{"id":69122,"date":"2023-02-17T08:09:16","date_gmt":"2023-02-17T10:09:16","guid":{"rendered":"https:\/\/www.pasveik.lt\/?p=69122\/sveikatos-ir-medicinos-naujienos"},"modified":"2023-02-10T05:46:18","modified_gmt":"2023-02-10T07:46:18","slug":"jatrogeninis-antinksciu-nepakankamumas","status":"publish","type":"post","link":"https:\/\/www.pasveik.lt\/lt\/naujausi-medicinos-straipsniai\/jatrogeninis-antinksciu-nepakankamumas\/69122\/","title":{"rendered":"<strong>Jatrogeninis antinks\u010di\u0173 nepakankamumas<\/strong>"},"content":{"rendered":"\n<p class=\"wp-block-paragraph\">Gliukokortikoidai (GKK) yra medikamentai, skirti u\u017edegimo sukeltam skausmui mal\u0161inti, tod\u0117l pla\u010diai naudojami gydant l\u0117tines, piktybines ligas, d\u0117l imunosupresinio poveikio&nbsp;\u2013 po organ\u0173 transplantacij\u0173, norint i\u0161vengti organ\u0173 atmetimo reakcijos&nbsp;[1, 2].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Su \u0161i\u0173 medikament\u0173 vartojimu yra susij\u0119 daug nepageidaujam\u0173 rei\u0161kini\u0173, vienas j\u0173&nbsp;\u2013 antinks\u010di\u0173 nepakankamumas&nbsp;[1\u20134]. Ilgalaikis GKK vartojimas veikia pagumburio, hipofiz\u0117s ir antinks\u010di\u0173 (PHA) a\u0161\u012f, sukeldamas gr\u012f\u017etam\u0105j\u012f slopinam\u0105j\u012f ry\u0161\u012f, tod\u0117l antinks\u010diuose nebesigamina endogeniniai GKK. Nutraukus GKK vartojim\u0105, da\u017enai gali i\u0161sivysti antinks\u010di\u0173 nepakankamumas, kuris yra gyvybei pavojingas nepageidaujamas GKK sukeltas rei\u0161kinys&nbsp;[1\u20133].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">J\u0173 vartojimas gali b\u016bti \u012fvairus&nbsp;\u2013 peroralinis, inhaliuojamasis, pavir\u0161inis, intraveninis, intranazalinis, leid\u017eiamas \u012f s\u0105narius, intraokulinis. Tyrimai parod\u0117, kad n\u0117ra jokios vaisto vartojimo formos, ligos, doz\u0117s ar gydymo trukm\u0117s, kuri\u0173 metu gal\u0117tume visi\u0161kai ekskliuduoti antinks\u010di\u0173 nepakankamumo rizik\u0105&nbsp;[1]. Nepaisant \u0161i\u0173 medikament\u0173 efektyvumo, norint i\u0161vengti j\u0173 sukeliamo antinks\u010di\u0173 nepakankamumo, pasiekus norim\u0105 gydymo rezultat\u0105, doz\u0119 reik\u0117t\u0173 palaipsniui ma\u017einti ir tik tada galutinai nutraukti.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Antinks\u010di\u0173 nepakankamumas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Didel\u0117s GKK doz\u0117s pagumburyje slopina kortikotropin\u0105 atpalaiduojan\u010dio hormono (KAH) i\u0161siskyrim\u0105 ir sintez\u0119, blokuoja trofin\u012f ir adrenokortikotropinio hormono (AKTH) sekrecin\u012f poveik\u012f priekin\u0117je hipofiz\u0117je. Hipofiz\u0117s kortikotropin\u0117se l\u0105stel\u0117se suma\u017e\u0117ja proopiomelanokortino (POMK) sintez\u0117 ir AKTH sekrecija, kit\u0173 POMK kilm\u0117s peptid\u0173. Ilgainiui suma\u017e\u0117ja ir hipofiz\u0117s kortikotropin\u0117s dalies dydis ir kortikotropini\u0173 l\u0105steli\u0173 kiekis&nbsp;[5].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Nesant AKTH stimuliacijai, fascikulin\u0117 ir retikulin\u0117 antinks\u010di\u0173 \u017eiev\u0117s zonos atrofuoja, tod\u0117l nebegali gaminti kortizolio. I\u0161sivysto tretinis antinks\u010di\u0173 nepakankamumas, kur\u012f sukelia GKK&nbsp;[6].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Norint \u012fvertinti PHA a\u0161ies slopinim\u0105, pacientai skirstomi \u012f 3 grupes. Pagal tai nusprend\u017eiama antinks\u010di\u0173 nepakankamumo rizika:<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>PHA a\u0161ies slopinimo tikimyb\u0117 labai didel\u0117 pacientams, kurie:<\/li>\n\n\n\n<li>gydomi GKK &gt;3 savaites ir per dien\u0105 suvartoja &gt;20&nbsp;mg prednizolono ar jo ekvivalent\u0173 (<em>1&nbsp;lentel\u0117<\/em>);<\/li>\n\n\n\n<li>vakaro&nbsp;\/&nbsp;naktin\u0117 doz\u0117 lygi \u22655&nbsp;mg prednizolono ir yra gydomi daugiau nei kelias savaites;<\/li>\n\n\n\n<li>gydant GKK pasirei\u0161k\u0117 Cushingo sindromo simptom\u0173.<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Tokiems pacientams atskiras i\u0161tyrimas d\u0117l antinks\u010di\u0173 nepakankamumo nereikalingas. Nutraukus GKK, jie tur\u0117t\u0173 b\u016bti gydomi kaip ir visi kiti pacientai, sergantys antriniu antinks\u010di\u0173 nepakankamumu.<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>PHA a\u0161ies supresija ma\u017eai tik\u0117tina. Tai pacientai, kurie:<\/li>\n\n\n\n<li>buvo gydomi bet kokia GKK doze trumpiau nei 3 savaites;<\/li>\n\n\n\n<li>dienos prednizolono doz\u0117 buvo &lt;10&nbsp;mg ar jo ekvivalent\u0173.<\/li>\n\n\n\n<li>Vidutin\u0117&nbsp;\/ neai\u0161ki rizika PHA supresijai:<\/li>\n\n\n\n<li>pacientai, kurie vartoja prednizolono 10\u201320&nbsp;mg\/d. ilgiau nei 3 savaites;<\/li>\n\n\n\n<li>pacientai, kurie vartoja GKK &lt;10&nbsp;mg\/d. ilgiau nei kelias savaites (n\u0117ra vienkartin\u0117 vakaro doz\u0117).<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\">Pama\u017eu nutraukti GKK rekomenduojama vidutin\u0117s ir neai\u0161kios rizikos pacientams. Jiems nereikia i\u0161tirti PHA a\u0161ies, nebent yra planuojamas staigus GKK nutraukimas ar planuojama operacija.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>1 lentel\u0117. Prednizolonas ir jo ekvivalentai <\/strong><strong>[6]<\/strong><strong><\/strong><\/p>\n\n\n\n<figure class=\"wp-block-table is-style-stripes\"><table><tbody><tr><td><strong>GKK<\/strong><strong><\/strong><\/td><td><strong>Doz\u0117s ekvivalentas<\/strong><strong><\/strong><\/td><\/tr><tr><td>Hidrokortizonas<\/td><td>20 mg<\/td><\/tr><tr><td>Prednizolonas<\/td><td>5 mg<\/td><\/tr><tr><td>Metilprednizolonas<\/td><td>4 mg<\/td><\/tr><tr><td>Deksametazonas<\/td><td>0,75 mg<\/td><\/tr><tr><td>Betametazonas<\/td><td>0,6 mg<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Klinika<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">GKK sukelto antinks\u010di\u0173 nepakankamumo klinika da\u017enai primena pirminio ir antrinio antinks\u010di\u0173 nepakankamumo klinik\u0105. Simptomai da\u017enai b\u016bna nespecifiniai, tod\u0117l pacientai po ilgalaikio GKK vartojimo tur\u0117t\u0173 b\u016bti atid\u017eiau stebimi&nbsp;[7]. Antinks\u010di\u0173 nepakankamumui b\u016bdingas svorio ma\u017e\u0117jimas, anoreksija, pykinimas, v\u0117mimas, letargija, silpnumas. Daugeliui gali pasireik\u0161ti hipotenzija, raumen\u0173 m\u0117\u0161lungis.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Esant ilgiau nediagnozuotam antinks\u010di\u0173 nepakankamumui, gali i\u0161sivystyti antinks\u010di\u0173 kriz\u0117, kuri pasirei\u0161kia \u016bmine hemodinamine dekompensacija&nbsp;\u2013 hipotenzija, tachikardija, hipovolemija, da\u017enai ir dezorientacija ar sutrikusia s\u0105mone. Adrenergin\u0117 kriz\u0117 da\u017eniausiai i\u0161sivysto organizmui patyrus stres\u0105, pavyzd\u017eiui, susirgus infekcija ar patyrus traum\u0105&nbsp;[7].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>PHA a\u0161ies slopinimo \u012fvertinimas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Nustatyti PHA slopinimo laipsn\u012f n\u0117ra lengva. Praktikoje antinks\u010di\u0173 funkcijos i\u0161tyrimas n\u0117ra taikomas prie\u0161 palaipsn\u012f GKK nutraukim\u0105. Tiesa, pavyzd\u017eiui, planuojant operacin\u012f gydym\u0105, i\u0161tyrimas gali b\u016bti rekomenduojamas. Tokiu atveju galima tirti rytinio kortizolio koncentracij\u0105, atlikti AKTH stimuliacijos testus&nbsp;[7\u20139].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Insulino tolerancijos ir metirapono testai n\u0117ra rekomenduotini rutinin\u0117je praktikoje d\u0117l medikament\u0173 tr\u016bkumo ir galimos rizikos, ypa\u010d kai AKTH stimuliacijos testas gali atmesti antinks\u010di\u0173 supresij\u0105&nbsp;[6].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Rytinio kortizolio matavimas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Po ilgalaik\u0117s GKK terapijos rytiniam kortizoliui esant &lt;138&nbsp;nmol\/l, pakaitin\u0117 GKK terapija yra labai rekomenduotina 24&nbsp;val. prie\u0161 ir per operacij\u0105&nbsp;[10].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>AKTH stimuliacijos testas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Atliekant test\u0105, \u012f ven\u0105 yra suleid\u017eiama 250&nbsp;\u00b5g sintetinio AKTH (sinakteno), matuojama kortizolio koncentracija prie\u0161 test\u0105 (0&nbsp;min.), po 30&nbsp;min. ir 60&nbsp;min. Kortizoliui esant &gt;500&nbsp;nmol\/l, antinks\u010di\u0173 nepakankamumo diagnoz\u0117 atmetama&nbsp;[3].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Ma\u017e\u0173 dozi\u0173 sinakteno testas taip pat naudojamas norint \u012fvertinti PHA a\u0161\u012f po ilgesnio GKK vartojimo. Tiesa, neai\u0161ku, ar \u0161is testas yra geresnis, palyginti su dideli\u0173 dozi\u0173 testu. Remiantis kai kuriais tyrimais, ma\u017e\u0173 dozi\u0173 testas gali b\u016bti jautresnis nustatant antinks\u010di\u0173 nepakankamum\u0105, kurio negalima diagnozuoti dideli\u0173 dozi\u0173 testu, nes jo metu yra suleid\u017eiama suprafiziologin\u0117 AKTH koncentracija, kuri gali i\u0161stimuliuoti i\u0161 dalies pa\u017eeistus antinks\u010dius.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">KAH testas gali taip pat b\u016bti naudojamas \u0161iems pacientams. Juo gali b\u016bti \u012fvertinami ir antinks\u010diai, ir AKTH atsakas&nbsp;[3, 6, 7].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Ma\u017e\u0173 dozi\u0173 AKTH stimuliacijos testas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">1&nbsp;\u00b5g sintetinio AKTH yra su\u0161virk\u0161\u010diama \u012f ven\u0105 ir matuojama kortizolio koncentracija kraujyje po 30&nbsp;min. ir 60&nbsp;min. Jei kortizolio koncentracija pakyla daugiau nei 500&nbsp;nmol\/l, antinks\u010di\u0173 nepakankamumo diagnoz\u0117 yra atmetama.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Reik\u0117t\u0173 atsiminti, kad sintetinio AKTH testas yra pageidaujamas metodas \u012fvertinti adrenokortikalin\u0119 funkcij\u0105. Tiesa, testas nesuteikia informacijos apie pagumburio funkcij\u0105&nbsp;[3].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Kiti testai arba neatspindi antinks\u010di\u0173 atsako \u012f stres\u0105 (pvz., plazmos kortizolio koncentracija, kortizolio ekskrecija \u0161lapime), arba yra neprakti\u0161ki d\u0117l vaist\u0173 prieinamumo (pvz., metirapono stimuliacijos testas), arba pavojingi d\u0117l sukeliamos rizikos (pvz., insulino testo sukelta hipoglikemija)&nbsp;[3].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Gydymas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Pacientams, gydomiems GKK, i\u0161sivysto fizin\u0117 priklausomyb\u0117 suprafiziologinei GKK koncentracijai, galimas reliatyvus atsparumas, tod\u0117l nutraukus GKK vartojim\u0105, padid\u0117ja antinks\u010di\u0173 nepakankamumo rizika.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Antinks\u010di\u0173 nepakankamumo sunkumo laipsnis priklauso nuo genetini\u0173 veiksni\u0173, paciento anamnez\u0117s, aplinkos. Da\u017eniausiai antinks\u010di\u0173 nepakankamumas i\u0161lieka apie 10 m\u0117nesi\u0173, ta\u010diau tai labai priklauso nuo PHA a\u0161ies u\u017eslopinimo lygio.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Antinks\u010di\u0173 nepakankamumas gydomas pakaitine hormon\u0173 terapija, tr\u016bkstam\u0105 hormono sekrecij\u0105 pakei\u010diant egzogeniniais GKK. Vidutin\u0117 kortizolio sekrecija sveikiems asmenims yra apie 2,7\u201314&nbsp;mg\/m<sup>2<\/sup>\/d.&nbsp;[11]. Pakaitin\u0117 doz\u0117 yra nustatoma individualiai d\u0117l skirtingo steroid\u0173 metobolizmo organizme. Viena doz\u0117 per dien\u0105 yra ma\u017eiau efektyvi, nei j\u0105 padalijus \u012f kelias dozes. Rekomenduojama prad\u0117ti nuo 10\u201312&nbsp;mg\/m<sup>2<\/sup> hidrokortizono, doz\u0119 padalijus \u012f 2 ar 3 dozes per dien\u0105&nbsp;[12]. Vaisto skiriant vartoti 2&nbsp;k.\/d., du tre\u010ddalius reik\u0117t\u0173 skirti ryte ir vien\u0105 tre\u010ddal\u012f po piet\u0173, norint atkartoti nat\u016bralaus kortizolio cirkadin\u012f ritm\u0105. Vartojant 3&nbsp;k.\/d., dozes reik\u0117t\u0173 padalyti: did\u017eiausia&nbsp;\u2013 rytin\u0117, ma\u017eesn\u0117&nbsp;\u2013 pietums, ma\u017eiausia&nbsp;\u2013 v\u0117lyvi piet\u016bs ar ankstyvas vakaras (pvz., 10\/5\/2,5&nbsp;mg). Dauguma rekomenduoja vengti vakarin\u0117s doz\u0117s tarp 18&nbsp;val. ir 3 val. ryto. [3, 13, 14].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Pacientus b\u016btina steb\u0117ti, pamokyti, kaip keisti doz\u0119 organizmui patyrus didesn\u012f stres\u0105. Antinks\u010di\u0173 funkcijai atsikuriant, GKK doz\u0117 ma\u017einama, kol nutraukiama visai, tod\u0117l svarbu \u012fvertinti paciento b\u016bkl\u0119, atlikti atitinkamus tyrimus ir laiku suma\u017einti ar padidinti GKK doz\u0119.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Prevencija<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Palaipsnis GKK nutraukimas<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Tyrimai parod\u0117, kad pacientams, vartojantiems GKK &lt;2 savaites, yra ma\u017ea tikimyb\u0117 PHA a\u0161ies supresijai i\u0161sivystyti, tod\u0117l jie gydym\u0105 gali nutraukti be palaipsnio doz\u0117s ma\u017einimo. I\u0161imtis pacientai, kurie da\u017enai gydomi ilgu GKK kursu, pavyzd\u017eiui, sergant astma. Tai jau yra ilgalaik\u0117 GKK terapija. M\u016bs\u0173 tikslas yra greitai suma\u017einti doz\u0105 iki fiziologinio lygio (7,5&nbsp;mg prednizolono per dien\u0105 ar ekvivalent\u0173), pavyzd\u017eiui, ma\u017einant po 2,5&nbsp;mg kas 3\u20134 dienas per kelias savaites, o tada i\u0161laikyti l\u0117tesn\u012f doz\u0117s ma\u017einim\u0105, siekiant visi\u0161ko PHA a\u0161ies atsigavimo.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Suma\u017einus doz\u0119 iki fiziologin\u0117s, v\u0117liau ma\u017einama po 1&nbsp;mg\/d. prednizolono ar jo ekvivalent\u0173 kas 2\u20134 savaites, priklausomai nuo paciento bendros b\u016bkl\u0117s, kol vaistas yra nutraukiamas. Pasiekus fiziologin\u0119 prednizolono doz\u0119 5\u20137,5 mg, galima j\u012f keiti \u012f hidrokortizon\u0105 20&nbsp;mg\/d. ir ma\u017einti po 2,5&nbsp;mg kas savait\u0119, kol 10&nbsp;mg doz\u0117 bus pasiekta. Po 2\u20133 m\u0117nesi\u0173 tos pa\u010dios doz\u0117s PHA a\u0161ies funkcija tur\u0117t\u0173 b\u016bti atsik\u016brusi. J\u0105 rekomenduojama \u012fvertinti AKTH (sinakteno) ar insulino tolerancijos testu. Jei testai i\u0161laikomi, GKK yra saugu nutraukti [6].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Jei ma\u017einant doz\u0119 i\u0161ry\u0161k\u0117ja antinks\u010di\u0173 nepakankamumo simptomai ar pasirei\u0161kia pagrindin\u0117s ligos recidyvo simptomai, GKK doz\u0117 tur\u0117t\u0173 v\u0117l b\u016bti didinama arba i\u0161laikoma ta pati, tik ilgesn\u012f laik\u0105. Pacientams, kuriems dar n\u0117ra visi\u0161ko PHA a\u0161ies atsigavimo, rekomenduojama didelio streso metu (operacija, l\u016b\u017eiai, sunki sistemin\u0117 infekcija, dideli nudegimai ir pan.) papildomai vartoti hidrokortizon\u0105 100\u2013150&nbsp;mg\/d.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Pacientai, kurie buvo gydomi ilga GKK terapija, v\u0117liau turi b\u016bti gydomi taip pat kaip ir sergant antriniu antinks\u010di\u0173 nepakankamumu\u00a0[6, 7].<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Modesta Petravi\u010di\u016bt\u0117<\/strong><br>Vilniaus universiteto ligonin\u0117s <em>Santaros<\/em> klinikos<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Literat\u016bra<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">1. Broersen LHA, Pereira AM, J\u00f8rgensen JOL, Dekkers OM. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2015 Jun 1;100(6):2171\u201380.<br>2. Mebrahtu TF, Morgan AW, Keeley A, Baxter PD, Stewart PM, Pujades-Rodriguez M. Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England. J Clin Endocrinol Metab. 2019 Sep 1;104(9):3757\u201367.<br>3.\u00a0Arlt W, Allolio B. Adrenal insufficiency. The Lancet. 2003 May 31;361(9372):1881\u201393.<br>4. Dixon WG, Bansback N. Understanding the side effects of glucocorticoid therapy: shining a light on a drug everyone thinks they know. Ann Rheum Dis. 2012 Nov 1;71(11):1761\u20134.<br>5. Lansang MC, Farmer T, Kennedy L. Diagnosing the unrecognized systemic absorption of intra-articular and epidural steroid injections. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2009 Apr;15(3):225\u20138.<br>6. Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP. Glucocorticoid Therapy and Adrenal Suppression. 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Clin Endocrinol (Oxf). 1999 Jun;50(6):759\u201365.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Gliukokortikoidai (GKK) yra medikamentai, skirti u\u017edegimo sukeltam skausmui mal\u0161inti, tod\u0117l pla\u010diai naudojami gydant l\u0117tines, piktybines ligas, d\u0117l imunosupresinio poveikio&nbsp;\u2013 po organ\u0173 transplantacij\u0173, norint i\u0161vengti organ\u0173 atmetimo reakcijos&nbsp;[1, 2]. Su \u0161i\u0173 medikament\u0173 vartojimu yra susij\u0119 daug nepageidaujam\u0173 rei\u0161kini\u0173, vienas j\u0173&nbsp;\u2013 antinks\u010di\u0173 nepakankamumas&nbsp;[1\u20134]. 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