מה ניתן ללמוד מתופעות הלוואי החמורות שהתגלו באספירין

דורית דינור | 11 באוקטובר 2021 | תרבות ואמנות | 2 דק׳

גלגוליו של האספירין כמקרה בוחן

ספרו החדש של ד"ר בנימין מוזס, רופא פנימי וחוקר בתחום האפידמיולוגיה הקלינית ומדיניות הבריאות, מעלה שאלות נוקבות לגבי האופן שבו נערכים היום ניסויים קליניים על תרופות ועל הדרך בה מתפרסמים מאמרי מחקר המשמיטים עובדות חשובות או מדגישים נתונים מסוימים. הוא עושה זאת באמצעות סיפורה של אחת מהתרופות הידועות והנמכרות בכל הזמנים – האספירין.

סיפורו של האספירין מתחיל עם החומצה הסליצילית, חומצה אורגנית פשוטה הנמצאת בטבע, המוכרת כבר 2,500 שנה. החכם היווני היפוקרטס, הנחשב לאבי הרפואה, הזכיר למשל כבר במאה הרביעית לפנה"ס את קליפת עץ הערבה (שניתן להפיק ממנה את החומצה) כאמצעי יעיל לטיפול בכאבים דלקתיים. גם בתרבויות אחרות השתמשו בקליפת העץ.

במאה ה-19, לאחר שכבר ידעו לזקק ולבודד מקליפת העץ את החומר המרפא לו קראו סליצין, גילו שיש לו תופעות לוואי של תחושת שריפה בגרון ובקיבה. הטיפול נפסק. אבל בחברת התרופות ”באייר" מיהרו לחפש נגזרת של סליצין שלא תגרה את רירית הקיבה. כך הצליחו כימאים לסנתז חומצה אצטילסליצילית בעלת דמיון כימי לסליצין. ב-1899 היא נרשמה בשם אספירין.

רוצה לקרוא עוד?

להמשך קריאה הירשמו או התחברו

בנימין מוזס, "רקוויאם לאספירין, הרפואה המדעית על פרשת דרכים", מאגנס, 2021

בנימין מוזס, "רקוויאם לאספירין, הרפואה המדעית על פרשת דרכים", מאגנס, 2021

תמונה למחשבה: הכאב שמוליד יופי

מאיה מזרחי

אנטון צ'כוב, "מעשה משעמם", תרגום מרוסית ואחרית דבר: נילי מירסקי, מרץ 2025

החיים שאחרי המוניטין

גלית דהן קרליבך

יובל שטייניץ, "הקומדיה הממשלתית", ידיעות ספרים, ינואר 2025

מה באמת קורה כשמזמינים את הרמטכ"ל לוועדה

נדב רט

מירי אליאב-פלדון, "הרנסנס של השטן", הוצאת מאגנס, 2024

הצד האפל של תקופת הרנסנס

גלית דהן קרליבך

שרון קרישק, "ואהבת לרעך כמוך", שהם קראוס, ינואר 2025

איך אפשר לאהוב מישהו שמכעיס אותנו?

דינה גורדון

דאגלס מאריי, "הקרב על המערב", שיבולת וסלע מאיר, 2024

המערב נגד עצמו: הקרב שמאיים לפרק את הציוויליזציה שלנו

נדב רט

הירשמו לניוזלטר שלנו וקבלו תוכן חדש למייל מדי חודש

",e=e.removeChild(e.firstChild)):"string"==typeof o.is?e=l.createElement(a,{is:o.is}):(e=l.createElement(a),"select"===a&&(l=e,o.multiple?l.multiple=!0:o.size&&(l.size=o.size))):e=l.createElementNS(e,a),e[Ni]=t,e[Pi]=o,Pl(e,t,!1,!1),t.stateNode=e,l=Ae(a,o),a){case"iframe":case"object":case"embed":Te("load",e),u=o;break;case"video":case"audio":for(u=0;u<$a.length;u++)Te($a[u],e);u=o;break;case"source":Te("error",e),u=o;break;case"img":case"image":case"link":Te("error",e),Te("load",e),u=o;break;case"form":Te("reset",e),Te("submit",e),u=o;break;case"details":Te("toggle",e),u=o;break;case"input":A(e,o),u=M(e,o),Te("invalid",e),Ie(n,"onChange");break;case"option":u=B(e,o);break;case"select":e._wrapperState={wasMultiple:!!o.multiple},u=Uo({},o,{value:void 0}),Te("invalid",e),Ie(n,"onChange");break;case"textarea":V(e,o),u=H(e,o),Te("invalid",e),Ie(n,"onChange");break;default:u=o}Me(a,u);var s=u;for(i in s)if(s.hasOwnProperty(i)){var c=s[i];"style"===i?ze(e,c):"dangerouslySetInnerHTML"===i?(c=c?c.__html:void 0,null!=c&&Aa(e,c)):"children"===i?"string"==typeof c?("textarea"!==a||""!==c)&&X(e,c):"number"==typeof c&&X(e,""+c):"suppressContentEditableWarning"!==i&&"suppressHydrationWarning"!==i&&"autoFocus"!==i&&(ea.hasOwnProperty(i)?null!=c&&Ie(n,i):null!=c&&x(e,i,c,l))}switch(a){case"input":L(e),j(e,o,!1);break;case"textarea":L(e),$(e);break;case"option":null!=o.value&&e.setAttribute("value",""+P(o.value));break;case"select":e.multiple=!!o.multiple,n=o.value,null!=n?q(e,!!o.multiple,n,!1):null!=o.defaultValue&&q(e,!!o.multiple,o.defaultValue,!0);break;default:"function"==typeof u.onClick&&(e.onclick=Fe)}Ve(a,o)&&(t.effectTag|=4)}null!==t.ref&&(t.effectTag|=128)}return null;case 6:if(e&&null!=t.stateNode)Ll(e,t,e.memoizedProps,o);else{if("string"!=typeof o&&null===t.stateNode)throw Error(r(166));n=yn(yu.current),yn(bu.current),Jn(t)?(n=t.stateNode,o=t.memoizedProps,n[Ni]=t,n.nodeValue!==o&&(t.effectTag|=4)):(n=(9===n.nodeType?n:n.ownerDocument).createTextNode(o),n[Ni]=t,t.stateNode=n)}return null;case 13:return zt(vu),o=t.memoizedState,0!==(64&t.effectTag)?(t.expirationTime=n,t):(n=null!==o,o=!1,null===e?void 0!==t.memoizedProps.fallback&&Jn(t):(a=e.memoizedState,o=null!==a,n||null===a||(a=e.child.sibling,null!==a&&(i=t.firstEffect,null!==i?(t.firstEffect=a,a.nextEffect=i):(t.firstEffect=t.lastEffect=a,a.nextEffect=null),a.effectTag=8))),n&&!o&&0!==(2&t.mode)&&(null===e&&!0!==t.memoizedProps.unstable_avoidThisFallback||0!==(1&vu.current)?rs===Qu&&(rs=Yu):(rs!==Qu&&rs!==Yu||(rs=Gu),0!==us&&null!==es&&(To(es,ns),Co(es,us)))),(n||o)&&(t.effectTag|=4),null);case 4:return wn(),Ol(t),null;case 10:return Zt(t),null;case 17:return It(t.type)&&Ft(),null;case 19:if(zt(vu),o=t.memoizedState,null===o)return null;if(a=0!==(64&t.effectTag),i=o.rendering,null===i){if(a)mr(o,!1);else if(rs!==Qu||null!==e&&0!==(64&e.effectTag))for(i=t.child;null!==i;){if(e=_n(i),null!==e){for(t.effectTag|=64,mr(o,!1),a=e.updateQueue,null!==a&&(t.updateQueue=a,t.effectTag|=4),null===o.lastEffect&&(t.firstEffect=null),t.lastEffect=o.lastEffect,o=t.child;null!==o;)a=o,i=n,a.effectTag&=2,a.nextEffect=null,a.firstEffect=null,a.lastEffect=null,e=a.alternate,null===e?(a.childExpirationTime=0,a.expirationTime=i,a.child=null,a.memoizedProps=null,a.memoizedState=null,a.updateQueue=null,a.dependencies=null):(a.childExpirationTime=e.childExpirationTime,a.expirationTime=e.expirationTime,a.child=e.child,a.memoizedProps=e.memoizedProps,a.memoizedState=e.memoizedState,a.updateQueue=e.updateQueue,i=e.dependencies,a.dependencies=null===i?null:{expirationTime:i.expirationTime,firstContext:i.firstContext,responders:i.responders}),o=o.sibling;return Mt(vu,1&vu.current|2),t.child}i=i.sibling}}else{if(!a)if(e=_n(i),null!==e){if(t.effectTag|=64,a=!0,n=e.updateQueue,null!==n&&(t.updateQueue=n,t.effectTag|=4),mr(o,!0),null===o.tail&&"hidden"===o.tailMode&&!i.alternate)return t=t.lastEffect=o.lastEffect,null!==t&&(t.nextEffect=null),null}else 2*ru()-o.renderingStartTime>o.tailExpiration&&1t)&&vs.set(e,t)))}}function Ur(e,t){e.expirationTimee?n:e,2>=e&&t!==e?0:e}function qr(e){if(0!==e.lastExpiredTime)e.callbackExpirationTime=1073741823,e.callbackPriority=99,e.callbackNode=$t(Vr.bind(null,e));else{var t=Br(e),n=e.callbackNode;if(0===t)null!==n&&(e.callbackNode=null,e.callbackExpirationTime=0,e.callbackPriority=90);else{var r=Fr();if(1073741823===t?r=99:1===t||2===t?r=95:(r=10*(1073741821-t)-10*(1073741821-r),r=0>=r?99:250>=r?98:5250>=r?97:95),null!==n){var o=e.callbackPriority;if(e.callbackExpirationTime===t&&o>=r)return;n!==Yl&&Bl(n)}e.callbackExpirationTime=t,e.callbackPriority=r,t=1073741823===t?$t(Vr.bind(null,e)):Wt(r,Hr.bind(null,e),{timeout:10*(1073741821-t)-ru()}),e.callbackNode=t}}}function Hr(e,t){if(ks=0,t)return t=Fr(),No(e,t),qr(e),null;var n=Br(e);if(0!==n){if(t=e.callbackNode,(Ju&(Wu|$u))!==Hu)throw Error(r(327));if(lo(),e===es&&n===ns||Kr(e,n),null!==ts){var o=Ju;Ju|=Wu;for(var a=Yr();;)try{eo();break}catch(t){Xr(e,t)}if(Gt(),Ju=o,Bu.current=a,rs===Ku)throw t=os,Kr(e,n),To(e,n),qr(e),t;if(null===ts)switch(a=e.finishedWork=e.current.alternate,e.finishedExpirationTime=n,o=rs,es=null,o){case Qu:case Ku:throw Error(r(345));case Xu:No(e,2=n){e.lastPingedTime=n,Kr(e,n);break}}if(i=Br(e),0!==i&&i!==n)break;if(0!==o&&o!==n){e.lastPingedTime=o;break}e.timeoutHandle=Si(oo.bind(null,e),a);break}oo(e);break;case Gu:if(To(e,n),o=e.lastSuspendedTime,n===o&&(e.nextKnownPendingLevel=ro(a)),ss&&(a=e.lastPingedTime,0===a||a>=n)){e.lastPingedTime=n,Kr(e,n);break}if(a=Br(e),0!==a&&a!==n)break;if(0!==o&&o!==n){e.lastPingedTime=o;break}if(1073741823!==is?o=10*(1073741821-is)-ru():1073741823===as?o=0:(o=10*(1073741821-as)-5e3,a=ru(),n=10*(1073741821-n)-a,o=a-o,0>o&&(o=0),o=(120>o?120:480>o?480:1080>o?1080:1920>o?1920:3e3>o?3e3:4320>o?4320:1960*Uu(o/1960))-o,n=o?o=0:(a=0|l.busyDelayMs,i=ru()-(10*(1073741821-i)-(0|l.timeoutMs||5e3)),o=i<=a?0:a+o-i),10 component higher in the tree to provide a loading indicator or placeholder to display."+N(i))}rs!==Zu&&(rs=Xu),l=yr(l,i),f=a;do{switch(f.tag){case 3:u=l,f.effectTag|=4096,f.expirationTime=t;var w=Ar(f,u,t);ln(f,w); break e;case 1:u=l;var E=f.type,k=f.stateNode;if(0===(64&f.effectTag)&&("function"==typeof E.getDerivedStateFromError||null!==k&&"function"==typeof k.componentDidCatch&&(null===ms||!ms.has(k)))){f.effectTag|=4096,f.expirationTime=t;var _=Ir(f,u,t);ln(f,_);break e}}f=f.return}while(null!==f)}ts=no(ts)}catch(e){t=e;continue}break}}function Yr(){var e=Bu.current;return Bu.current=Cu,null===e?Cu:e}function Gr(e,t){eus&&(us=e)}function Jr(){for(;null!==ts;)ts=to(ts)}function eo(){for(;null!==ts&&!Gl();)ts=to(ts)}function to(e){var t=Fu(e.alternate,e,ns);return e.memoizedProps=e.pendingProps,null===t&&(t=no(e)),qu.current=null,t}function no(e){ts=e;do{var t=ts.alternate;if(e=ts.return,0===(2048&ts.effectTag)){if(t=br(t,ts,ns),1===ns||1!==ts.childExpirationTime){for(var n=0,r=ts.child;null!==r;){var o=r.expirationTime,a=r.childExpirationTime;o>n&&(n=o),a>n&&(n=a),r=r.sibling}ts.childExpirationTime=n}if(null!==t)return t;null!==e&&0===(2048&e.effectTag)&&(null===e.firstEffect&&(e.firstEffect=ts.firstEffect),null!==ts.lastEffect&&(null!==e.lastEffect&&(e.lastEffect.nextEffect=ts.firstEffect),e.lastEffect=ts.lastEffect),1e?t:e}function oo(e){var t=qt();return Vt(99,ao.bind(null,e,t)),null}function ao(e,t){do lo();while(null!==gs);if((Ju&(Wu|$u))!==Hu)throw Error(r(327));var n=e.finishedWork,o=e.finishedExpirationTime;if(null===n)return null;if(e.finishedWork=null,e.finishedExpirationTime=0,n===e.current)throw Error(r(177));e.callbackNode=null,e.callbackExpirationTime=0,e.callbackPriority=90,e.nextKnownPendingLevel=0;var a=ro(n);if(e.firstPendingTime=a,o<=e.lastSuspendedTime?e.firstSuspendedTime=e.lastSuspendedTime=e.nextKnownPendingLevel=0:o<=e.firstSuspendedTime&&(e.firstSuspendedTime=o-1),o<=e.lastPingedTime&&(e.lastPingedTime=0),o<=e.lastExpiredTime&&(e.lastExpiredTime=0),e===es&&(ts=es=null,ns=0),1u&&(c=u,u=l,l=c),c=Ue(w,l),f=Ue(w,u),c&&f&&(1!==k.rangeCount||k.anchorNode!==c.node||k.anchorOffset!==c.offset||k.focusNode!==f.node||k.focusOffset!==f.offset)&&(E=E.createRange(),E.setStart(c.node,c.offset),k.removeAllRanges(),l>u?(k.addRange(E),k.extend(f.node,f.offset)):(E.setEnd(f.node,f.offset),k.addRange(E)))))),E=[];for(k=w;k=k.parentNode;)1===k.nodeType&&E.push({element:k,left:k.scrollLeft,top:k.scrollTop});for("function"==typeof w.focus&&w.focus(),w=0;w=t&&e<=t}function To(e,t){var n=e.firstSuspendedTime,r=e.lastSuspendedTime;nt||0===n)&&(e.lastSuspendedTime=t),t<=e.lastPingedTime&&(e.lastPingedTime=0),t<=e.lastExpiredTime&&(e.lastExpiredTime=0)}function Co(e,t){t>e.firstPendingTime&&(e.firstPendingTime=t);var n=e.firstSuspendedTime;0!==n&&(t>=n?e.firstSuspendedTime=e.lastSuspendedTime=e.nextKnownPendingLevel=0:t>=e.lastSuspendedTime&&(e.lastSuspendedTime=t+1),t>e.nextKnownPendingLevel&&(e.nextKnownPendingLevel=t))}function No(e,t){var n=e.lastExpiredTime;(0===n||n>t)&&(e.lastExpiredTime=t)}function Po(e,t,n,o){var a=t.current,i=Fr(),l=su.suspense;i=jr(i,a,l);e:if(n){n=n._reactInternalFiber;t:{if(J(n)!==n||1!==n.tag)throw Error(r(170));var u=n;do{switch(u.tag){case 3:u=u.stateNode.context;break t;case 1:if(It(u.type)){u=u.stateNode.__reactInternalMemoizedMergedChildContext;break t}}u=u.return}while(null!==u);throw Error(r(171))}if(1===n.tag){var s=n.type;if(It(s)){n=Dt(n,s,u);break e}}n=u}else n=Al;return null===t.context?t.context=n:t.pendingContext=n,t=on(i,l),t.payload={element:e},o=void 0===o?null:o,null!==o&&(t.callback=o),an(a,t),Dr(a,i),i}function Oo(e){if(e=e.current,!e.child)return null;switch(e.child.tag){case 5:return e.child.stateNode;default:return e.child.stateNode}}function Ro(e,t){e=e.memoizedState,null!==e&&null!==e.dehydrated&&e.retryTime"+t.valueOf().toString()+"",t=ba.firstChild;e.firstChild;)e.removeChild(e.firstChild);for(;t.firstChild;)e.appendChild(t.firstChild)}}),Ia={animationend:Y("Animation","AnimationEnd"),animationiteration:Y("Animation","AnimationIteration"),animationstart:Y("Animation","AnimationStart"),transitionend:Y("Transition","TransitionEnd")},Fa={},ja={};na&&(ja=document.createElement("div").style,"AnimationEvent"in window||(delete Ia.animationend.animation,delete Ia.animationiteration.animation,delete Ia.animationstart.animation),"TransitionEvent"in window||delete Ia.transitionend.transition);var Da,Ua,Ba,qa=G("animationend"),Ha=G("animationiteration"),Va=G("animationstart"),Wa=G("transitionend"),$a="abort canplay canplaythrough durationchange emptied encrypted ended error loadeddata loadedmetadata loadstart pause play playing progress ratechange seeked seeking stalled suspend timeupdate volumechange waiting".split(" "),Qa=new("function"==typeof WeakMap?WeakMap:Map),Ka=null,Xa=[],Ya=!1,Ga=[],Za=null,Ja=null,ei=null,ti=new Map,ni=new Map,ri=[],oi="mousedown mouseup touchcancel touchend touchstart auxclick dblclick pointercancel pointerdown pointerup dragend dragstart drop compositionend compositionstart keydown keypress keyup input textInput close cancel copy cut paste click change contextmenu reset submit".split(" "),ai="focus blur dragenter dragleave mouseover mouseout pointerover pointerout gotpointercapture lostpointercapture".split(" "),ii={},li=new Map,ui=new Map,si=["abort","abort",qa,"animationEnd",Ha,"animationIteration",Va,"animationStart","canplay","canPlay","canplaythrough","canPlayThrough","durationchange","durationChange","emptied","emptied","encrypted","encrypted","ended","ended","error","error","gotpointercapture","gotPointerCapture","load","load","loadeddata","loadedData","loadedmetadata","loadedMetadata","loadstart","loadStart","lostpointercapture","lostPointerCapture","playing","playing","progress","progress","seeking","seeking","stalled","stalled","suspend","suspend","timeupdate","timeUpdate",Wa,"transitionEnd","waiting","waiting"];Se("blur blur cancel cancel click click close close contextmenu contextMenu copy copy cut cut auxclick auxClick dblclick doubleClick dragend dragEnd dragstart dragStart drop drop focus focus input input invalid invalid keydown keyDown keypress keyPress keyup keyUp mousedown mouseDown mouseup mouseUp paste paste pause pause play play pointercancel pointerCancel pointerdown pointerDown pointerup pointerUp ratechange rateChange reset reset seeked seeked submit submit touchcancel touchCancel touchend touchEnd touchstart touchStart volumechange volumeChange".split(" "),0),Se("drag drag dragenter dragEnter dragexit dragExit dragleave dragLeave dragover dragOver mousemove mouseMove mouseout mouseOut mouseover mouseOver pointermove pointerMove pointerout pointerOut pointerover pointerOver scroll scroll toggle toggle touchmove touchMove wheel wheel".split(" "),1),Se(si,2);for(var ci="change selectionchange textInput compositionstart compositionend compositionupdate".split(" "),fi=0;fi=ji),Bi=String.fromCharCode(32),qi={beforeInput:{phasedRegistrationNames:{bubbled:"onBeforeInput",captured:"onBeforeInputCapture"},dependencies:["compositionend","keypress","textInput","paste"]},compositionEnd:{phasedRegistrationNames:{bubbled:"onCompositionEnd",captured:"onCompositionEndCapture"},dependencies:"blur compositionend keydown keypress keyup mousedown".split(" ")},compositionStart:{phasedRegistrationNames:{bubbled:"onCompositionStart",captured:"onCompositionStartCapture"},dependencies:"blur compositionstart keydown keypress keyup mousedown".split(" ")},compositionUpdate:{phasedRegistrationNames:{bubbled:"onCompositionUpdate",captured:"onCompositionUpdateCapture"},dependencies:"blur compositionupdate keydown keypress keyup mousedown".split(" ")}},Hi=!1,Vi=!1,Wi={eventTypes:qi,extractEvents:function(e,t,n,r){var o;if(Fi)e:{switch(e){case"compositionstart":var a=qi.compositionStart;break e;case"compositionend":a=qi.compositionEnd;break e;case"compositionupdate":a=qi.compositionUpdate;break e}a=void 0}else Vi?dt(e,n)&&(a=qi.compositionEnd):"keydown"===e&&229===n.keyCode&&(a=qi.compositionStart);return a?(Ui&&"ko"!==n.locale&&(Vi||a!==qi.compositionStart?a===qi.compositionEnd&&Vi&&(o=at()):(Ri=r,Li="value"in Ri?Ri.value:Ri.textContent,Vi=!0)),a=Mi.getPooled(a,t,n,r),o?a.data=o:(o=pt(n),null!==o&&(a.data=o)),ot(a),o=a):o=null,(e=Di?ht(e,n):mt(e,n))?(t=Ai.getPooled(qi.beforeInput,t,n,r),t.data=e,ot(t)):t=null,null===o?t:null===t?o:[o,t]}},$i={color:!0,date:!0,datetime:!0,"datetime-local":!0,email:!0,month:!0,number:!0,password:!0,range:!0,search:!0,tel:!0,text:!0,time:!0,url:!0,week:!0},Qi={change:{phasedRegistrationNames:{bubbled:"onChange",captured:"onChangeCapture"},dependencies:"blur change click focus input keydown keyup selectionchange".split(" ")}},Ki=null,Xi=null,Yi=!1;na&&(Yi=se("input")&&(!document.documentMode||9=document.documentMode,fl={select:{phasedRegistrationNames:{bubbled:"onSelect",captured:"onSelectCapture"},dependencies:"blur contextmenu dragend focus keydown keyup mousedown mouseup selectionchange".split(" ")}},dl=null,pl=null,hl=null,ml=!1,bl={eventTypes:fl,extractEvents:function(e,t,n,r,o,a){if(o=a||(r.window===r?r.document:9===r.nodeType?r:r.ownerDocument),!(a=!o)){e:{o=Z(o),a=ta.onSelect;for(var i=0;inu?Hl:function(){return Hl()-nu},ou={current:null},au=null,iu=null,lu=null,uu=!1,su=ma.ReactCurrentBatchConfig,cu=(new Do.Component).refs,fu={isMounted:function(e){return!!(e=e._reactInternalFiber)&&J(e)===e},enqueueSetState:function(e,t,n){e=e._reactInternalFiber;var r=Fr(),o=su.suspense;r=jr(r,e,o),o=on(r,o),o.payload=t,void 0!==n&&null!==n&&(o.callback=n),an(e,o),Dr(e,r)},enqueueReplaceState:function(e,t,n){e=e._reactInternalFiber;var r=Fr(),o=su.suspense;r=jr(r,e,o),o=on(r,o),o.tag=1,o.payload=t,void 0!==n&&null!==n&&(o.callback=n),an(e,o),Dr(e,r)},enqueueForceUpdate:function(e,t){e=e._reactInternalFiber;var n=Fr(),r=su.suspense;n=jr(n,e,r),r=on(n,r),r.tag=2,void 0!==t&&null!==t&&(r.callback=t),an(e,r),Dr(e,n)}},du=Array.isArray,pu=gn(!0),hu=gn(!1),mu={},bu={current:mu},gu={current:mu},yu={current:mu},vu={current:0},wu=ma.ReactCurrentDispatcher,Eu=ma.ReactCurrentBatchConfig,ku=0,_u=null,xu=null,Su=null,Tu=!1,Cu={readContext:tn,useCallback:Sn,useContext:Sn,useEffect:Sn,useImperativeHandle:Sn,useLayoutEffect:Sn,useMemo:Sn,useReducer:Sn,useRef:Sn,useState:Sn,useDebugValue:Sn,useResponder:Sn,useDeferredValue:Sn,useTransition:Sn},Nu={readContext:tn,useCallback:Vn,useContext:tn,useEffect:jn,useImperativeHandle:function(e,t,n){return n=null!==n&&void 0!==n?n.concat([e]):null,In(4,2,Bn.bind(null,t,e),n)},useLayoutEffect:function(e,t){return In(4,2,e,t)},useMemo:function(e,t){var n=Nn();return t=void 0===t?null:t,e=e(),n.memoizedState=[e,t],e},useReducer:function(e,t,n){var r=Nn();return t=void 0!==n?n(t):t,r.memoizedState=r.baseState=t,e=r.queue={pending:null,dispatch:null,lastRenderedReducer:e,lastRenderedState:t},e=e.dispatch=Kn.bind(null,_u,e),[r.memoizedState,e]},useRef:function(e){var t=Nn();return e={current:e},t.memoizedState=e},useState:zn,useDebugValue:Hn,useResponder:xn,useDeferredValue:function(e,t){var n=zn(e),r=n[0],o=n[1];return jn(function(){var n=Eu.suspense;Eu.suspense=void 0===t?null:t;try{o(e)}finally{Eu.suspense=n}},[e,t]),r},useTransition:function(e){var t=zn(!1),n=t[0];return t=t[1],[Vn(Qn.bind(null,t,e),[t,e]),n]}},Pu={readContext:tn,useCallback:Wn,useContext:tn,useEffect:Dn,useImperativeHandle:qn,useLayoutEffect:Un,useMemo:$n,useReducer:Rn,useRef:An,useState:function(){return Rn(On)},useDebugValue:Hn,useResponder:xn,useDeferredValue:function(e,t){var n=Rn(On),r=n[0],o=n[1];return Dn(function(){var n=Eu.suspense;Eu.suspense=void 0===t?null:t;try{o(e)}finally{Eu.suspense=n}},[e,t]),r},useTransition:function(e){var t=Rn(On),n=t[0];return t=t[1],[Wn(Qn.bind(null,t,e),[t,e]),n]}},Ou={readContext:tn,useCallback:Wn,useContext:tn,useEffect:Dn,useImperativeHandle:qn,useLayoutEffect:Un,useMemo:$n,useReducer:Ln,useRef:An,useState:function(){return Ln(On)},useDebugValue:Hn,useResponder:xn,useDeferredValue:function(e,t){var n=Ln(On),r=n[0],o=n[1];return Dn(function(){var n=Eu.suspense;Eu.suspense=void 0===t?null:t;try{o(e)}finally{Eu.suspense=n}},[e,t]),r},useTransition:function(e){var t=Ln(On),n=t[0];return t=t[1],[Wn(Qn.bind(null,t,e),[t,e]),n]}},Ru=null,Lu=null,zu=!1,Mu=ma.ReactCurrentOwner,Au=!1,Iu={dehydrated:null,retryTime:0};Pl=function(e,t){for(var n=t.child;null!==n;){if(5===n.tag||6===n.tag)e.appendChild(n.stateNode);else if(4!==n.tag&&null!==n.child){n.child.return=n,n=n.child;continue}if(n===t)break;for(;null===n.sibling;){if(null===n.return||n.return===t)return;n=n.return}n.sibling.return=n.return,n=n.sibling}},Ol=function(){},Rl=function(e,t,n,r,o){var a=e.memoizedProps;if(a!==r){var i=t.stateNode;switch(yn(bu.current),e=null,n){case"input":a=M(i,a),r=M(i,r),e=[];break;case"option":a=B(i,a),r=B(i,r),e=[];break;case"select":a=Uo({},a,{value:void 0}),r=Uo({},r,{value:void 0}),e=[];break;case"textarea":a=H(i,a),r=H(i,r),e=[];break;default:"function"!=typeof a.onClick&&"function"==typeof r.onClick&&(i.onclick=Fe)}Me(n,r);var l,u;n=null;for(l in a)if(!r.hasOwnProperty(l)&&a.hasOwnProperty(l)&&null!=a[l])if("style"===l)for(u in i=a[l])i.hasOwnProperty(u)&&(n||(n={}),n[u]="");else"dangerouslySetInnerHTML"!==l&&"children"!==l&&"suppressContentEditableWarning"!==l&&"suppressHydrationWarning"!==l&&"autoFocus"!==l&&(ea.hasOwnProperty(l)?e||(e=[]):(e=e||[]).push(l,null));for(l in r){var s=r[l];if(i=null!=a?a[l]:void 0,r.hasOwnProperty(l)&&s!==i&&(null!=s||null!=i))if("style"===l)if(i){for(u in i)!i.hasOwnProperty(u)||s&&s.hasOwnProperty(u)||(n||(n={}),n[u]="");for(u in s)s.hasOwnProperty(u)&&i[u]!==s[u]&&(n||(n={}),n[u]=s[u])}else n||(e||(e=[]),e.push(l,n)),n=s;else"dangerouslySetInnerHTML"===l?(s=s?s.__html:void 0,i=i?i.__html:void 0,null!=s&&i!==s&&(e=e||[]).push(l,s)):"children"===l?i===s||"string"!=typeof s&&"number"!=typeof s||(e=e||[]).push(l,""+s):"suppressContentEditableWarning"!==l&&"suppressHydrationWarning"!==l&&(ea.hasOwnProperty(l)?(null!=s&&Ie(o,l),e||i===s||(e=[])):(e=e||[]).push(l,s))}n&&(e=e||[]).push("style",n),o=e,(t.updateQueue=o)&&(t.effectTag|=4)}},Ll=function(e,t,n,r){n!==r&&(t.effectTag|=4)};var Fu,ju="function"==typeof WeakSet?WeakSet:Set,Du="function"==typeof WeakMap?WeakMap:Map,Uu=Math.ceil,Bu=ma.ReactCurrentDispatcher,qu=ma.ReactCurrentOwner,Hu=0,Vu=8,Wu=16,$u=32,Qu=0,Ku=1,Xu=2,Yu=3,Gu=4,Zu=5,Ju=Hu,es=null,ts=null,ns=0,rs=Qu,os=null,as=1073741823,is=1073741823,ls=null,us=0,ss=!1,cs=0,fs=500,ds=null,ps=!1,hs=null,ms=null,bs=!1,gs=null,ys=90,vs=null,ws=0,Es=null,ks=0;Fu=function(e,t,n){var o=t.expirationTime;if(null!==e){var a=t.pendingProps;if(e.memoizedProps!==a||Fl.current)Au=!0;else{if(o=n?cr(e,t,n):(Mt(vu,1&vu.current),t=hr(e,t,n),null!==t?t.sibling:null);Mt(vu,1&vu.current);break;case 19:if(o=t.childExpirationTime>=n,0!==(64&e.effectTag)){if(o)return pr(e,t,n);t.effectTag|=64}if(a=t.memoizedState,null!==a&&(a.rendering=null,a.tail=null),Mt(vu,vu.current),!o)return null}return hr(e,t,n)}Au=!1}}else Au=!1;switch(t.expirationTime=0,t.tag){case 2:if(o=t.type,null!==e&&(e.alternate=null,t.alternate=null,t.effectTag|=2),e=t.pendingProps,a=At(t,Il.current),en(t,n),a=Cn(null,t,o,e,a,n),t.effectTag|=1,"object"==typeof a&&null!==a&&"function"==typeof a.render&&void 0===a.$$typeof){if(t.tag=1,t.memoizedState=null,t.updateQueue=null,It(o)){var i=!0;Ut(t)}else i=!1;t.memoizedState=null!==a.state&&void 0!==a.state?a.state:null,nn(t);var l=o.getDerivedStateFromProps;"function"==typeof l&&cn(t,o,l,e),a.updater=fu,t.stateNode=a,a._reactInternalFiber=t,hn(t,o,e,n),t=ur(null,t,o,!0,i,n)}else t.tag=0,tr(null,t,a,n),t=t.child;return t;case 16:e:{if(a=t.elementType,null!==e&&(e.alternate=null,t.alternate=null,t.effectTag|=2),e=t.pendingProps,T(a),1!==a._status)throw a._result;switch(a=a._result,t.type=a,i=t.tag=yo(a),e=Yt(a,e),i){case 0:t=ir(null,t,a,e,n);break e;case 1:t=lr(null,t,a,e,n);break e;case 11:t=nr(null,t,a,e,n);break e;case 14:t=rr(null,t,a,Yt(a.type,e),o,n);break e}throw Error(r(306,a,""))}return t;case 0:return o=t.type,a=t.pendingProps,a=t.elementType===o?a:Yt(o,a),ir(e,t,o,a,n);case 1:return o=t.type,a=t.pendingProps,a=t.elementType===o?a:Yt(o,a),lr(e,t,o,a,n);case 3:if(sr(t),o=t.updateQueue,null===e||null===o)throw Error(r(282));if(o=t.pendingProps,a=t.memoizedState,a=null!==a?a.element:null,rn(e,t),un(t,o,null,n),o=t.memoizedState.element,o===a)er(),t=hr(e,t,n);else{if((a=t.stateNode.hydrate)&&(Lu=$e(t.stateNode.containerInfo.firstChild),Ru=t,a=zu=!0),a)for(n=hu(t,null,o,n),t.child=n;n;)n.effectTag=n.effectTag&-3|1024,n=n.sibling;else tr(e,t,o,n),er();t=t.child}return t;case 5:return En(t),null===e&&Gn(t),o=t.type,a=t.pendingProps,i=null!==e?e.memoizedProps:null,l=a.children,We(o,a)?l=null:null!==i&&We(o,i)&&(t.effectTag|=16),ar(e,t),4&t.mode&&1!==n&&a.hidden?(t.expirationTime=t.childExpirationTime=1,t=null):(tr(e,t,l,n),t=t.child),t;case 6:return null===e&&Gn(t),null;case 13:return cr(e,t,n);case 4:return vn(t,t.stateNode.containerInfo),o=t.pendingProps,null===e?t.child=pu(t,null,o,n):tr(e,t,o,n),t.child;case 11:return o=t.type,a=t.pendingProps,a=t.elementType===o?a:Yt(o,a),nr(e,t,o,a,n);case 7:return tr(e,t,t.pendingProps,n),t.child;case 8:return tr(e,t,t.pendingProps.children,n),t.child;case 12:return tr(e,t,t.pendingProps.children,n),t.child;case 10:e:{o=t.type._context,a=t.pendingProps,l=t.memoizedProps,i=a.value;var u=t.type._context;if(Mt(ou,u._currentValue),u._currentValue=i,null!==l)if(u=l.value,i=ul(u,i)?0:0|("function"==typeof o._calculateChangedBits?o._calculateChangedBits(u,i):1073741823),0===i){if(l.children===a.children&&!Fl.current){t=hr(e,t,n);break e}}else for(u=t.child,null!==u&&(u.return=t);null!==u;){var s=u.dependencies;if(null!==s){l=u.child;for(var c=s.firstContext;null!==c;){if(c.context===o&&0!==(c.observedBits&i)){1===u.tag&&(c=on(n,null),c.tag=2,an(u,c)),u.expirationTimeB.length&&B.push(e)}function p(e,t,n,o){var a=typeof e;"undefined"!==a&&"boolean"!==a||(e=null);var i=!1;if(null===e)i=!0;else switch(a){case"string":case"number":i=!0;break;case"object":switch(e.$$typeof){case k:case _:i=!0}}if(i)return n(o,e,""===t?"."+m(e,0):t),1;if(i=0,t=""===t?".":t+":",Array.isArray(e))for(var l=0;l>>1,o=e[r];if(!(void 0!==o&&0a(l,n))void 0!==s&&0>a(s,l)?(e[r]=s,e[u]=n,r=u):(e[r]=l,e[i]=n,r=i);else{if(!(void 0!==s&&0>a(s,n)))break e;e[r]=s,e[u]=n,r=u}}}return t}return null}function a(e,t){var n=e.sortIndex-t.sortIndex;return 0!==n?n:e.id-t.id}function i(e){for(var t=r(z);null!==t;){if(null===t.callback)o(z);else{if(!(t.startTime<=e))break;o(z),t.sortIndex=t.expirationTime,n(L,t)}t=r(z)}}function l(e){if(D=!1,i(e),!j)if(null!==r(L))j=!0,c(u);else{var t=r(z);null!==t&&f(l,t.startTime-e)}}function u(e,n){j=!1,D&&(D=!1,d()),F=!0;var a=I;try{for(i(n),A=r(L);null!==A&&(!(A.expirationTime>n)||e&&!p());){var u=A.callback;if(null!==u){A.callback=null,I=A.priorityLevel;var s=u(A.expirationTime<=n);n=t.unstable_now(),"function"==typeof s?A.callback=s:A===r(L)&&o(L),i(n)}else o(L);A=r(L)}if(null!==A)var c=!0;else{var h=r(z);null!==h&&f(l,h.startTime-n),c=!1}return c}finally{A=null,I=a,F=!1}}function s(e){switch(e){case 1:return-1;case 2:return 250;case 5:return 1073741823;case 4:return 1e4;default:return 5e3}}var c,f,d,p,h;if("undefined"==typeof window||"function"!=typeof MessageChannel){var m=null,b=null,g=function(){if(null!==m)try{var e=t.unstable_now();m(!0,e),m=null}catch(e){throw setTimeout(g,0),e}},y=Date.now();t.unstable_now=function(){return Date.now()-y},c=function(e){null!==m?setTimeout(c,0,e):(m=e,setTimeout(g,0))},f=function(e,t){b=setTimeout(e,t)},d=function(){clearTimeout(b)},p=function(){return!1},h=t.unstable_forceFrameRate=function(){}}else{var v=window.performance,w=window.Date,E=window.setTimeout,k=window.clearTimeout;if("undefined"!=typeof console){var _=window.cancelAnimationFrame;"function"!=typeof window.requestAnimationFrame&&console.error("This browser doesn't support requestAnimationFrame. Make sure that you load a polyfill in older browsers. https://fb.me/react-polyfills"),"function"!=typeof _&&console.error("This browser doesn't support cancelAnimationFrame. Make sure that you load a polyfill in older browsers. https://fb.me/react-polyfills")}if("object"==typeof v&&"function"==typeof v.now)t.unstable_now=function(){return v.now()};else{var x=w.now();t.unstable_now=function(){return w.now()-x}}var S=!1,T=null,C=-1,N=5,P=0;p=function(){return t.unstable_now()>=P},h=function(){},t.unstable_forceFrameRate=function(e){0>e||125i?(e.sortIndex=p,n(z,e),null===r(L)&&e===r(z)&&(D?d():D=!0,f(l,p-i))):(e.sortIndex=a,n(L,e),j||F||(j=!0,c(u))),e},t.unstable_shouldYield=function(){var e=t.unstable_now();i(e);var n=r(L);return n!==A&&null!==A&&null!==n&&null!==n.callback&&n.startTime<=e&&n.expirationTime-1?t:e}function f(e,t){t=t||{};var n=t.body;if(f.prototype.isPrototypeOf(e)){if(e.bodyUsed)throw new TypeError("Already read");this.url=e.url,this.credentials=e.credentials,t.headers||(this.headers=new o(e.headers)),this.method=e.method,this.mode=e.mode,n||(n=e._bodyInit,e.bodyUsed=!0)}else this.url=e;if(this.credentials=t.credentials||this.credentials||"omit",!t.headers&&this.headers||(this.headers=new o(t.headers)),this.method=c(t.method||this.method||"GET"),this.mode=t.mode||this.mode||null,this.referrer=null,("GET"===this.method||"HEAD"===this.method)&&n)throw new TypeError("Body not allowed for GET or HEAD requests");this._initBody(n)}function d(e){var t=new FormData;return e.trim().split("&").forEach(function(e){if(e){var n=e.split("="),r=n.shift().replace(/\+/g," "),o=n.join("=").replace(/\+/g," ");t.append(decodeURIComponent(r),decodeURIComponent(o))}}),t}function p(e){var t=new o,n=(e.getAllResponseHeaders()||"").trim().split("\n");return n.forEach(function(e){var n=e.trim().split(":"),r=n.shift().trim(),o=n.join(":").trim();t.append(r,o)}),t}function h(e,t){t||(t={}),this.type="default",this.status=t.status,this.ok=this.status>=200&&this.status<300,this.statusText=t.statusText,this.headers=t.headers instanceof o?t.headers:new o(t.headers),this.url=t.url||"",this._initBody(e)}if(!e.fetch){var m={searchParams:"URLSearchParams"in e,iterable:"Symbol"in e&&"iterator"in Symbol,blob:"FileReader"in e&&"Blob"in e&&function(){try{return new Blob,!0}catch(e){return!1}}(),formData:"FormData"in e,arrayBuffer:"ArrayBuffer"in e};o.prototype.append=function(e,r){e=t(e),r=n(r);var o=this.map[e];o||(o=[],this.map[e]=o),o.push(r)},o.prototype.delete=function(e){delete this.map[t(e)]},o.prototype.get=function(e){var n=this.map[t(e)];return n?n[0]:null},o.prototype.getAll=function(e){return this.map[t(e)]||[]},o.prototype.has=function(e){return this.map.hasOwnProperty(t(e))},o.prototype.set=function(e,r){this.map[t(e)]=[n(r)]},o.prototype.forEach=function(e,t){Object.getOwnPropertyNames(this.map).forEach(function(n){this.map[n].forEach(function(r){e.call(t,r,n,this)},this)},this)},o.prototype.keys=function(){var e=[];return this.forEach(function(t,n){e.push(n)}),r(e)},o.prototype.values=function(){var e=[];return this.forEach(function(t){e.push(t)}),r(e)},o.prototype.entries=function(){var e=[];return this.forEach(function(t,n){e.push([n,t])}),r(e)},m.iterable&&(o.prototype[Symbol.iterator]=o.prototype.entries);var b=["DELETE","GET","HEAD","OPTIONS","POST","PUT"];f.prototype.clone=function(){return new f(this)},s.call(f.prototype),s.call(h.prototype),h.prototype.clone=function(){return new h(this._bodyInit,{status:this.status,statusText:this.statusText,headers:new o(this.headers),url:this.url})},h.error=function(){var e=new h(null,{status:0,statusText:""});return e.type="error",e};var g=[301,302,303,307,308];h.redirect=function(e,t){if(g.indexOf(t)===-1)throw new RangeError("Invalid status code");return new h(null,{status:t,headers:{location:e}})},e.Headers=o,e.Request=f,e.Response=h,e.fetch=function(e,t){return new Promise(function(n,r){function o(){return"responseURL"in i?i.responseURL:/^X-Request-URL:/m.test(i.getAllResponseHeaders())?i.getResponseHeader("X-Request-URL"):void 0}var a;a=f.prototype.isPrototypeOf(e)&&!t?e:new f(e,t);var i=new XMLHttpRequest;i.onload=function(){var e={status:i.status,statusText:i.statusText,headers:p(i),url:o()},t="response"in i?i.response:i.responseText;n(new h(t,e))},i.onerror=function(){r(new TypeError("Network request failed"))},i.ontimeout=function(){r(new TypeError("Network request failed")); },i.open(a.method,a.url,!0),"include"===a.credentials&&(i.withCredentials=!0),"responseType"in i&&m.blob&&(i.responseType="blob"),a.headers.forEach(function(e,t){i.setRequestHeader(t,e)}),i.send("undefined"==typeof a._bodyInit?null:a._bodyInit)})},e.fetch.polyfill=!0}}("undefined"!=typeof self?self:this)}]));