TR2022015947A2 - PARTICLE STRUCTURE THAT CLEARS HEAVY METAL CHELATION IN BODY FLUIDS OR ORGANS - Google Patents
PARTICLE STRUCTURE THAT CLEARS HEAVY METAL CHELATION IN BODY FLUIDS OR ORGANSInfo
- Publication number
- TR2022015947A2 TR2022015947A2 TR2022/015947 TR2022015947A2 TR 2022015947 A2 TR2022015947 A2 TR 2022015947A2 TR 2022/015947 TR2022/015947 TR 2022/015947 TR 2022015947 A2 TR2022015947 A2 TR 2022015947A2
- Authority
- TR
- Turkey
- Prior art keywords
- particle structure
- chelator
- acid
- blood
- heavy metal
- Prior art date
Links
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Abstract
Buluş, vücut kan veya diğer sıvılarından ağır metal şelasyonunu böbrek ve diğer organları redistribüsyona ve şelatörlerin yan etkilerine maruz bırakmadan temizleyen parçacık yapılanması (A) ile ilgilidir. (Şekil - 1)The invention relates to the particle structure (A) that clears heavy metal chelation from body blood or other fluids without exposing the kidneys and other organs to redistribution and side effects of chelators. (Figure 1)
Description
TARIFNAME VÜCUT SIVILARI VEYA ORGAN LARDAKI AGIR METAL SELASYONUNU TEMIZLEYEN PARÇACIK YAPILANMASI Teknik Alan Bulus, vücut kan veya diger sivilarindan agir metal selasyonunu böbrek ve diger organlara redistribüsyona ve selatörlerin yan etkilerine maruz birakmadan temizleyen parçacik yapilanmasi ile ilgilidir. Bulusun Altyapisi Son yillarda hidrojeolojik kökenli (örn. arsenik, kursun, kadmiyum, civa ve bakir) agir metallere maruz kalma insanlarda sagliga zararli etkileri nedeni ile küresel bir halk sagligi endisesi dogurmaktadir. Dünya Saglik Örgütü ve Uluslararasi Kanser Arastirmalari Ajansi, arsenik ve kadmiyum metallerini grup l insan kanserojeni olarak tanimlamaktadir. Arsenik, dünyanin ikinci önde gelen su kaynakli ölüm nedenidir. Arsenik gibi metaloidler siklikla agir metallerle benzerlikleri nedeniyle agir metaller kategorisine girerler. Arsenik, kadmiyum ve diger toksik metaller mesane, böbrek, karaciger ve cilt kanseri ile iliskili bulunmustur. Bu toksik metallerin daha düsük seviyelerinde bile yaygin olumsuz etkiler görülebilmektedir. Toksik metallerin kardiyovasküler hastaliklar, infertilite, nörolojik hastaliklar ile iliskisine dair bir çok kanit vardir. Vücuda çevreden giren metal iyonlari, proteinler ve polisakkaritler de dahil olmak üzere vücut dokularindaki birçok moleküle baglanabilir. Ayrica, bu metallerin çogu biyolojik olarak aktiftir ve çesitli farkli fizyolojik ve patofizyolojik reaksiyonlara katilir. Toksik metallerin etkileri miktara, beslenme durumuna, yasa ve cinsiyete de baglidir. Metale maruz kalma miktari ve yolu, doku dagilimi, elde edilen konsantrasyon ve atilim hizi da toksisitenin belirleyicileri arasindadir. Toksisite mekanizmalari, enzim aktivitesinin ve proteinin inhibisyonunu, nükleik asit sentez ve fonksiyonunda degisiklikler ve hücre zari geçirgenliginde degisikleri de içerir. Vücuttaki tüm organlar ve organik sistemler agir metallerden etkilenebilir. Özellikle gelismekte olan genç organizmalardaki metal birikimleri geri dönüsü olmayan hasarlar birakabilmektedir. Yüksek agir metal seviyesine sahip kisiler "selatörler" adi verilen ilaçlarla tedavi edilir. Bu ilaçlar kan dolasimindaki metallere baglanir; bu metal-selatör bilesigi daha sonra idrarda elimine edilir. Selasyon tedavisinin temel amaci; toksik metal kompleksini biyolojik ligandlarla toksik olmayan yeni bir komplekse dönüstürüp organizmadan atilabilir hale getirmektir. Selatörler degerli ilaçlar olsa da, özellikle kursun, civa, arsenik ve demir nedeniyle agir metal toksisitesi içeren birkaç tibbi durumla kullanimlarini sinirlayan yan etkileri Tibbi terapötikler baglaminda selasyon, organik selatör moleküllerinin kana verildigi ve hedef metal iyonlarini yüksek afinite ile bagladiklari bir islemdir. Selatör ve metal iyon kompleksi, böbrek tarafindan filtrelenene veya karaciger tarafindan atilana kadar kan içerisinde kalir, böylece metal iyonlari vücuttan uzaklastirilir. Ilk olarak 1930'larda Almanya'da sentezlenen sentetik bir selatlama maddesi olan edetat disodyum, metal iyonlarini tutmak ve sarmak için alti adede kadar baglanma bölgesine sahiptir. Koroner kalp hastaliklarinda metal selasyon tedavileri tartismali sonuçlar dogurmasina ragmen daha önce denenmistir ve halen gündemden düsmemistir. Insanlarda kullanilan selatlayici ilaçlarin çogunun farmakokinetik verileri, klinik kullanimlari ve yan etkileri her selatlayici ilaç için farklidir. Dünya çapinda uygulamasi olan bazi selatlayici ilaçlar sunlardir: dimerkaprol (BAL), succimer (mezo-DMSA), Monoisoamyl DMSA (MiADMSA), Monomethyl DMSA (MmDMSA), Monocyclohexyl DMSA (MchDMSA), unithiol (DMPS), D-penisilamin (DPA), N-asetil-Dpenisilamin (NAPA), Nitrilotriacetic Acid (NTA), kalsiyum disodyum etilendiamintetraasetat (CaNa2EDTA), kalsiyum trisodyum veya çinko trisodyum dietilentriaminpentaasetat (CaNa3DTPA, ZnNa3DTPA), deferoksamin (DFO), deferipron (L1), trietilentetraamin (trientin), N-asetilsistein (NAC) ve Prusya mavisi (PB). Birkaç yeni sentetik homologlar ve deneysel selatlama maddeleri, metal baglamalari için in vivo olarak tasarlanmis ve test edilmistir. Söz konusu selatörlerin metallerin doku ve serum dagilimi üzerindeki etkisi düzenli bir model olarak henüz gösterilememistir. Kemik ve yumusak dokularda tutulan toksik elementler tamamen immobilize degildir. Kandan selatörler ile agir metal çekildiginde hassas organlara kan araciligi ile redistribüsyon gösterebilirler ve sekonder toksik etkiye neden olurlar. Selatörlerin dokulardan agir metalleri toplamasi sonrasi karaciger, böbrek, beyin ve kalbe redistribüsyon gözlenmesi ciddi bir sorun olusturmakta ve selasyon tedavisinin faydali etkilerini ortadan kaldirmaktadir. Hidrofilik selatörler hücre disi metal havuzlari ile sinirli kalip renal atilimi arttirirken; lipofilik selatörler hücre içi depolara erisebilir ve bunlari azaltabilir ancak toksik metalleri hassas bölümlere yeniden dagitabilir. Selatlama ajanlari ile plazmadaki agir metaller birkaç saat veya gün içinde oldukça hizli bir sekilde atilir. Toksik agir metaller ise farkli zaman dilimleri içerisinde vücudun çesitli bölümlerinde kompartmentalize olurlar ve selatlama ajanlari için esit derecede erisilebilir degildir. Genellikle bir selatlama maddesi en kolay sekilde harekete geçecek metalleri tipik olarak plazma, böbrek, karaciger ve daha sonra daha az ölçüde kemik ve merkezi sinir sistemi seklinde uzaklastirir. Kandaki temizlik sonrasi redistribüsyon sirasinda da kanda agir metali emip tamponlayacak uzun süreli selatörlerin bulunmasi çok önemlidir fakat mevcut selatörler bunu saglayamamaktadir. Bu durum çok hayati bir etkinlik-güvenlik paradoksu yaratmaktadir. Böbreklerin filtrelenebilir ancak yeniden emilebilir bir metal veya selata sürekli maruz kalmasi nefrotoksisiteye neden olmaktadir. Benzer sekilde, enterohepatik dolasim bir metal, ligand veya selata devam eden gastrointestinal maruziyete neden olup organ toksisitesi olusturabilmektedir. Radyoaktif elementler çevrede dogal olarak bulunabilmesine ragmen, zararli radyonüklidlerin çogu askeri, endüstriyel veya tibbi süreçlerden salinan antropojenik kökenlidir. Nükleer reaktör kazalari, çalisanlarin maruz kalmasina neden olabilir. Çernobil ve Fukushima kazalarindan sonraki raporlar, 137Cs ve 131l radyoizotoplarinin hava dagilimi ve serpintisindeki büyük miktarda zararli kirletici maddeyi olusturdugunu ortaya koydu. Gelecekte içme suyunu kirletebilecek terör saldirilari daha büyük popülasyonlarin radyonüklid maruziyetine neden olabilir. Tibbi ve endüstride kullanilan radyoaktif kaynaklara kaza ile maruz kalmada önemli bir intoksikasyon nedenidir. Radyonüklidlerin alimi sonrasi acil tedavinin birincil amaci, kontamine bireylerin radyasyon dozunu en aza indirmektir. Uranyum; endüstriyel ögütme, madencilik ve rafine uranyum ile kirlenmis toprak, maden veya atiklarin çevresel olarak iyilestirilmesi ve nükleer yakit üretimi ve islenmesi yoluyla önemli maruziyet meydana getirebilir. Dogal ortamda uranyum maruziyeti en yaygin olarak kontamine yiyecek veya içme suyundan agiz yoluyla gerçeklesir. Talyum ve sezyum zehirlenmesinin tedavisinde kullanilabilen Prusya mavisi, 2003 yilinda FDA tarafindan onaylanmistir. 2004 yilinda FDA, plütonyum, amerikyum veya küriyum dahil olmak üzere çesitli radyoaktif nüklidlerin eliminasyonunu artirmak için kalsiyum DTPA ve çinko DTPA'yi onaylamistir. Halihazirda kullanilan selatlama ajanlarinin böbrek yetmezligi, aritmiler, tetani, hipotansiyon, kemik iligi depresyonu, trombositopeni, lökositopeni, uzamis kanama zamani, konvülsiyonlar, solunum durmasi, kalsiyum, çinko, bakir, manganez miktarinda düsmeler gibi ciddi yan etkileri vardir. Gebelikte, aktif böbrek hastaliklarinda, anüride ve hepatitte bu ajanlar genelde kontrendikedir. Bu nedenle toksisitesi düsük ve selasyon için daha etkili selatlar gelistirmeye acil ihtiyaç vardir. Literatürde CN107141468 numarali Çin patent basvurusunda konu ile ilgili olarak sirkülasyonlu demir selatör, iyi biyouyumluluklu polietilen glikol monometil eter ve pH'a duyarli bir kimyasal bag araciligiyla deferoksamin baglanarak olusturulur. Bulus ayrica uzun sirkülasyonlu demir selatlayicinin bir hazirlama yöntemini açiklar ve hazirlama yöntemi, polietilen glikol monometil eterin bir esterlestirme reaksiyonu yoluyla karboksibenzaldehit ile baglanmasi ve hazirlamak için bir ara ürünün bir schiff bazi araciligiyla deferoksamin ile reaksiyona girmesinin saglanmasi adimlarini içerir. pH tepki özelligine sahip uzun sirkülasyonlu demir selatörü deferoksamin ile karsilastirildiginda, açiklanan demir selatör, uzun etki ve lezyon lokasyonunun asit mikro-ortamina tepki özelliklerine sahiptir ve asiri demir yüklenmesi ile ilgili hastaliklarin tedavisinde potansiyel bir uygulama degerine sahiptir." ifadelerine yer verilmektedir. Bahsedilen basvuruda pH tepki özelligine sahip uzun sirkülasyonlu demir selatör ifsa edilmektedir. Yine literatürde CN107281498 numarali Çin patent belgesinde ise konu ile ilgili olarak "Bulus, bir polietilen glikol ile modifiye edilmis demir iyonik selatlayiciyi ve bunun bir hazirlama yöntemini açiklar. Demir iyonik selatör, iyi biyouyumluluk ve deferoksamin ile polietilen glikol türevlerinden hazirlanir. Hazirlama yöntemi, karboksilatli polietilen glikol monometil eterin veya formillenmis polietilen glikol monometil eterin deferoksamin ile kovalent baglanmasiyla polietilen glikol modifiye demir iyonik selatlayicinin hazirlanmasi adimini içerir. Deferoksamin ile karsilastirildiginda, demir iyonik selatör, uzun etki ve düsük toksisite avantajlarina sahiptir ve asiri demir yüklenmesi ile ilgili hastaliklarin tedavisinde potansiyel uygulama degerine sahiptir." ifadelerine yer verilmektedir. Bahsedilen uygulamada ise Polietilen glikol modifiye demir iyonik selatör yapilanmasi açiklanmaktadir. Yine literatürde RU2696981 numarali Rus patent belgesinde ise konu ile ilgili olarak yolunda kompleman sistemi aktivasyonu ile lizise karsi insan eritrosit duyarliliginin belirlenmesiyle ilgilidir. Insan eritrositleri için lizise duyarlilik, kompleman sistemi, fibrin ile baglantili yüksek trombin aktivitesine sahip sitrat plazma kullanilarak bir trombin yolunda aktive edildiginde degerlendirilir. Bilinen üç yoldan (klasik, alternatif veya lektin) biri ile kompleman aktivasyonunu engellemek için, Ca ve Mg'yi baglamak için bir selatör olarak sodyum sitrat kullanilir. Fibrin ile iliskili yüksek trombin aktivitesinin varliginda, CS bileseni aktive olur ve insan eritrositlerinin lizizi ile belirlenen bir zar-saldiri kompleksi olusur. HE liziz derecesi, %100 lizizin su ilavesiyle insan eritrositlerinin tam lizisi ve spontan liziz için eritrosit kontrolünün - %0 lizis oldugu bir kalibrasyon egrisinden belirlenir. Paralel, standart HE kan grubu teknigi ile belirlenir. Parçalanmaya en duyarli insan eritrositleri A kan grubuna sahip insan eritrositleri, ikinci sirada AB kan grubuna sahip HE, üçüncü sirada HE ise B kan grubuna sahip insan eritrositleridir. En stabil olani 0 kan grubuna sahip insan eritrositleridir. ETKI: bu test, kompleman sisteminin trombin yolu ile kompleman aktivasyonu ile reperfüzyon sendromunun ciddiyetinin kisilestirilmis tahmini için ve ayrica verilen patolojik durumlarda tedavi yaklasimi seçimi için kullanilabilir." Bahsedilen patentte ise trombin yolu üzerindeki tamamlayici sistem aktivasyonu ile insan eritrositinin lizse hassasiyetinin belirlenmesi yöntemi ifsa edilmektedir. Yukarida bahsedilen sebeplerden dolayi vücut sivilari veya organlardaki agir metal selasyonunu böbrek ve diger organlari redistribüsyona ve selatörlerin yan etkilerine maruz birakmadan temizleyen parçacik yapilanmasina ihtiyaci duyulmustur. Bulusun Amaci Teknigin bu konumundan yola çikilarak bulusun amaci, mevcut dezavantajlari ortadan kaldiran, vücut sivilari veya organlardaki agir metal selasyonunu böbrek ve diger organlari redistribüsyona ve selatörlerin yan etkilerine maruz birakmadan temizleyen parçacik yapilanmasi ortaya koymaktir. Bulusun bir diger amaci, çesitli agir metal zehirlenmesi vakalarinin önüne geçerek agir metal selasyonu için önerilen ajanlara sinirlama ve toksisite problemini ortadan bir yapi ortaya koymaktir. Bulusun bir diger amaci, toksik metali kandan ve yumusak dokulardan hemen uzaklastirabilecek hizli, etkili bir yapi ortaya koymaktir. Bulusun bir diger amaci, sayisiz yan etki, spesifik olmayan baglanma ve uygulama zorlugu gibi dezavantajlari ortadan kaldiran bir yapi ortaya koymaktir. Bulusun bir diger amaci, oral veya intravenöz olarak verilen selatörler ile böbrek araciligi ile vücuttan kontrolsüz atilan kalsiyum, magnezyum, manganez, çinko gibi iyonlarin sebep oldugu sorunlari ortadan kaldiran bir yapi ortaya koymaktir. Bulusun bir diger amaci, dekorporasyon (vücut tarafindan emilen radyoaktif maddenin terapötik olarak uzaklastirilmasi) basarili olsa bile atilim sirasinda böbreklerin yüksek radyasona maruz kalma riskini ortadan kaldiran bir yapi ortaya koymaktir. Bulusun bir diger amaci, vücut sivisini disariya alip süperparamagnetik parçaciklar ve onlara bagli selatörler ile temizligi disarida yaptiktan sonra siviyi vücuda geri verdigi için yeni nesil selatörlerin daha rahat ve güvenli kullanimina izin veren bir yapi ortaya koymaktir. Sekillerin Açiklanmasi Sekil - 1 Bulusa konu olan agir metal temizleyen parçacik yapilanmasinin temsili görünümü Referans Numaralari A- Parçacik Yapilanmasi 1. Süper Paramanyetik Demir Oksit Çekirdek 2. Biyouyumlu Kaplama 3. Selatör Kaplama Katmani Bulusun Detayli Açiklamasi Bu detayli açiklamada, bulus konusu yenilik sadece konunun daha iyi anlasilmasina yönelik hiçbir sinirlayici etki olusturmayacak örneklerle açiklanmaktadir. Bulus, vücut kan veya diger sivilarindan agir metal selasyonunu böbrek ve diger organlari redistribüsyona ve selatörlerin yan etkilerine maruz birakmadan temizleyen parçacik yapilanmasi (A) olup özelligi; bahsedilen parçacik yapilanmasinin (A) kan veya vücut sivisi içine verilerek veya kan veya vücut sivisinin kateter ile disari alinip parçacik yapilanmasi (A) ile karistirilmasi sonrasi, kan ve vücut sivilarindaki agir metalin üzerinde barindirdigi selatöre baglanmasini saglayan selatör kaplama katmani (3) içermesiyle karakterize edilmesidir. Sekil - 1'de bulusa konu olan agir metal temizleyen parçacik yapilanmasinin (A) temsili görünümü resmedilmektedir. Bulusa konu olan parçacik yapilanmasi (A); bahsedilen parçacik yapilanmasinin (A) kan veya vücut sivisi içine verilerek veya kan veya vücut sivisinin kateter ile disari alinip parçacik yapilanmasi (A) ile karistirilmasi sonrasi, kan ve vücut sivilarindaki agir metalin üzerinde barindirdigi selatöre baglanmasini saglayan selatör kaplama katmani (3), bahsedilen parçacik yapilanmasinin (A) agir metal baglanmasi sonrasi kalici veya elektromanyetik miknatislarla kandan veya vücut sivisindan daha kolay çekilmesini beraberinde de agir metalin izole edilmesini saglayan süper paramanyetik demir oksit çekirdek (1), bahsedilen süper paramanyetik demir oksit çekirdegi (1) dolasimdan izole ederek üzerine selatör kaplama katmani (3) olarak konumlandirilmis selatörün üzerine baglanmasini saglayan biyouyumlu kaplama (2) ana parçalarindan meydana gelmektedir. Bahsedilen parçacik yapilanmasi (A), vücut kan veya diger sivilarindan agir metal selasyonunu böbrek ve diger organlari redistribüsyona ve selatörlerin yan etkilerine maruz birakmadan temizlemektedir. Bahsi geçen parçacik yapilanmasi (A) merkezinde süper paramanyetik demir oksit çekirdegi (1), üzerinde biyouyumlu kaplama (2) ve hücre içine girebilen Iipofilik selatör kaplama katmani (3) (Monomethyl DMSA, Monocyclohexyl DMSA vb.) veya hücre içine giremeyip plazmada kalan lipofobik selatör kaplama katmani (3) (CaNa2EDTA, Meso 2,3-Dimercaptosuccinic Acid (DMSA) vb) içermektedir. Ayrica asagida isimleri sunulmus olan selatörler tekli veya farkli kombinasyonlarda farkli metalleri tek parçacikla baglamak için kullanilabilmektedirler. - DMSA (2,3-bis(suIfanyl)butanedioic acid; Dimercaptosuccinic acid; Succimer; Dimercaptosuccinic acid; Suximer; Tin Salt; Succicaptal; Chemet) - DMPS (Sodium 2,3-bis(sulfanyl)propane-1-sulfonate; Sodium Dimercaptopropane sulfonate; Unithiol; Dimaval; Unitiol) - EDTA (Etilen Diamin Tetra Asetik asit; 2-[2-[bis(carboxymethyl)amino]ethyl- (carboxymethyl)amino] acetic acid; Ethylene diamine tetra acetic acid; Edetic acid; Edathamil; Endrate; Versene acid; Sequestrol; TitripleX; Havidote; Cheelox; Versene; Calcium Disodium Versenate) - CaNa2EDTA (Kalsiyum Disodyum Etilendiamin Tetraasetik Asit) - BAL (2,3-bis(sulfanyl)propan-1-ol (Dimercaprol; British Anti-Lewisite; 2,3- Dimercaptopropanol; Sulfactin; Dicaptol; Dimersol; Antoxol; Panobal; Dithioglycerine; Dithioglycerol) - DFO (Deferoksamin) - Deferipron (L1) - DMSA Analoglari: Monoizoamil DMSA (MiADMSA), Monometil DMSA (MmDMSA), Monosikloheksil DMSA (MchDMSA - DPA (28-2-amino-3-methyl-3-sulfanyl butanoic acid; 3-Sulfanyl-D-valine; Penicillamine; D-Penicillamine; Cuprimine; Depen; Penicillamine; Mercaptyl; Artamine; Cuprenil; Perdolat; Trolovol - Monoisoamyl DMSA (MiADMSA) - N-(alpha-L-Arabinofuranos-1-yl)-L-cysteine - Kliokinol gibi "metal protein zayiflatici bilesikler" (MPAC'Ier) - Trientine, Sistem ile kullanilabilen selatör kaplamalar yukarida sayilanlarla sinirli olmayip olusturulan platform üzerinde farkli selatörlerin de kullanilmasina müsaade etmektedir. Bulusun uygulanmasinda vücut sivilari kateter ile disari alinip parçacik yapilanmasi (A) ile karistirilarak sividaki agir metaller selatör kaplama katmani (3) vasitasiyla parçacik yapilanmasina (A) baglanmasi saglanmaktadir. Bahsedilen parçacik yapilanmasi (A) ve bagli agir metaller vücut disinda güçlü miknatislar ile parçacik yapilanmasi (A) içerisinde tutularak temizlenmis vücut sivisi hastaya geri verilmektedir. Disarida agir metal izolasyonu yapilarak temizlenmis vücut sivisi agir metal, selatör veya parçacik yapilanmasi (A) olmadan vücuda geri verilmekte bu sayede selatörler toksisitesi ortadan kalkmaktadir. Bahsedilen parçacik yapilanmasi (A), hidrofobik veya hidrofilik özellikli olarak kateter ile kan veya diger sivilara verilip vücut sivisi disari alinarak agir metal izolasyonu da yapilabilmektedir. Bahsedilen parçacik yapilanmasi (A), temel olarak süper paramanyetik demir oksit çekirdegi (1) sayesinde paramagnetik etkiyi kullanarak agir metal bagli parçacik yapilanmasi (A) üzerindeki selatör kaplama katmani (3) ve selatör kaplama katmani (3) üzerindeki selatörlere bagli agir metalleri permanant veya elektromiknatislar ile çekerek ayristirmaktadir. Kan veya agir metal izolasyonu yapilacak vücut sivisi vücut disina alinip parçacik yapilanmasi (A) ile karistirilarak içerisinde agir metallerin parçacik yapilanmasina (A) baglanmasi ve permanant veya elektromiknatis sistemi olan süper paramanyetik demir oksit çekirdegi (1) ile parçacik yapilanmasi (A) ve bagli agir metallerin ayristirilarak temiz kan veya vücut sivisi hastaya geri verilmesi prensibine dayanmaktadir. Bahsi geçen parçacik yapilanmasi (A), farkli cihaz ve uygulama kombinasyonlarinda kullanilabilmektedir. Parçacik yapilanmasi (A) damar yolu ile hastaya doku ve organlardan agir metal temizligi için verilmekte, vücut içerisinde bir süre kaldiktan sonra da hastanin kani vücut disina alinmaktadir. Disariya alinan kana antikoagülan eklenmekte (heparin, bivaluridin vb.) ve kan içerisindeki parçacik yapilanmasi (A) ve ona bagli agir metaller güçlü miknatislarla çekilerek geri alinmakta, kanin diger kismi ise agir metallerden temizlenmis olarak vücuda geri verilmektedir. Hastanin ihtiyacina göre esansiyel elementler de geri verilen kana verilebilmektedir. TR TR TR DESCRIPTION PARTICLE STRUCTURE THAT CLEARS HEAVY METAL SELETION IN BODY FLUIDS OR ORGANS Technical Field The invention is related to the particle structure that clears heavy metal chelation from body blood or other fluids without exposing the kidneys and other organs to redistribution and side effects of chelators. Background of the Invention In recent years, exposure to heavy metals of hydrogeological origin (e.g. arsenic, lead, cadmium, mercury and copper) has caused a global public health concern due to their harmful effects on human health. The World Health Organization and the International Agency for Research on Cancer define arsenic and cadmium metals as group 1 human carcinogens. Arsenic is the world's second leading cause of waterborne death. Metalloids such as arsenic often fall into the heavy metals category due to their similarities with heavy metals. Arsenic, cadmium and other toxic metals have been associated with bladder, kidney, liver and skin cancer. Even at lower levels of these toxic metals, widespread adverse effects can occur. There is a lot of evidence regarding the relationship of toxic metals with cardiovascular diseases, infertility and neurological diseases. Metal ions entering the body from the environment can bind to many molecules in body tissues, including proteins and polysaccharides. Moreover, most of these metals are biologically active and participate in a variety of different physiological and pathophysiological reactions. The effects of toxic metals also depend on the amount, nutritional status, age and gender. The amount and route of exposure to the metal, tissue distribution, achieved concentration and excretion rate are also among the determinants of toxicity. Toxicity mechanisms also include inhibition of enzyme activity and protein, changes in nucleic acid synthesis and function, and changes in cell membrane permeability. All organs and organic systems in the body can be affected by heavy metals. Metal accumulations, especially in young developing organisms, can cause irreversible damage. People with high heavy metal levels are treated with medications called "chelators." These drugs bind to metals in the bloodstream; This metal-chelator compound is then eliminated in the urine. The main purpose of chelation therapy is; It transforms the toxic metal complex into a new non-toxic complex with biological ligands and makes it excretable from the organism. Although chelators are valuable drugs, their side effects limit their use to several medical conditions, especially those involving heavy metal toxicity due to lead, mercury, arsenic, and iron. In the context of medical therapeutics, chelation is a process in which organic chelator molecules are delivered into the blood and bind target metal ions with high affinity. The chelator and metal ion complex remain in the blood until filtered by the kidney or excreted by the liver, thus removing the metal ions from the body. Edetate disodium, a synthetic chelating agent first synthesized in Germany in the 1930s, has up to six binding sites to retain and entrap metal ions. Although metal chelation treatments in coronary heart diseases have controversial results, they have been tried before and are still on the agenda. The pharmacokinetic data, clinical uses and side effects of most chelating drugs used in humans are different for each chelating drug. Some chelating drugs with worldwide application are: dimercaprol (BAL), succimer (meso-DMSA), Monoisoamyl DMSA (MiADMSA), Monomethyl DMSA (MmDMSA), Monocyclohexyl DMSA (MchDMSA), unithiol (DMPS), D-penicillamine (DPA). , N-acetyl-Dpenicillamine (NAPA), Nitrilotriacetic Acid (NTA), calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa3DTPA, ZnNa3DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC) and Prussian blue (PB). Several novel synthetic homologues and experimental chelating agents have been designed and tested in vivo for metal binding. The effect of these chelators on the tissue and serum distribution of metals has not yet been demonstrated as a regular pattern. Toxic elements retained in bone and soft tissues are not completely immobilized. When heavy metals are withdrawn from the blood with chelators, they may redistribute to sensitive organs through the blood and cause secondary toxic effects. Observation of redistribution to the liver, kidney, brain and heart after the chelators collect heavy metals from the tissues constitutes a serious problem and eliminates the beneficial effects of chelation therapy. While hydrophilic chelators remain limited to extracellular metal pools and increase renal excretion; lipophilic chelators can access and reduce intracellular stores but redistribute toxic metals to sensitive compartments. With chelating agents, heavy metals in the plasma are eliminated quite rapidly within a few hours or days. Toxic heavy metals, on the other hand, compartmentalize in various parts of the body in different time periods and are not equally accessible to chelating agents. Generally, a chelating agent removes the most readily mobilized metals, typically in the plasma, kidney, liver, and then to a lesser extent bone and central nervous system. It is very important to have long-term chelators that will absorb and buffer heavy metal in the blood during redistribution after cleaning in the blood, but existing chelators cannot provide this. This situation creates a vital effectiveness-safety paradox. Repeated exposure of the kidneys to a filterable but reabsorbable metal or chelate causes nephrotoxicity. Similarly, enterohepatic circulation can lead to ongoing gastrointestinal exposure to a metal, ligand, or chelate, resulting in organ toxicity. Although radioactive elements can occur naturally in the environment, most harmful radionuclides are of anthropogenic origin, released from military, industrial or medical processes. Nuclear reactor accidents can result in worker exposure. Reports after the Chernobyl and Fukushima accidents revealed that radioisotopes 137Cs and 131l constituted large amounts of harmful pollutants in airborne distribution and fallout. Future terrorist attacks that could contaminate drinking water could expose larger populations to radionuclides. Accidental exposure to radioactive sources used in medicine and industry is an important cause of intoxication. The primary goal of emergency treatment after ingestion of radionuclides is to minimize the radiation dose to contaminated individuals. Uranium; Significant exposure may occur through industrial milling, mining and environmental remediation of refined uranium-contaminated soil, mines or waste, and nuclear fuel production and processing. Exposure to uranium in the natural environment most commonly occurs orally from contaminated food or drinking water. Prussian blue, which can be used in the treatment of thallium and cesium poisoning, was approved by the FDA in 2003. In 2004, the FDA approved calcium DTPA and zinc DTPA to enhance the elimination of various radioactive nuclides, including plutonium, americium, or curium. Currently used chelating agents have serious side effects such as renal failure, arrhythmias, tetany, hypotension, bone marrow depression, thrombocytopenia, leukocytopenia, prolonged bleeding time, convulsions, respiratory arrest, and decreases in the amount of calcium, zinc, copper and manganese. These agents are generally contraindicated in pregnancy, active kidney diseases, anuria and hepatitis. Therefore, there is an urgent need to develop chelates with lower toxicity and more effective chelation. In the literature, in the Chinese patent application numbered CN107141468, the circulating iron chelator is created by connecting good biocompatible polyethylene glycol monomethyl ether and deferoxamine through a pH-sensitive chemical bond. The invention further discloses a method of preparation of long-circulation iron chelator, and the method of preparation includes the steps of coupling polyethylene glycol monomethyl ether with carboxybenzaldehyde through an esterification reaction and allowing an intermediate to react with deferoxamine through a schiff base to prepare "Compared with the long-circulation iron chelator deferoxamine, which has pH response properties, the disclosed iron chelator has the characteristics of long action and response to the acid microenvironment of the lesion location, and has a potential application value in the treatment of diseases related to iron overload." A long-circulation iron chelator with response properties is disclosed. Also in the literature, in the Chinese patent document numbered CN107281498, it is stated that "The invention describes a polyethylene glycol-modified iron ionic chelator and a preparation method thereof. The iron ionic chelator is prepared from polyethylene glycol derivatives with good biocompatibility and deferoxamine. The preparation method includes the step of preparing the polyethylene glycol modified iron ionic chelator by covalent bonding of carboxylated polyethylene glycol monomethyl ether or formylated polyethylene glycol monomethyl ether with deferoxamine. "Compared with deferoxamine, iron ionic chelator has the advantages of long effect and low toxicity and has potential application value in the treatment of diseases related to iron overload." The patent document deals with the determination of human erythrocyte sensitivity to lysis by complement system activation in the pathway. For human erythrocytes, sensitivity to lysis is evaluated in three known ways ( To inhibit complement activation by either classical, alternative or lectin, sodium citrate is used as a chelator to bind Ca and Mg. In the presence of high thrombin activity associated with fibrin, the CS component is activated and a membrane-attack complex is determined by lysis of human erythrocytes. consists of The degree of HE lysis is determined from a calibration curve where 100% lysis is complete lysis of human erythrocytes with the addition of water and the erythrocyte control for spontaneous lysis is 0% lysis. The parallel is determined by the standard HE blood group technique. The human erythrocytes most sensitive to lysis are human erythrocytes with blood group A, second are HE with blood group AB, and third are HE with blood group B. The most stable are human erythrocytes with blood group O. EFFECT: this test can be used for personalized prediction of the severity of reperfusion syndrome by complement activation of the complement system via thrombin, as well as for the selection of treatment approaches in given pathological situations." In the mentioned patent, the method of determining the susceptibility of human erythrocyte to lysis by activation of the complement system on the thrombin pathway is disclosed. For the above-mentioned reasons, there was a need for a particle structure that cleans heavy metal chelation in body fluids or organs without exposing the kidneys and other organs to redistribution and the side effects of chelators. Purpose of the Invention Based on this position of the technique, the aim of the invention is to eliminate heavy metal chelation in body fluids or organs, eliminating the existing disadvantages. It is to reveal a particle structure that cleans the kidneys and other organs without exposing them to redistribution and side effects of chelators. Another aim of the invention is to prevent various cases of heavy metal poisoning and to provide a structure that eliminates the problem of limitation and toxicity of the agents recommended for heavy metal chelation. Another aim of the invention is to reveal a fast, effective structure that can immediately remove toxic metal from blood and soft tissues. Another aim of the invention is to present a structure that eliminates disadvantages such as numerous side effects, non-specific binding and difficulty in application. Another aim of the invention is to introduce a structure that eliminates the problems caused by ions such as calcium, magnesium, manganese and zinc, which are uncontrolledly excreted from the body through the kidney, with chelators administered orally or intravenously. Another aim of the invention is to introduce a structure that eliminates the risk of exposure of the kidneys to high radiation during excretion, even if deporporation (therapeutic removal of the radioactive substance absorbed by the body) is successful. Another aim of the invention is to introduce a structure that allows more comfortable and safe use of new generation chelators, as it takes the body fluid out, cleans it with superparamagnetic particles and the chelators attached to them, and then returns the fluid to the body. Explanation of Figures Figure - 1 Representative view of the heavy metal cleaning particle structure that is the subject of the invention Reference Numbers A- Particle Structuring 1. Super Paramagnetic Iron Oxide Core 2. Biocompatible Coating 3. Cellator Coating Layer Detailed Description of the Invention In this detailed explanation, the innovation that is the subject of the invention is only for more information about the subject. It is explained with examples that will not create any limiting effect on its good understanding. The invention is a particle structure (A) that cleans heavy metal chelation from body blood or other fluids without exposing the kidneys and other organs to redistribution and side effects of chelators. It is characterized by the fact that the said particle structure (A) contains a chelator coating layer (3) that allows the heavy metal in the blood and body fluids to bind to the chelator it contains after being administered into the blood or body fluid or after the blood or body fluid is taken out with a catheter and mixed with the particle structure (A). . Figure - 1 depicts the representative view of the heavy metal cleaning particle structure (A) which is the subject of the invention. The particle structure that is the subject of the invention (A); After the said particle structure (A) is introduced into the blood or body fluid or the blood or body fluid is taken out with a catheter and mixed with the particle structure (A), the chelator coating layer (3), which ensures the heavy metal in the blood and body fluids to bind to the chelator it contains, is formed on the said particle. The super paramagnetic iron oxide core (1), which allows the structure (A) to be more easily withdrawn from the blood or body fluid with permanent or electromagnetic magnets after heavy metal binding, as well as isolating the heavy metal, isolating the said super paramagnetic iron oxide core (1) from the circulation, with a chelator coating on it. It consists of the main parts of the biocompatible coating (2), which allows the chelator positioned as layer (3) to be attached to it. The mentioned particle structure (A) clears heavy metal chelation from body blood or other fluids without exposing the kidneys and other organs to redistribution and side effects of chelators. The said particle structure (A) has a super paramagnetic iron oxide core (1) at its center, a biocompatible coating (2) on it and a Lipophilic chelator coating layer (3) that can enter the cell (Monomethyl DMSA, Monocyclohexyl DMSA, etc.) or a lipophobic particle that cannot enter the cell and remains in the plasma. It contains the chelator coating layer (3) (CaNa2EDTA, Meso 2,3-Dimercaptosuccinic Acid (DMSA), etc.). In addition, the chelators whose names are given below can be used individually or in different combinations to bind different metals with a single particle. - DMSA (2,3-bis(suIfanyl)butanedioic acid; Dimercaptosuccinic acid; Succimer; Dimercaptosuccinic acid; Suximer; Tin Salt; Succicaptal; Chemet) - DMPS (Sodium 2,3-bis(sulfanyl)propane-1-sulfonate; Sodium Dimercaptopropane sulfonate; Unithiol; Dimaval; Unitiol) - EDTA (Ethylene Diamine Tetra Acetic acid; 2-[2-[bis(carboxymethyl)amino]ethyl- (carboxymethyl)amino] acetic acid; Ethylene diamine tetra acetic acid; Edathamil ; Endrate; Versene acid; TitripleX; Versene; Calcium Disodium Ethylenediamine Tetraacetic Acid) -Lewisite; 2,3- Dimercaptopropanol; Dimersol; Dithioglycerine; Dithioglycerol) - DMSA Analogues: Monoisoamyl DMSA (MmDMSA). DMSA (MchDMSA - DPA (28-2-amino-3-methyl-3-sulfanyl butanoic acid; 3-Sulfanyl-D-valine; Penicillamine; D-Penicillamine; Cuprimine; Depen; Penicillamine; Mercaptyl; Artamine; Cuprenil; Perdolat; Trolovol - Monoisoamyl DMSA (MiADMSA) - N-(alpha-L-Arabinofuranos-1-yl)-L-cysteine - "Metal protein attenuating compounds" (MPAC's) such as clioquinol - Trientine, chelator coatings that can be used with the system are limited to those listed above. It allows the use of different chelators on the created platform. In the application of the invention, body fluids are taken out with a catheter and mixed with the particle structure (A), and the heavy metals in the liquid are bound to the particle structure (A) through the chelator coating layer (3). The mentioned particle structure (A) and the bound heavy metals are kept in the particle structure (A) by strong magnets outside the body, and the cleaned body fluid is returned to the patient. The body fluid, which has been cleaned by heavy metal isolation outside, is returned to the body without heavy metal, chelator or particle structure (A), thus eliminating the toxicity of chelators. Heavy metal isolation can also be performed by administering the mentioned particle structure (A), hydrophobic or hydrophilic, to blood or other fluids via a catheter and taking it out of the body fluid. The said particle structure (A) basically uses the paramagnetic effect, thanks to the super paramagnetic iron oxide core (1), to permanant or decompose the heavy metals bound to the chelator coating layer (3) on the heavy metal-bound particle structure (A) and the chelators on the chelator coating layer (3). It is separated by pulling with electromagnets. Blood or body fluid for heavy metal isolation is taken out of the body and mixed with the particle structure (A) and the heavy metals are bound to the particle structure (A) and the particle structure (A) and the bound heavy metals are formed with the super paramagnetic iron oxide nucleus (1), which is a permanent or electromagnetic system. It is based on the principle of separating metals and returning clean blood or body fluid to the patient. The aforementioned particle structure (A) can be used in different device and application combinations. Particle structure (A) is given to the patient intravenously to clean heavy metal from tissues and organs, and after remaining in the body for a while, the patient's blood is taken out of the body. Anticoagulant is added to the blood taken out (heparin, bivaluridine, etc.), and the particle structure (A) and the heavy metals attached to it are pulled back by strong magnets, and the other part of the blood is returned to the body after being cleaned of heavy metals. Essential elements can also be given to the returned blood according to the patient's needs.TR TR TR
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2022015947A2 true TR2022015947A2 (en) | 2022-11-21 |
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