti-inflammatory agent according to the present methods may function preventing excessive pro-inflammatory cytokine production, signaling, and downstream nuclear factor KB (NF-KB) activation.
  • NF-KB nuclear factor KB
  • siRNAs small interfering RNA molecules
  • other biological inhibitors are considered promising treatments.
  • the biologic may be a mesenchymal stem cell.
  • the subject treated by the present invention is generally a mammal, preferably a human being, male or female, in whom treatment of infection is required in a discrete area of the body.
  • the anti-infective agent and/or embolic agent is typically administered in a therapeutically effective amount, meaning an amount of the agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, physician or other clinician.
  • treatment means alleviating, inhibiting, slowing or arresting the development, reversing and/or relieving a condition related to infection including any disease, disorder, state, syndrome, symptom or aesthetic condition to which such term is associated. It is not intended that these terms are used to indicate a complete cure of any condition.
  • prevent means preventing of the development of, or alleviating to some extent, a condition related to infection including any disease, disorder, state, syndrome, symptom or aesthetic condition to which such term is associated. It is not intended that these terms are used to indicate a complete prevention of any condition.
  • compositions described in this section may use any of the compositions described in this section below, and in that regard the contents of this section is imported into the description herein relating to methods.
  • the composition derives novelty in the context of the methods described herein, and in other embodiments the composition per se is novel.
  • composition is intended to encompass a product comprising an anti-infective (optionally in a specified amount), or any product which results, directly or indirectly, from combination of an anti -infective agent and/or embolic agent with any other active or inert chemical species or solvent.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising active agent(s), optionally inert ingredient(s), as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the agents/ingredients, or from dissociation of one or more of the agents/ingredients, or from other types of reactions or interactions of one or more of the agents/ingredients.
  • compositions of the present invention encompass any composition made by admixing an anti-infective agent and/or embolic agent and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other agents/ingredients of the formulation and not deleterious to the subject recipient thereof.
  • the anti-infective may be administered in active form, or alternatively in non-active form as a pro-drug and converted to active form after administration.
  • an enzyme of the target tissue may convert a pro-drug to a drug.
  • the pro-drug is considered an anti-infective agent and/or embolic agent in the context of the present invention.
  • the composition comprises a combination of anti-infective agent and/or embolic agent and a contrast agent.
  • a combination composition facilitates the concomitant introduction of therapeutic agent whilst allowing visualization of the vessels supplying the inflamed tissue.
  • the composition may be formulated so as to allow for the co-solution of the anti-infective agent and/or embolic agent and the contrast agent concerned.
  • the skilled person is entirely familiar with various contrast agents useful in fluorography (such as iodinated agents) or MRI (such as magnetically active agents) and given the benefit of the present specification is enabled to produce useful combinations.
  • the concentration of anti-infective agent and/or embolic agent in the present compositions may be higher compared with compositions used for parenteral administration or oral administration.
  • the present invention allows for more highly targeted administration of agent to target tissue.
  • a saturated or even supersaturated solution may be prepared from administration to a target tissue according to the present methods.
  • the agent may have a certain solubility value in water (or other solvent) at 25 degrees Celsius, and so the composition may be prepared by adding a saturating or supersaturating amount of the anti-infective agent and/or embolic agent to a set volume of the desired solvent.
  • a lower concentration is required in which case an amount of about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the saturating or supersaturating amount is added to the set volume.
  • the absolute amount of agent added to the set volume will of course vary depending on the agent itself, given the differences in solubility between agents and the difference in the ability of different solvents to solubilise a given agent.
  • compositions of the present invention contain at least one pharmaceutically acceptable anti-infective agent and/or embolic agent and, where appropriate, one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include, for example, physiologically harmless buffers (such as bicarbonate, phosphate, citrate), stabilizers (such as DTPA, sodium edetate, calcium disodium edetate), electrolytes (such as sodium chloride), antioxidants (such as ascorbic acid) or a substance to achieve a desired osmolality (such as mannitol, or glucose).
  • heparin may be added to inhibit blood clotting during or after performance of the method.
  • the compositions are of aqueous base.
  • solubilizers such as ethanol, dimethyl sulfoxide, propylene glycol, TweenTM 80, or TritonTM X-100 may be required in some cases.
  • compositions may be configured as a depot and may be in the form of a gel or present in some type of matrix causing the slow release of the agent to the target tissue.
  • the depot may be of low viscosity when passing through the catheter but then solidify or partially solidify once deposited.
  • a depot may be formed by the use of drug eluting beads, stents, coated stents, dissolving stents, cages or balloons.
  • Such compositions may use polyethylene glycol as a slow-release excipient.
  • the present methods may include the step of embolizing the vessels used to introduce the anti-infective agent and/or embolic agent.
  • the embolization may occur at the same time as the introduction, for example by the composition having an embolic agent (such as an embosphere) or an embolic solvent (such as an alcohol).
  • the depot may be deposited into a vessel by the present methods, and the vessel subsequently embolized.
  • the embolization may be temporary so as to allow for the introduction of further anti-infective agent and/or embolic agent at a later date, or may be permanent.
  • a further advantage of the highly targeted administration of anti-infective agent and/or embolic agent is that lower amounts of agent may be used to achieve a desired clinical endpoint. While many antibiotics are considered inexpensive drugs, more exotic agents such as biologies are very expensive and therefore used sparingly in a clinical environment. For example recombinant antibiotic peptides such as defensins may be capable of achieving useful control of infection however the high cost associated with systemic administration may be economically prohibitive.
  • a further advantage is that the anti -infective agent and/or embolic agent may be introduced to vessels that supply intra-osseous and periarticular tissues. This provides an advantage over intra-articular delivery whereby such tissues may not be exposed to an anti- infective agent and/or embolic agent.
  • a bonus effect of the present invention may be the treatment of conditions other than osteoarthritis or cancer according to the present methods.
  • Localized pathological infection may be involved in other conditions of the mammalian body, and may therefore be more effectively treatable by the present methods.
  • cancers include cancer of the breast, colon, rectum, gallbladder, pancreas, lung, oesophagus and stomach, as well as melanoma and sarcoma.
  • the cancer may be a primary cancer or a metastatic cancer.
  • infection may play a role in the establishment, progression, or aggressiveness of a malignancy.
  • the infection may have a direct role in the cancer.
  • some antibiotics can have a direct effect on cancer cells.
  • the antibiotic doxycycline may negatively affect mitochondria of human cells, and therefore preferentially slow or arrest multiplication of cancer cells.
  • tumor microenvironment plays an important role in carcinogenesis.
  • An inflammatory component may be present and contributes to tumor proliferation, angiogenesis, metastasis and resistance to hormonal and chemotherapy.
  • Pro-inflammatory factors such as cytokines may be useful targets in that regard, particularly cytokines produced in the course of tumor metastasis.
  • An inflammatory environment comprising immune cells and their secreted cytokines, chemokines and growth factors cis contemplated to contribute significantly to the invasive and metastatic traits of cancer cells.
  • metastasis is a major cause of cancer mortality and accordingly inhibiting that process by disrupting inflammatory pathways using an anti-infective agent and/or embolic agent introduced in a highly targeted manner according to the present methods may lower mortality or otherwise extend lifespan.
  • the present methods may be used slow tumor progress and/or metastasis by flooding neoplastic cells with high levels of anti-infective agent and/or embolic agent. Again, high levels of anti-infective agent and/or embolic agent may be provided without concern for toxicity on other tissues of the body. Furthermore, the levels may be significantly higher than those achievable by another route of administration.
  • the anti-infective agent and/or embolic agent may be provided in a combination composition with an antineoplastic agent, or an anti-angiogenesis agent, or an embolic agent.
  • additional agents may also be administered in a highly targeted manner according to the present methods. Synergistic effects between the actives may result to further improve the treatment of a solid tumor.
  • a further aspect of the present invention is predicated at least in part on the proposal that inflammation of any aetiology in a discrete region of the mammalian body may be treated or prevented by delivering an anti-infective agent and/or embolic agent in a targeted manner to the inflamed region.
  • the present invention provides a method of treating and/or preventing an inflammation in a subject in need thereof, the method comprising the step of introducing an anti-infective agent and/or embolic agent into an afferent blood vessel of a target bodily tissue that is inflamed or is liable to become inflamed, and causing or allowing the anti-infective agent and/or embolic agent to pass via the afferent blood vessel to the target bodily tissue.
  • EXAMPLE 1 Transcatheter arterial delivery of anti-infective agent to subject having moderate osteoarthritis of the knee.
  • the subject for treatment has moderate knee pain, as determined by a visual analog scale (VAS).
  • VAS visual analog scale
  • the subject’s pain is not improved by conservative treatment such as oral pain medications, physiotherapy or intra-articular injection of hyaluronic acid.
  • radiography the patient is assessed as having osteoarthritis of less than grade 3 by Kellgren-Lawrence grading. The subject does not have an infective arthritis.
  • the subject is assessed by a physician, physiotherapist or other health professional. Assessment includes knee examination to determine range of motion and pain tenderness of the knee joint. Assessment further includes scoring by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaire which considers pain, stiffness, and physical function in the context of normal daily activities.
  • WOMAC Western Ontario and McMaster University Osteoarthritis Index
  • a sample of synovial fluid is taken, and assessed for the presence of a bacterium.
  • a bacterium is cultured from the fluid, and the species identified.
  • An antibiotic is selected so as to inhibit the replication of the bacterial species.
  • Transcatheter arterial delivery is performed under local anaesthesia.
  • a 3F introducer sheath was used to obtain percutaneous arterial access.
  • the subject’s femoral artery is accessed by puncturing in an ipsilateral anterograde fashion, and 2,000 IU heparin administered via the IV route.
  • a 3F angiographic catheter is passed through the introducer and advanced toward the popliteal artery.
  • the descending genicular artery, superior and inferior lateral genicular arteries, superior and inferior medial genicular arteries, and the median genicular artery are visualized.
  • Abnormal neovessels are visually identified, and accessed by way of a 2.4F microcatheter inserted coaxially via the 3F catheter and selectively located in the identified abnormal neovessels.
  • the selected antibiotic is introduced into the abnormal neovessels via the 2.4F microcatheter.
  • the antibiotic is amoxicillin sodium, presented in a form for injection prepared 250 mg in 5 mL water for injection.
  • a contrast agent is mixed with the amoxicillin composition.
  • an anti-infective agent may cause embolization, or may be mixed with an embolization agent in which case the contrast agent may assist in monitoring embolization.
  • the anti -infective agent and/or embolic agent is coadministered with other biologically active agents such as a vasodilator, vasoconstrictor, embolic agent, immune modulator, or an analgesic.
  • Success of the treatment is determined by subsequent assessment by VAS (for pain) and WOMAC scoring (for pain stiffness and physical function).
  • EXAMPLE 2 Experimental trial of transcatheter arterial delivery of embolization composition to subjects having osteoarthritis of the knee demonstrating better efficacy using complete embolization.
  • the treatment group received angiography and embolization; the control group received a placebo embolization procedure.
  • One interventional radiologist trained in vascular embolization performed all procedures. The procedures, real or placebo, were performed within a 30-60 min duration.
  • embolic agents may be used, including liquid agents (such as glue, onyx, alcohol, ALGEL), particle-type agents (such as polyvinyl alcohol, and embospheres), and other agents useful in the occlusion of small vessels.
  • liquid agents such as glue, onyx, alcohol, ALGEL
  • particle-type agents such as polyvinyl alcohol, and embospheres
  • Participants in the control group received light sedation with midazolam and fentanyl and a local anaesthetic injection and incision into their groin.
  • the radiologist simulated the insertion of a guide wire and catheter into the femoral artery and completion of the embolization procedure. No wire or catheter was in fact introduced. No radiation was used. No contrast was administered.
  • the participant viewed pre-recorded video images of an angiogram and genicular artery vascular embolization. A dressing was applied to the incision site.
  • the results in FIG. 1 relate to participants that underwent complete intervention (i.e. complete occlusion of blood flow to the target tissue area).
  • positive differences (95% CI) are noted, indicating an improvement in the parameter concerned. Improvements were noted in all five parameters at 12 months post treatment. Particularly large improvements were seen for physical function and quality of life. Less favourable results overall were noted for the other two categories of treatment (i.e. single vessel intervention, or incomplete intervention (multi-vessel)).
  • EXAMPLE 3 Transcatheter arterial delivery of anti -infective agent to subject having a solid malignant tumour.
  • a cancerous tissue requiring exposure to an anti-infective agent may be accessed via central venous access device such as a port-a-catheter, Hickman catheter, pheresis catheter or a peripherally inserted central catheter (PICC) line.
  • central venous access device such as a port-a-catheter, Hickman catheter, pheresis catheter or a peripherally inserted central catheter (PICC) line.
  • PICC peripherally inserted central catheter
  • an artery of the neck may be used for arterial access.
  • an artery of the arm may be used to access a cancerous tissue in the arm or hand, and an artery of the leg may be used to access a cancerous tissue in the arm or hand.
  • the antibiotic is amoxicillin sodium, presented in a form for injection prepared 250 mg in 5 mL water for injection.
  • a contrast agent is mixed with the amoxicillin composition.
  • an anti-infective agent may cause embolization, or may be mixed with an embolization agent in which case the contrast agent may assist in monitoring embolization.
  • a chemotherapeutic agent may be mixed with the amoxicillin composition.
  • the two-dimensional anatomical information provided by fluoroscopy is insufficient or at least ambiguous. This may not allow the physician to properly resolve a target tissue, and the connection between any candidate blood vessel and a target tissue.
  • an interventional magnetic resonance system also termed XMR system
  • XMR systems allow for real-time interventional procedures to be performed in a clinical setting providing the ability to fully visualize the target tissue in three-dimensions and fully monitor any nontarget distribution.
  • Some XMR systems can also perform fluoroscopy. Accordingly catheter placement may be guided by fluoroscopy, and then the system switched to magnetic resonance mode to gain a more complete understanding of the target anatomy and the connection between various target tissues and afferent blood vessels in the region.
  • the anti-infective agent and/or embolic agent is associated with a visualization agent so as to be radiopaque (to be detectable by fluoroscopy) or magnetically active (to be detectable by MRI).
  • a visualization agent so as to be radiopaque (to be detectable by fluoroscopy) or magnetically active (to be detectable by MRI).
  • the present invention is described by reference to osteoarthritis as an exemplary musculoskeletal disorder.
  • musculoskeletal disorders that may amenable to treatment or prevention by the present methods or treatable by the present compositions include rheumatoid arthritis, infection of the joint capsule (such as in adhesive capsulitis), tendonitis, tendinopathies, enthesopathies and the like.

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Abstract

La présente invention concerne de manière générale le traitement ou la prévention de l'arthrose et d'autres maladies telles que le cancer chez des sujets mammifères. Dans des modes de réalisation de l'invention, non exclusivement, des procédés font appel à des techniques de radiologie interventionnelle pour administrer des composés thérapeutiques tels que des agents anti-infectieux et/ou des agents emboliques de manière hautement ciblée. Dans un mode de réalisation, l'invention est mise en œuvre dans un procédé de traitement et/ou de prévention d'une pathologie musculo-squelettique ou d'un cancer chez un sujet en ayant besoin, le procédé comprenant l'étape consistant à introduire un agent anti-infectieux et/ou un agent embolique dans un vaisseau sanguin afférent d'un tissu corporel cible associé à une pathologie muscolosquelettique ou un cancer ou qui est susceptible d'être associé à une pathologie muscolosquelettique ou un cancer, et provoquer ou permettre le passage de l'agent anti-infectieux et/ou de l'agent embolique par le vaisseau sanguin afférent au tissu corporel cible.
PCT/AU2021/051029 2020-09-04 2021-09-03 Nouvelles utilisations d'agents anti-infectieux et/ou d'agents emboliques dans des procédures minimalement invasives WO2022047545A1 (fr)

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