Ukuseta i-TEMPO: Sifunde ntoni malunga nokukhuthaza i-dopamine ye-D1/D5 kwisifo sikaParkinson?

Ingqwalasela yethu yinkqubo ye-TEMPO, ingakumbi, uvavanyo lwe-TEMPO-2 olusandula ukupapashwa oluvavanye i-tavapadon yedosi eguquguqukayo njenge-monotherapy kubantu abanesifo sikaParkinson kwasekuqaleni. Kwaye ndiyavuya ukuba nomntu ofanelekileyo ukuxoxa ngale datha nam namhlanje, uNjingalwazi uHubert Fernandez waseCleveland Clinic, eCleveland, eOhio, ongumbhali ophambili wempapasho ye-TEMPO-2.

Njingalwazi Fernandez, wamkelekile kwi [00:01:00] "MDS Podcast." Kuluvuyo ukuba nawe.

UDkt. Hubert Fernandez: Enkosi ngokundibona.

UDkt. Divyani Garg: Mhlawumbi eyona ndawo ilungileyo yokuqala ayikokuba ngamanani, kodwa masingene kwibhayoloji kunye nesizathu seklinikhi esisemva kwale nkqubo. Sichithe amashumi eminyaka sisebenzisa ii-dopamine receptor agonists ezikhuthaza kakhulu ii-D2, ii-D3 receptors. Ngoko ke yayiyintoni isizathu sokujolisa ngokukhetha ii-D1 receptors, kwaye yintoni obunethemba lokuyifezekisa engenakufezwa zii-agonists eziqhelekileyo?

Kwaye ingaba eyona nto iphambili yayinxulumene kakhulu nokuphepha ezinye zeziganeko ezimbi, okanye ngaba bekukho isizathu esibanzi sempilo esinxulumene neendlela ze-basal ganglia?

UDkt. Hubert Fernandez: Ewe, ndicinga ukuba lo ngumbuzo omhle kwaye enkosi kwakhona ngokundinceda. Isizathu sokuphuhlisa i-D1 family dopamine agonist receptor, evuselela i-D1 kunye ne-D5 receptors ngokukodwa, sivela kwimpumelelo esiyifumeneyo ngokusebenza kakuhle kwi-D2, [00:02:00] D3, D4 receptor agonism.

Ngoko ke, ezi zii-D2 family receptor agonism. Oku, kwiindawo ezahlukeneyo zehlabathi, mhlawumbi yi-pramipexole okanye i-ropinirole okanye i-piribedil. Kwaye akukho mathandabuzo ukuba oogqirha kunye nezigulane bayayixabisa indlela esebenza ngayo ekuphuculeni iimpawu zikaParkinson kwezi zigulane ze-dopamine agonists zesizukulwana esidala.

Kwaye ndiziqhelise ixesha elide ngokwaneleyo ukuba ndikhumbule imihla apho phantse wonke umntu osandul’ ukuxilongwa yiParkinson wayefakwa kwi-dopamine agonist. Kwaye ukuba izigulana ezisebenzisa i-levodopa zinokuguquguquka kwemisipha, phantse wonke umntu ubuncinci ebeya kuvavanywa kwi-dopamine agonist yesizukulwana esidala.

Kodwa ke, ihlabathi lawa xa saqala ukuqaphela iziphumo ebezingalindelekanga ezingaqhelekanga zezi dopamine agonists. Ukuphazamiseka kokuziphatha kokulawula impembelelo [00:03:00], ukuqala kokulala ngequbuliso, esikubiza ngokuba kukuhlaselwa kukulala. Ndicinga ukuba oogxa bethu bokulala abalithandi kakhulu elo gama. Kodwa ke ezinye izinto ezinje ngokutyeba, ukudumba kwemilenze, nezinto ezinjalo.

Ezi ziphumo bezingalindelekanga, iziphumo ebezingalindelekanga ezingaqhelekanga, kuthiwa zibangelwa kukusasazwa kwezi receptors zosapho lwe-D2. Azisasazeki nje kuphela kwindlela ye-striatonigral, kodwa nakwiindlela ze-mesolimbic kunye ne-cortical kunye nezinye iindlela. Kwaye ke, ukuba uvuselela ezi receptors zosapho lwe-D2, awufumani nje kuphela izinto ezilungileyo, kodwa mhlawumbi neziphumo ebezingalindelekanga.

Ngoku, inyani ixelelwe, ezi ziphumo ebezingalindelekanga ze-dopaminergic zinokubonwa nakweyiphi na imithi ye-dopaminergic, amayeza okuphucula i-dopamine, kodwa ngokwenene zazikwipesenti eziphezulu xa kuthelekiswa, masithi, [00:04:00] levodopa okanye i-MAO-B inhibitors, ii-COMT inhibitors. Kwanezo ziqhelekileyo, esizibiza ngokuba ziziphumo ebezingalindelekanga ezifana nokubona izinto ezingekhoyo, i-orthostatic hypotension, ukozela kakhulu emini kwenzeke kwipesenti ephezulu kwezi agonists ze-dopamine zesizukulwana esidala.

Ngenxa ye-agonism ye-D1/D5 receptor ekhethiweyo ngakumbi, ithemba yayikukuba iya kuba ntle njengala ma-dopamine agonists esizukulwana esidala ekuphuculeni iimpawu ze-motor zeParkinson's, kodwa ngezihlandlo ezimbalwa zokuphuhlisa ezi ziphumo ze-dopamine agonists ezingaqhelekanga, kwaye mhlawumbi nezihlandlo ezimbalwa zokuphuhlisa iziphumo ebezingalindelekanga zamayeza e-dopaminergic.

Ngoko ke yayililo elo themba, okanye elo yayilithemba elaqhubela phambili olu phuhliso lwe-D1 [00:05:00] family selective dopamine agonist. Ngoku, kukho, inyani, ii-D1 agonist compounds zangaphambili eziye zafundwa ngaphambili, kwaye ngokwenene zaphucula iimpawu zokunyakaza, kodwa mhlawumbi zaziphucula kakhulu, kwaye zazinotyekelo lokuphuhlisa i-dyskinesias. Ngoko ke azizange zithengiswe ngakumbi ekuphuhlisweni. Okwahlukileyo nge-tavapadon akupheleli nje ekubeni yi-selective D1/D5 receptor agonist, kodwa ikwayiloo nto siyibiza ngokuba yi-partial agonist.

Oko kuthetha ukuba i-agonism ayigcwele, ukuze ibangele ii-dyskinesias ezininzi, kodwa ikhetha ngokwaneleyo ukunciphisa esi siphumo esingaqhelekanga. Eyona meko besiyithemba kukuba iya kusebenza ngokulinganayo njenge-dopamine [00:06:00] agonist yayo yesizukulwana esidala ekhoyo, ii-agonists ze-D2 receptor.

Kodwa ilungile kwaye ilungile njengee-agonists ezindala ze-D1 ezingaphuhliswanga, kodwa ayinakwenzeka ukuba ibangele iziphumo ebezingalindelekanga ezingaqhelekanga kwaye ayinakwenzeka ukuba ibangele needyskinesias. Leyo yindlela yethu engcono kakhulu.

UGqr. Divyani Garg: Oko kuluncedo kakhulu. Ngoko ke oko kusizisa kumbuzo wokuqala ophambili malunga nenkqubo yeklinikhi. Ngoko ke i-TEMPO-1 kunye ne-TEMPO-2 zombini zifunde isifo sikaParkinson kwasekuqaleni, kodwa zineendlela ezahlukeneyo zokulinganisa. Ngoko ke i-TEMPO-1 yayinesicwangciso sedosi esimiselweyo kwaye i-TEMPO-2 yayinesicwangciso sedosi esiguquguqukayo. Ngoko ke yintoni eyongeziweyo yi-TEMPO-2 ngaphandle kokuphinda nje isignali yokusebenza ebonwe kwi-TEMPO-1?

Xa sithetha ngokuthatha idosi eguquguqukayo kuvavanyo, ngaba oko kuthetha ukuba izigulane zinikwe ithuba lokufikelela kwidosi ephezulu ukuba ziyakwazi ukuyinyamezela?

UGqr. Hubert Fernandez: Ewe. Inyaniso kukuba, i-TEMPO-1, eyidosi emiselweyo, sifunde iimiligram ezi-5 [00:07:00] kunye neemiligram ezili-15 kuba uvavanyo lwangaphambili lwesigaba sesi-2 lubonise ukuba mhlawumbi idosi efanelekileyo mhlawumbi iphakathi kwe-5 kunye ne-15. Nantoni na engaphezulu kwe-15 ibangele iziphumo ebezingalindelekanga ezingaphezulu, kwaye nantoni na engaphantsi kwe-5 yayingasebenzi ngokungathi ufikelela kwi-5.

Ngoko ke eyona nto siqikelelayo kukuba phakathi kwezo dosi zimbini. Kodwa besingenaso isiqiniseko, ngoko ke enye bekufuneka ibe yidosi eguquguqukayo. Kodwa kusenokwenzeka ukuba iphakathi kwezi zimbini, ngoko ke ngaxeshanye, senze uphando lweTEMPO-2 kunye neTEMPO-1 zonke. Ngoko ke ukuba ubuyindawo, wabelwe iTEMPO-1 okanye iTEMPO-2, kodwa bezisenzeka kunye.

Kwaye umahluko kuyilo, kutheni ufuna idosi eguquguqukayo kwaye kutheni ufuna idosi emiselweyo? Ngoko ke kukho iingenelo kunye nokungalungi kwayo nayiphi na. Idosi eguquguqukayo, ngokucacileyo inzuzo [00:08:00] kukuba, kuthekani ukuba idosi efanelekileyo yi-10 milligrams okanye i-9 milligrams, ngoko ubungayi kwazi ukuba ukuba idosi emiselweyo yayiyeyona nto ibalulekileyo ozama ukuyenza, akunjalo?

Kwaye ukuba ulungise u-5, 10, kunye no-15, kuya kufuneka uphando olukhulu kakhulu uzama ukufumana inani elifanelekileyo kwi-randomization nganye, kwaye kuya kuba yi-randomization engalinganiyo ye-i enye ukuya kwenye, kuba ukufaka eyokugqibela yi-placebo. Ngoko ke uya kuba ne-three is to one treatment randomization, engafaniyo kancinci.

Ngoko ke, yiloo nto inzuzo yoko kunokwenziwa yidosi eguquguqukayo... Kungakunika kufutshane nenyaniso kwidosi efanelekileyo, ukusebenza kakuhle kunye nokhuseleko. Ngoku, kutheni ungasebenzisi nje idosi eguquguqukayo, ukuba oko kukuxelela yonke into oyifunayo? Kukho into embi kwidosi eguquguqukayo, kuba ukuba awumnyanzeli umntu ukuba ahambe umgama othile, [00:09:00] banokwaneliseka yidosi ephantsi, uze ube neyeza elisebenzayo, kodwa elingekho semgangathweni njengoko ubungathanda.

Mhlawumbi kuya kubakho ukuphucuka kwamanqaku amathathu kuphela kumanqaku e-Parkinson motor score xa kuthelekiswa namanqaku ama-6 ukuba uyabanyanzela, kwaye bakwazile ukunyamezela, ngoko ke ufumana okulungileyo kuzo zombini ihlabathi. Ngoko ke, sivakalelwa kukuba sifuna kancinci kuzo zombini. Besifuna amava asondeleyo kwihlabathi lokwenyani kwidosi eguquguqukayo apho baya kuwela khona ukuba banikwe ithuba lokuma nangaliphi na ixesha.

Kodwa besikwafuna ukwazi ukuba singaphucuka kangakanani xa sibanyanzela ukuba basebenzise idosi ephantsi kwaye ukuba sibanyanzela ukuba basebenzise idosi ephezulu, kwaye bangaphi abantu abafumana i-drop-offs? Bangaphi abantu abangayi kunyamezela i-15 ukuba leyo yayiyeyona ndlela yokukhetha kuphela ababenayo [00:10:00]? Bobabini basinike izifundo ezibalulekileyo, kwaye ndicinga ukuba ukujonga emva kuhlala kungama-20/20, kwaye sonwabile kuba senze i-TEMPO-1 kunye ne-TEMPO-2.

UDkt. Divyani Garg: Oko kunomdla ngokwenene, kwaye enkosi ngokuchaza isizathu sokuba zombini zazibalulekile ngeendlela zazo. Masiqhubekele kwingxoxo yesiphumo, kuba ndicinga ukuba kulapho kukho ingxoxo ebalulekileyo yendlela yokusebenza. Kutheni ke ngoko sikhethe i-MDS-UPDRS Icandelo II kunye ne-III ezidibeneyo njengesiphumo esiphambili?

Kwabaphulaphuli bethu, iCandelo lesiBini libamba iinkalo zentshukumo yomzimba kumava obomi bemihla ngemihla, ngelixa iCandelo lesiThathu lisiphumo sentshukumo yomzimba esilinganiswe ngoogqirha. Kutheni ke ngoku zidityaniswe ezi zimbini?

UGqr. Hubert Fernandez: Ewe, yiloo nto ke, ngumbuzo omhle, kutheni unemisebenzi yokuphila yemihla ngemihla kunye ne-motor score elinganiswe ngoogqirha kunye njengesiphelo sakho esiphambili? Oku mhlawumbi kuqhutywa kakhulu zii-arhente ezilawulayo. Ngoko ke i-US Food and Drug Administration, umzekelo [00:11:00], igxininisa ngokutsha ukuthi iziphumo eziphambili kufuneka zihambelane nezigulana kwaye zifanele zixatyiswe zizigulana, akunjalo?

Ngoko ke eyona isondeleyo apho kukusebenza kwabo kwemihla ngemihla, imisebenzi yabo yemihla ngemihla, ngoko ke oko kuchazwe ngokucacileyo kwiCandelo lesiBini le-UPDRS. Kwelinye icala, ngamanye amaxesha ukuba sisiphumo esiqhutywa sisigulana kuphela, kukho uluvo oluthile kuso. Abazi. Banolindelo lokuba bangaboni kwaye bafunde amayeza kwaye banethemba lokufumana amayeza okwenyani nezinto ezinjalo.

Ngoko ke ukuba isekelwe kwisimo sengqondo kuphela, iyakwazi ukunxulumana, kodwa ikwaxhomekeke kwisimo sengqondo, akunjalo? Ngoko ke udinga isilinganiselo esijolise kwinjongo. Isilinganiselo esijolise kwinjongo yi-Parkinson motor score elinganiswe ngogqirha, iCandelo lesiThathu le-MDS-UPDRS, elivavanywe ixesha elide kangangeminyaka emininzi. Ngoko ke [00:12:00] sinethemba lokufumana, kwakhona, eyona ilungileyo kuzo zombini ihlabathi, efana kakhulu ne-D1 selective kodwa partial agonist efumana eyona ilungileyo kuzo zombini ihlabathi ngokwendlela yokusebenza, kodwa apha kwisilinganiselo sesiphumo esiphambili. Ukuba udibanisa isiphumo esixhomekeke kwisigulane kunye nesiphumo esizinzileyo nesilawulwa ngogqirha, ngoko ufumana eyona ilungileyo kuzo zombini ihlabathi.

Ngoko ke, ukuzalwa kweCandelo II kunye neCandelo III i-MDS-UPDRS kudibene.

UDkt. Divyani Garg: Ewe, oko kunomdla ngokwenene, kwaye oko kusenokunika ukukhanya okuthile malunga nokuba kutheni la manqaku adibeneyo abonise isiphumo esihle sonyango olukhulu, kodwa iCandelo lesiBini lodwa libonise isiphumo esincinci ngakumbi, kwaye isalathisi sesishwankathelo sePDQ-39, eneneni, asibonisanga phuculo lubalulekileyo. Oko kusenokuba yindlela enye yokulungelelanisa olu hlobo lwezimvo ezibonwe kuvavanyo.

Ucinga ukuba oko kunengqiqo?

UGqr. Hubert Fernandez: Ewe. Ewe, kodwa kukho into ethile engalunganga koku, akunjalo? Ngoko ke, [00:13:00] unayo into oyibiza ngokuba yi-MCID, umahluko obalulekileyo ngokwezonyango, kwiCandelo lesiBini, imisebenzi yokuphila kwemihla ngemihla. Nokuba uyakholelwa okanye awuyikholelwa, yinqaku eli-1 kuphela. Ukuba unenqaku elingaphezulu kwe-1.5 ngaphambi okanye emva okanye emva ngokuchasene nangaphambili, ngoko unomahluko obalulekileyo ngokwezonyango.

Izifundo zibonise ukuba kwiCandelo lesiThathu, inxalenye yentshukumo yomzimba, udinga amanqaku ama-3. Ngoko ke ukuba amanqaku akho ngelo xesha ayeyi-15 kwaye amanqaku akho emva kophando lokudibana neziyobisi njengomguli ngoku ayi-12, oko kukuphucuka kwamanqaku ama-3 ukuze kube ngcono. Oko kubalulekile ngokwezonyango. Nangona ukuba uphucuke ukusuka kwi-15 ukuya kwi-13 okanye kwi-15 ukuya kwi-14, oko kukuphucuka kwamanani, kodwa oko mhlawumbi akubalulekanga ngokwezonyango, ubuncinane kwizifundo zethu, akunjalo?

Ngoko ke umahluko omncinci owuphawulileyo kwiCandelo II [00:14:00] ngokuqinisekileyo, umncinci ngokwenani, kodwa uphindwe kabini kunomlinganiselo we-1, nto leyo esiyidingayo. Ngoko ke kwizifundo zeTEMPO, umzekelo, kwidosi eguquguqukayo, uvavanyo lweTEMPO-2, umahluko odibeneyo xa uthelekiswa ne-placebo ye-II kunye ne-III ye-UPDRS yayingamanqaku ali-9.

Ngoko ke ukuba ubala umahluko obalulekileyo ngokwezonyango we-2 kunye ne-3, uza kuba ngu-1 kunye ne-3, uza kuba ngu-4. Ngoko ke u-4 ngumlinganiselo wakho wento edibeneyo, kwaye sifumene u-9, ngoko ke uphindwe kabini ngaphezu koko sikuxabisileyo. Ngoku, kulapho ndiza kubuyela khona kwinto ebendiyithetha, ukuba unyanzela abantu ukuba banyuke baye phezulu logama nje beyinyamezela, kwaye ubaxelele, "Musa ukuyeka, yiya kwi-15. Yiyo loo nto ujolise kuyo yi-15." Ngoko ke kwi-15 milligrams yonyango lwesifundo sokulinganisa esiguquguqukayo [00:15:00], umahluko odibeneyo we-II kunye ne-III MDS-UPDRS xa kuthelekiswa nesiseko ngamanqaku ali-12, ngoko ke uphindaphinde kathathu umahluko obalulekileyo ngokwezonyango ngokunyanzela abantu.

Ngoko ke, isifundo apha kukuba ukuba isigulana sakho sikwazile ukunyamezela i-15, kusenokwenzeka ukuba kubekho isiphumo esikhulu ngakumbi sonyango. Kwi-5 milligrams, bekukho umahluko wamanqaku ali-11. Kakade ke, aba abathathi-nxaxheba abafanayo, hayi iisayithi ezifanayo, kuba kuya kufuneka ukhethe phakathi kokuba ukwi-TEMPO-1 okanye kwi-TEMPO-2.

Ngoko ke kukho umahluko omncinci, kodwa eyona nto ibalulekileyo kukuba, ewe, nangona kubonakala ngathi kuncinci kwiCandelo lesiBini, umahluko omncinci obalulekileyo ngokwezonyango ukwamncinci kakhulu kwiCandelo lesiBini xa kuthelekiswa neCandelo lesiThathu.

Ngokuphathelele umbuzo wakho kwiPDQ-39, oko akumangalisi kuthi.

Amava ethu ovavanyo lweklinikhi abonise ukuba [00:16:00] umgangatho wobomi ngowokugqibela ukuhambisa inaliti. Zihlala zibonwa kwizifundo zexesha elide. Udinga iinyanga ezi-6, ngcono unyaka omnye, wokuvezwa ukuze wenze utshintsho kumgangatho wobomi. Yintoni enengqiqo, akunjalo? Ngoko ke, kwimisebenzi yobomi bemihla ngemihla, uhlola ntoni?

Nokuba unganxiba lula, ungatshintsha impahla ngokulula, indlela obhala ngayo, intetho yakho, nezinto ezinjalo. Eli linqanaba lokuqala lokuphucula. Kumgangatho wobomi, sijonga unxibelelwano nabanye, ukuzehlukanisa nabantu, izinto ezinjalo.

Ngoko ke loo nto iphucula kakhulu ocinga ngayo. Ngoko ke ngokucacileyo, ukuba uphucula umsebenzi wakho imihla ngemihla, ngaxa lithile kuya kuguqulela ekubeni ube nonxibelelwano olungcono noluntu, unxibelelwano olungcono, nezinto ezinjalo. Kodwa ayikhawulezi. Kunzima kakhulu [00:17:00] ukuyiqonda loo nto kwiinyanga ezi-3 emva kokuvezwa.

Ngokwesiqhelo, uza kuyibona loo nto kwiinyanga ezi-6 kwaye ngokuqinisekileyo ngonyaka. Izifundo zethu zithathe iiveki ezingama-26. Ngoko ke uninzi lwazo, luvavanyo lweklinikhi lwexesha elifutshane. Ngoko ke akumangalisi ukuba i-PDQ-39 ayizukushukuma kakhulu.

UGqr. Divyani Garg: Ewe. Ngoko ke isignali yokusebenza kakuhle, njengoko ucacisile, iyamangalisa. Kodwa into ephawulekayo kukuba i-tavapadon yezinga lokuyeka eliyi-38% xa ithelekiswa ne-15% ene-placebo kwaye kukho iziganeko ezimbi kwi-24% xa kuthelekiswa ne-4%. Kwaye singathetha ngaloo nto okwethutyana, kodwa singayitolika njani loo nto xa sicinga ngokunyamezeleka kwe-tavapadon kwihlabathi lokwenyani?

Kwaye ingaba oku kunento yokwenza nemolekyuli okanye nendlela eyalinganiswa ngayo? Kuba apha siphinda sithetha ngokunyuka kwayo.

UDkt. Hubert Fernandez: Ndicinga ukuba ubethe entlokweni yam, ndicinga ukuba zombini ezi zinto. Imalunga nemolekyuli kwi [00:18:00] ithetha ukuba iseyi-dopamine agonist, kwaye i-levodopa iya kubangela isicaphucaphu nokuhlanza kunye nobunzima bokulala. I-Rasagiline iya kwenza into efanayo, i-entacapone iya kwenza into efanayo.

Ngoko ke eli yeza alikhutshelwanga kuloo nto. Kodwa ndicinga ukuba kufuneka silitolike eli tyala ngononophelo. Sifanele sazi kweli tyala ukuba kufuneka silumke ngalo mba. Kodwa isiqingatha sebali endikholelwa ngokwenene kukuba nalo lithetha ukuba i-titration iyasebenza. Kwizilingo zeklinikhi, kufuneka uhambe kancinci ukuze izigulane zikwazi ukunyamezela uphando kwaye zibe selufundweni.

Kodwa kufuneka ukhawuleze kuba ukuba kucotha kakhulu, uza kulahlekelwa zizigulane. Usenokungaziboni kwakhona emva kokulandela. Uphononongo luza kuba lude. Luza kubiza kakhulu. Iveki nganye ulwandiso lophando luchitha izigidi zeedola. Kwi-TEMPO-2, umzekelo, sinezigulane ezingaphezu kwama-500 [00:19:00] kwiindawo ezili-100 zovavanyo lweklinikhi.

Khawucinge nje ukuba ukulibaziseka kwesifundo esinye okanye ezimbini ngenxa yokucotha kakhulu kungabiza imali eninzi kunye nezixhobo. Ngoko ke kusoloko kuyisayensi kunye nobugcisa ekuyileni isifundo esinokwenzeka kodwa siya kuba nethuba eliphezulu lokubonisa oko unako.

Ngoko ke le yeyona ndlela ilungileyo yokufumana indlela yolonwabo. Kodwa mna ngokwam, uvavanyo lweklinikhi lubonisa ukuba eyona ndlela ingcono yokuqikelela inokuba kancinci nangakumbi, ndicinga. Ngoko ke iindaba ezimnandi malunga noku zikwihlabathi lokwenyani, singacotha kangangoko sifuna. Kwaye njengabagqirha, sinqumla i-levodopa phakathi, kwiikota, nangayiphi na indlela esiyifunayo.

Sixelela izigulane zethu, kwabo banengxaki kakhulu kwiziphumo ebezingalindelekanga, ukuba bathathe isiqingatha sethebhulethi kathathu ngemini kangangeeveki ezintathu. Silandela oko izigulane zethu [00:20:00] zisixelela kona, kwaye akukho nto isithintela ekubeni nobuchule ngakumbi kwaye sicothe kwi-titration. Ngoko ke, ndiqikelela ukuba, kwihlabathi lokwenyani, kusenokwenzeka ukuba i-titration iyancipha kunento esiyenzileyo kuvavanyo lweklinikhi kwabanye izigulane, kungekhona kubo bonke izigulane.

Kodwa kuza kwenzeka. Ezi ziphumo ebezingalindelekanga ziza kuqhubeka zikhona nangona sineenjongo ezintle. Kwaye ke kwabanye abaguli, kusenokwenzeka ukuba asiloyeza, kodwa ndicinga ukuba uninzi lwabanye abaguli, ukuba sikwenza ngesantya esiphantsi, sibacebisa ngokwaneleyo abaguli bethu ngaphambi kokuba baqale ukulisebenzisa, baya kulixabisa kakhulu elo thuba.

Ewe.

UGqr. Divyani Garg: Ndicinga ukuba into endiyifumana inomdla kakhulu kukuba iyeza elifanayo liye laphandwa kwasekuqaleni kwesi sifo kwaye njenge-adjunct ye-levodopa kamva. Yintoni i-TEMPO-3, xa ithetha nje nge-TEMPO-3 okwethutyana, ucinga ukuba yintoni esixelela ngayo ukuba olu khuthazo lwe-D1/D5 lungangena phi kwindlela yesifo sikaParkinson [00:21:00]?

Kwaye nokuqonda ukuba ezi mvavanyo zijonge isifo sikaParkinson sasekuqaleni kunye nezigulana eziphucukileyo mhlawumbi ezisele zisebenzisa i-levodopa njenge-adjunct. Kodwa kukho iqela elikhulu lezigulana eziphakathi kwezi zimbini. Uninzi lwezigulana zethu lusenokuwela kuloo nto.

Ucinga ukuba ukuvuselelwa kwe-D1/D5 kuhambelana phi?

UGqr. Hubert Fernandez: Ewe. Ndicinga ukuba ngulo-- ngumbuzo omhle kakhulu. Kodwa ndicinga ukuba kulapho ukuqhubeka kwethu siqaphele kwaye sijonge indlela esetyenziswa kakuhle ngayo le mithi kuya kusinceda khona, akunjalo? Kuba sinezilingo ezintathu kuphela zeklinikhi, iimvavanyo zeklinikhi ezibalulekileyo, kwiindawo ezingaphaya kwamandla oluntu.

Ayigqithisanga kakhulu kuba isiphelo esigqithisileyo kwi-advanced singaphezulu kwezilingo zeklinikhi kwiindlela zonyango ezincediswa zizixhobo nezinto ezinjalo. Ngoko ke incinci, iphakathi, iphucuke kakhulu luphononongo olunye, uze emva koko ube nezifundo ezimbini kwangethuba. Kwaye unabantu abaninzi [00:22:00] abaqhuba kakuhle kwi-levodopa kathathu ngemini.

Ngokwenyani azipheli, kodwa zinokungenelwa kukuphucuka, akunjalo? Unayo yonke into. Kwaye ngaba kufuneka silinde ukuba iphele ngaphambi kokuba sizame umntu osebenzisa i-tavapadon, umzekelo, ngumbuzo wakho. Asinawo, kodwa ndicinga ukuba xa ... njengoko sifunda indlela yokusebenzisa amayeza, ndingakhuthaza oogqirha ukuba bawasebenzise ngokwemiyalelo esemthethweni kuqala.

Oko kuthetha ukuba unesigulana esisandula ukuxilongwa ngokuba neParkinson. Ngoku baneempawu. Bakulungele unyango. Oku kuya kuba yinto efanelekileyo ukuyiqwalasela. Une-levodopa, ungazama i-tavapadon, iyeza elitsha, xa sele lifumaneka, okanye ungazama ezinye, i-rasagiline, umzekelo, okanye ezinye izithinteli ze-MAO-B.

Zonke ezo ziindlela, akunjalo? Kwaye ke xa besebenzisa i-levodopa kwaye befumana utshintsho lwe-motor [00:23:00], bafumana ixesha lokungasebenzisi i-OFF emva kwedosi nganye, oko kuya kuba yindawo elungileyo ye-tavapadon. Eli liphakathi lisenokungasasebenzi kakuhle kwaye lifuna intuthuzelo yakho ngokubanzi malunga nokuba le mithi yenza ntoni kwaye nendlela yokuyisebenzisa ukuba i-titration ifanele ikhawuleze okanye icothe kangakanani, kwaye nguwuphi umntu omele umfune.

Kulapho ke ubugcisa bezonyango buqala khona. Inyaniso kukuba, sizamile, amaxesha ambalwa, uluntu oluphakathi olufunayo kwaye sonke silufuna. Kuthekani ngoluntu oluphakathi? Kwaye oluphakathi, ngelishwa, kwiimvavanyo zeklinikhi lunzima kakhulu. Sinamayeza asebenzayo ekuqaleni nakwizinga eliphezulu.

Uyibeka embindini, akukho mahluko ngaphandle kwe-placebo. Kukho into malunga noku mhlawumbi ii-endpoints zethu ziphambene kancinci, mhlawumbi sinayo [00:24:00] yokuchaza uluntu ngakumbi, kodwa abo bathi, "Eh, ndilungile. Ndingangcono, kodwa andibi mbi," kwaye uyabavavanya, ngesiqhelo kuyingozi enkulu kakhulu kushishino lokutyala imali kuloo nto kuba ababonisi mahluko, baze emva koko babe nesilingo esibi, uze uchithe yonke loo mali simahla.

Ngoku, ihlabathi litshintshile. Njengoko uqaphela, ngoku sibandakanya iCandelo lesiBini njengenxalenye yesiphelo esiphambili. Asizange sikwenze oko ngelo xesha kuba besisoloko siyinxalenye yesiThathu, kwaye mhlawumbi ngokuqwalaselwa koxabiso lwesigulana, iqela eliphakathi ngoku linokuba nomqondiso walo. Ngoko ke isatshintsha kwaye ewe, ngokuqinisekileyo le podcast indinike loo mbono wokuba mhlawumbi simele sizame kwakhona oku kodwa sibe neCandelo lesiBini nelesiThathu ezidibeneyo.

Ewe.

UDkt. Divyani Garg: Kuhle kakhulu oko. Ngoku, lo ngumbuzo wam wokugqibela kuwe. Ngoko ke ukuba ubunokunika umyalezo omnye osebenzayo malunga ne-tavapadon kugqirha weengxaki zokunyakaza [00:25:00] ophulaphule le podcast, ingaba yintoni?

UDkt. Hubert Fernandez: Ndicinga ukuba isifundo esikhulu endinokusinika sona kukuba sebenzisa ulwazi olukwizilingo zeklinikhi njengendawo yokuqala xa ufuna ukucinga ngokusebenzisa i-tavapadon. Kusekho izinto ezininzi ekufuneka sizazi, kwaye ngokuqinisekileyo isigulana ngasinye sahlukile, akunjalo?

Zive ukhululekile ukucotha kancinci kunokuba kufuneka kwizigulana ezinobuthathaka kakhulu okanye ezikhawulezayo kunokuba kufuneka kwizigulana ezingenamonde kwaye zifuna ulawulo lweempawu ngokukhawuleza kakhulu, ngokulula. Ngoko ke uvavanyo lweklinikhi lukhokelo lwakho lokuqala. Kodwa indlela, uhambo, ngokwenene ludweliswe nguwe kunye nesigulana sakho kunye.

Kwaye esinye isifundo kukuba musa ukugxeka kakhulu olu hlobo lwe-D1 agonism. Naliphi na iyeza le-dopaminergic linokubangela naziphi na iziphumo ebezingalindelekanga. Iipesenti [00:26:00] kufuneka zibe phantsi ngendlela efanelekileyo yokusebenza, kodwa azikho. Musa ukudimazeka ziziphumo ebezingalindelekanga ezimbalwa apha naphaya.

Ayisiyomolekyuli egqibeleleyo. Ngokuqinisekileyo, ngokoluvo lwethu, yimolekyuli ephucuke kakhulu, kodwa ayisiyomolekyuli egqibeleleyo.

UDkt. Divyani Garg: Le yimiyalezo emihle yokuphelisa i-podcast ngayo. Enkosi kakhulu, Njingalwazi Fernandez, ngokundijoyina namhlanje.

UDkt. Hubert Fernandez: Ndiyavuya