I-Javascript ivaliwe kwibrawuza yakho ngoku.Ezinye iifitsha zale webhusayithi aziyi kusebenza xa i-javascript ivaliwe.
Bhalisa ngeenkcukacha zakho ezithile kunye neyeza elithile elinomdla kwaye siya kuthelekisa ulwazi osinike lona kunye namanqaku akwisiseko sedatha esibanzi kwaye sikuthumelele ikopi yePDF kwangoko.
Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Imbalelwano: Tafere Mulaw Belete Tel +251 918045943Email [i-imeyile ekhuselweyo] Abstract: Malaria yeyona ngxaki inkulu yezempilo yehlabathi ebangela ukufa okubalulekileyo kunye nezigulo minyaka le. .Ukhetho lonyango lunqongophele kwaye lucelwa umngeni kakhulu ngokuvela kweentlobo ze-parasite ezixhathisayo, ezibeka umqobo omkhulu kulawulo lwemalariya.Ukuthintela iimeko ezingxamisekileyo zempilo yoluntu, inoveli yamachiza okulwa nesifo seengcongconi ngonyango lwedosi enye, amandla onyango olubanzi, kunye neendlela ezintsha zokwenza. zifuneka ngokukhawuleza.Uphuhliso lwamachiza e-Antimalarial lungalandela iindlela ezahlukeneyo, ukusuka ekuguqulweni kwamachiza asele ekhona ukuya kuyilo lwamachiza anoveli ajolise kwiithagethi ezintsha.Inkqubela phambili yangoku kwi-biology ye-parasite kunye nokufumaneka kobuchwepheshe obuhlukeneyo be-genomic kunika uluhlu olubanzi lweethagethi ezintsha. kuphuhliso lwezonyango ezintsha.Izininzi ezithembisayo targI-ets yokungenelela kweziyobisi ibonakaliswe kwiminyaka yamuva nje.Ngoko ke, olu hlaziyo lujolise kwinkqubela phambili yesayensi kunye nezobuchwepheshe ekufumaneni nasekuphuhliseni inoveli yezidakamizwa ze-antimalarial.Iiprotheyini ezijoliswe kwi-antimalarial enomdla kakhulu ezifundwe ngoku zibandakanya i-proteases, i-protein kinases, i-plasmodium sugar. i-transporter inhibitors, i-aquaporin i-3 inhibitors, i-choline transport inhibitors, i-dihydroorotate dehydrogenase inhibitors, i-pentadiene biosynthesis inhibitor, i-farnesyltransferase inhibitor kunye ne-enzymes ezibandakanyekayo kwi-lipid metabolism kunye ne-DNA replication.Olu hlaziyo lushwankathela iithagethi ezintsha ze-molecular kumagama e-antimalaribi ukuchasana neziyobisi kunye nokuphuhliswa kweziyobisi. , iithagethi ezintsha, amayeza okulwa nesifo seengcongconi, indlela yokwenza, i-malaria parasite
Isifo seengcongconi sisifo esosulelayo esibulalayo, ngakumbi kwi-Afrika engezantsi kweSahara, kwiindawo zaseAsia naseMzantsi Melika.Nangona kukho iinzame ezininzi, namhlanje sesinye sezona zizathu ziphambili zokugula nokufa ikakhulu kubafazi abakhulelweyo kunye nabantwana.Ngokutsho kweWorld Health Umbutho (WHO) ingxelo ka-2018, bekukho i-228 yezigidi zeemeko zesifo seengcongconi kunye nokufa kwe-405,000 kwihlabathi jikelele.Phantse isiqingatha sabemi behlabathi basengozini yesifo seengcongconi, kunye neemeko ezininzi (93%) kunye nokufa (94%) okwenzeka e-Afrika. Malunga I-125 lezigidi zamabhinqa akhulelweyo asemngciphekweni wesifo seengcongconi nyaka ngamnye, yaye abantwana abangama-272 000 abangaphantsi kweminyaka emi-5 babulawa sisifo seengcongconi.1 Isifo seengcongconi sikwangunobangela wobuhlwempu nomqobo omkhulu kuphuhliso lwezoqoqosho, ingakumbi eAfrika.2 Iindidi ezintlanu ezichongiweyo zesifo seengcongconi IPlasmodium ebanga isifo seengcongconi ebantwini yiP. vivax, P. knowlesi, P. ovale, P. malaria kunye neP. falciparum. Kwezi, iPlasmodium falciparum yeyona nto ibulalayo kwaye ixhaphakile kwiPlasmodium.3
Ukungabikho kwesitofu sokugonya esisebenzayo, ukusetyenziswa konyango lwamachiza okulwa nesifo seengcongconi kuhlala kukuphela kwendlela yokulawula kunye nokuthintela isifo seengcongconi.Izifundo ezininzi zibonise ukuba ukusebenza kwamachiza amaninzi okulwa nesifo seengcongconi kuchaphazeleka ziimeko ezingxamisekileyo kwiPlasmodium spp.4 Ukunganyangeki kweziyobisi kuye kwaxelwa phantse zonke iziyobisi ze-antimalarial ezikhoyo, ukuqinisa ukuphuhliswa kwamachiza amatsha e-antimalarial ngokuchasene neethagethi ezikhoyo eziqinisekisiweyo kunye nokukhangela Inqanaba le-gametophytic lokudluliselwa kwe-gametophytic linokuthi lisebenze kwi-asexual proliferation ngaphakathi kwe-erythrocytes, ngakumbi kwiintlobo ze-parasite ezixhatshazwayo.6 Ii-enzyme ezininzi, i-ion imijelo, abathuthi, iimolekyuli ezisebenzisanayo Ukuhlasela kweeseli ezibomvu zegazi (RBC), kunye neemolekyuli ezinoxanduva loxinzelelo lwe-parasite oxidative, i-lipid metabolism, kunye nokuthotywa kwe-hemoglobin zingundoqo kuphuhliso lwamachiza amatsha e-antimalarial ngokuchasene nokuguquka ngokukhawuleza kwe-malaria Ethembisa iinjongo ezintsha ze-protozoa.7
Ubunakho bamachiza amatsha okulwa nesifo seengcongconi bujongwa ngokweemfuno ezininzi: indlela entsha yokwenza, akukho ukuchasana namachiza e-antimalarial yangoku, unyango lwedosi enye, ukusebenza kakuhle ngokuchasene nenqanaba legazi le-asexual kunye ne-gametocytes enoxanduva losulelo. iziyobisi ezichasene nemalariya kufuneka zibe nokusebenza kakuhle ekukhuseleni ukusuleleka (i-chemoprotectants) kunye nokucoca isibindi se-P. vivax hypnotics (i-anti-relapse agents).8
Ukufunyanwa kwechiza lemveli kulandela iindlela ezininzi zokuchonga ichiza elitsha lokulwa nesifo seengcongconi. Ezi kukuphucula iirejimeni zamachiza kunye nokwakhiwa kwamachiza akhoyo, ukuguqula amayeza asele ekhona okulwa nesifo seengcongconi, ukuhlola iimveliso zendalo, ukwahlula ii-agent ezithintela umva, ukusebenzisa iindlela ezidityanisiweyo zechemotherapy, kunye nokuphuhlisa amayeza. kwezinye izinto.8,9
Ukongeza kwiindlela zokufunyanwa kweziyobisi zesintu ezisetyenziselwa ukuchonga amayeza e-antimalarial anoveli, ulwazi lwe-Plasmodium cell biology kunye ne-genome lubonakaliswe njengesixhobo esinamandla sokutyhila iindlela zokuxhathisa kumachiza, kwaye lunamandla okwenza amachiza anomsebenzi ophezulu wokulwa nemalariya kunye ne-antimalarial.Amandla amakhulu kumachiza amatsha.Ukulwa nokuphazamiseka kokusasazeka kwesifo seengcongconi kube kanye.10 Ukuhlolwa kwemfuzo yePlasmodium falciparum ichonge i-2680 yofuzo ebalulekileyo ekukhuleni kwesigaba segazi se-asexual, ngaloo ndlela kuchongwa iinkqubo eziphambili zeselula ezibaluleke kakhulu ekuphuhliseni amachiza amatsha.10,11 Entsha. amayeza afanele: (i) ajongane nokunganyangeki kumachiza, (ii) enze ngokukhawuleza, (iii) akhuseleke, ngakumbi ebantwaneni nakumabhinqa akhulelweyo, yaye (iv) anyange isifo seengcongconi ngethamo elinye. Zonke ezi mpawu.Injongo yolu hlaziyo kukunika umbono weenjongo ezintsha zokunyanga iintsholongwane zemalariya, ezifundwa ziinkampani ezininzi, ukuze abafundi baziswe ngomsebenzi wangaphambili.
Okwangoku, uninzi lwamachiza alwa nesifo seengcongconi lujolise kwisigaba se-asexual sosulelo lwemalariya ebangela isifo esineempawu.Inqanaba le-pre-erythrocytic (isibindi) lihlala lingathandeki kuba akukho zimpawu zekliniki ziveliswayo.Amachiza e-Antimalarial abonisa ukukhetha kwesigaba esikhulu (jonga uMfanekiso 1). iimveliso zendalo, i-semi-synthetic kunye ne-synthetic compounds eziphuhliswe ukususela ngo-1940s.13 Amachiza e-antimalarial akhoyo awela kwiindidi ezintathu ezibanzi: i-quinoline derivatives, i-antifolates kunye ne-artemisinin derivatives.Akukho chiza elinye elisele lifunyenwe okanye lenziwe elinokuphelisa zonke iintlobo ze-malaria parasites. Ngoko ke, ukuze isebenze ngokuchasene nosulelo lwemalariya, imidibaniso yamachiza idla ngokusetyenziswa ngaxeshanye.IQuinoline lelona chiza lisetyenziswa kakhulu lokunyanga isifo seengcongconi, iQuinine, ialkaloid ekwanti kwixolo lomthi wecinchona, yaba lichiza lokuqala lokulwa nesifo seengcongconi. ukunyanga izifo ngenkulungwane ye-17. Ukusukela phakathi kwiminyaka yoo-1800 ukuya kweyee-1940,elithoba yayilunyango oluqhelekileyo lwemalariya.14 Ukongeza kubutyhefu, ukuvela kweentlobo ze-P. falciparum ezinganyangekiyo ngamayeza kuthintele ukusetyenziswa kwequinine kunyango.Noko ke, iquinine isasetyenziselwa ukunyanga isifo seengcongconi, amaxesha amaninzi idityaniswa ne-quinine. iyeza lesibini lokunciphisa ixesha lonyango kunye nokunciphisa iziphumo ebezingalindelekanga.15,16
Umfanekiso woku-1 Umjikelo wobomi bePlasmodium ebantwini.Amanqanaba kunye neentlobo zezifunxi-gazi apho iindidi ezahlukeneyo zamachiza okulwa nemalariya.
Kwi-1925, abaphandi baseJamani bafumanisa i-antimalarial drug yokuqala yokwenziwa, i-pamaquin, ngokuguqula i-methylene blue.Pamaquin inokusebenza okulinganiselweyo kunye ne-toxicity kwaye ayinakusetyenziselwa ukunyanga i-malaria.Kodwa i-pamaquin inikezela i-lead compounds ukuphuhlisa izidakamizwa ezingcono zokulwa ne-malarial.Mepacrine (quinacrine) yenye enye i-derivative ye-methylene blue esetyenziselwa ukunyanga isifo seengcongconi ngexesha leMfazwe Yehlabathi II.17
I-Chloroquine yaphuhliswa ngexesha leMfazwe Yehlabathi II ukunyanga isifo seengcongconi.I-Chloroquine liyeza elikhethiweyo lokunyanga isifo seengcongconi ngenxa yokusebenza kwayo, ukhuseleko kunye neendleko eziphantsi.Kodwa ukusetyenziswa kwayo okungenangqondo ngokukhawuleza kwakhokelela ekuveleni kweentlobo ze-Cloroquine-resistant P. falciparum. 18 IPrimaquine isetyenziswa ngonyango ukunyanga iPlasmodium vivax ebuyela umva ebangelwa yihypnosis.Primaquine inamandla egeticidal ngokuchasene nePlasmodium falciparum.Primaquine ibangela i-hemolytic anemia kwizigulana ezinokusilela kweglucose-6-phosphate dehydrogenase (G6PD). -P.Umsebenzi wamaxesha onke.19
Izinto ezintsha eziphuma kwiquinoline zenziwe zadityaniswa, zakhokelela kumachiza amatsha afana nepiperaquine kunye ne-amodiaquine.Emva kokuvela kokumelana ne-chloroquine, i-amodiaquine, i-phenyl-substituted analog ye-chloroquine, ibonise ukusebenza kakuhle ngokuchasene ne-chloroquine-resistant ntlobo ze-Plasmodyrum20 falfazil ichiza le-antimalarial elisisiseko elaphuhliswa e-China ngo-1970. Liyasebenza ngokuchasene neentlobo ze-P. falciparum, i-P. vivax, i-P. malaria kunye ne-P. ovale.Pyronadrine ngoku ifumaneka njenge-ACT nge-artesunate, ebonise ukusebenza kakuhle kubo bonke. I-malaria parasites.21 I-Mefloquine yaphuhliswa phakathi kwe-1980 kwaye ngoku iyacetyiswa ukuba i-chemoprevention ye-malaria ebangelwa zizo zonke iintlobo, kubandakanywa ne-chloroquine-resistant strains.Nangona kunjalo, ukusetyenziswa kwayo kuhambelana nemiphumo ethile kunye nokunyanzeliswa kweziyobisi.22 Amachiza avela kwi-Quinoline asebenza ikakhulu kwinqanaba legazi lesifunxi-gazi, kodwa amanye amachiza okulwa nesifo seengcongconi asebenza kwinqanaba lesibindi.I-ex kunye ne-heme kwi-vacuoles yokutya ye-parasite. Ngoko ke, i-polymerization ye-heme ivaliwe.Ngenxa yoko, i-heme ekhutshwe ngexesha lokuchithwa kwe-hemoglobin iqokelela kumanqanaba anetyhefu, ibulala i-parasite ngenkunkuma enetyhefu.ezingamashumi amabini anesithathu.
I-Antifolates iziyobisi ze-antimalarial ezivimbela ukuhlanganiswa kwe-folic acid, eyimfuneko ekuhlanganiseni i-nucleotides kunye ne-amino acids.I-Antifolates ibhloka ukuhlukana kwenyukliya yeentlobo ze-Plasmodium ngexesha lesigaba se-schizont kwi-erythrocytes kunye ne-hepatocytes.I-Sulfadoxine inesakhiwo esifanayo kwi-para-aminobenzoic acid. (PABA), icandelo le-folic acid.Bavimbela i-dihydrofolate synthesis ngokuvimbela i-dihydrofolate synthase, i-enzyme ephambili kwi-nucleic acid biosynthesis.amashumi amabini anesine
I-Pyrimethamine kunye ne-proguanil ziyi-schizont antimalarial iziyobisi ezisebenza kwifomu ye-asexual ye-Plasmodium.La machiza avimbela i-enzyme dihydrofolate reductase (DHFR), evimbela ukunciphisa i-dihydrofolate kwi-tetrahydrofolate, ebalulekileyo kwi-biosynthesis ye-amino acids kunye ne-nucleic acids. I-Proguanil yi-prodrug ye-metabolized to cyclic guanidine.I-Proguanil yayiyiyeza lokuqala le-antifolate elisetyenziselwa unyango lwe-malaria.Isizathu kukuba itshabalalisa iiseli ezibomvu zegazi ngaphambi kokuba i-parasite ihlasele ngexesha lokungena kwigazi.Kwakhona, i-proguanil ikhuselekile drug.Pyrimethamine isetyenziswa ikakhulu kunye namanye amachiza asebenza ngokukhawuleza.Nangona kunjalo, ukusetyenziswa kwayo kwehlile ngenxa yokunganyangeki kweziyobisi.24,25
I-Atovaquone lichiza lokuqala elivunyiweyo le-antimalarial elijolise kwi-mitochondria ye-Plasmodium parasite.I-Atovaquone inqanda ukuthuthwa kwe-electron ngokusebenza njenge-analog ye-ubiquinone ukuvala inxalenye ye-cytochrome b ye-cytochrome bc1 complex.Xa idibene ne-proguanil, i-atovaquone ikhuselekile kwaye iyasebenza kubasetyhini abakhulelweyo kunye nabantwana.I-Atovaquone iyasebenza ngokuchasene nenqanaba lezesondo le-parasite yengingi kunye neengcongconi.Ngoko ke, inqanda usulelo lwemalariya ukusuka kwiingcongconi ukuya ebantwini.Indibaniselwano esisigxina kunye neproguanil ephuhliswe phantsi kwegama lezorhwebo elithi Malarone.24,26
I-Artemisinin yakhutshwa kwi-Artemisia annua ngo-1972. I-Artemisinin kunye nezinto eziphuma kuyo eziquka i-artemether, i-dihydroartemisinin, i-artemether kunye ne-artesunate zinomsebenzi omninzi. i-gametocytes ukusuka ebantwini ukuya kwiingcongconi.27 I-Artemisinin kunye nezinto eziphuma kuyo ziyasebenza ngokuchasene ne-chloroquine- kunye ne-mefloquine-resistant strains.Zikhuselekile, ziyasebenza kwaye zisebenza ngokukhawuleza kwi-schizonts yegazi kuzo zonke iintlobo ze-Plasmodium.Nangona kunjalo, i-artemisinin ayizange iwususe umva we-hepatic latency we-hepatic latency ye-hepatic latency ye-hepatic latency I-parasite.La machiza anobomi obufutshane obufutshane kunye nokungafumaneki kakuhle kwe-bioavailability, okukhokelela ekuxhathiseni ichiza, kubenza bangasebenzi njenge-monotherapy.Ngoko ke, izinto eziphuma kwi-artemisinin ziyacetyiswa kunye namanye amachiza e-antimalarial.28
Impembelelo ye-antimalarial ye-artemisinin inokuba ngenxa yokuveliswa kwee-radicals zamahhala ezibangelwa ukuqhekeka kwe-artemisinin endoperoxide bridges in parasite food vesicles, ngaloo ndlela inhibisa i-parasite calcium ATPase kunye ne-proteasome.29,30 i-Artemether isetyenziswa njenge-monotherapy.Ukufunxa ngokukhawuleza komlomo kwi-Bioavailability. iphindwe kabini xa ilawulwa phambi kokutya.Kwakuba kumjikelezo wenkqubo, i-artemether ifakwe i-hydrolyzed kwi-dihydroartemisinin emathunjini nesibindi.
I-Artesunate yi-semi-synthetic derivative ngenxa yefuthe layo elikhawulezayo le-antimalarial, ukungabikho kokunyanzeliswa kweyeza kunye nokunyibilika okukhulu kwamanzi.Kucetyiswa njengeyeza lokuqala lemalariya enzima.31
I-Tetracyclines kunye ne-macrolides ngamachiza alwa nemalariya asebenza kade asetyenziswa njengonyango loncediso kwiquinine kwi-falciparum malaria.I-Doxycycline ikwasetyenziselwa i-chemoprophylaxis kwiindawo ezinoxhathiso oluphezulu.32 Isicwangciso-qhinga sangoku esisetyenziselwa ukulwa nokunganyangeki kumachiza e-antimalarial kusetyenziso lonyango lwendibaniselwano yamachiza. iqhinga lisetyenzisiwe kwixesha elidlulileyo ngokusebenzisa imidibaniso esisigxina.I-WHO incoma i-artemisinin-based based combination therapy (ACT) njengonyango lokuqala lwe-falciparum malaria engantsonkothanga.Isizathu kukuba ukudibanisa kwamachiza kunciphisa ukunganyangeki kweyeza kunye nemiphumo emibi.33
UMTHETHO uqulethe icandelo elinamandla le-artemisinin elisusa ngokukhawuleza i-parasites, kunye neyeza elide eliphelisa iintsholongwane ezishiyekileyo kunye nokunciphisa ukuxhathisa kwe-artemisinin.I-ACTS ecetyiswa yi-WHO yi-artesunate / amodiaquine, i-artemether / i-benzfluorenol, i-artesunate / i-mefloquine, i-artesunate / i-pyrroartelinidine ipiperaquine, i-Artesunate/sulfadoxine/pyrimethamine, i-artemether/piperaquine kunye ne-artemisinin/piperaquine/primaquine.I-Chloroquine plus primaquine ihleli ilichiza lokuqala lokuphelisa i-Plasmodium vivax.I-Quinine + tetracycline/doxycycline inonyango oluphezulu, kodwa inonyango oluphezulu, iziphumo kwaye azivumelekanga kubantwana kunye nabasetyhini abakhulelweyo34.
I-Mefloquine, i-atovaquone/proguanil, okanye i-doxycycline iyacetyiswa kwiirejimeni ze-chemoprevention kubahambi abasuka kwiindawo ezingenasiphelo ukuya kwiindawo ezixhatshazwayo.35 Unyango oluyithintelo lwangaphakathi kumaqela asemngciphekweni luyakhuthazwa, kubandakanywa i-sulfadoxine/pyrimethamine ngexesha lokukhulelwa kunye ne-amodiaquine/sulfadoxine-pyrimethamine njengexesha lonyaka. .36 I-Halofantrine ayifanelekanga ukusetyenziswa kwonyango ngenxa ye-cardiotoxicity.I-Dapsone, i-mepalyline, i-amodiaquine, kunye ne-sulfonamides zihoxisiwe ekusebenziseni unyango ngenxa yemiphumo yazo. 1.
Amachiza akhoyo ngoku afumanekayo okulwa nesifo seengcongconi asekelwe kwiiyantlukwano kwiindlela ezinkulu zemetabolism phakathi kweentlobo ze-Plasmodium kunye nemikhosi yazo.Izifunxi-gazi iindlela ezinkulu zemetabolism, kubandakanywa ukuchithwa kwe-heme, ukuhlanganiswa kwe-fatty acid, i-nucleic acid synthesis, i-fatty acid synthesis, kunye noxinzelelo lwe-oxidative, zezinye zenoveli. iindawo zokuyila iziyobisi.38,39 Nangona uninzi lwamachiza e-antimalarial asetyenziswe iminyaka emininzi, ukusetyenziswa kwawo okwangoku kulinganiselwe ngenxa yokunganyangeki kweziyobisi.Ngokoncwadi, akukho machiza athotyiweyo e-antimalarial afunyenweyo anqanda iithagethi ezaziwayo zamachiza.7,40 In ngokuchaseneyo, amaninzi amachiza e-antimalarial afunyenwe kwizilwanyana kwi-vivo okanye kwi-vitro model studies.Ngoko ke, indlela yokusebenza yamachiza amaninzi e-antimalarial ayiqinisekanga.Ngaphezu koko, iindlela zokuchasana neziyobisi ezininzi ze-antimalarial azicacanga.39
Ukulawulwa kwe-malaria kufuna izicwangciso ezilungelelanisiweyo ezifana nokulawulwa kwe-vector, i-antimalarial esebenzayo kunye ne-antimalarial ekhuselekileyo, kunye nezitofu ezisebenzayo.Ukuqwalasela ukufa okuphezulu kunye nokugula kwe-malaria, ungxamiseko kunye nokusabalalisa ukuchasana kweziyobisi, ukungasebenzi kweziyobisi ezichasene ne-malarial ezichasene ne-non-erythrocyte kunye nezigaba zesondo. , ukuchongwa kwamachiza amatsha okulwa nesifo seengcongconi ngokuqonda iindlela ezisisiseko zemetabolism zemalariya.Amayeza emalariya abalulekile.izifunxi-gazi.Ukufezekisa le njongo, uphando lwamachiza kufuneka lujolise ekujoliswe kuko okutsha, okuqinisekisiweyo ukwahlula iikhompawundi ezintsha zokukhokela.39,41
Kukho izizathu ezininzi zemfuneko yokuchonga iithagethi ezintsha zemetabolism.Okokuqala, ngaphandle kwe-atovaquone kunye ne-artemisinin-derived drug, amachiza amaninzi e-antimalarial awahlukanga ngokwemichiza, nto leyo enokukhokelela ekunqandeni.Okwesibini, ngenxa yeendidi ezininzi ezahlukeneyo iithagethi ze- putative chemotherapeutic, ezininzi azikaqinisekiswa.Ukuba ziqinisekisiwe, zinokuvelisa ezinye iikhompawundi ezisebenzayo nezikhuselekileyo.Ukuchongwa kweethagethi zamachiza amatsha kunye nokuyilwa kweekhompawundi ezintsha ezisebenza kwizinto ekujoliswe kuzo zisetyenziswa ngokubanzi kwihlabathi jikelele namhlanje ukujongana. iingxaki ezivela ekuveleni kokuchasana namachiza asele ekhona.40,41 Ngoko ke, uphononongo lwenoveli ekujoliswe kuyo kwiprotheyini ethile ye-Plasmodium isetyenziselwe ukuchongwa kwethagethi yeziyobisi.Ukususela ekutyhilweni kwe-P. falciparum genome, iithagethi ezininzi ezintsha zeziyobisi. ukungenelela kuye kwavela.La mayeza anokuthi alwe nemalariya ajolise kwi-metabolite biosynthesis engundoqo, ukuthuthwa kwe-membrane kunye neenkqubo zokubonisa iimpawu, kunye neenkqubo zokunciphisa i-hemoglobin.40,42
I-Plasmodium protease yi-enzyme ye-catalytic kunye ne-regulatory ubiquitous edlala indima ebalulekileyo ekusindeni kwe-protozoan parasites kunye nezifo ezibangelayo.I-catalyzes i-hydrolysis ye-peptide bond.43 Iindima ze-proteases kwi-malaria yesifo se-pathogenesis ibandakanya ukungena kweseli / izicubu, i-immune. ukuphepha, ukusetyenziswa kokuvuvukala, ukuhlasela kwe-erythrocyte, ukuchithwa kwe-hemoglobin kunye nezinye iiprotheni, i-autophagy, kunye nophuhliso lwe-parasite.44
I-Malaria proteases (i-glutamic aspartic acid, i-cysteine, isinyithi, i-serine kunye ne-threonine) zithembisa ujoliso lonyango kuba ukuphazamiseka kofuzo lwe-malaria protease kuthintela ukuthotywa kwe-hemoglobin kunye nenqanaba le-erythrocyte lesifunxi-gazi.uphuhliso.45
Ukuqhekeka kwe-erythrocytes kunye nokuhlasela okulandelayo kwe-merozoites kufuna i-malaria proteases.I-peptide yokwenziwa (i-GlcA-Val-Leu-Gly-Lys-NHC2H5) inqanda i-Plasmodium falciparum schizont cysteine protease Pf 68. icebisa ukuba iiproteases zidlala indima ephambili kuhlaselo lwesifunxi-gazi kwiiseli ezibomvu zegazi.Ngoko ke, iiproteases zilujoliso oluthembisayo ekuphuhliseni ichiza lokulwa nesifo seengcongconi.46
Kwi-Plasmodium falciparum ukutya vacuoles, ezininzi aspartic proteases (plasma proteases I, II, III, IV) kunye cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) ziye zodwa, Isetyenziselwa ukuthoba ihemoglobin, njengoko kubonisiwe. kuMfanekiso 2.
Ukufukanyelwa kweP. falciparum parasites eneprotease inhibitors leupeptin kunye ne-E-64 kubangele ukuqokelelwa kweglobin engekaphuculwa.Leupeptin inhibits cysteine kunye nezinye serine proteases, kodwa i-E-64 inhibits ngokukodwa icysteine ,48 emva kweeproteases. Uphononongo oluninzi lubonise ukuba i-cystatin inhibitors ayithinteli nje ukuthotywa kweglobin, kodwa ikwanqanda amanyathelo okuqala okuqhekeka kwe-hemoglobin, efana ne-hemoglobin denaturation, ukukhutshwa kweheme kwiglobin, kunye nokuveliswa kwe-heme. .49 Ezi ziphumo zibonisa ukuba i-cysteine proteases iyadingeka kwisigaba sokuqala.Amanyathelo ekuthotyweni kwe-hemoglobin nge-Plasmodium falciparum.Zombini i-E-64 kunye ne-pepstatin synergistically block P. falciparum development.Nangona kunjalo, kuphela i-E-64 ivaliwe i-globin hydrolysis. I-48,49 ezininzi ze-cysteine protease inhibitors, ezifana ne-fluoromethyl ketone kunye ne-vinyl sulfone, inhibit ukukhula kwe-P. falciparum kunye ne-hemoglobin degraKwimodeli yezilwanyana ze-malaria, i-fluoromethyl ketone inhibits P. vinckei protease umsebenzi kwaye iphilisa i-80% ye-malaria ye-murine infections.Ngoko ke, i-protease inhibitors ngabaviwa abathembisayo kwi-antimalarial drug. ethintela i-parasite metabolism kunye nophuhliso.50
I-Serine proteases ibandakanyeka kwi-schizont rupture kunye ne-erythrocyte reinvasion ngexesha lomjikelezo wobomi be-Plasmodium falciparum.Inokuthi ivalwe ngamaninzi amaninzi e-serine protease inhibitors kwaye iyona nto ingcono kakhulu kuba akukho homolog ye-enzyme yomntu ekhoyo.I-protease inhibitor LK3 eyodwa kwi-Streptomyces sp.ithoba i-malaria serine protease.51 I-Maslinic acid yi-pentacyclic triterpenoid yendalo evimbela ukuvuthwa kwee-parasites ukusuka kwinqanaba le-ring ukuya kwinqanaba le-schizont, ngaloo ndlela iphelisa ukukhululwa kwe-merozoites kunye nokuhlasela kwazo. -2 kunye ne-falcipain-3.52 statins kunye nokuvinjelwa kwe-plasma proteases nge-allophenostatin-based inhibitors ukukhusela ukuchithwa kwe-hemoglobin kunye nokubulala ama-parasites.Iininzi ze-cysteine protease blockers zikhoyo, kuquka i-Epoxomicin, i-lactacystin, i-MG132, i-WEHI-8416, i-WEHI-8416, i-WEHI-8416, i-WEHI-8916 .
I-Phosphoinositide lipid kinases (PIKs) ziyi-enzymes ezihlala kuyo yonke indawo i-phosphorylate lipids yokulawula ukwanda, ukusinda, ukurhweba, kunye ne-intracellular signaling.Iiklasi ze-PIK ezifundwa kakhulu kwii-parasites ze-53 yi-phosphoinositide 3-kinase (PI3K) kunye ne-phosphoinoselseprosel4 (K) kunye ne-phosphoinoselseprosel4 (K) Ukuvinjelwa kwezi enzymes ichongiwe njengento ekujoliswe kuyo ekuphuhlisweni kweziyobisi ezichasene nemalariya kunye neeprofayili ezinqwenelekayo zomsebenzi wokuthintela, unyango kunye nokupheliswa kwe-malaria. (4)K kwaye inqanda uphuhliso lwe-intracellular yeentlobo ezininzi ze-Plasmodium kwinqanaba ngalinye losulelo lwe-host.Ngoko ke, ukujoliswa (PI3K) kunye ne-PI (4)K kunokuvula iindlela ezintsha ezisekelwe ekufumaneni iziyobisi ekujoliswe kuzo ukuchonga inoveli amachiza e-antimalarial.KAF156 okwangoku kwiSigaba sesi-II solingo lwezonyango.55,56 MMV048 yikhompawundi enezinto ezilungileyo kwi-vivo prophylactic umsebenzi ngokuchasene ne-P. cynomolgi kunye nokunokubakhoI-MMV048 ngoku iphantsi kweSigaba IIa solingo lwezonyango e-Ethiopia.11
Ukukhula ngokukhawuleza kwiiseli ezibomvu zegazi ezosulelekileyo, iintlobo ze-Plasmodium zifuna inani elaneleyo le-substrates ukuququzelela i-metabolism enamandla.Ngoko ke, ii-parasites zilungiselela i-erythrocytes yomkhosi ngokunyanzelisa abathuthi abakhethekileyo abahluke kakhulu kubathuthi beeseli ezibambayo ekuthatheni nasekususeni i-metabolites.Ngoko ke, abathuthi bathanda i-metabolites. Iiprotheyini ze-carrier kunye neziteshi zijoliswe ekujoliswe kuyo ngenxa yeendima zabo ezibalulekileyo ekuthuthweni kwe-metabolites, i-electrolytes kunye nezondlo.57 Le yi-Plasmodium surface anion channel (PSAC) kunye ne-parasitic vacuolar membrane (PVM), enika indlela eqhubekayo yokusabalalisa izondlo. kwi-intracellular parasite.58
I-PSAC yeyona njongo ithembisayo kuba ifumaneka kwiindidi ezahlukeneyo zezondlo (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid kunye ne-choline) ukufumana iindima eziphambili kwi-intracellular parasites.I-PSAC ayinayo i-homology ecacileyo. kwijenethi eyaziwayo yejenethi yejelo.58,59 I-Phloridizin, i-dantrolene, i-furosemide, kunye ne-niflunomide zi-anion transporter blockers ezinamandla.Iziyobisi ezifana ne-glyburide, i-meglitinide, kunye ne-tolbutamide zivimbela ukungena kwe-choline kwiiseli zegazi ezibomvu ezine-parasitic.60,61
Uhlobo lwegazi lwePlasmodium falciparum luxhomekeke phantse ngokupheleleyo kwi-glycolysis yokuvelisa amandla, ngaphandle kokugcinwa kwamandla;ixhomekeke ekufumaneni rhoqo i-glucose.I-parasite iguqula i-pyruvate kwi-lactate ukuvelisa i-ATP, efunekayo ukuphindaphinda ngaphakathi kweeseli ezibomvu zegazi. i-erythrocyte membrane kunye ne-parasite-induced 'new permeation pathway'.63 I-Glucose ihanjiswa kwi-parasites yi-Plasmodium falciparum hexose transporter (PFHT) .PFHT ineempawu eziqhelekileyo zokuthutha iswekile.I-GLUT1 ikhetha i-D-glucose, ngelixa i-PFHT inokuthutha I-D-glucose kunye ne-D-fructose.Ngoko ke, ukungafani kwi-GLUT1 kunye ne-PFHT ukusebenzisana kunye ne-substrates kubonisa ukuba inhibition ekhethiweyo ye-PFHT yinto entsha ethembisayo ekuphuhlisweni kwezidakamizwa ze-antimalarial inoveli.64 I-chain chain O-3-hexose derivative (compound) I-3361) inqanda i-glucose kunye ne-fructose i-PFHT, kodwa ayithinteli ukuthuthwa kwe-hexose yi-glucose enkulu yamammalian kunye nabathuthi be-fructose (GLUT1 kunye ne-5) .I-361 iphinde ivimbele ukufunyanwa kwe-glucose ngu-P. vivax ye-PFHT.Kwizifundo zangaphambili, i-compound 3361 yabulala i-P. falciparum kwinkcubeko kunye nokunciphisa ukuveliswa kwe-P. berghei kwiimodeli zemouse.65
I-Plasmodium blood grouping ixhomekeke ubukhulu becala kwi-anaerobic glycolysis ukuze ikhule kwaye iphuhlise indlela ye-H + ye-symporter kwindawo yangaphandle.66 Ukuthunyelwa kwe-lactate kunye nokunyuka kwe-glucose kubaluleke kakhulu ekugcineni iimfuno zamandla, i-intracellular pH, kunye ne-parasite osmotic stability.I-Lactate:H+ symporter system inhibition yinto ekujoliswe kuyo entsha ethembisayo kuphuhliso lwamachiza amatsha.Iikhompawundi ezininzi, ezifana ne-MMV007839 kunye ne-MMV000972, zibulala i-asexual blood-stage P. falciparum parasites ngokunqanda i-lactate:H+ transporter.67
Njengezinye iintlobo zeeseli, iiseli ezibomvu zegazi zigcina amanqanaba aphantsi e-Na + yangaphakathi. Nangona kunjalo, i-parasites yandisa ukunyanzeliswa kwe-membrane ye-erythrocyte kwaye iququzelele ukungena kwe-Na +, okukhokelela ekunyuseni kwe-erythrocyte cytoplasmic Na + concentration ukuya kwinqanaba le-extracellular medium.Ngoko ke, iiparasites bazifumana kwimidiya ephezulu ye-Na + kwaye kufuneka bakhuphe i-Na + ion kwi-membrane ye-plasma ukuze bagcine amanqanaba aphantsi e-cytoplasmic Na + ukuze baphile naphezu kobukho babo kwiindawo ze-intracellular. Kulo mzekelo, ukungena kwe-Na + kwi-parasite ilawulwa ngokusebenzisa i-P-type ATPase. i-transporter (PfATP4), esebenza njengeyona ndlela yempompo ye-parasite ephambili ye-Na+-efflux, njengoko kubonisiwe kuMfanekiso 3.68, inqanda lo mthuthi Kuya kukhokelela ekwandeni komthamo we-Na+ ngaphakathi kwi-parasite, eya kuthi ekugqibeleni ikhokelele ekufeni kwentsholongwane. I-malaria parasite.Iikhompawundi ezininzi, kuquka i-sipagamin kwisigaba se-2, (+)-SJ733 kwisigaba 1, kunye ne-KAE609 kwisigaba sesi-2, sinendlela yokusebenza ejolise kwi-PfATP4.67,69
Umzobo 3. Indlela ecetywayo ye-parasite-induced PfATP4 kunye ne-V-type H + -ATPase ekufeni okusulelekileyo kwe-erythrocyte emva kwe-cipargamin inhibition.
Iintlobo zePlasmodium zilawula amanqanaba abo e-Na + ngokusebenzisa i-P-type ATPase transporter.Ibuye ingenise i-H + ngendlela efanayo.Ukulawula ukunyuka kwe-H + kunye nokugcina i-intracellular pH ye-7.3, i-malaria parasite isebenzisa i-V-type ye-ATPase ehambelanayo gxotha i-H + .Ukuphuhlisa iyeza elitsha yinjongo ethembisayo.MMV253 inqanda i-V-type H + ATPase njengendlela yokwenza isenzo ngokukhetha ukuguqulwa kunye nokulandelelana kwe-genome epheleleyo.70,71
I-Aquaporin-3 (AQP3) yiprotheni ye-aquaglycerol ye-channel eyenza ukuhamba kwamanzi kunye ne-glycerol kwiiseli ze-mammalian.I-AQP3 ifakwe kwi-hepatocytes yabantu ekuphenduleni ukusuleleka kwintsholongwane kwaye inendima ebalulekileyo ekuphindaphindeni kwe-parasite.I-AQP3 inikeza ukufikelela kwi-glycerol kwi-P .berghei kwaye iququzelele ukuphindaphinda kwe-parasite kwinqanaba le-asexual erythrocyte.72 Ukuchithwa kwe-Genetic ye-AQP3 kucinezele kakhulu umthwalo we-parasite kwinqanaba lesibindi se-P. I-falciparum parasitemia kwi-erythrocytes, ebonisa ukuba iiprotheni ezibamba iiprotheni zidlala indima ebalulekileyo kwizigaba ezahlukeneyo zobomi be-parasite. ukuqonda kweenkqubo zesibindi ezichatshazelwe lusulelo lwePlasmodium kwaye iqaqambisa amandla ale proiyayeka njengamachiza okulwa nemalariya kwixesha elizayo.71,72
I-Phospholipids idlala indima ephambili kumjikelezo wobomi be-intra-erythrocyte ye-Plasmodium falciparum, zombini njengamacandelo esakhiwo se-membrane kunye nanjengeamolekyuli ezilawulayo ezilawula imisebenzi yee-enzymes ezahlukeneyo.Ezi molekyuli ziyimfuneko ekuzaleni kwe-parasite ngaphakathi kweeseli ezibomvu zegazi.Emva kokuhlasela kwe-erythrocyte, Amanqanaba e-phospholipid ayanda, apho i-phosphatidylcholine iyona lipid iphambili kwiinqununu zabo zeseli. okubangela ukufa kwe-parasite.74 I-Albitiazolium, iyeza eliye langena kwizilingo zeSigaba II, lisebenza ngokuyinhloko ngokuthintela ukuthuthwa kwe-choline kwi-parasite.I-Albitiazolium iqokelela ukuya kwi-1000-fold kwi-Plasmodium kwaye inqanda ukukhula kwe-parasite ngaphandle kokuphindaphinda.Isebenza ngokukrakra ngokukrakra. iimeko. Okuqaphelekayo, inaliti enye yaphilisa pamanqanaba e-arasitemia.75,76
I-Phosphocholine cytidyltransferase yinqanaba lokunciphisa izinga kwi-de novo biosynthesis ye-phosphatidylcholine.77 I-diquaternary ammonium compound G25 kunye ne-dictic compound T3 inhibit i-phosphatidylcholine synthesis kwi-parasites.G25 yi-1000-fold-fold less toxic drugs lead the mammalian drugs. iikhompawundi ekufumaneni nasekuphuhliseni ichiza le-antimalarial.78,79
Isinyathelo esibalulekileyo ekusasazeni kweentlobo ze-Plasmodium kwimikhosi yabantu kukuhlukana okubanzi kunye nokukhawuleza kwe-DNA ye-parasite, exhomekeke ekufumanekeni kwee-metabolites ezibalulekileyo ezifana ne-pyrimidines.KwiPlasmodium, i-pyrimidine nucleotides idlala indima ebalulekileyo kwi-synthesis ye-DNA, i-phospholipids kunye I-glycoproteins.I-Nucleotide synthesis ilandela iindlela ezimbini eziphambili: indlela yokulondoloza kunye ne-de novo.I-Dihydroorotate dehydrogenase (i-DHODH) yi-enzyme ebalulekileyo eyenza i-oxidation ye-dihydroorotate i-orotate, inqanaba lokunciphisa izinga kwi-de novo pyrimidine synthesis, i-DHODH ngoko ke. imele into ekujoliswe kuyo enokuthi ithembise ukuphuhliswa kweziyobisi ezilwa nemalariya.80 Iiseli zomntu zifumana i-pyrimidines ngokuhlangula i-pyrimidines esele yenziwe okanye nge-de novo synthesis.Ukuba i-de novo biosynthetic pathway ivaliwe, iseli iya kuxhomekeka kwindlela yokulondoloza kwaye iseli ayiyi kufa. Nangona kunjalo, ukuvinjelwa kwe-de novo pyrimidine biosynthesis kwi-parasites kubangela ukufa kwezi seli ngenxa yokubaIparasite yemalariya ayinayo ipyrimidine salvage pathway, eyenza iparasite ibe sesichengeni sokuthintelwa yiDHODH.81 DSM190 kunye neDSM265 ziinhibitors ezikhethiweyo zeparasite DHODH enzyme, okwangoku kwiSigaba 2 solingo lwezonyango.P218 sisithinteli seDHODH esisebenza kuzo zonke iipyrimethamine- iintlobo ezixhathisayo okwangoku kwiSigaba 1.KAF156 (Ganaplacide) okwangoku kwiSigaba se-2b solingo lwekliniki kunye ne-phenylfluorenol.82
I-Isoprenoids iyadingeka kwi-post-translational lipid modification of proteins kunye ne-asexual replication ye-Plasmodium falciparum.Isoprenoids yenziwe kwi-five-carbon precursor isopentyl diphosphate (IPP) okanye i-isomer yayo, i-dimethylallyl diphosphate (DMAPP), ngenye yeendlela ezimbini ezizimeleyo.Mevalonate. indlela kunye ne-2C-methyl-D-erythritol 4-phosphate (MEP) indlela.Kwii-microorganisms ezininzi, ezi ndlela zimbini zihambelana ngokufanayo.I-Bacteria kunye ne-Plasmodium falciparum zixhomekeke ngokupheleleyo kwindlela ye-MEP, ngelixa abantu bengekho.Ngoko ke, i-enzymes Indlela ye-MEP iphononongwa njengeethagethi ezintsha zonyango ezinokubakho.I-Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) icatalyzes the rate-limiting step in MEP pathway, okwenza le enzyme yeparasite ijolise ekuphuhlisweni kwenoveli yamachiza antimalarial. .83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum iyakhula kwaye ayinayo ityhefu kwiiseli zabantu.I-PfDXR yinto ekujoliswe kuyo entshauphuhliso lwamachiza e-antimalarial.83 Fosmidomycin, MMV019313 kunye ne-MMV008138 inhibit i-DOXP reductoisomerase, i-enzyme ephambili ye-DOXP yendlela engekho ebantwini.Ngenxa yokuba ukuvinjelwa kwe-protein prenylation kwi-Plasmodium kuphazamisa ukukhula kwe-asexual target as anti85 parasites.
Iiprotheyini ze-prenylated zidlala indima ebalulekileyo kwiinkqubo ezahlukeneyo zeselula ezibandakanya ukuthengiswa kwe-vesicle, ukuhanjiswa kwesignali, ukulawulwa kokuphindaphinda kwe-DNA, kunye nokwahlulahlulwa kweseli. ukudluliselwa kweqela le-farnesyl, i-15-carbon isoprenoid lipid unit, ukusuka kwi-farnesyl pyrophosphate ukuya kwi-C-terminus yeeprotheni eziqukethe i-CaaX motif.Farnesyltransferase yinjongo entsha ethembisayo yokuphuhliswa kwezidakamizwa ezichasene ne-malarial ngenxa yokuba inhibition yayo ibulala i-parasite.86
Ngaphambili, i-evolution yokuchasana ne-parasites yi-farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline ibonise ukuguqulwa kwiprotheni ye-peptide substrate-binding domain.Ekukhethweni kwenye i-tetrahydroquinoline kunye ne-BMS-339,941, ukuguqulwa kwafunyanwa kwi-farnesyl ye-pocket pyrophosphate. .Kwesinye isifundo, ukuguqulwa kwenguqu kufunyenwe kwi-beta subunit ye-farnesyltransferase ye-MMV019066-resistant strain ye-P. falciparum. Uphononongo lwe-Modeling lubonise ukuba ukuguqulwa kwenguqu kuphazamisa indawo engundoqo yokunxibelelana ye-molecule encinci kunye ne-farnesylation site esebenzayo, okubangelwa ukuxhathisa kweziyobisi. .87
Enye yeenjongo ezithembisayo zokuphuhlisa amachiza amatsha kukuthintela i-P. falciparum ribosome, kunye nezinye iinxalenye zoomatshini bokuguqulela abanoxanduva lweprotein synthesis.Iintlobo zePlasmodium zineejenomes ezintathu: i-nucleus, mitochondria, kunye ne-acroplasts (ukusuka kwi-chloroplasts eseleyo). Zonke iigenomes zifuna oomatshini bokuguqulela ukuze basebenze.Iprotein synthesis inhibitors inempumelelo ebalulekileyo yezonyango njengamayeza okubulala iintsholongwane.I-Doxycycline, clindamycin, kunye ne-azithromycin zinesixhobo sonyango lwe-antimalarial ngenxa yokuba zithintela iiribosomes kwi-parasite mitochondria kunye ne-aplastoplasts, zinika ezi organelles ngokungasebenziyo,88 I-P. falciparum ribosome ithatha indawo ephakathi kwe-evolution phakathi kwe-prokaryotes kunye ne-eukaryotes, iyahlula ngokuphawulekayo kwi-ribosome yabantu kwaye ngaloo ndlela ibonelela ngethemba elitsha elithembisayo. iiribosomes ecaleni kokungcolaenger RNA kwaye ibalulekile kwiprotein synthesis kwi-eukaryotes.PfEF2 yabekwa yodwa njengento ekujoliswe kuyo entsha yophuhliso lwamachiza e-antimalarial.87,89
Ukuvinjelwa kwe-protein synthesis Thatha ukufunyanwa kwe-sordarin, imveliso yendalo ekhusela ngokufanelekileyo i-protein ye-fungal synthesis ngokuthintela i-yeast eukaryotic elongation factor 2. Ngokufanayo, i-M5717 (eyayiyi-DDD107498), i-inhibitor ekhethiweyo ye-80S ribosome-interacting, i-P ngoku i-P. Izifundo ze-1, eziqinisekisa amandla e-PfEF2 njengento ekujoliswe kuyo esebenzayo kumachiza e-antimalarial.88,90
Iimpawu eziphambili ze-malaria enzima kukuhluthwa kwe-erythrocytes ene-parasite, ukuvuvukala, kunye nokuvaleka kwe-microvasculature.I-Plasmodium falciparum isebenzisa i-heparan sulfate njengoko inamathele kwi-endothelium kunye nezinye iiseli zegazi, ezibangela ukuthintela ukuhamba kwegazi.Ukuthintela ezi seli ezingaqhelekanga kunye ne-pathogen. -ukusebenzelana kweziyobisi kubuyisela ukuhamba kwegazi okuvaliweyo kwaye kuchaphazela ukukhula kwe-parasite.91
Izifundo ezininzi zibonise ukuba i-sevuparin, i-polysaccharide echasene ne-adhesion eyenziwe kwi-heparin, ineempembelelo ze-antithrombin-eliminating. ukuya kwi-N-terminal extracellular heparan sulfate-binding structure ye-Plasmodium falciparum erythrocyte membrane protein 1, i-Duffy-binding-like domain 1α (DBL1α), kwaye kucingelwa ukuba yinto ebalulekileyo ekufumaneni i-erythrocytes echaphazelekayo.92,93 Enye iThebhile 2 ishwankathela izilingo zeklinikhi kwizigaba ezahlukeneyo.
Ixesha lokuposa: Mar-24-2022