WO2009130518A1

WO2009130518A1 - Intraprostatic stent coil-bar-pin infusion /injection method

Info

Publication number: WO2009130518A1
Application number: PCT/GR2009/000027
Authority: WO
Inventors: Nikolao Dimofilos
Original assignee: Nikolao Dimofilos
Priority date: 2008-04-24
Filing date: 2009-04-23
Publication date: 2009-10-29
Also published as: GR1006552B

Abstract

With the patented Cypher, {Cordis company} (same item - new application), along with innovative additions (NEW) of potential constructional mechanical forms / drugs, etc., whether new or newly-conceived parameters (e.g. SHIGA toxin (Stx) / StxA toxin etc.}, the whole system will be used depending on the case at hand, in order to inhibit the development of hyperplastic tissues (smooth tissues in general), whether benign or cancerous; this is possible since rapamycin can act exactly on the site of interest in the same manner as in the case of lymphocytes (lymph tissue). The coil stent will have known mechanical properties; enriched with the toxin, it will induce further immuno-stimulation. Also to be patented is the proposed imaging potential of rapamycin through targeted bonding and consequent imaging of the tumor potential-environment, pharmaceutical effect [drug vector] on lymph tissues in general as well as through the conceptual/methodological protection of all its uses whatever its form [single, bound, smear, etc.] in fields of urology [referenced as kidney, prostate, testis, associated lymphnodes, ureters...], as well as on lymph tissues (liquid - compact), administered in liquid form per os or directly onto the tumor, single or bound, as fully described in the text.

Description

DESCRIPTION

INTRAPROSTATIC STENT

COIL - BAR -PIN INFUSION / INJECTION METHOD

GOAL

Therapeutic approaches with overlapping RAPAMYCIN (SIROLIMUS) and VEBOCYTOTOXINE (a toxin-like agent) (SHIGA-LIKE TOXIN) in localized prostatic cancer, or with ruptured capsule and urethral expansion, and in benign urethral hyperplasias, as well as other proposed [below mentioned] solutions in purely urological fields or in different reported actions and proposals of registration.

METHOD

CONFIGURATION OF A COIL-LIKE TUBULAR FIXATION GRID (i.e. STENT) [URINATION PROCESS SECURED]. Among the threads of the coil, there are thicker threads coated with polymer material [widely marketed] at a 2/1 or 1/1 rate, indicatively; (verbal imaging of one of the forms that the "instrument" proposed for registration may have, apart from the one already existing and proposed for a new and innovative use). Suppose that the "coil" (stent), is composed by 10 threads. For example, the first or/and the second thread are of a diameter of 0,8 mm, while the third or/and the fourth are of 10 mm and so on and so forth, so that its final configuration is "stepped" / tapered. Of course, all the threads are coated with rapamycin/sirolimus or/and Shiga - toxin, according to the extension/depth of the tissue, as already demonstrated (cancerous: both agents / not cancerous: sirolimus only), aiming at inhibiting its growth or stimulating the local immunoreaction of the body, by soaking them with endotoxin also. Thus an explosive triggering of the apoptosis cascade (a known programmed cell death process] will be induced. [The result is "sure" as it appears from the paper of Nakagawa et al, in experimental setting of Acute Renal Failure]. The cascade then triggers the homing of the tumor necrosis factor a/b, iπterleukin 2 & 6- (TNFa / β,IL-2,IL-6), etc., which are immune-induced factors, while the lipopolysaccharide of toxin (LPS TOXIN) is already acting as a signalling/traction factor, thus creating a modulated/desired immuno- induction/immuno-reaction.

FURTHERMORE, the same tubular coil stent will be also covered by a coat of polymer, soaked (acting as a tank) in rapamycin [sirolimus] and then by a layer of a drug-free polymer, which acts as a barrier to the diffusion of the agent. The polymer allows for the gradual release of the agent, maintaining at low levels the cytokine kinase-dependant m TOR (mammalian target of rapamycin), thus preventing the transition from phase G1 (growth phase) to phase S (DNA REPLICATION PHASE).

The sirolimus is active only when it is bound to its binding protein [FKBP], which can be found only in the cells of the muscular fibres and the lymphocytes, thus providing a successful action on the target. It is also known that the STROMA [smooth muscle fibres] / ADENOMA RATIO is 5/1. Besides, that is the reason why the endotoxin-free stent (i.e. with sirolimus only) may (and will) be used for the treatment of prostatic benign hyperplasia also {as the 'Cypher¹ is}. With its supplementary coating, i.e. the toxin, it will be used in prostatic cancer, as well as in the other applications in a different standardized form, as already mentioned... ].

ALSO, tapered or pin-like bars may be implanted endoscopically as exactly/similarly to the bars of radioactive material composed by both layers of materials, i.e. sirolimus or vebocytotoxin (shlGA like TOXIN) with double induced results. FURTHERMORE, doses of sirolimus and Shiga endotoxin (sic), may be injected transurethral^,

[i.e. endoscopically], directly into the prostatic parenchyma with an interval of 2-3 weeks, with the same result (sirolimus first), which is something like replication of the method of alcohol infusion in liver cancer. The same may be used in benign hyperplasia also, i.e. periodical administration of sirolimus only.

Furthermore, the use of the above mentioned sirolimus-coated coil stent of a smaller diameter or diameters, according to the requirements, may be extended to cases of occlusion/marked stenosis-fibrosis of the ureterocystic junction (either with sirolimus only or along with the toxin also), due either to allogenic cancer (as it usually happens) or following radiotherapy of the uterus, the ovaries, etc., fibrosis-stenosis of the pelvico- ureteric junction, congenital ureteral stenosis or urethral catheter with a 1^st sirolimus surface coating (regardless the primary catheter material, e.g. latex, silicon, etc), a 2^nd layer of antibiotic of any known wide-range urological use, a 3^rd (potential) layer of dexamethasone, diluted into the layer of polymer alone or with the antibiotic, in any order/concept of use and layer order, e.g. 1+2+3/1+3+2, 2+1+3, etc., or with the use of a different storage-binding material, e.g. liposomes. Also, the use of any other various similar toxin-lipopolysaccharide, different from the above mentioned, is to be patented. The said use will be based conceptually/thematically/methodologically (as an entity of method and immunological action) on my above described method.

Also, sirolimus in liquid form (per os), bound on any chemotherapeutical agent (anthracyclines, taxanes, etc. and generally agents universally used for the treatment of diseases with the involvement of lymphocytes/lymph tissue in general), and labelled with a contrast medium (all those that are already known in the international imaging practice), will be administered as a treatment for diseases, such as leukaemia, lymphoma (all forms) and in all the related diseases because of its properties. I.e., it will be used 1) as a contrast medium and 2) as a special vector of therapeutic agents, that will be bound on its structure (heading for the therapeutic target, due to its inherent docking/binding property).

METHODS/CONCEPTUAL OUTLOOK

My proposal regards the manufacturing of a 'tubular stent' with a triple scope: 1. The urination will proceed unhindered, because there will be a patent mechanical canal in the prostate (in this case, the metallic constructional substrate may be thermodilatable, 2^nd The coating of this stent, soaked in rapamycin, will be able to be manufactured in many forms, always tubular, and in many diameters, according to the field of application in the whole urinary system. According to the disease to be treated, e.g. cancer, stenosis, hyperplasia, etc., rapamycin itself may inhibit the development of smooth muscular fibres in the body (see text) on the one hand or maybe bound with lymph tissue in general (see text), 3^rd The soaked stent coating also soaked in an E.Colli toxin- like -see text- will trigger immunoreaction mechanisms, useful in cancerous tumors (e.g. prostate etc.).

Besides the data regarding rapamycin and endotoxin and the (referred) modes of patenting presented in the text, we are placing under a new innovative use the already marketed Cypher stent by Cordis (used in a totally new field of medical application) that will be used as such, for the treatment of hyperplastic conditions (in the urinary system in general) or even in cancers, and the prevention of expansion of hyperplastic cancerous tumors, before the immediate intervention, with the new designs of our stents.

Claims

1. WE PROPOSE: lntraprostatic stent (coiled/tubular stent) (coated with 1 or 2 layers of soaked polymer / [other design = bars - pins // of other "use": Liquid- flowable, single rapamycin infusion or per os administration - labelled or not labelled or even injectable into the tumor as a suggestion of treatment method in cases of solid or not solid cancers of organs of general urological interest or lymphnodes / lymphomas / leukaemias, in general, regardless the primary or not primary localisation and aetiology [both in humans and animal model applications]. The method can be applied in concomitant or separate administration of standardized Rapamycin - [sirolimus] & Vebocytotoxin [ShlGA-Like Toxin {Stx/ StxA}] in prostate cancer [localized or with capsule rupture and expansion in the urethra], as well as in benign hyperplasia.

The transurethral [endoscopically administered] dosages of sirolimus, & shiga endotoxin, are to be injected directly into the prostatic parenchyma, with an interval of 2-3 weeks, with the same result [sirolimus first], which is similar to the procedure of alcohol infusion in cases of hepatic cancer... The same may be used in benign hyperplasia, i.e. periodic administration of sirolimus only. Use of sirolimus-coated stent of a smaller diameter(s) however [according to the requirements], in the treatment of occlusion or marked stenosis — fibrosis of the ureterocystic junction, [either with sirolimus only or with the toxin also, according to the condition and the cause], due to 'allergenic' cancer, [as it usually happens following radiotherapy, e.g. of the uterus, the ovaries, etc.], and also in fibrosis - stenosis of the pelvicoureteric junction and congenital ureteral stenosis. It may be also used in the form of clinical application of the coating of a ureteric [pigtail] catheter with sirolimus surface coating, regardless the primary material of the catheter, e.g. = silicon, latex, metal (e.g. thread], etc. The second layer of polymer: with antibiotic of any widely known urological use/practice. The [potential] third layer - a strategic choice of ours: Dexamethasone, diluted into the layer of polymer, alone or along with the antibiotic, in any order/concept of use and order of layer that will be decided, e.g.: 1+2+3 / 1+3+2,2+1+3, etc., or use of a different storage-binding material, e.g. liposomes. The fourth layer: Polymer, soaked in the toxin for the same reason of immuno-reaction.

2. WE PROPOSE: [It is worth pointing out] that any use of a different toxin - lipopolysaccharide than the above mentioned, that will be based conceptually/thematically/methodologically [as an entity of method and immunological reaction but also as a similar scientific analysis / argumentation], on the above presented method and which will use other agents in its thematic approach, should be considered as piracy.

3. WE PROPOSE: The use of Sirolimus in liquid form, per os, in the form of a complex bound on any chemotherapy agent [Anthracyclines, Taxanes, etc., and generally agents used worldwide for the treatment of diseases involving lymphocytes / lymph tissue / marrow, labelled with contrast medium {all agents that are already known in the international imaging practice but also all agents that are in experimental stage and due to be marketed, as well as all those that may be produced in the future}, be given as treatment for diseases such as leukaemia / lymphoma [all forms] and all the thematically related diseases (see specific binding capacity]. On the other hand, it appears already that it will also act as an auxiliary-imaging medium.

4. WE PROPOSE: A new use of the "CYPHER" stent under the self-same form produced by the JOHNSON & JOHNSON-affiliated company [CORDIS], for any urological use, in the narrow / wide sense of the term, aiming at delaying the growth of benign tissue in the urinary system fields [organs], and for the delay/blocking from further growth / expansion of malignant tissues or cancerous urinary or other organs. The scope of application in the other cancers regards or includes smooth muscle fibres (or concerns lymphocytes-lymph tissue [an other localisation of FKBP], using infusion of liquid rapamycin in the circulation labelled with the known methods and contrast media, in its bound form. Also, for the monitoring of the action or not of the applied therapeutic treatment with any form of rapamycin labelled with any radio-imaging medium [agent], as well as in its conventional form. Similarly, patenting of its use as a drug vector [i.e., of chemotherapy agents] for targeted penetrations in targets of mostly lymphocytic composition, e.g. follicular tumors, leukemic tumors, leukemic foci, lymphnodes, etc., [always, due to FKBP[U!], as well as of the use of the agent ShIGA Like Toxin [Stx-StxA]-"Vebocytotoxin", to achieve development of immunological response [immunostimulation] in the whole human body [meaning clearly the different respective organs].

5. WE PROPOSE: The use of the nail/bar/spike-like form, as well as the use of injection [LV. / SC /LP. (intraperitoneal) / LM], in any way, with use of an instrument [where the term 'instrument' implies the use of a mechanical means of any composition/material (e.g. catheter, puncture trocar, etc.), that will pertain to the presence of a liquid/solid/semifluid/colloid solution [with a pegylated or not form of rapamycin, as well as of the above mentioned agent ShIGA like toxin (Stx-StxA), in this order of coating or in any other order of coating with metals noble or not, heat-treated or not, heat-resistant or not, in any concept and order. Furthermore, we propose to patent all the approximate forms of coils / springs / sponges [of different size and coating layers] / bars / wire sponges [with different respective lengths of interlacing bands of enriched polymer] with a central core or not; all the hypoallergenic biodegradable materials [polymers, cellulosic or metallic - (of subsequent endoscopic -or not-retrieval) - etc.]; all 'tubular' engraved or not forms with holes of various sizes / shapes or not, with mixed materials [alloys], thermodilatable, that are universally known.

6. WE PROPOSE: The manufacturing [of stents] from complex threads/fine polymer bands soaked with rapamycin or/and STXtoxin, in the wire sponge-like form, of various dimensions and shapes, e.g. round, longitudinal, ellipsoidal, obtuse-angled, etc., and in any other potential anatomical prefabricated forms [according to the targeted anatomic organ position], that are to be placed intrarenally - intrapelvically or with a renoscope, or a flexible/semi-rigid ureteroscope, for local treatment-regression and increase of the immunoreaction of necrotic changes as well as of the narrowness or neoprocess at the ureteropelvical junction.

Due to the existing holes by design [perforated shape], it is not possible to prejudice the whole procedure of urine collection-drainage. At any moment with any instrument [ureteroscope, renoscope] we are able to re-intervene, either to remove or replace sponges, already known to be biodegradable. The layers of polymer enriched with, e.g. 2 successive layers of rapamycin and entotoxine, may compose the whole "sponge" or after X cm (e.g. 1 ,5 or 2, etc.), the thread continues only coated with single rapamycin or single endotoxin, in intervals [infinite practically intended manufacturing options...].