Allurar rigakafin Nicotine

**Alurar rigakafin Nicotine** Ta kasance wata sabuwar rigakafi ce domin magance jarabar nicotine .  Alurar rigakafin nicotine yana amfani da rigakafi mai aiki azaman hanyar da za ta haifar da ƙwayoyin rigakafi na polyclonal zuwa antigens, waɗanda ake amfani da su domin magance cin zarafin miyagun ƙwayoyi.  Sa'an nan kuma tsarin rigakafi zai iya gano nicotine a matsayin wani abu na waje kuma ya fara maganin rigakafi da ke niyya da miyagun ƙwayoyi. Sakamakon haka, adadin nicotine da ke shiga cikin kwakwalwa zai ragu bayan an yi maganin alurar riga kafi.  A cikin bincike na yau da kullun, allurar rigakafin nicotine sun nuna ikon magance mummunan tasirin cutar ta nicotine, amma babu ɗayan allurar rigakafin da aka haɓaka da aka ba da izini don amfani da su a cikin gwaje-gwajen asibiti azaman dabarun daina shan taba.  A ka'ida, rage tasirin nicotine mai lada ya kamata ya haifar da daina shan taba. Wasu kamfanoni sun gwada rigakafin ɗan takara a gwaje-gwajen asibiti, amma shaida ta kasa nuna isassun martanin rigakafin ƙwayoyin cuta ko kuma nuna ingantaccen inganci ga abubuwan da suka shafi placebo. 

## Shaƙuwa da Janjewa

Manufar rigakafin nicotine shine don hana sake komawa shan taba. Nazarin da suka gabata sun gano cewa yankin ventral tegmental yanki (VTA) wanda ke cikin neurons dopaminergic, shine inda nicotine ke ɗaure da kunna mai karɓar nAChR ɗin sa, wanda ya haifar da sakin dopamine.  Baya ga saki na dopamine, akwai ƙarin ƙwayoyin cuta waɗanda aka saki, waɗanda suka haɗa da norepinephrine, acetylcholine, serotonin, γ-aminobutyric acid (GABA), glutamate, da endorphins . 

Taba, wanda Hukumar Lafiya ta Duniya ta yi la'akari da amfani da ita a matsayin annoba ta duniya, yana dauke da sinadarin nicotine.  Ƙara yawan matakan dopamine yana ƙaruwa wanda ke haifar da dogara ga miyagun ƙwayoyi, wanda masu shan taba sukan fuskanci matsaloli yayin aiwatar da janyewar nicotine. 

Babban neurotransmitter dopamine yana ba da gudummawa mai ƙarfi ga tsarin lada  wanda masu shan sigari suka samu kuma sun ruwaito, kamar tashin hankali, ingantaccen aiki, jin daɗi da ingantacciyar yanayi, waɗanda duk jihohin tunani ne da ake so.

Alamun janyewar nicotine sun haɗa da damuwa, damuwa, fushi, yanayin damuwa, wahalar maida hankali, ƙara jin yunwa, ƙara yawan ci, rashin barci, da jaraba ga taba.  Masu shan taba da suka ci karo da waɗannan alamun janyewar mara kyau sun zaɓi su guje wa irin waɗannan abubuwan mara kyau kuma su sake shan taba don sauƙaƙe alamun janyewar nicotine, wanda ke haifar da koma baya. 

## Tsarin tsari
Tsarin tsarin rigakafi na nicotine ya ƙunshi ƙarin adjuvants zuwa haɗin kai tsakanin abubuwan da aka samo asali na miyagun ƙwayoyi  wanda ke raba kamanceceniya da nicotine, da furotin mai ɗaukar hoto na immunogenic. Gabaɗaya, an san wannan tsari da maganin alurar riga kafi.

Mai haɗawa yana da mahimmanci don haɗa hapten zuwa furotin mai ɗauka, yana samar da madaidaicin lissafi don ɗaure hapten zuwa ƙwayoyin B. Masu haɗawa kuma suna tabbatar da cewa adadin nicotine haptens da ake samu don ɗaure ga ƙwayoyin B shine mafi kyau. Sunadaran da aka yi amfani da su duka suna iya samar da amsawar rigakafi.

## Hanyar aiki

Nicotine, wani abu na dabi'a na jaraba da ke cikin taba, yana aiki a matsayin agonist don mai karɓar nicotinic acetylcholine (nAChR). Alurar riga kafi yana haifar da ƙoƙari na yin koyi da tsarin nicotine tun lokacin da ake samu na nicotine (rabin rayuwar nicotine = 1-2).&nbsp;sa'o'i) ba su da ƙarancin aiki na physiologically fiye da mahallin iyaye.  Alurar rigakafin nicotine immunogens ne da ke tattare da magungunan roba da ke faruwa waɗanda ke da alaƙa da masu ɗauke da ƙwayoyin cuta, waɗanda daga nan aka tattara su a cikin adjuvants don haɓaka rigakafi .  Alurar riga kafi yana haifar da amsawar rigakafi mai ƙarfi daga jiki ta hanyar ƙarfafa samar da ƙwayoyin rigakafi, wanda ake gudanarwa ta hanyar allurar rigakafi .

Kwayoyin magani tare da tsarin tsarinsa da aka canza kuma ana kiran mai haɗin sinadarai a matsayin hapten. Sashin rigakafi na rigakafi yana da alaƙa da abin da ke faruwa ta hanyar haɗin furotin / macromolecular. Dukkanin tsarin ana kiransa furotin-conjugated protein/macromolecular carrier. Adjuvants abubuwa ne da abun ciki na aluminium waɗanda ke ƙarfafa rigakafi ta hanyar haɓaka halayen rigakafi ga antigen. Ana yawan amfani da adjuvant na rigakafi don hana shan muggan kwayoyi. 

Ana allurar rigakafi masu haɗaka don isar da maganin, wanda ke kunna ƙwayoyin B da T a cikin hanyar da ta dogara da tantanin halitta na polyclonal anti-nicotine antibodies. Alurar riga kafi yana fallasa zuwa ga lymphocytes ta sel masu gabatar da antigen. Akwai gane peptide antigen ta masu karɓar T-cell.  Tare da shigar da cytokines da ƙwayoyin B, an haifar da amsa mai ban dariya , wanda ya haifar da kira na ƙwayoyin cuta. Kwayoyin Plasmatic suna samar da immunoglobulins, anti-nicotine antibodies wanda ke ɗaure ga nicotine. Nicotine da takamaiman ƙwayoyin rigakafin nicotine an haɗa su tare, suna yin hadaddun. Rukunin yana hana nicotine wucewa ta shingen kwakwalwar jini, saboda haka yana hana shi kaiwa nAChRs na kwakwalwa. 

Bayanin wannan shine lokacin da ƙwayoyin rigakafin nicotine suka ɗaure ga ƙwayoyin nicotine ana samun karuwa a cikin girman kwayoyin halitta.  Wannan yana toshe shi daga wucewa ta shingen kwakwalwar jini, don haka nicotine ba zai iya samar da nau'ikan da yawa don nuna tasirin CNS ba. Wannan yana hana haɓakar adrenaline da dopamine,  waɗanda ke da alaƙa da tasirin CNS masu lada waɗanda ke haifar da jaraba, ta haka ne ke hana tasirin magunguna na nicotine.

## Madadin daina shan taba

Kawai maye gurbin nicotine (faci ko danko), bupropion antidepressant, da agonist mai karɓa na nicotinic varenicline an yarda da su don taimakawa masu amfani da taba su rage shan taba yayin gudanar da jaraba.  Duk da haka, kasa da kashi ɗaya bisa uku na masu karɓar magani sun daina aiki, kuma kashi ɗaya bisa uku ne kawai suka yi nasarar barin fiye da watanni shida.  Bugu da ƙari, fiye da rabin waɗanda suka karɓi maganin daina shan taba sun dawo.  Ana buƙatar sabbin dabaru don magance wannan muhimmin al'amari na kiwon lafiya a tsakiyar waɗannan cikas don haɓaka daina shan taba.

Hanyoyin tushen rigakafi, irin su amfani da alluran rigakafi don magance jaraba, an rubuta su a cikin wallafe-wallafen tun 1960s da 1970s.  Yawancin masu bincike sun sake kimanta rigakafin yayin da illolin da ke da alaƙa da amfani da maye gurbin nicotine lasisi suka taso.  Saboda iyawar su don samar da manyan ƙwayoyin rigakafin IgG anti-magungunan, allurar rigakafin haɗin gwiwa suna nuna yuwuwar a matsayin madadin hanyar magance rikice-rikicen amfani da miyagun ƙwayoyi . 

Jerin allurar rigakafin nicotine da aka haɓaka kuma an haɗa su cikin gwaji sun haɗa da Nic-QB (NIC002), NicVax, Niccine da TA-NIC. 

### Kalubalen ci gaba
Duk da ƙwaƙƙwaran ƙoƙarin da aka yi don bincikar ingancin abubuwan da ke faruwa na tushen nicotine tare da tsayi daban-daban, polarities, da sassauƙa, samun isasshen isasshen ƙarfi da kwanciyar hankali na rigakafi na tsawon lokaci babban ƙalubale ne. 

Duk da cewa yin amfani da allurar rigakafin nicotine na iya haifar da manyan matakan rigakafin nicotine don ɗaure dukkan ƙwayoyin nicotine da rage tasirin nicotine akan kwakwalwa ta hanyar hana rarrabawar ta, ƙimar rarrabawa akai-akai (Kd) zai ƙayyade ko akwai yuwuwar juyawa. dauri.

## Sashi
Jimlar alluran farko guda uku da aka raba tsakanin makonni 2-4 ana amfani da su a cikin tsarin rigakafin haɗin gwiwa. Ayyukan rigakafi ya dogara da abubuwa biyu. Fasali na farko shine “ titer ”, wanda ke nufin adadin ƙwayoyin rigakafin da ke akwai, kuma abu na biyu shine “ƙaunar” anti-nicotine antibody zuwa nicotine.

Ana kaiwa matakin titer mafi girma tsakanin makonni 2-4 bayan allura guda ɗaya sannan a fara raguwa har sai an ba da allurar ƙara don kiyaye matakan rigakafin nicotine, saboda lalacewa  na rigakafi. Abubuwan ƙarfafa rigakafin sun dace don amfani, yawanci watanni 2-3 bayan allurar farko ta ƙarshe.   Ko da yake rigakafin cututtuka na iya zama da amfani na shekaru da yawa ba tare da allura masu ƙarfafawa ba, maganin rigakafi na iya buƙatar ɗan gajeren lokaci na tsawon shekara ɗaya ko ƙasa da haka. 

### Dalilin ƙarfafawa
Karamin girman kwayoyin nicotine yana samar da ƙananan nauyin kwayoyinsa, kuma tsarin garkuwar jikin mutum ba zai iya amsawa tare da amsawar rigakafi ba. Don haka hanya da aiki da ke bayan allurar nicotine ta hanyar gudanar da maganin alurar rigakafi akai-akai don kiyaye mahimman matakan ƙwayoyin rigakafin nicotine. Wannan dalili ya samo asali ne daga la'akari da lalatawar ƙwayar cuta ta therapeutic. 

Manufar yin amfani da abin ƙarfafawa ya bambanta da tsarin rigakafin farko na rigakafin nicotine-conjugate. Alurar riga kafi na farko alama ce ta farko ta tsarin rigakafi tare da antigen, wanda shine yadda ƙwaƙwalwar ƙwayar cuta ke aiki.  Maganin ƙarfafawa shine don samar da ƙwayoyin rigakafi waɗanda ke amfani da ƙwaƙwalwar tsarin rigakafi game da haɗuwa da antigens. Wannan dabarar za ta ba da damar maganin rigakafi don samar da mafi sauri da ingantaccen amsa ga antigen . 

## Tasiri mara kyau
Nazarin asibiti tare da hodar iblis da nicotine, waɗanda aka saba amfani da allurai na 200 ko 400 micrograms a kowane kashi, sun nuna tabbataccen shaida cewa allurai na magungunan rigakafi, har zuwa 2&nbsp;MG a kowace kashi, an daidaita su daidai da matakan titer .   Tunda babu tasirin rufin, waɗannan binciken suna nuna cewa mafi kyawun kashi shine mafi girman kashi na maganin da za'a iya gudanarwa ba tare da haifar da mummuna ba. Ya zuwa yanzu, babu wani binciken maganin alurar riga kafi na asibiti da ya sami wasu manyan munanan halayen ga magungunan ƙwayoyi ko alluran rigakafin. 

## Ribobi da rashin amfani
Dabarar da aka fi so don magance matsalolin amfani da miyagun ƙwayoyi ita ce rigakafi mai aiki saboda yana da ingantacciyar lafiya da dacewa saboda tasirin yana dawwama ko da bayan allurai da yawa na maganin.  Idan aka kwatanta da ƙananan magungunan ƙwayoyin cuta, alluran rigakafi suna da tsayin lokaci na aiki saboda suna haifar da ƙwayoyin rigakafi na IgG tare da tsawon rabin rayuwa. 

Haɗaɗɗen rigakafin rigakafi suna aiki azaman masu adawa da rigakafi waɗanda ke hana ingancin abubuwan da ake nufi. Magungunan rigakafin ƙwayoyin cuta ba su shafar masu karɓar ƙwayoyi a cikin kwakwalwa ko kewaye, sabili da haka, illolin da ke tattare da su ba su da kyau. 

Wani ƙarin fa'ida na allurar haɗin gwiwa shine cewa su na duniya ne kuma ana iya ƙirƙira su don kai hari ga kowane magani ɗaya ko haɗin magunguna a ka'idar. 

Duk da yana da tasiri mai dorewa, martanin rigakafin rigakafin dabarun rigakafin yana da jinkirin kwatankwacinsa. 

Ba a kafa tasirin hanyar rigakafin aiki ba a cikin canjin hali. Ba sa rage alamun janyewa ko sha'awar ƙwayoyi. 

## inganci

### Gwajin dabbobi
Don samar da ƙwayoyin rigakafi don auna adadin nicotine a cikin jinin ɗan adam da fitsari, an haɗa trans-3′-succinimidylmethyl nicotine conjugate zuwa KLH kuma an ba da shi ga zomaye.  Ba da daɗewa ba, an ƙirƙiri wani 6- (p-aminobenzamide) na nicotine conjugate na tushen BSA-conjugated maganin rigakafi, kuma an sake nuna shi don haifar da samfurin dabba don samar da amsawar rigakafi akan nicotine.  An gano ƙwayoyin rigakafin da aka samar suna da babban alaƙa ga nicotine a wurare daban-daban na ɗaure, waɗanda ke da ƙarfi da ƙarfi don amfani da su.  Bayan karbar maganin alurar riga kafi tare da alurar riga kafi da aka yi da 6-(carboxymethylurea)-() -nicotine conjugate hade tare da KLH, berayen sun samar da kwayoyin rigakafin da ke daure nicotine sosai a cikin plasma amma ba su da tasiri akan matakan nicotine a cikin kwakwalwa, yana iyakance maganin alurar. m inganci.  Nazarin dabbobi ya sami nasara yayin amfani da ƙarin hanyoyin zamani.  Matakan nicotine a cikin kwakwalwar bera da aikin motsa jiki na bera don amsa ƙalubalen nicotine an saukar da su ta hanyar rigakafi ta hanyar amfani da haɗin gwiwar da ba nicotine ba wanda ke da alaƙa da KLH ta hanyar furotin mai haɗin gwiwa (wanda aka yiwa lakabi da NIC). 

A cikin primates waɗanda ba na ɗan adam ba, haɗin nicotine na ƙarni na biyu da ake kira NIC7 ya nuna yuwuwar samar da ƙwayoyin rigakafin nicotine, wanda zai iya rage ƙwayar ƙwayar cuta a cikin kwakwalwa.   An nuna cewa allurar rigakafin nicotine gaba ɗaya (SEL-068) wanda ke ƙunshe da hapten da ba a tantance ba yana hana wariyar nicotine a cikin waɗanda ba na ɗan adam ba.  

### Gwajin asibiti na ɗan adam
Sakamako na 'yan takarar rigakafin da dama da suka kai ga gwajin ɗan adam, gabaɗaya, sun kasance masu karaya. 

A cikin gwaji na Phase I wanda ya shafi masu shan taba 68, maganin 3'-AmNic-rEPA, wanda kuma aka sani da "NicVax," 3'-aminomethyl nicotine conjugate da aka haɗa zuwa Pseudomonas aeruginosa exoprotein A, ya nuna amsa mai kyau.  Yawancin allurai sun haifar da matakan ƙauracewa mafi girma, kuma maganin yana da ingantaccen bayanin martaba.  Bincike mai kyau daga gwaji na kashi na II ya nuna sakamako mai ƙarfi na antibody da kuma mafi girman yawan barin kashi a cikin rukunin jiyya idan aka kwatanta da rukunin placebo.  An ci gaba da rigakafin zuwa gwajin lokaci na III, amma ya kasa cimma ƙarshensa a matsayin saƙo guda ɗaya ko a hade tare da varenicline da shawara. 

A cikin gwaje-gwajen, maganin rigakafi na Niccine tetanus toxoid conjugate, wanda ke da ingantaccen bayanin martaba, ya nuna tasiri mai kama da haka ba tare da canza halayen masu shan taba ba.  NIC-002 yana ƙunshe da nicotine da aka haɗa zuwa ƙwayoyin cuta-kamar ƙwayoyin cuta, kuma ya kasa cimma manyan maƙasudin ƙarshen asibiti a cikin gwaji.  Ya nuna ɗan ƙaramin adadin daina shan taba a cikin watanni biyu amma babu wani canji a cikin watanni shida.  An janye TA-NIC tun lokacin da ta kasa kai ga ƙarshen asibiti. 

Duk da gwaje-gwajen asibiti da yawa, har yanzu akwai ƙarancin shaidar da ke goyan bayan alluran rigakafin a matsayin ingantaccen maganin hana shan miyagun ƙwayoyi. Karancin martanin antibody, martanin antibody na ɗan gajeren lokaci, bambance-bambancen mutum a cikin martanin antibody, da ci gaba da amfani da abubuwa a gaban amsawar rigakafin suna ba da gudummawa ga ingancin da ba a so. 

## Manazarta